Diastology: Clinical Approach to Diastolic Heart Failure

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 DIASTOLOGY: CLINICAL APPROACH TO DIASTOLIC HEART FAILU...

Author: Allan L. Klein MD | Mario J. Garcia MD FACC

101 downloads 1324 Views 26MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

DIASTOLOGY: CLINICAL APPROACH TO DIASTOLIC HEART FAILURE

ISBN: 978-1-4160-3754-5

Copyright © 2008 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.

Notice Knowledge and best practice in this ﬁeld are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioners, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Library of Congress Cataloging-in-Publication Data Diastology : clinical approach to diastolic heart failure / [edited by] Allan L. Klein, Mario J. Garcia.—1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-3754-5 1. Congestive heart failure. 2. Heart—Left ventricle—Pathophysiology. 3. Diastole (Cardiac cycle) I. Klein, Allan L. II. Garcia, Mario J. III. Title: Clinical approach to diastolic heart failure. [DNLM: 1. Heart Failure, Congestive. 2. Diagnostic Techniques, Cardiovascular. 3. Diastole— physiology. 4. Ventricular Dysfunction, Left. WG 370 D541 2008] RC685.C53D53 2008 616.1′29—dc22 2007042084

Executive Publisher: Natasha Andjelkovic Project Manager: Mary B. Stermel Design Direction: Karen O’Keefe Owens Marketing Manager: Todd Liebel Developmental Editor: Pamela Hetherington

Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org

Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

Contributors NASER M. AMMASH, MD, FACC

ROBERT O. BONOW, MD, FACC

Associate Professor of Medicine Mayo Clinic Rochester, Minnesota

Goldberg Distinguished Professor Northwestern University Feinberg School of Medicine Chief, Division of Cardiology Co-Director Bluhm Cardiovascular Institute Northwestern Memorial Hospital Chicago, Illinois

CHRISTOPHER P. APPLETON, MD, FACC Professor of Medicine Division of Cardiovascular Diseases Mayo Clinic Arizona Phoenix, Arizona

CRAIG R. ASHER, MD, FACC Cardiology Fellowship Director Cleveland Clinic Florida Weston, Florida

GERARD P. AURIGEMMA, MD, FACC, FASE, FAHA Professor of Medicine and Radiology Director, Cardiology Fellowship Program University of Massachusetts Medical School Director, Non-Invasive Cardiology Umass Memorial Healthcare Worcester, Massachusetts

CATALIN F. BAICU, PhD Assistant Professor of Medicine Gazes Cardiac Research Institute Medical University of South Carolina Charleston, South Carolina

AJAY BHARGAVA, MD Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

EDMUND A. BERMUDEZ, MD, MPH, FACC Assistant Professor of Medicine Tufts University School of Medicine Boston, Massachusetts Consultant, Cardiac and Vascular Disease Florida Cardiac Consultants Sarasota, Florida

D. DIRK BONNEMA, MD Cardiology Fellow Division of Cardiology Department of Medicine Medical University of South Carolina Charleston, South Carolina

BARRY A. BORLAUG, MD Assistant Professor of Medicine Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

SHEMY CARASSO, MD University of Toronto HCM Clinic, Division of Cardiology Department of Medicine, Toronto General Hospital University Health Network University of Toronto Toronto, Ontario, Canada

MANUEL D. CERQUEIRA, MD, FACC, FAHA Professor of Radiology Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Chairman, Department of Nuclear Medicine and Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

KRISHNASWAMY CHANDRASEKARAN, MD Professor of Medicine Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

HSUAN-HUNG CHUANG, MBBS, MRCP (UK), FAMS, FESC, FACC Consultant Cardiologist Mount Elizabeth Hospital Visiting Consultant Heart Failure and Transplantation Program National Heart Center Singapore

v

vi

Contributors

RONAN CURTIN, MD, MSc

BRIAN D. HOIT, MD, FACC, FASE

Associate Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

Professor of Medicine and Physiology and Biophysics Case Western Reserve University Director of Echocardiography University Hospitals Case Medical Center Cleveland, Ohio

BENJAMIN W. EIDEM, MD

JERRY M. JOHN, MD, MS

Associate Professor of Pediatrics Divisions of Pediatric Cardiology and Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

Cardiovascular Fellow Division of Cardiovascular Medicine University of Toledo Toledo, Ohio

KANIZ FATEMA, MBBS, PhD

TRACI L. JURRENS, MD

Research Fellow in Cardiovascular Diseases Mayo School of Graduate Medical Education Mayo Clinic Rochester, Minnesota

Cardiovascular Fellow Mayo Clinic Rochester, Minnesota

ANNE S. KANDERIAN, MD

GARY S. FRANCIS, MD

Advanced Fellow in Cardiovascular Imaging Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Head, Section of Clinical Cardiology Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

HIDEKATSU FUKUTA, MD, PhD Postdoctoral Research Fellow Wake Forest University School of Medicine Wake Forest University Baptist Medical Center Winston-Salem, North Carolina Department of Cardio-Renal Medicine and Hypertension Nagoya City University Graduate School of Medical Sciences Nagoya, Japan

WILLIAM H. GAASCH, MD, FACC Professor of Medicine University of Massachusetts Medical School Worcester, Massachusetts Senior Consultant in Cardiology Director of Cardiovascular Research Lahey Clinic Burlington, Massachusetts

MARIO J. GARCIA, MD, FACC, FACP Professor of Medicine and Radiology Mount Sinai School of Medicine Director of Cardiac Imaging Mount Sinai Heart Institute New York, New York

RICHARD A. GRIMM, DO, FACC, FASE Director, Echocardiography Laboratory Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

DAVID A. KASS, MD Abraham and Virginia Weiss Professor of Cardiology Professor of Medicine Professor of Biomedical Engineering Johns Hopkins Medical Institutions Attending Physician Division of Cardiology, Department of Medicine Johns Hopkins Hospital Baltimore, Maryland

DALANE W. KITZMAN, MD, FACC Professor of Internal Medicine, Cardiology and Gerontology Wake Forest University Health Sciences Winston-Salem, North Carolina

ALLAN L. KLEIN, MD, FRCP(C), FACC, FAHA, FASE Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Director, Cardiovascular Imaging Research Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

LIVIU KLEIN, MD, MS Fellow in Cardiovascular Disease Northwestern University, The Feinberg School of Medicine Bluhm Cardiovascular Institute Northwestern Memorial Hospital Chicago, Illinois

SANJAY KUMAR, MD Hospitalist Department of Hospital Medicine Ohio Permanente Medical Group Kaiser Permanente Cleveland, Ohio

Contributors

DOUGLAS S. LEE, MD, PhD, FRCP(C)

SHERIF F. NAGUEH, MD, FACC

Assistant Professor of Medicine, University of Toronto Scientist, Institute for Clinical Evaluative Sciences Attending Physician, Division of Cardiology, University Health Network Toronto, Ontario, Canada

Professor of Medicine Weill Cornell Medical College Associate Director, Echocardiography Laboratory Methodist DeBakey Heart Center Houston, Texas

STEVEN J. LESTER, MD, FACC, FRCPC, FASE

SATOSHI NAKATANI, MD, PhD, FACC

Associate Professor of Medicine, Mayo Clinic Director, Cardiovascular Ultrasound Imaging and Hemodynamic Laboratory Consultant Division of Cardiovascular Diseases Mayo Clinic Arizona Scottsdale, Arizona

Staff Cardiologist Department of Cardiology National Cardiovascular Center Suita, Osaka, Japan

BENJAMIN D. LEVINE, MD, FACC Professor of Medicine University of Texas Southwestern Medical Center at Dallas Director, Institute for Exercise and Environmental Medicine S. Finley Ewing Jr. Chair for Wellness at Presbyterian Hospital of Dallas Harry S. Moss Heart Chair for Cardiovascular Research Presbyterian Hospital of Dallas Dallas, Texas

WILLIAM C. LITTLE, MD, FACC McMichael Professor and Vice Chair of Internal Medicine Chief of Cardiology Wake Forest University School of Medicine Winston-Salem, North Carolina

VOJTECH MELENOVSKY, MD, PhD Department of Cardiology Institute for Clinical and Experimental Medicine-IKEM Prague, Czech Republic

ARUMUGAM NARAYANAN, MD Research Fellow Cardiology Division, Department of Medicine University of Massachusetts Medical School University of Massachusetts Memorial Health Care Worcester, Massachusetts

M. GARY NICHOLLS, MD, ChB, FAHA, FACC, FRCP Professor of Medicine Department of Medicine Christchurch School of Medicine and Health Sciences University of Otago Christchurch, New Zealand

JAE K. OH, MD, FACC, FAHA Professor of Medicine Codirector, Echocardiography Laboratory Director, Pericardial Clinic Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

MARTIN OSRANEK, MD, MSc ANNITTA J. MOREHEAD, BA, RDCS, CCRC, FASE Manager, Cardiovascular Imaging Core, C5 Research Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

JAMES P. MORGAN, MD, PhD Professor of Medicine Tufts University Chief of Cardiovascular Medicine Caritas Carney Hospital and Caritas St. Elizabeth’s Medical Center Director of the Cardiovascular Center Caritas Christi Healthcare System Boston, Massachusetts

ROSS MURPHY, MD Consultant Cardiologist St James’s Hospital Dublin, Ireland

Assistant Professor of Medicine Research Associate, Cardiovascular Disease Mayo Clinic Rochester, Minnesota

YUTAKA OTSUJI, MD, PhD, FACC Professor of Medicine The Second Department of Internal Medicine Director Department of Cardiovascular and Renal Disease University of Occupational and Environmental Health, Japan School of Medicine Kitakyushu, Japan

ZORAN B. POPOVIĆ, MD, PhD Project Staff Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

vii

viii

Contributors

ANAND PRASAD, MD

SRIKANTH SOLA, MD, FACC, FAHA

Interventional Cardiology Fellow Department of Medicine, Division of Cardiology University of California–San Diego San Diego, California

Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Staff Cardiologist Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

MIGUEL A. QUINONES, MD, FACC Professor of Medicine Weill Cornell Medical College Chairman, Department of Cardiology The Methodist Hospital Houston, Texas

AMBEREEN QURAISHI, MD Clinical Instructor Senior Cardiovascular Fellow Department of Cardiovascular Medicine Caritas St. Elizabeth Medical Center Boston, Massachusetts

HARRY RAKOWSKI, MD, FRCPC, FACC, FASE Professor of Medicine Department of Medicine University of Toronto Douglas Wigle Research Chair in Hypertrophic Cardiomyopathy Development Director Peter Munk Cardiac Imaging Centre, Division of Cardiology, Department of Medicine Toronto General Hospital, University Health Network Toronto, Ontario, Canada

JAY RITZEMA-CARTER, BM, MRCP Cardiology Research Fellow Department of Medicine Christchurch School of Medicine and Health Sciences University of Otago Christchurch, New Zealand

L. LEONARDO RODRIGUEZ, MD, FACC Director, Stress Laboratory Program Director, Advanced Cardiovascular Imaging Fellowship Program Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

JAMES B. SEWARD, MD, FACC John M. Nasseff Sr. Professorship in Cardiology and Professor of Medicine and Pediatrics Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

DAVID H. SPODICK, MD, DSc, FACC Professor of Medicine Cardiovascular Medicine University of Massachusetts Medical School St. Vincent Hospital Worcester, Massachusetts

RANDALL C. STARLING, MD, MPH, FACC Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Vice Chairman, Department of Cardiovascular Medicine Section Head, Heart Failure and Cardiac Transplant Medicine Medical Director, Kaufman Center for Heart Failure Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

A. JAMIL TAJIK, MD, FACC Thomas J. Watson, Jr. Professor in honor of Dr. Robert L. Frye Professor of Medicine and Pediatrics Chairman (Emeritus) Zayed Cardiovascular Center Mayo Clinic Rochester, Minnesota Consultant, Division of Cardiovascular Diseases, Internal Medicine and Pediatric Cardiology Mayo Clinic Scottsdale, Arizona

W. H. WILSON TANG, MD, FACC, FAHA Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Staff Cardiologist, Section of Heart Failure and Cardiac Transplantation Medicine Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

CHUWA TEI, MD, FACC Professor and Chairman Department of Cardiovascular, Respiratory, and Metabolic Medicine Graduate School of Medicine, Kagoshima University Kagoshima, Japan

Contributors

JAMES D. THOMAS, MD, FACC, FAHA, FESC

RAMACHANDRAN S. VASAN, MD, DM, FACC, FAHA

Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Charles and Lorraine Moore Chair of Cardiovascular Imaging Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

Professor of Medicine Boston University School of Medicine Framingham Heart Study Framingham, Massachusetts

FILIPPOS TRIPOSKIADIS, MD, FESC, FACC Professor of Cardiology Director, Department of Cardiology Larissa University Hospital Larissa, Greece

RICHARD W. TROUGHTON, MB, ChB, PhD Associate Professor Department of Medicine Christchurch School of Medicine and Health Sciences University of Otago Christchurch, New Zealand

TERESA S. M. TSANG, MD Professor of Medicine Consultant, Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

MICHAEL R. ZILE, MD, FACC Charles Ezra Daniel Professor of Medicine Attending Physician Department of Medicine, Division of Cardiology Medical University of South Carolina Director of the Medical Intensive Care Unit Ralph H. Johnson Department of Veteran’s Affairs Medical Center Charleston, South Carolina

WILLIAM A. ZOGHBI, MD, FACC Professor of Medicine Weill Medical College of Cornell University William L. Winters Chair in Cardiovascular Imaging Director, Cardiovascular Imaging Center The Methodist DeBakey Heart Center Houston, Texas

ix

Foreword

Doctors Klein and Garcia have attacked a controversial yet extraordinarily problematic clinical challenge with aggressiveness, insight, and thoroughness. Their text, Diastology: Clinical Approach to Diastolic Heart Failure, is one of the few organized eﬀorts to bring together noted experts and synthesize today’s knowledge base regarding this fascinating problem. The depth and breadth of topics covered in this text are extraordinary, and the editors and individual contributors are to be congratulated. The importance of this subject cannot be overemphasized because it is now well established that almost half of all patients admitted to the hospital for symptomatic congestive heart failure have relatively preserved or normal left ventricular systolic function. It is assumed that some degree of abnormality in diastolic function contributes to the presentation of these patients and, indeed, predicts decompensation. Knowing that well over 5 million patients in North America alone have heart failure makes, then, the importance of this syndrome high. The debate about syndrome nomenclature has been entertaining. Should we be referring to the diﬃculty as “diastolic heart failure” or “heart failure in the setting of preserved left ventricular systolic function”? Doctors Klein and Garcia are not shy about their opinion of facts, as the title of the text indicates. Diastolic dysfunction can be deﬁned as the inability of the heart to perform adequately under a normal ﬁlling pressure, and this generally results in impaired exercise tolerance resulting from varying combinations of inadequate forward cardiac output and elevated left ventricular end-diastolic pressure. Perhaps the most

important intrinsic left ventricular abnormality is slowing of the rate of left ventricular relaxation and increased stiﬀness of the chamber. The nuances of this ﬁnding and, indeed, the spectrum of deﬁnitions are well characterized and addressed in this text. Recognition of the importance of diastolic heart failure has been relatively recent, but there is now a large spectrum of data that gives us more precise information regarding the pathophysiology, epidemiology, and prognosis, and there are even a few recent trials studying therapy in these patients. Perhaps the latter is the most disappointing with little to guide us regarding the best approaches for reducing the substantive morbidity and mortality seen with this syndrome. Again, Doctors Klein and Garcia and their contributing authors are to be applauded for their thorough review of the current knowledge base regarding diastolic dysfunction and heart failure in the setting of preserved or relatively normal left ventricular systolic function. This text will capture the interests of clinicians, clinical investigators, and basic scientists interested in gaining insight into heart failure more generally. James B. Young, MD Chairman, Medicine Division Professor and Chairman George and Linda Kaufman Chair Cleveland Clinic Cleveland, Ohio

xiii

Foreword

In the past two decades, there have been remarkable advances in our appreciation of how cardiac diastolic function is important for patient well being. My ﬁrst encounter with this occurred as a fellow in training in the early 1980s, when in Baltimore we were seeing so many elderly, predominantly females, with hypertension and hypercontractile left ventricles—but the seemingly paradoxical presentation with heart failure. It is interesting to reﬂect back on how ignorant we were back then with respect to the primacy of cardiac ﬁlling and relaxation and how far we have come since that time. In this book, the ﬁeld of diastolic function and dysfunction is fully dissected. All of the major intersecting processes, such as hypertension, coronary artery disease, pericardial disease, valvular abnormalities, diabetes, and so many others, are tackled. The recent surge in the use of biventricular “resynchronization” and atrio-ventricular optimization has markedly accentuated the role of the interaction of systole and diastole in clinical practice—and we still have much to learn in selecting patients who will beneﬁt from this “big ticket” technology. The simple notion that ideal patients would have a markedly dilated heart with left bundle branch block certainly has not held up for long. Our enhanced understanding of ventricular interaction and diastole, per se, should make a diﬀerence. New and improved imaging modalities

xiv

such as tissue Doppler imaging and strain rate imaging have given us a keener ability to quantify and diﬀerentiate “normal” and abnormal diastolic function. A variety of new indices, methods, and innovative imaging tools including torsion imaging will undoubtedly help illuminate the ﬁeld in the years ahead. The book is as good as it gets in laying out a comprehensive assessment of where we are and where we are going in the comprehensive ﬁeld of diastology. Drs. Klein and Garcia and the superb group of authors they have engaged have done quite an exceptional job in providing a panoramic view of a very dynamic ﬁeld. Cardiologists in training, those in practice who have an interest in cardiac physiology, and virtually all academic cardiologists and sonographers who want to enhance their understanding of the implications of cardiac relaxation and ﬁlling will beneﬁt from this ﬁne contribution to cardiovascular medicine. Eric J. Topol, MD Professor of Translational Genomics, TSRI Director, Scripps Translational Science Institute Chief Academic Oﬃcer, Scripps Health Senior Consultant, Division of Cardiovascular Diseases Scripps Clinic La Jolla, California

Preface

A 65-year-old woman with hypertension presents to the emergency room with shortness of breath. Chest x-ray shows interstitial edema, and two-dimensional and Doppler echocardiography demonstrate an ejection fraction of 60%, concentric left ventricular (LV) hypertrophy, atrial enlargement, and stage 2 (moderate) LV diastolic dysfunction. The brain natriuretic peptide level is elevated at 800 pg/dl. This prototypic patient has evidence of classical diastolic heart failure, which is the inability to ﬁll the left ventricle with normal ﬁlling pressures. This timely book addresses how diastolic heart failure is diagnosed and treated. It also comprehensively discusses the general principles of diastolic dysfunction, including the molecular biology, hemodynamics, epidemiology, clinical presentation, and principles of treatment. The contents of this book are targeted to a broad audience encompassing noninvasive and invasive cardiologists, physiology scientists, cardiology fellows, and cardiac sonographers. Multiple cardiovascular disorders cause diastolic dysfunction and subsequent diastolic heart failure. There is a raging controversy about whether diastolic heart failure exists as an independent entity or whether it is always accompanied by systolic dysfunction in the setting of a normal ejection fraction. In this book, we have elected to use the term diastolic heart failure; however, we recognize that systolic-ventricular interaction and arterial stiﬀening can deﬁnitely play a signiﬁcant role in causing symptoms of heart failure in these patients. Why study diastolic heart failure? The answer is that a complete understanding of the pathophysiology of LV ﬁlling is essential to managing the patient with congestive heart failure syndromes. There has been a tremendous interest in diastology during the past 50 years, with over 16,000 original manuscripts published during this period.

Historical Perspective Since the heart was determined to be a pump, most biologists and physicians have focused on the study of systolic function. However, as early as in the renaissance period, Leonardo da Vinci described that the lower cardiac chambers of the heart ﬁlled with blood by drawing it from the upper chambers. In the 1940s, Carl J. Wiggers proposed the term inherent elasticity to describe the passive properties of the heart. In the 1970s, cardiac physiologists assessed the properties of active ventricular relaxation and passive ﬁlling using invasive quantiﬁcation of intracavity pressure and volume. During the following decade, clinicians recognized that diastolic heart failure was an important cause of congestive heart failure, and Doppler echocardiography emerged as an important noninvasive method to assess the diastolic ﬁlling properties of the heart. The term “diastology” was coined in the early 1990s; imaging modalities, such as Doppler tissue imaging, color Mmode Doppler, and magnetic resonance imaging (MRI), advanced

our understanding of diastolic function. Over the past 10 years, new techniques and indices for assessing diastolic function have continued to evolve. Recent epidemiology-based studies have shown that diastolic heart failure is increasing in prevalence and that it is as common as systolic heart failure and just as fatal. In the past 5 years, there has been a shift from research in developing diagnostic techniques to large-scale clinical trials to determine targeted treatment for patients with diastolic heart failure.

Our Interest in the Field In the late 1980s, Allan Klein started his interest in this ﬁeld as a Canadian Heart Foundation fellow at the Mayo Clinic studying Doppler assessment of LV ﬁlling during acute myocardial infarction and after reperfusion. His ﬁrst impression was that the quick bedside echocardiographic evaluation, including the mitral E/A ratio and deceleration time, was a simple but powerful measure of LV diastolic ﬁlling, relaxation, and prognosis. Also, he was struck by how the stages of diastolic ﬁlling related to the clinical exam, including the extra heart sounds (S3 and S4). As a student of the ﬁeld, he also learned that the study of diastolic function was more complex than the simple analysis of the mitral E/A ratio. During his training, Dr. Klein was very fortunate to have excellent mentors, including Liv Hatle, Jamil Tajik, and James Seward. Dr. Mario Garcia developed his interest in the ﬁeld while at the Cleveland Clinic in the early days of tissue Doppler echocardiography, color M-mode Doppler, and strain rate imaging. His clinical observations and hemodynamic validation of early annular velocities (Em) and the slope of the ﬂow propagation (Vp) as well as the relationship of mitral early ﬁlling/annular e wave (E/Em) and mitral early ﬁlling/ﬂow propagation slope (E/vp) as measures of LV ﬁlling pressure were important for the advancement of the ﬁeld. Their interest led to many diastology symposiums where leaders congregated in Cleveland, Ohio, and Scottsdale, Arizona, to discuss their advances. These summits sparked our interest to publish a state-of-the-art book on diastology.

Contents of the Book This book is organized into ﬁve main sections: basic determinants, diagnosis, speciﬁc cardiac diseases, emerging topics, and treatment. It includes a comprehensive analysis of the major areas of knowledge in this ﬁeld from the molecular, genetic, and cellular mechanisms to clinical presentation and treatment of diastolic heart failure. This book discusses conventional and newer methods of diagnosis, including two-dimensional and Doppler echocardiographic techniques as well as cardiac MRI. An important practical chapter of how to actually perform a diastolic function examination written by one of the leading cardiac sonographers in the ﬁeld xv

xvi

Preface is also included. A review of the prototypical diseases that manifest diastolic dysfunction, including hypertension, coronary artery disease, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and pericardial diseases, provides an important clinical perspective. Newer topics that are addressed include the role of neurohormones, pacing, aging, and vascular cardiac interactions in diastolic heart failure. Finally, the general treatment, echocardiographic guided therapy, and ongoing clinical trials are covered in depth by the leading experts in the ﬁeld. In the past, treatment of heart failure has focused purely on the treatment of systolic heart failure. However, there have been an increasing number of clinical trials, including The Candesartan in Heart Failure, Assessment of Reduction in Mortality and Morbidity (CHARM) preserved trial, the Perindopril for Elderly Patients with Chronic Heart Failure (PEP-CHF) trial, as well as

ongoing studies, including the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) and the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials, that address the treatment of diastolic heart failure. The importance of new drugs including endothelial receptor antagonists and glucose cross-link breakers that evaluate the targeted treatment of diastolic heart failure is also reviewed in this book. Finally, it is important to recognize that the ﬁeld of diastology is a fast-moving target and we have tried to be as current as possible while also avoiding overlap in the chapters. We surely hope that you enjoy this exciting book. Allan L. Klein Mario J. Garcia

Acknowledgments

We would like to thank Marilyn, Jared, Lauren, and Jordan Klein and Cheryl, Melinda, and Olivia Garcia as well as our parents for their encouragement and support while editing this book. We especially would like to express our thanks to Marie Campbell, who helped and guided us in the journey of putting this book together. Finally, we would like to express our gratitude to the editors of Elsevier for their guidance in making this book a great success.

xvii

1

AMBEREEN QURAISHI, MD JAMES P. MORGAN, MD, PhD

Molecular, Gene, and Cellular Mechanisms INTRODUCTION PATHOPHYSIOLOGY Excitation-Contraction and RepolarizationRelaxation Coupling The Failing Human Heart Abnormal Calcium Regulation in Heart Failure Sarcolemmal Receptors and Mechanisms Sarcoplasmic Reticulum Altered Calcium Responsiveness of Myofibrillar Tension TREATMENT, GENE THERAPY, AND THE FUTURE

INTRODUCTION Heart failure is an ancient diagnosis. Some of the earliest known descriptions are attributed to Hippocrates, circa 460–370 bce. He reported dozens of clinical case histories with examples of dyspnea, as seen in left heart failure, and dropsy, as seen in right heart failure.1 Over the centuries, it has become apparent that the symptoms of heart failure are the result of complex pathophysiologic processes that alter both anatomic and physiologic properties of the heart. In the United States alone, approximately 5 million people are aﬄicted by heart failure, with an annual incidence of 500,000 new diagnoses and 300,000 deaths.2,3 One third of patients with symptomatic heart failure have a normal ejection fraction, and only in the last decade has there been a shift in the paradigm, focusing attention on diagnosing and understanding diastolic dysfunction. In many cases, diastolic dysfunction is caused by one or more abnormalities of cardiac structure, such as hypertrophy, ﬁbrosis, inﬁltrative disease, or pericardial constriction. However, many patients appear to have diastolic dysfunction due to cellular abnormalities of myocyte relaxation, which is reversible and transient and occurs mainly in the setting of ischemia or hypoxia. Other causes include cellular calcium overload or ATP depletion.

Metabolic processes such as alkalosis, cardiovascular drugs, and the hypertrophy process itself can also alter the contractile and metabolic phenotype.4 This chapter will focus on the cellular mechanisms of normal and impaired myocardial relaxation. Calcium plays a crucial role in this process. Its movement into the cytosol, caused by excitation at the surface membrane, stimulates contraction. This physiologic phenomenon is appropriately termed excitation-contraction coupling. The reverse of this process, which is dependent on the movement of calcium and sodium, can be thought of as repolarization-relaxation coupling.4 In normal hearts, sympathetic stimulation can increase contractility by exerting a positive inotropic eﬀect as part of the excitation-contraction (E-C) process and can also increase the rate of relaxation, a positive lusitropic (relaxation-enhancing) eﬀect, by facilitating Ca2+ removal from the sarcoplasm. Myocyte control of relaxation occurs through the regulation of calcium concentrations within the cytosol via four main pathways involving sarcoplasmic reticulum (SR) Ca2+ATPase, sarcolemmal Na+/Ca2+ exchange, sarcolemmal Ca2+ATPase, or mitochondrial Ca2+ uniport.5 The latter two pathways have been studied and appear to have no signiﬁcant eﬀect on the beat-to-beat regulation of intracellular calcium.6,7 We will discuss the other two mechanisms in detail along with myoﬁbrillar calcium responsiveness, as much research is being directed in trying to develop novel therapeutic interventions targeted toward repolarization-relaxation coupling in an eﬀort to maximize positive lusitropic eﬀects.

PATHOPHYSIOLOGY Excitation-Contraction and RepolarizationRelaxation Coupling The E-C coupling process activates contraction by coupling the signal generated by the action potential (excitation) at the myocyte cell surface to the delivery of calcium into the cytosol that initiates contraction.1 After spontaneous depolarization of the surface membrane, Ca2+ enters the myocyte through voltage-gated L-type channels (which are dihydropyridine receptive and will be referred 3

Ch001-X3754.indd 3

1/17/2008 6:02:21 PM

4

Chapter 1 • Molecular, Gene, and Cellular Mechanisms to as DHRs). This inﬂux serves as a trigger for the release of stored Ca2+ from the SR via Ca2+ release channels called ryanodine receptor 2 (RyR2). This process is known as calcium-induced calcium release (CICR).8,9 The transverse tubule system, unique to the mammalian heart, allows for the close proximity of the DHRs to clusters of RyR2. The initial inﬂux of calcium through L-type channels activates the RyR2 channels within its domain in a synchronized fashion, spontaneously increasing local concentration of calcium and producing a Ca2+ spark (named according to its appearance by confocal microscopy), which can also be thought of as a local Ca2+ transient.10 During E-C coupling, several thousand Ca2+ sparks occur in synchrony, overlapping in time and space, thus allowing for a global and uniform calcium transient that is suﬃcient for myocardial contraction. Another channel within the SR membrane, inositol triphosphate, has been reported to induce the release of calcium, but the rate and extent of release is much lower, and it is not triggered by CICR. It is important to understand the cardiac contractile apparatus from the vantage point of troponin-C, the Ca2+ receptor protein. When cytosolic calcium levels are low, there is minimal or no calcium bound to troponin-C. The troponin-tropomyosin complex inhibits the formation of the actomyosin complex. Once calcium is released from the SR, Ca2+ binds to troponin-C, changing the conﬁguration of the troponin-tropomyosin complex, removing the inhibition of the actin-myosin interaction, and thus allowing cross-bridge cycling and contraction. Another important messenger that modulates E-C coupling is cyclic adenosine monophosphate (cAMP). This pathway is initiated by activation of the β-adrenergic receptors, which then activate adenylate cyclase and generate cAMP. This nucleotide activates a series of phosphorylating enzymes (i.e., protein kinases). Protein kinase A (PKA) binds to A-kinase anchoring proteins (AKAPs)11,12 and phosphorylate calcium regulatory proteins at multiple subcellular sites. Phosphorylation of both the voltagegated L-type channels and RyR2 channels (Ca2+ release channels) leads to a net eﬀect of increased Ca2+ entry and a greater calcium release (a function of the amount of Ca2+ stored) from the SR, producing an increase in the rate and magnitude of force generation (positive inotropic eﬀect).13 This is balanced by the phosphorylation of phospholamban on the SR, which regulates the sarcoendoplasmic reticulum Ca2+ (SERCA)-ATPase pump and allows for greater reuptake of calcium from the cytosol, enhancing the rate of relaxation (positive lusitropic eﬀect). Finally, the phosphorylation of troponin-I, part of the regulatory complex of the contractile apparatus, facilitates the dissociation of calcium from troponin-C by altering the myoﬁlament calcium sensitivity, also causing a positive lusitropic eﬀect. These changes increase the amplitude of the systolic Ca2+ transient and decrease its duration, thus increasing myocyte contractility and generation of force. When the β-adrenergic pathway is activated in times of increased cardiac output demand, there is an increased heart rate and simultaneous increase in force (positive force frequency)14 and an increase in rate of relaxation, which ensures that suﬃcient calcium is available from the SR for the next beat.

The Failing Human Heart In the failing human heart, adrenergic eﬀects are blunted.13 Numerous studies of mammalian heart models have been done to better understand the mechanism that leads to abnormal adrenergic signaling. The normal human atrial and ventricular myocardium expresses β1- and β2-adrenergic receptors at a ratio of about

Ch001-X3754.indd 4

70:30.15 In the early stages of heart failure, there is an increase in sympathetic stimulation in order to maintain adequate blood pressure and cardiac output. As the syndrome progresses, the continuous activation eventually leads to a downregulation of β1 receptors by almost 60% to 70% and desensitization of the remaining receptors, which depresses cAMP levels, hence contributing to altered calcium regulation and reducing intracellular calcium levels.16–18 The overall eﬀect is a depressed and negative force-frequency relationship. In vitro studies of nonfailing and failing human myocytes have been done of contractility under varying conditions (i.e., varying muscle length and loading conditions as seen with pressure or volume changes in vivo, slow rates, [Ca2+], and catecholamine stimulation).19,20 These studies concluded that during basal conditions, the contractile properties of normal and failing myocytes is similar. Conversely, the same is not true during increased inotropic stimulation. The normal myocyte is able to increase force generation, but in failing myocytes, the developed force either decreases or remains unchanged. Therefore, during low workload states, contractility is preserved, but “contractility reserve” (the ability to increase contractility with heart rate or sympathetic stimulation) is severely reduced in failing myocytes.13 The proposed mechanism at this time is that the amount of calcium that is released by the SR of failing myocytes is less than in normal myocytes, which may be due to decreased SR Ca2+ stores or abnormal SR Ca2+ loading21; however, there is a need for more investigational studies to fully understand the mechanisms behind the E-C coupling defects that contribute to dysfunctional Ca2+ handling.

Abnormal Calcium Regulation in Heart Failure Abnormal modulation of intracellular calcium is a major mechanism that underlies both systolic and diastolic dysfunction and develops with cardiac hypertrophy and failure. The heart spends more than half of its time in diastole (i.e., relaxation and ﬁlling), yet there is controversy in the deﬁnition of diastolic dysfunction and diastolic heart failure. Abnormal calcium regulation comprises a spectrum of changes that include slowed force (or pressure) decline and cellular re-lengthening (increased ventricular stiﬀness), increased (or decreased) early ﬁlling rates and deceleration, an elevated diastolic pressure-volume relationship, and a ﬁlling-rate–dependent pressure elevation (increased end-diastolic pressure).22 These changes occur due to abnormal regulation of Ca2+ homeostasis within the myocyte. Although the cellular and molecular regulation of calcium in failing myocardium has been studied, the exact mechanism of abnormal calcium regulation is still not well understood (Fig. 1-1). Normally, the systolic calcium transient occurs with the release of calcium from the SR, which is triggered by the L-type channel Ca2+ inﬂux. The magnitude of calcium release is dependent on the Ca2+ inﬂux and the amount of calcium stored in the SR.23 Calcium reuptake is mediated by the SR Ca2+-ATPase pump and the sarcolemmal Na+-Ca2+ exchanger (NCX), which results in the decay of the Ca2+ transient and normal relaxation. In failing myocytes, there are numerous changes (e.g., expression levels of these membrane proteins), which result in abnormal Ca2+ transient, particularly in its termination. This also causes a prolonged action-potential duration and delayed relaxation. At slow pacing rates, the Ca2+ transients of normal and failing myocytes are very similar. However, when the heart rate increases, the Ca2+ transient becomes signiﬁcantly diﬀerent due to a negative force-frequency relationship and decreased SR Ca2+ release, as discussed earlier.

1/16/2008 2:31:17 PM

Chapter 1 • Molecular, Gene, and Cellular Mechanisms

B-ar

P

5

NCX LTC Na+

cAMP 2 1

P

Figure 1-1 Major Cellular Mechanisms of Diastolic Dysfunction. 1. Inhibition of cyclic AMP (cAMP) formation via adenylate cyclase. cAMP mediates phosphorylation of SERCA2 and the myofilaments, which reduces Ca2+ uptake and increases myofilament Ca2+ responsiveness (MyoCAr), respectively. Ca2+ entry via the L-type Ca2+ channels (LTC) is also increased. 2. Enhancement of Na+/Ca2+ exchange. 3. Blockade of reuptake of Ca2+ by SERCA2 by non–cAMPdependent mechanisms. 4. Decreased myofilament Ca2+ responsiveness by non–cAMP-dependent mechanisms. B-ar, β-adrenergic receptor; p, phosphorylation site; SR, sarcoplasmic reticulum.

Ca2+

SERCA2 SR Re-uptake X3 Released Ca2+ Ca2+

Sarcolemmal Receptors and Mechanisms The cardiac sarcolemma is a complex structure that contains multiple channels, exchangers, and pumps that are necessary for normal E-C coupling and myocyte contraction. In recent years, the sarcolemmal NCX has surfaced as one of the primary agents necessary to extrude calcium with each heart beat to allow normal relaxation. By virtue of the NCX mechanism, the role of the electrochemical sodium gradient has also been studied in various mammalian species as a potential determinant of [Ca2+]i.24,25 The NCX is a bidirectional electrogenic ion transporter that utilizes the Na+ electrochemical gradient to exchange one calcium for three sodium ions. During repolarization, the negative membrane potential and elevated [Ca2+]i drive the NCX toward a forward mode (Na+ in/Ca2+ out), resulting in extrusion of calcium from the cell in diastole. When the membrane potential is positive ([Na+]i is increased), the NCX functions in reverse mode (Na+ out/Ca2+ in), resulting in calcium inﬂux, which may help regulate SR Ca2+ load and also, in conjunction with the Ca2+ current induced by activated DHRs, regulate SR Ca2+ release.21,26 There still remain some conﬂicting data in regard to the eﬀects of CICR on SR by the reverse mode INaCa. CICR occurs mainly in the dyadic cleft space in the T-tubular regions.27 Several studies using the detubulation method in rat ventricular myocytes concluded that a majority of the NCX was localized to the T-tubules.28 However, Scriven et al. studied the distribution of these proteins using high-resolution imaging and showed that the NCX was localized to areas outside of the dyadic cleft space and that the spatial proximity of DHR with RyR2 was higher than with NCX29; therefore, any triggered SR Ca2+ release by the reverse mode INaCa seems highly ineﬃcient.30 Several animal models with myocyte hypertrophy demonstrated elevated [Na+]i compared with normal. Pieske and Houser measured [Na+]i in failing and nonfailing human myocytes using multiple techniques and were the ﬁrst to report elevated [Na+]i levels in failing human myocytes.24 The exact mechanism of this is under further investigation. Several studies have tried to describe the processes that lead to Na+ inﬂux in the failing

Ch001-X3754.indd 5

Ca2+

X

4

“MyoCar”

Myofilaments

myocyte and the role of this inﬂux in governing calcium homeostasis. One proposed mechanism suggests that sodium inﬂux occurs through sodium channels and raises levels within the Na+ microdomain activating the NCX in reverse mode (Ca2+ inﬂux), which is complementary to the inﬂux generated by L-type calcium channels. Because the NCX is dependent on the Na+ electrochemical gradient for functioning, any changes that occur in sodium regulation in heart failure, when taken to an extreme, can result in [Ca2+]i overload and diastolic dysfunction. Few studies have addressed the role of the Na+-H+ exchanger in failing myocytes, which has a 1:1 stoichiometry of Na+ inﬂux for H+ eﬄux. Its stimulation may be increased in heart failure and lead to elevated [Na+]i. Decrease in intracellular pH (which increases H+) can also increase Na+ by means of the Na+-H+ exchanger, secondarily increasing Ca2+ by means of the NCX. Alteration of these exchanges may contribute to prolongation of the action potential, slowed decay of the Ca2+ transient, and a delayed relaxation in failing myocardium. Several models of heart failure and hypertrophy have also shown an increase in expression of NCX,31,32 which may be partially controlled by the decreased sympathetic stimulation, leading to decreased SERCA activity.33 Terraciano et al.25,34 showed that in myocytes from transgenic (heterozygous) mice with upregulation of NCX, there was an increase in reverse-mode function resulting in an increase in SR calcium stores compared with wildtype myocytes. It is important to remember that in smaller mammals (mice and rats), the action potential is shorter than the duration of the calcium transient, which means that repolarization is occurring during most of the calcium transient, favoring forwardmode NCX.35 In these species there are lower levels of NCX, so any eﬄux via NCX makes a very small contribution to the decay of the calcium transient, even when overexpressed.20 However, there is a high [Na+]i in smaller mammals,36 favoring Ca2+ entry by reverse mode during the latter part of the calcium transient, which becomes more pronounced in myocytes overexpressing NCX, explaining the ﬁndings reported by Terraciano’s group. In normal human myocytes, the action-potential duration is prolonged, and SERCA release and reuptake occur during the

1/16/2008 2:31:17 PM

6

Chapter 1 • Molecular, Gene, and Cellular Mechanisms plateau phase, when NCX is not in forward mode, indicating that most of the elimination of cytosolic calcium is dependent on reuptake by the SERCA pump. However, in failing myocardium, the interaction between these two proteins changes due to an increase in the ratio of NCX to SERCA levels. To better understand whether increased NCX activity in the setting of reduced SERCA activity aﬀects diastolic function, a study discriminating failing human hearts into three groups based on diastolic dysfunction with increased stimulation rate was performed.37 The investigators discovered three diﬀerent phenotypes with varying expression of SERCA and NCX with impaired systolic function, but the overall trend in the ratio of NCX to SERCA was an increase by a factor of 2 to 4 in all groups of failing myocytes compared with normal. The phenotypes at either end of the spectrum ranged from increased levels of NCX and unchanged SERCA levels (group I) to decreased levels of SERCA and unchanged NCX levels (group III). Only the latter phenotype demonstrated both systolic and diastolic dysfunction, suggesting that both SR calcium uptake and the capacity to eliminate calcium from the cytosol are impaired, whereas in group I, the SR calcium uptake is impaired (causing systolic dysfunction), and global capacity to eliminate calcium is higher (preserving diastolic dysfunction). Therefore, the overexpression of NCX has positive correlation with diastolic function in failing myocytes.

Sarcoplasmic Reticulum The SR is an intracellular structure that is the most important store of calcium in the mammalian heart. The sarcoplasmic membrane proteins (RyR2 and SERCA) maintain a tight control of calcium release and uptake in E-C coupling, contractility, and relaxation. There is a 10,000-fold Ca2+ gradient maintained across the SR membrane by the SR Ca2+-ATPase pump.38 Molecular analysis has identiﬁed three homologous genes (SERCA1, SERCA2, and SERCA3) encoding the SERCA pumps. The SERCA2 gene is spliced into four variants that encode the isoforms. SERCA2a is the primary isoform expressed in cardiac muscle39 at high levels; however, there are regional diﬀerences, age-related eﬀects, and variation due to thyroid hormone levels that aﬀect expression levels. Experimental models in animals and humans have demonstrated that the expression level of SERCA in the atrium versus the ventricle is twofold and may account for shorter contraction time in atria versus ventricles.40 In fact, in heart failure models, it is well established that defective SR Ca2+ uptake correlates with decreased contractility, which could be attributed to signiﬁcant decline in SERCA protein levels or an alteration in SR Ca2+ transport function.41 Several studies induced left ventricular pressure overload hypertrophy/failure in rats by thoracic aortic banding and consistently found an overall decrease in SERCA mRNA levels,42–44 suggesting that downregulation of SERCA2a gene expression in these models partly occurs at the transcriptional level.38 Feldman et al. also deduced that decreased SERCA mRNA levels could be a marker of transition from compensated hypertrophy to decompensated hypertrophy/failure.43 In human heart models, SERCA mRNA levels are reduced in failing compared with nonfailing hearts, yet there remains controversy regarding simultaneous decrease in SERCA protein expression.29 Recently, data from larger studies have successfully shown a reduction of SERCA protein levels in failing human hearts, but not in compensated hypertrophied human hearts, suggesting that perhaps a decrease in protein level is a sign of developing failure.6,45,46 A decrease in

Ch001-X3754.indd 6

SERCA2a expression at the level of mRNA or protein is inversely related to duration of cardiac contraction,47–49 correlates with decreased myocardial function, alters the force-frequency response,50 and may also slow the velocity of relaxation, suggesting the importance of SERCA pump level in maintaining myocardial function. Yet it is still diﬃcult to describe the actual relationship between cardiac muscle and the SERCA pump because of the complexity of its regulation and all the changes in other calcium-regulating proteins (such as NCX) that occur in concert with each other within the myocyte and the heart as the syndrome of heart failure progresses. The SERCA pump is modulated by both direct and indirect factors. Phospholamban is the primary indirect regulator that activates the SERCA2a pump. In its dephosphorylated state, phospholamban inhibits SERCA2a aﬃnity for calcium. The phosphorylation of phospholamban can occur at three diﬀerent sites—serine-16 by cAMP-dependent PKA, threonine-17 by Ca2+/calmodulin-dependent protein kinase II, and serine-10 by Ca2+-activated phospholipid-dependent protein kinase.34 When phospholamban is phosphorylated by cAMP-dependent PKA (the most important mediator), the inhibitory eﬀect is removed and the calcium aﬃnity (not the maximal velocity of SERCA2a) increases, resulting in enhanced relaxation and an increase in SR Ca2+ load. Ca2+/calmodulin-dependent protein kinase II (CaMK II) is the other modulator, which directly phosphorylates SERCA2 and increases Vmax (maximal activity) without altering the calcium aﬃnity of SERCA2.51 CaMK II also phosphorylates the threonine-17 site in phospholamban, which also increases the calcium aﬃnity of SERCA2a. In heart failure, the blunting of the β-adrenergic pathway leads to alteration not only in phosphorylation of phospholamban at the serine-16 site, but also in CaMK-dependent phosphorylation, ultimately altering SERCA2a activity. Most studies of human heart failure have suggested that although there is a decrease in phospholamban mRNA levels, there is no diﬀerence in protein expression between failing and nonfailing myocytes.52,53 Therefore, protein expression of SERCA2a in relation to phospholamban is always diminished in heart failure, which may explain the increased phospholamban-to-SERCA2a ratios, leading to an increase in inhibition of the SERCA2a pump and an overall decrease in its basal activity level and contributing to abnormal calcium handling.

Altered Calcium Responsiveness of Myofibrillar Tension Cardiac contractility and relaxation are altered not only because of changes in calcium availability, but also because of changes in myoﬁlament responsiveness to calcium. In ﬁbers rendered hypermeable to Ca2+, a change in responsiveness can manifest as either a change in sensitivity or potency or as maximal Ca2+-activated force. The actual mechanism responsible for this eﬀect has not been deﬁnitively determined, but based on numerous studies, it appears that isoform composition and phosphorylation status of the contractile proteins are altered, which increases the Ca2+ sensitivity of the contractile apparatus in end-stage heart failure. Most studies have concentrated on changes of a single factor. Van der Velden et al.54 focused on a combination of contractile protein changes that occur during heart failure by studying isometric force and its Ca2+ sensitivity in left ventricular myocytes from nonfailing and end-stage failing donor hearts. They concluded that the combined decrease in phosphorylation status of

1/16/2008 2:31:17 PM

Chapter 1 • Molecular, Gene, and Cellular Mechanisms troponin-I and myosin light chain 2 resulted in an increase in Ca2+ sensitivity, and not due to contractile protein isoform change. However, other studies have shown that the phosphorylation of myosin light chain 2 increases Ca2+ responsiveness.55 Earlier reports showed that end-stage heart failure in humans is not associated with myoﬁbrillar Ca2+ sensitivity.56–58 Until now, no real consensus has been reached to explain if, why, and how Ca2+ sensitivity increases in heart failure patients. Therapeutically, Ca2+ sensitizers pose a problem due to the mechanism of action. An increased aﬃnity of Ca2+ for troponin-C would enhance the actin-myosin interaction, which, theoretically, prolongs relaxation. This has been shown in vivo and in vitro in animals and in humans.57

TREATMENT, GENE THERAPY, AND THE FUTURE Congestive heart failure is a leading cause of morbidity and mortality in the United States. The remodeling process that occurs after myocyte injury from multiple causes leads to contractile dysfunction and abnormal intracellular calcium handling, which delays normal relaxation, as discussed in detail thus far. Although there is no universal agreement regarding the mechanisms, it is generally accepted that calcium handling is altered in failing hearts. The NCX and the SERCA2a pump are the two main players that regulate cytosolic calcium levels during relaxation on a beat-to-beat basis. Therefore, multiple studies using gene transfer methodologies are exploring the overexpression of these two mechanisms that could potentially return calcium handling to normal, as most of the conventional therapies that we currently oﬀer utilize mainly multiple medications, the actions of which are not completely understood.59 The sodium-calcium exchanger is a complex transport protein that functions in reverse and forward modes. In normal mice myocytes, it is the most dominant Ca2+ eﬄux mechanism that helps maintain calcium homeostasis.60 In humans, only 25% of the calcium is extruded by the NCX, and the other 75% is removed by SERCA2a pumps.61 Some models of heart failure have described an increase in expression of NCX in response to the pathologic decrease in SERCA2a pumps attributed to the delayed and smaller Ca2+ transient.14 This is felt to be a compensatory mechanism for the decreased eﬃciency of SR calcium re-uptake. Because the actual quantitative contribution of the two regulatory mechanisms under pathologic conditions is poorly understood, so is the relationship between the changes in protein expression and the functional consequences.34 Terraciano et al. noted that the degree of compensation that may be achieved with a two- to threefold increase of NCX, the same measured in failing human hearts, has not been tested.34 They compared transgenic mice overexpressing NCX with nontransgenic mice and conﬁrmed that a reduction in SERCA2a function can be compensated by overexpression of NCX. A 2.4-fold increase in the function of NCX compensated for a 28% reduction in SERCA2a and maintained Ca2+ transient. Although these ﬁndings may not necessarily be extrapolated to human hearts, it is a starting point for understanding such mechanisms and developing future therapies. The expression of SERCA2a pump level has also been an increasing area of interest given its central role in SR Ca2+ handling. Several models utilizing in vitro adenoviral-mediated gene transfer have been created to express varying levels of SERCA2a, which has allowed for a better understanding of the role of SERCA2a pump levels in maintaining Ca2+ homeostasis and

Ch001-X3754.indd 7

7

cardiac function.62–64 As discussed earlier, decrease in SERCA2a activity and/or expression has been identiﬁed as one of the major defective mechanisms responsible for impaired relaxation. By disrupting the SERCA2a gene using homologous recombination, Periasamy et al.65 obtained a better understanding of how the pathologic decrease in SERCA2a pump levels can alter cardiac function. In homozygous mice, the outcome was lethal. Heterozygous mice were able to function, but the Vmax of SR Ca2+ uptake was decreased by 35%. The peak amplitude of the Ca2+ transients in normal heterozygous myocyte was decreased by more than 30%, which led to a decrease in the maximal rate of contraction and relaxation, as conﬁrmed by measurements obtained via transducers in the left ventricles and right femoral arteries of anesthetized mice. These ﬁndings prove that there is a direct relationship between SERCA2a level and cardiac contractility. Therefore, recent studies have used the adenoviral-mediated gene transfer to increase SERCA2a pump activity as a potential means for therapy. Hajjar et al.66 showed that increased expression of SERCA2a in rat myocytes led to increased contractility and faster decay of the Ca2+ transient. The question remained in the ability to restore function in failing human myocytes. Del Monte et al.67 addressed this very question by isolating human cardiomyocytes from the left ventricles of 10 patients with end-stage heart failure. Gene transfer of SERCA2a led to an increase in protein expression and pump activity, induced a faster contraction velocity, and enhanced relaxation velocity, thus reversing contractile abnormalities of the failing heart. Although the results were promising in the in vitro model, this method did not predict the outcome in vivo. Hajjar and colleagues used a catheter-based technique of gene transfer to allow for global overexpression of SERCA2a in an animal model of pressure-overload hypertrophy in transition to failure. SERCA2a overexpression restored both systolic and diastolic dysfunction to normal levels, decreased left ventricular size, and restored the slope of the end-systolic pressure-dimension relationship to that of control levels.68 The SERCA gene therapy studies described above demonstrate not only that it is possible to increase the expression of SERCA protein but that its eﬀects can normalize the abnormalities of calcium handling and contraction. However, this raises several important concerns, such as the long-term eﬀects of inducing these changes, impacts on the phospholamban and SERCA interaction, and the eﬀect on the NCX. As heart failure continues to pose a major clinical challenge for patients and physicians, the limitations of current treatment modalities are reﬂected in the grave statistics of minimal improvement in overall mortality within the last century. Gene transfer targeted toward speciﬁc pathways in the failing human heart is a novel therapeutic option that can potentially reverse the abnormalities of diastolic dysfunction and transform heart failure into a chronic survivable condition.

REFERENCES 1. Katz AM: Heart failure: Pathophysiology, molecular biology, and clinical management. Philadelphia, Lippincott Williams & Wilkins, 2000:6. 2. Owan TE, Redﬁeld MM: Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 2005;47:320. 3. Hunt HA, Baker DW, Chin MH, et al: ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure). Circulation 2001;104: 2996–3007.

1/16/2008 2:31:17 PM

8

Chapter 1 • Molecular, Gene, and Cellular Mechanisms 4. Apstein CS, Morgan JP: Diastolic relaxation of the heart, 2nd ed. London, Lea and Febiger, 1994:3–24. 5. Bers DM: Cardiac excitation-contraction coupling. Nature 2002;415: 198–205. 6. Hasenfuss G, Pieske B: Calcium cycling in congestive heart failure. J Molec Cell Cardiol 2002;34:951–969. 7. Bassani RA, Bassani JWM, Bers DM: Mitochondrial and sarcolemmal Ca transport can reduce [Ca]i during caﬀeine contractures in rabbit cardiac myocytes. J Physiol (London) 1992;453:591–608. 8. Scoote M, Poole-Wilson PA, Williams AJ: The therapeutic potential of new insights into myocardial excitation-contraction coupling. Heart 2003;89: 371–376. 9. Fabiato A: Calcium induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 1983;245:C1–C14. 10. Cheng H, Lederer WJ, Cannell MB: Calcium sparks: Elementary events underlying excitation-contraction coupling in the heart muscle. Science 1993;262:740–744. 11. Bauman AL, Scott JD: Kinase- and phosphatase-anchoring proteins: Harnessing the dynamic duo. Nature (Cell Biol) 2002;4:E203–E206. 12. Fink MA, Zakhary DR, Mackey JA, et al: AKAP-mediated targeting of protein kinase A regulates contractility in cardiac myocytes. Circ Res 2001;88:291–297. 13. Houser SR, Margulies KB: Is depressed myocyte contractility involved in heart failure? Circulation 2003;92:350–358. 14. Gwathmey JK, Copelas L, MacKinnon R, et al: Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res 1987;61:70–76. 15. Lohse MJ, Engelhardt S, Eschenhagen T: What is the role of β-adrenergic signaling in heart failure? Circ Res 2003;93:896–906. 16. Brodde OE: β-adrenoreceptors in cardiac disease. Pharmacol Ther 1993;60:405–430. 17. Bristow MR: The adrenergic nervous system in heart failure. NEJM 1984;311:850–851. 18. Ungerer M, Bohm M, Elce JS, et al: Altered expression of β-adrenergic receptor kinase and β1-adrenergic receptors in the failing human heart. Circulation 1993;87:454–463. 19. Houser SR, Piacentino V 3rd, Mattiello J, et al: Functional properties of failing human ventricular myocytes. Trends Cardiovasc Med 2000;10: 101–107. 20. Houser SR, Piacentino V 3rd, Weisser J: Abnormalites of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol 2000;32: 1595–1607. 21. Pieske B, Maier LS, Bers DM, et al: Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. Circ Res 1999;85:38–46. 22. Kass DA, Bronzwaer JGF, Paulus WJ: What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 2004;94:1533–1542. 23. Bassani JW, Yuan W, Bers DM: Fractional SR Ca2+ release is regulated by trigger Ca2+ and SR Ca2+ content in cardiac myocytes. Am J Physiol 1995;268:C1313–C1319. 24. Pieske B, Houser SR: [Na+]i handling in the failing human heart. Cardiovasc Res 2003;57:874–886. 25. Blaustein MP, Lederer WJ: Sodium/calcium exchange: Its physiologic implications. Physiol Rev 1999;79:763–854. 26. Goldhaber JI, Scott TL, Walter DO, et al: Local regulation of the threshold for calcium sparks in rat ventricular myocytes: Role of sodium-calcium exchange. J Physiol (London) 1999;520(pt 2):431–438. 27. Reuter H, Pott C, Goldhaber JI, et al: Na+-Ca2+ exchange in the regulation of cardiac excitation-contraction coupling. Cardiovasc Res 2005;67: 198–207. 28. Kawai M, Hussain M, Orchard CH: Excitation-contraction coupling in rat ventricular myocytes after formamide-induced detubulation. Am J Physiol 1999;277:H603–H609. 29. Scriven DR, Dan P, Moore ED: Distribution of proteins implicated in excitation-contraction coupling in rat ventricular myocytes. Biophys J 2000;79:2682–2691. 30. Sipido K, Macs M, van de Werf F: Low eﬃciency of Ca2+ entry through the Na+-Ca2+ exchanger as triggers for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na+Ca2+ exchange. Circ Res 1982;50:651–662. 31. Hasenfuss G: Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 1998;37:279–289. 32. Flesch M, Schwinger RHG, Schiﬀer F, et al: Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium. Circulation 1996;94:992–1002.

Ch001-X3754.indd 8

33. Golden KL, Ren J, O’Connor J, et al: In vivo regulation of Na/Ca exchanger expression by adrenergic eﬀectors. Am J Physiol (Heart Circ Physiol) 2001;280:H1376–H1382. 34. Terraciano CM, Philipson KD, MacLeod KT: Overexpression of the Na(+)/ Ca(2+) exchanger and inhibition of the sarcoplasmic reticulum Ca(2+)ATPase in ventricular myocytes from transgenic mice. Cardiovasc Res 2001;49:38–47. 35. Piacentino V 3rd, Weber CR, Gaughan JP, et al: Modulation of contractility in failing human myocytes by reverse-mode Na/Ca exchange. Ann NY Acad Sci 2002;976:466–471. 36. Hasenfuss G, Pieske B: Calcium cycling in congestive heart failure. J Molec Cell Cardiol 2002;34:951–969. 37. Hasenfuss G, Schillinger W, Lehnert SE, et al: Relationship between Na+Ca2+ exchanger protein levels and diastolic function of failing human myocardium. Circulation 1999;99:641–648. 38. Frank KF, Bölck B, Erdmann E, et al: Sarcoplasmic reticulum Ca2+-ATPase modulates cardiac contraction and relaxation. Cardiovasc Res 2003;57:20–27. 39. Zarain-Herzberg A, MacLennan DH, Periasamy M: Characterization of rabbit cardiac sarco(endo)-plasmic reticulum Ca2+-ATPase gene. J Biol Chem 1990;265:4670–4677. 40. Luss I, Boknika P, Jones LR, et al: Expression of cardiac calcium regulatory proteins in atrium v ventricle in diﬀerent species. J Molec Cell Cardiol 1999;31:1299–1314. 41. Periasamy M, Huke S: SERCA pump level is a critical determinant of Ca2+ homeostasis and cardiac contractility. J Molec Cell Cardiol 2002;33: 1053–1063. 42. Dumas AR, Wisnewsky C, Boheler KR, et al: The sarco(endo)plasmic reticulum Ca2+-ATPase gene is regulated at the transcriptional level during compensated left ventricular hypertrophy in the rat. Academie des sciences 1997;320:963–969. 43. Feldman AM, Weinberg EO, Ray PE, et al: Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ Res 1993;73: 184–192. 44. Aoyagi T, Yonekura K, Eto Y, et al: The sarcoplasmic reticulum Ca2+ATPase (SERCA2) gene promoter activity is decreased in response to severe left ventricular pressure-overload hypertrophy in rat hearts. J Molec Cell Cardiol 1999;31:919–926. 45. Dash R, Frank KF, Carr AN, et al: Gender inﬂuences on sarcoplasmic reticulum Ca2+ handling in failing human myocardium. J Molec Cell Cardiol 2001;33:1345–1353. 46. Di Paola NR, Sweet WE, Stull LB, et al: Beta-adrenergic receptors and calcium cycling protein in non-failing, hypertrophied and failing human hearts: Transition from hypertrophy to failure. J Molec Cell Cardiol 2001;33:1283–1295. 47. Chen F, Ding S, Lee BS, Wetzel GT: Sarcoplasmic reticulum Ca(2+)ATPase and cell contraction in developing rabbit heart. J Molec Cell Cardiol 2000;32:745–755. 48. Gombosova I, Bokník P, Kirchhefer U, et al: Postnatal changes in contractile time parameters, calcium regulatory proteins and phosphatases. Am J Physiol 1998;274:H2123–H2132. 49. Cain BS, Meldrum DR, Joo KS, et al: Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol 1998;32:458–467. 50. Hasenfuss G, Reinecke H, Studer R, et al: Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+ATPase in failing and nonfailing myocardium. Circ Res 1994;75: 434–442. 51. Toyofuku T, Kurzydlowski K, Narayanan N, et al: Identiﬁcation of Ser38 as a site in cardiac sarcoplasmic reticulum Ca2+-ATPase that is phosphorylated by Ca2+/calmodulin-dependent protein kinase. J Biol Chem 1991;266:11144–11152. 52. Schwinger RH, Böhm M, Schmidt U, et al: Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca2+-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with non-failing hearts. Circulation 1995;92:3220–3228. 53. Meyer M, Schillinger W, Pieske B, et al: Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 1995;92:778–784. 54. Van der Velden J, Papp Z, Zaremba R, et al: Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins. Cardiovas Res 2003;57: 37–47.

1/16/2008 2:31:17 PM

Chapter 1 • Molecular, Gene, and Cellular Mechanisms 55. Morano I, Arndt H, Gärtner C, et al: Skinned ﬁbers of human atrium and ventricle: Myosin isoenzymes and contractility. Circ Res 1988;62: 632–639. 56. Hajjar RJ, Gwathmey JK, Briggs GM, et al: Diﬀerential eﬀect of DPI 201– 206 on the sensitivity of myoﬁlaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest 1988;82:1578. 57. Wankerl M, Böhm M, Morano I, et al: Calcium sensitivity and myosin light chain pattern of atrial and ventricular stunned cardiac ﬁbers from patients with various kinds of cardiac disease. J Molec Cell Cardiol 1990;22:1425. 58. D’Angelo A, Luciani GB, Mazzucco A, et al: Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circulation 1992;85:518–525. 59. Hoshijima M: Gene therapy targeted at calcium handling as an approach to the treatment of heart failure. Pharmacol Ther 2005;105:211– 228. 60. Goldhaber JI, Henderson SA, Reuter H, et al: Eﬀects of Na+-Ca2+ exchange expression on excitation-contraction coupling in genetically modiﬁed mice. Ann NY Acad Sci 2005;1047:122–126. 61. Hasenfuss G: Calcium pump overexpression and myocardial function: Implications for gene therapy of myocardial failure. Circ Res 1998; 83:966–968.

Ch001-X3754.indd 9

9

62. He H, Giordano FJ, Hilal-Dandan R, et al: Overexpression of the rat sarcoplasmic reticulum Ca2+-ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest 1997;100:380–389. 63. Baker DL, Hashimoto K, Grupp IL, et al: Targeted expression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts. Circ Res 1998;83:1205–1214. 64. Müeller OJ, Katus HA, Bekeredjian R: Targeting the heart with gene therapy-optimized gene delivery methods. Cardiovasc Res 2007;73: 453–462. 65. Periasamy M, Reed TD, Liu LH, et al: Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 1999;274: 2556–2562. 66. Hajjar RJ, Kang JX, Gwathmey JK, et al: Physiological eﬀects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation 1997;95:423–429. 67. Del Monte F, Harding SE, Schmidt U, et al: Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 1999;100:2308–2311. 68. Miyamoto MI, del Monte F, Schmidt U, et al: Adenoviral gene transfer of SERCA2a improves left ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci USA 2000;97:793–798.

1/16/2008 2:31:18 PM

D. DIRK BONNEMA, MD CATALIN F. BAICU, PhD MICHAEL R. ZILE, MD

2

Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness INTRODUCTION PATHOPHYSIOLOGY Normal Diastolic Function Measurements of Diastolic Function Left Ventricular Diastolic Function During Exercise CARDIOVASCULAR STRUCTURE AND FUNCTION IN DIASTOLIC HEART FAILURE Left Ventricular Chamber Remodeling Left Ventricular Diastolic Function in Diastolic Heart Failure Cardiomyocyte Diastolic Function in Diastolic Heart Failure

Left Ventricular Systolic Function in Diastolic Heart Failure Abnormal Diastolic Function in Decompensated Diastolic Heart Failure Abnormal Diastolic Function in Diastolic Heart Failure During Exercise CLINICAL RELEVANCE Ischemic Diastolic Dysfunction Left Ventricular Concentric Hypertrophy Trigger Mechanisms of Noncardiac Factors in Acute Decompensated Diastolic Heart Failure FUTURE RESEARCH

INTRODUCTION Heart failure (HF) can be deﬁned physiologically as an inability of the heart to provide suﬃcient forward output to meet the perfusion and oxygenation requirements of the tissues while maintaining normal ﬁlling pressures. Chronic heart failure can be divided into two broad categories: systolic heart failure (SHF) and diastolic heart failure (DHF). Classifying patients in these two broad categories should be based on characteristic changes in cardiovascular structure and function (see Chapter 28).1,2 SHF is characterized by progressive chamber dilation, eccentric remodeling, and dominant abnormalities in systolic properties. Clinical manifestations of left ventricular (LV) systolic dysfunction include decreased cardiac output, increased heart rate, and peripheral vasoconstriction. However, patients with SHF frequently have additional symptoms of shortness of breath at rest or with exertion.3 These symptoms of pulmonary congestion are due, at least in part, to LV diastolic dysfunction.4–6 Therefore, patients with SHF (particularly when they have

symptomatic decompensation) do not have an “isolated” abnormality in systolic properties; rather, from the pathophysiologic point of view, they have predominant abnormalities in systolic properties and eccentric remodeling, with associated or secondary abnormalities in diastolic function. By contrast, patients with DHF are characterized by normal LV volume, concentric remodeling, and normal LV chamber systolic properties, but dominant abnormalities in diastolic properties.2,7–11 These patients have abnormalities in diastolic relaxation, ﬁlling, and/or distensibility. Clinical manifestations of LV diastolic dysfunction include shortness of breath at rest or with exertion and peripheral edema. However, abnormalities in regional systolic shortening have also been identiﬁed in some patients with DHF.2,11 Therefore, patients with DHF do not have “isolated” abnormalities in diastolic properties; rather, from the pathophysiologic point of view, they have predominant abnormalities in diastolic properties and concentric remodeling. “Diastolic dysfunction” and “diastolic heart failure” are not synonymous terms.12 Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, ﬁlling, or distensibility of the 11

12

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness left ventricle—regardless of whether the ejection fraction is normal or abnormal and regardless of whether the patient is asymptomatic or has symptoms and signs of HF. Thus, diastolic dysfunction comprises abnormal mechanical (diastolic) properties of the ventricle and is present in virtually all patients with heart failure. Diastolic heart failure denotes signs and symptoms of clinical heart failure with normal ejection fraction and LV diastolic dysfunction. Similar distinctions apply to the terms “systolic dysfunction” and “systolic heart failure” (Boxes 2-1 and 2-2).

PATHOPHYSIOLOGY The pathophysiology of diastolic heart failure will be reviewed here, beginning with a discussion of the factors involved in normal diastolic relaxation and ﬁlling. Understanding normal diastolic function permits an easier understanding of some of the clinical features of DHF.

Normal Diastolic Function Cardiac function is critically dependent upon diastolic physiologic mechanisms to provide adequate LV ﬁlling (cardiac input) in Box 2-1

Definitions Diastolic Dysfunction: Abnormal diastolic properties of LV (abnormal relaxation, filling dynamics, distensibility) • EF may be normal or low. • Patient may be symptomatic or asymptomatic. Diastolic Heart Failure: Clinical heart failure, normal ejection fraction, abnormal diastolic function Systolic Dysfunction: Abnormal systolic properties of LV (abnormal performance, function, contractility)

parallel with LV ejection (cardiac output) both at rest and during exercise. Adequate pulmonary function is also dependent upon LV diastolic function. During diastole, the left ventricle, left atrium, and pulmonary veins form a “common chamber” that is continuous with the pulmonary capillary bed. LV diastolic pressure is determined by the volume of blood in the left ventricle during diastole and the diastolic distensibility or compliance of the entire cardiovascular system, principally the left ventricle (but it may also include the left atrium, pulmonary vessels, right ventricle, and systemic arteries). Thus, an increase in LV diastolic pressure (whether this occurs at rest or during exercise) will increase pulmonary capillary pressure, which, if high enough, causes dyspnea, exercise limitation, pulmonary congestion, and edema (Fig. 2-1). Relaxation of the contracted myocardium begins at the onset of diastole. This is a dynamic process that takes place during isovolumic relaxation (the period between aortic valve closure and mitral valve opening during which LV pressure declines with no change in volume) and then continues during auxotonic relaxation (the period between mitral valve opening and mitral valve closure during which the left ventricle ﬁlls at variable pressure) (Fig. 2-2). The rapid pressure decay and the concomitant “untwisting” and elastic recoil of the left ventricle produce a suction eﬀect that augments the left atrial-ventricular pressure gradient and pulls blood into the ventricle, thereby promoting diastolic ﬁlling. During exercise in normal patients, relaxation rate is increased and early diastolic pressures decrease, augmenting elastic recoil and diastolic suction and resulting in more rapid ﬁlling during a shortened diastolic ﬁlling period at increasing heart rates (Fig. 2-3). During the later phases of diastole, the normal left ventricle is composed of completely relaxed cardiomyocytes and is very compliant and easily distensible, oﬀering minimal resistance to LV ﬁlling over a normal volume range. Atrial contraction near the end of diastole contributes 20%–30% to total LV ﬁlling volume and increases diastolic pressures by less than 5 mmHg. As a result,

• EF is low (and diastolic dysfunction may coexist). • Patient may be symptomatic or asymptomatic. Pulmonary capillaries

Systolic Heart Failure: Clinical heart failure, low ejection fraction, abnormal systolic function (From Circulation 2006;113:296–304.)

Pulmonary vein

Box 2-2

Diastolic Heart Failure—Diagnostic Criteria Required Criteria 1. Clinical evidence of heart failure • Framingham or Boston criteria • Plasma brain natriuretic peptide and/or chest x-ray • Cardiopulmonary exercise testing 2. Normal ejection fraction (= 50%) Confirmatory Evidence 1. LVH or concentric remodeling 2. Left atrial enlargement (in absence of atrial fibrillation) 3. Echo Doppler or catheter evidence of diastolic dysfunction Exclusion Nonmyocardial disease

Ao

LA

LV

Figure 2-1 Elevated left ventricular end diastolic pressure causes pulmonary congestion. The heart is seen in diastole when the mitral valve open and the left ventricle (LV), left atrium (LA), and pulmonary veins form a common chamber, continuous with the pulmonary capillary bed. The left ventricular end diastolic pressure determines the pulmonary capillary pressure and the presence or absence of pulmonary congestion or edema. Ao, aorta.

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness REST

EXERCISE

20

Isovolumic pressure decline

Left atrium Systole

PLA 0

mL/sec

Left ventricle

PLV

mmHg

Aorta

150

dV/dt

Minimum PLV

E

0 500 msec

Diastole

LV volume

CHF REST

CHF EXERCISE

40

I

Isovolumic relaxation

Slow filling

Atrial filling

Auxotonic relaxation

Figure 2-2 Changes in left ventricular pressure and volume throughout the cardiac cycle. The cardiac cycle is divided into systole, the time period from mitral valve closure (MVC) to aortic valve closure (AVC), and diastole. Diastole is further divided into isovolumic relaxation (the time period from AVC to mitral valve opening [MVO] during which LV pressure declines with no change in volume) and auxotonic relaxation (the time period from MVO to MVC during which LV volume increases at variable pressure). AVO, atrial valve opening.

LV ﬁlling can normally be accomplished by very low ﬁlling pressures in the left atrium and pulmonary veins, preserving a low pulmonary capillary pressure (<12 mmHg) and a high degree of lung distensibility. Loss of normal LV diastolic relaxation and distensibility, from structural and functional causes, impairs LV pressure decline and ﬁlling, resulting in increases in LV diastolic, left atrial (LA), and pulmonary venous pressures, which directly increase pulmonary capillary pressure.

Measurements of Diastolic Function Complete characterization of LV diastolic properties requires simultaneous measurement (often using a high-ﬁdelity micromanometer) of LV diastolic pressure and LV volume using invasive and/or noninvasive methods. Diastolic function can be assessed using the following measurements: ❒

❒

❒

Rate of isovolumic relaxation: peak (−)dP/dt, the time constant of the isovolumic LV pressure decay (Tau) and the isovolumic relaxation time (IVRT). When relaxation rate is decreased, (−)dP/dt and Tau are increased (Fig. 2-4). Rate and extent of LV ﬁlling: ﬁlling rate, the time-to-peak ﬁlling rate (TPFR), transmitral ﬂow velocity, tissue velocity, and strain and strain rate. When there is prolonged relaxation, the early ﬁlling rate and extent are decreased, TPFR is prolonged, and the ﬁlling rate and extent that results from atrial contraction are increased (Fig. 2-5). Passive elastic stiﬀness properties: diastolic pressure-volume (P-V) relationship. When stiﬀness is increased (distensibility is decreased) the diastolic pressure versus volume relationship is shifted upward (Fig. 2-6).

mL/sec

Rapid MVO filling AVC

mmHg

PLV MVC AVO

E

PLA 0 150

Minimum PLV E E

dV/dt 0

Figure 2-3 Effects of exercise on left ventricular (LV) filling dynamics. Changes in LV pressure (PLV), left atrial pressure (PLA), and the rate of change of LV volume (dV/dt) at rest and during exercise. Top panel: During exercise in normal patients, minimal PLV decreases without any change in PLA, leading to an increase in the peak mitral valve gradient and producing a higher peak filling rate (E). Bottom panel: In congestive heart failure (CHF), the peak LV filling rate (E) increases during exercise due to an increase in the early transmitral valve pressure gradient. However, the gradient is produced by an increase in PLA instead of a reduction in PLV as occurs in normal patients. (From Cheng CP et al: Mechanism of augmented rate of left ventricle filling during exercise. Circ Res 1992;70:9.)

Left Ventricular Pressure Decline Isovolumic relaxation can be quantiﬁed by measurement of LV pressure with a high-ﬁdelity micromanometer catheter and calculation of the peak instantaneous rate of LV pressure decline (peak − dP/dt) and the time constant of LV isovolumic pressure decline (Tau).13 When the natural log of LV diastolic pressure is plotted versus time, Tau equals the slope of this linear relationship. Stated in more conceptual terms, Tau is the time required for LV pressure to fall by approximately two thirds of its initial value. When isovolumic pressure decline is slowed, Tau is prolonged and its numerical value increases. Noninvasive estimates of the total IVRT can be made using echocardiographic techniques. However, no index of relaxation (isovolumic or auxotonic) can be considered an index of “intrinsic” relaxation rate unless loading conditions (and other modulators) are held constant or are at least speciﬁed. Therefore, changes in afterload (systolic pressure) and diastolic load (LA diastolic pressures) may change measurements of isovolumic and auxotonic relaxation without changing intrinsic relaxation properties.

Left Ventricular Filling A detailed description of the Doppler echocardiographic assessment of diastolic dysfunction is provided in other chapters (10–12 and 15). The normal left ventricle has a characteristic

13

14

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 5 LV pressure

Left ventricular pressure (mmHg)

Left ventricular pressure (mmHg)

AVC

100

Peak (–)dP/dt

50

Abnormal τ = 55 msec

4

3 Normal τ = 34 msec 2

1

MVO

LV dP/dt

P = P0e–t/τ

0

0 0

500

1000

0

Time (msec)

50

100

Time (msec)

Time to peak filling rate

Figure 2-4 Left ventricular (LV) isovolumic relaxation. LV pressure versus time and the rate of change of LV pressure (dP/dt) in a normal subject (solid line) versus a patient with diastolic heart failure (dashed line). Isovolumic relaxation can be quantified by calculating the peak instantaneous rate of LV pressure decline (peak −dP/dt) and the time constant of LV isovolumic pressure decline (Tau). When the natural log of LV diastolic pressure is plotted versus time, Tau equals the slope of this linear relationship (right panel). Stated in more conceptual terms, Tau is the time required for LV pressure to fall by approximately two thirds of its initial value. When isovolumic relaxation is abnormal, LV pressure decline is slower, −dP/dt has a more negative value; the time constant Tau is prolonged, and its numerical value is increased (depicted by the dashed lines in both figure panels).

Peak rapid filling rate

Peak atrial filling rate

LV dV/dt

LV volume

Contribution of atrial systole to LV filling

End diastole

Total LV stroke volume

Rapid filling fraction End systole

Rapid filling

Slow filling (diastatis)

pattern of ﬁlling and inﬂow velocities. LV inﬂow velocity and the rate of LV ﬁlling are greatest early (E) in diastole, immediately after mitral valve opening, and are responsible for the normally tall E wave of the transmitral inﬂow Doppler echocardiogram (Fig. 2-7). Since most atrial-to-ventricular transfer of blood occurs in early and mid-diastole, the amount of blood transported by atrial contraction is relatively small, the velocity imparted by the atrial contraction (the A wave of the transmitral inﬂow Doppler echocardiogram) is relatively low, and the normal E/A wave ratio is greater than 1 and approaches a value of 2 in younger individuals. Doppler echocardiographic assessment of LV ﬁlling has limitations, since diastolic ﬁlling parameters are inﬂuenced by multiple

Atrial systole

Figure 2-5 Left ventricular (LV) filling dynamics. LV volume versus time and the rate of change of LV volume (dV/dt) in a normal subject (solid line) versus a patient with diastolic heart failure (dashed line). With the onset of systole, the LV volume decreases and reaches its minimum at the end systole. Diastolic filling has three distinct phases: rapid filling of the left ventricle, during which dV/dt reaches it maximum and the peak filling rate occurs; a slow filling phase (diastasis), during which there is little change in LV volume; and an atrial systole phase, during which active atrial contraction fills the left ventricle and allows it to attain its end diastolic volume. Important diastolic parameters include the peak filling rate, the time to peak filling rate, the rapid filling fraction (percent of total stroke volume reached during rapid filling), and the percent contribution of atrial systole to LV filling.

factors, the most important of which are loading conditions. The typical, but nonspeciﬁc, mitral ﬁlling pattern associated with diastolic dysfunction (termed abnormal relaxation) is a pattern of increased IVRT and decreased E/A ratio. However, this pattern can be altered or pseudonormalized by changes in LA pressure. When diastolic dysfunction occurs, relaxation is slowed and incomplete, early LV diastolic pressures rise, early diastolic suction falls, and LV ﬁlling becomes increasingly dependent on an increase in LA pressure to push blood into the left ventricle during diastole. As LA pressures rise, the value of the E wave increases and E/A increases to a “normal” (or pseudonormal) value. When LA pressures are severely increased, a “restrictive” pattern may develop in which the IVRT may be decreased and the E/A ratio further

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

LV diastolic pressure (mmHg)

30 DHF

25 20

SHF 15 10 Normal

5 0 0

50

100

150

200

250

300

LV diastolic volume (ml) Figure 2-6 Diastolic pressure versus volume relationships in patients with heart failure. Left ventricular (LV) diastolic pressure-volume data from normal controls (solid line), patients with diastolic heart failure (DHF) (dotted line), and patients with systolic heart failure (SHF) (dashed line). In patients with DHF, the diastolic pressure-volume curve is shifted up and left, indicating an increase in passive stiffness and a decrease in distensibility of the left ventricle. In contrast, in patients with SHF, the diastolic pressure-volume curve is shifted down and right, indicating a decrease in passive stiffness and an increase in distensibility of the left ventricle. These data clearly indicate that all patients with heart failure, whether diastolic or systolic, have a significant increase in LV diastolic pressure; however, the mechanisms responsible for these increased pressures are different between these two different patient groups. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)

Diastolic dysfunction Normal

Impaired relaxation Stage 1 Mild

LV press

Pseudonormal Stage 2 Moderate

Restrictive Stage 3 Severe

LA press E A

E

E

E

A

A

Mitral Doppler velocity

A

Decel IVRT S Doppler tissue imaging

A' E'

E' E'

A'

E'

A'

A'

Figure 2-7 Doppler findings in diastolic heart failure. Schematic representation of left ventricular (LV) and left atrial (LA) pressures during diastole (top panel), transmitral Doppler LV inflow velocity (middle panel), and Doppler tissue velocity (bottom panel) in normal patients and in different types of diastolic dysfunction. This schema divides patients into four filling patterns: normal pattern of relaxation and filling (column 1 far left); impaired relaxation or stage I mild diastolic dysfunction; pseudonormal relaxation, or stage II moderate diastolic dysfunction; and restrictive filling pattern, or stage III severe diastolic dysfunction. Patients with an impaired filling pattern have a reduced E′, a prolonged E decel of early diastolic filling, and an increased A. A pseudonormal filling pattern is denoted by an increased E wave in the face of a decreased E′. A restrictive filling pattern is denoted by an even larger E wave and even smaller E′, with a shortened IVRT and a decreased E decel. It should be noted that these abnormal filling patterns may also be seen in patients with systolic heart failure. In all patients with heart failure, these filling patterns have important prognostic value. For example, the presence of a restrictive pattern predicts an increase in mortality rate, particularly in patients with systolic heart failure. E, peak early diastolic flow velocity; A, peak late diastolic flow velocity caused by atrial contraction; E decel, E-wave diastolic deceleration time; IVRT, isovolumic relaxation time; S, myocardial velocity during systole; E′, myocardial velocity during early filling; and A′, myocardial velocity during filling produced by atrial contraction. (From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387.)

15

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness increased.14 Recently developed echocardiographic and Doppler echocardiographic techniques can be used to distinguish these three patterns of abnormal LV ﬁlling.15 When transmitral Doppler ﬂow patterns are examined in concert with more recently developed Doppler echocardiographic techniques, patterns of normal versus impaired relaxation versus pseudonormal versus restriction can be determined because these newer techniques provide information about LV ﬁlling pressure and the LA/LV diastolic pressure gradient. These techniques include measuring pulmonary venous ﬂow velocity, tissue Doppler myocardial velocity, strain and strain rate, and color M-mode ﬂow acceleration patterns. In particular, measures of myocardial velocities made by tissue Doppler imaging (TDI) appear less sensitive to alteration in LV loading conditions (Fig. 2-8). E′ measures the rate of early diastolic myocardial lengthening and, when combined with transmitral Doppler E-wave data, can be used to estimate pulmonary capillary wedge pressure (PCWP) = 2 + 1.3 (E/E′).16

nondistensible ventricle will require higher pressures to achieve ﬁlling of a given volume. Thus, an increase in LV diastolic chamber stiﬀness or a decrease in distensibility shifts the LV diastolic P-V curve upward and often increases its slope. Deﬁning the entire LV ﬁlling curve throughout diastole requires the simultaneous measurement of LV diastolic pressure and volume either throughout a single cardiac cycle (to deﬁne the diastolic P-V relationship) or by way of the end diastolic P-V coordinate over variably loaded cardiac cycles (to deﬁne the end diastolic P-V relationship). The volume measurements can be made by angiography, echocardiography, or radionuclide imaging techniques simultaneous with invasive measurements of LV diastolic pressure. Alternatively, noninvasive Doppler echocardiographic techniques can be used to estimate PCWP (see earlier description). Together with echocardiographically measured end diastolic volume, an index of instantaneous diastolic stiﬀness (ratio of PCWP-to-end diastolic volume) can be derived.17

Left Ventricular Stiffness/Distensibility

Left Ventricular Diastolic Function During Exercise

LV ventricular diastolic stiﬀness and distensibility are quantiﬁed by the position and shape of the LV diastolic P-V relationship, which plots LV diastolic pressure as a function of LV diastolic volume throughout diastole (see Fig. 2-6). A relatively stiﬀ,

A detailed description of the mechanisms and clinical relevance of diastolic dysfunction during exercise is provided in Chapter 17. The cardiac output can increase several fold during exercise, an appropriate response to the enhanced needs of exercising muscle.

TISSUE DOPPLER IMAGING DHF patient Velocity (cm/sec)

4 0 –4 –8

4 0 –4 –8

0

0

–5

–5

Strain (%)

Strain (%)

Velocity (cm/sec)

Normal patient

–10 –15 –20 Systole

–10 –15 –20

Diastole

3

Systole

Diastole

3 Strain rate (sec–1)

Strain rate (sec–1)

16

2 1 0 –1 –2 0

0.2

0.4

0.6

Time (sec)

0.8

1

2 1 0 –1 –2

0

0.2

0.4

0.6

0.8

1

Time (sec)

Figure 2-8 Examples of tissue Doppler imaging. Derived velocity (top), strain (middle), and strain rate (bottom) in a normal control patient (left) and a patient with diastolic heart failure (DHF) (right). These tissue Doppler images were taken from the mitral annulus. The relaxation pattern during early diastolic filling is marked by the block arrows. The strain data are similar to a left ventricular (LV) filling curve. The patient with DHF had a slow filling pattern, as evidenced by a marked decrease in the slope of the line during early diastolic filling compared with the normal patient. The velocity and the strain rate are both reduced. The relaxation pattern during late diastolic filling is marked by the thin arrows. The strain data show that the patient with DHF had a more robust filling as a result of atrial contraction than had the normal patient. This indicates a shift in LV filling pattern from early to late diastole. The velocity and the strain rate are both increased during atrial contraction. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness Multiple factors contribute to this response, including an increase in heart rate, a modest rise in stroke volume, a reduction in peripheral vascular resistance, and an elevation in contractile force, which increases LV, arterial systolic pressure, and the force of ejection. The increase in LV output must be matched by a rise in LV input. The left ventricle cannot accomplish this task by the same mechanisms that increase output during exercise. For example, tachycardia shortens the duration of diastole, the time during which LV ﬁlling must occur. As a result, the diastolic ﬁlling rate during exercise may be increased out of proportion to cardiac output. A rise in ﬂow rate across the mitral valve requires an increase in the transmitral diastolic pressure gradient. If this were achieved by increasing the pressure in the left atrium, this would have the deleterious eﬀects of increasing pulmonary capillary pressure and causing pulmonary congestion, dyspnea, and respiratory compromise. Rather, the normal left ventricle permits a remarkable increase in diastolic ﬁlling rate during exercise by rapidly and markedly decreasing LV pressure during early diastole, thereby creating a relative LV “suction” eﬀect, which enhances the transmitral pressure gradient without increasing LA pressure (see Fig. 2-3).18–21 Several mechanisms contribute to the left ventricular diastolic suction eﬀect during exercise: ❒

❒

The increased force of contraction during systole enhances early diastolic myocardial elastic recoil due to greater systolic shortening forces and the extent of systolic ﬁber shortening, which is manifested as a smaller end systolic volume (ESV).20 Thus, an increase in systolic shortening results in an increase in restoring forces during diastole, which allow enhanced diastolic ﬁlling. Acceleration of myocyte relaxation occurs during exercise, due to an increased rate of calcium uptake by the sarcoplasmic reticulum (SR). Increased cyclic adenosine monophosphate (cAMP), generated by the β-adrenergic response to exercise, phosphorylates the regulatory SR membrane protein, phospholamban, to increase the rate of calcium uptake by the SR during diastole.22

Some of the mechanisms that allow an increase in cardiac output and in cardiac input during exercise act in concert on systolic and diastolic functions: ❒

❒

The Treppe eﬀect creates a relationship between the heart rate (or frequency of contraction)/LV pressure (or systolic force development) and ejection fraction (or shortening) such that in a normal heart, an increase in heart rate is associated with an increase in stroke volume over a physiologic range of heart rate. This has been called the systolic force-frequency relationship. In addition, the same mechanism governs the relationship between heart rate and diastolic relaxation rate where increased heart rate in a normal heart is associated with an increased relaxation rate, which in part allows LV diastolic pressures and PCWP to remain normal during exercise. A second example of the determinants of systolic and diastolic function acting in concert during exercise is the relationship between increased stroke volume and diastolic distensibility. During normal exercise, end systolic volume decreases and end diastolic volume increases. The increase in end diastolic volume allows the left ventricle to use the Frank-Starling mechanism to augment stroke volume.

However, it is the normal stiﬀness and distensibility of the left ventricle that allows an increase in end diastolic volume with a negligible change in late diastolic pressure and no signiﬁcant change in PCWP. In summary, the normal heart during exercise has an elegant balance of physiologic mechanisms to ensure that cardiac input keeps pace with cardiac output, with preservation of a low pulmonary capillary pressure. These mechanisms result in an increase in measured LV distensibility, as manifested by a downward shift of the LV diastolic P-V curve, especially during early diastole (Fig. 2-9).23,24

CARDIOVASCULAR STRUCTURE AND FUNCTION IN DIASTOLIC HEART FAILURE DHF is typically associated with signiﬁcant remodeling that aﬀects the LV and LA chambers, the cardiomyocytes, and the extracellular matrix. The structural remodeling that occurs in DHF diﬀers dramatically from that in SHF.

Left Ventricular Chamber Remodeling Patients with DHF generally exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by a normal or near-normal end diastolic volume, increased wall thickness, and an increased ratio of mass-to-volume with an increased ratio of wall thickness-to-chamber radius. By contrast, patients with SHF exhibit a pattern of eccentric remodeling with an increase in end diastolic volume (which is usually progressive over time), an increase in LV mass but little increase in wall thickness, and a substantial decrease in the ratios of mass to volume and thickness to radius (Fig. 2-10).1,2,9,11,17,25,26

Cardiomyocyte and Extracellular Matrix Remodeling The dramatic diﬀerences in organ morphology and geometry noted previously are paralleled by anatomic diﬀerences at the microscopic level. In DHF, the cardiomyocyte exhibits an increased diameter, with little or no change in length; this corresponds to the increase in LV wall thickness with no change in LV volume (Fig. 2-11). By contrast, in SHF, the cardiomyocytes are elongated, with little or no change in diameter; this corresponds to the increase in LV volume with no change in LV wall thickness. It is easy to imagine how the geometric structural remodeling of these cardiomyocytes causes the remodeling seen in the LV chambers that they populate. In DHF, there is an increase in the amount of collagen, with a corresponding increment in the width and continuity of the ﬁbrillar components of the extracellular matrix (Fig. 2-12). In SHF, at least early in its development, there is degradation and disruption of the ﬁbrillar collagen.2,25,26 In end-stage SHF, replacement ﬁbrosis and ischemic scarring may result in an overall increase in ﬁbrillar collagen within the extracellular matrix.

Left Ventricular Diastolic Function in Diastolic Heart Failure Abnormal LV diastolic function is a universal ﬁnding in patients with DHF. Indeed, these abnormalities in diastolic function form

17

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness CONTROL

ISCHEMIA

Rest Exercise

20

30

20

10

10

60

120

160

Left ventricular volume (ml)

200

30

20

10

0

0

Rest Exercise

40 LV pressure (mmHg)

30

SCAR

Rest Exercise

40 LV pressure (mmHg)

40 LV pressure (mmHg)

18

0 100

140

180

Left ventricular volume (ml)

220

140

180

220

260

Left ventricular volume (ml)

Figure 2-9 Left ventricular (LV) pressure-volume (P-V) relationships. Shown are the relationships at rest and during exercise at early, mid-, and end diastole. The simultaneous measurements of LV diastolic pressure and volume define distensibility or compliance. In the normal individual with normal compliance (left panel), exercise causes a downward shift of the diastolic P-V curve in early diastole, indicating an increase in LV distensibility; the increase in cardiac output occurs without an increase in LV diastolic pressure. In a patient with ischemia (middle panel), exercise causes a marked upward shift in the curve, indicating a reduction in LV distensibility, or diastolic dysfunction, and there is a significant increase in LV and pulmonary capillary wedge pressures as LV volume or cardiac output increases. This may result in the development of pulmonary congestion and respiratory symptoms. In the patient with a previous myocardial infarction and an LV scar (right panel), the early increase in diastolic distensibility with exercise is lost, but there is no change in the P-V curve in the absence of ischemia. (From Carroll JD et al: Dynamics of left ventricular filling at rest and during exercise. Circulation 1983;68:59.)

Normal

Systolic heart failure

Disastolic heart failure

Figure 2-10 Left ventricular (LV) remodeling in heart failure. Autopsy examples of the left ventricle imaged at the midventricular cross section in a normal heart (left), systolic heart failure (center), and diastolic heart failure (right). Diastolic heart failure is characterized by a pattern of concentric LV remodeling with a normal or near-normal end diastolic volume, increased wall thickness and mass, and a high ratio of mass to volume. By contrast, patients with systolic heart failure exhibit eccentric remodeling with an increased end diastolic volume, little change in wall thickness, and a low ratio of mass to volume. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)

the dominant pathophysiologic basis for the development of DHF.7–11,15,17,25,26 The major abnormalities in LV diastolic function that contribute to or occur during the development of DHF include: ❒ ❒ ❒ ❒ ❒ ❒

Slowed, delayed, and incomplete myocardial relaxation Impaired rate and extent of LV ﬁlling Shift of ﬁlling from early to late diastole Decreased early diastolic suction/recoil Augmented LA pressure during the early ﬁlling Altered passive elastic properties of the ventricle, resulting in increased passive stiﬀness and decreased diastolic distensibility

❒ ❒ ❒ ❒

Inability to suﬃciently augment cardiac output during exercise Inability to suﬃciently augment relaxation during exercise Inability to utilize the Frank-Starling mechanism during exercise Increased diastolic LV, LA, and pulmonary venous pressures at rest or during exercise

In a given patient, impairment of one or more of these parameters will result in decreased LV chamber distensibility, as manifested by an increase in diastolic pressure at any given LV volume. When myocardial relaxation is impaired in diastolic dysfunction,

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness POH-Diastolic heart failure

POH-Diastolic heart failure

Normal

Normal

DCM-Systolic heart failure

DCM-Systolic heart failure Figure 2-11 Cardiomyocyte remodeling in heart failure. Isolated cardiac muscle cells taken from (bottom) an animal model of dilated cardiomyopathy (DCM) that produces systolic heart failure; (middle) a normal heart; and (top) an animal model of pressure-overload hypertrophy (POH) that produces diastolic heart failure, in which the cardiomyocyte diameter is increased. By contrast, in systolic heart failure, the cardiomyocyte length is increased. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)

the rate and amount of early diastolic LV ﬁlling are reduced, with a relative shift of LV ﬁlling to the later part of diastole (see Fig. 2-5). The Doppler E wave is decreased, the hemodynamic load on the atrium is increased, and atrial contraction makes a more important contribution to ventricular ﬁlling than in normal subjects. This is reﬂected by an increase in the Doppler A wave and a decrease in the E/A ratio (see Fig. 2-7). The chronic atrial overload may eventually result in atrial ﬁbrillation, which can result in the loss of atrial contraction; dramatic reductions in LA emptying, LV ﬁlling, and LV stroke volume; and a signiﬁcant increase in LV diastolic pressures. The redistribution of ﬁlling from early to late diastole also means that LV ﬁlling and LA emptying are compromised more in patients with diastolic dysfunction than in normal patients by the occurrence of tachycardia. An increase in heart rate shortens the duration of diastole and truncates the important late phase of diastolic ﬁlling.

Cardiomyocyte Diastolic Function in Diastolic Heart Failure The signiﬁcant abnormalities in LV diastolic function observed at the chamber level are paralleled by the abnormalities in cardiomyocyte diastolic function observed at the cellular level. Cardiomyocyte diastolic function was directly addressed in two studies in which patients with DHF underwent endomyocardial biopsy and single cardiomyocytes were isolated to assess cellular diastolic performance.25,26 The cardiomyocytes had an increased resting tension in the absence of calcium that was almost twice as high

Figure 2-12 Extracellular matrix remodeling in heart failure. Scanning electron micrographs taken from (bottom) an animal model of dilated cardiomyopathy (DCM) that produces systolic heart failure; (middle) a normal heart; and (top) an animal model of pressure-overload hypertrophy (POH) that produces diastolic heart failure, in which there is an increase in the amount of collagen, with a corresponding increment in the width and continuity of the fibrillar components of the extracellular matrix. By contrast, in systolic heart failure, there is degradation and disruption of the fibrillar collagen. (From Aurigemma GP et al: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296.)

as control cardiomyocytes. These in vitro cell data corresponded to an in vivo increase in LV end diastolic pressure in these patients with DHF. These data indicate that cardiomyocytes from patients with DHF have increased stiﬀness and decreased distensibility compared with normal cardiomyocytes. Therefore, these clinical studies, along with studies using animal models of DHF, showed that there are clear parallels in the abnormalities in diastolic function between the LV chamber and individual cardiac muscle cells that constitute the myocardium.27

Left Ventricular Systolic Function in Diastolic Heart Failure A detailed description of the systolic function in patients with DHF is provided in Chapter 28. The dominant functional abnormality in patients with SHF is abnormal LV systolic function. Ejection fraction is normal in patients with DHF, but whether

19

20

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness abnormalities in LV systolic properties contribute to the pathophysiology of DHF has remained an area of active investigation. Recent studies have carefully examined LV global and regional systolic properties in patients with deﬁnite DHF. These studies have clearly demonstrated that global LV systolic properties are normal in patients with DHF. The most commonly used index of LV systolic properties is the ejection fraction; however, a full assessment of the contractile behavior of the ventricle requires the combined use of indices that reﬂect LV systolic performance, function, and contractility, as well as a consideration of global and regional functions. The following measurements have been made in patients with deﬁnite DHF: ❒ ❒

LV performance measured as stroke work LV function measured as ejection fraction and preload recruitable stroke work LV contractility measured as peak (+)dP/dt, end systolic elastance, and the endocardial stress-shortening relationship

❒

Patients with DHF have no signiﬁcant change in any of these measurements compared with age- and gender-matched normal control subjects.11 While these global measurements of LV systolic properties are normal in patients with DHF, regional systolic properties such as midwall fractional shortening and long axis shortening extent and rate may be abnormal in some patients (>50%) with DHF. However, these regional abnormalities do not appear to be causally linked to either the pathophysiology of diastolic dysfunction or the development of DHF.2

As previously discussed, abnormal LV diastolic function is a universal ﬁnding in patients with DHF. Indeed, these abnormalities in diastolic function form the dominant pathophysiologic basis for the development of DHF. Even in patients with “compensated” DHF (NYHA classes II–III), abnormal relaxation, ﬁlling, and stiﬀness lead to increased diastolic pressures (Fig. 2-13). Further changes in diastolic function occur when patients develop decompensated DHF.28,29 For example, atrial ﬁbrillation, tachycardia, or uncontrolled hypertension can lead to rapid increases in LA pressures and the development of decompensated DHF. Under these circumstances, the rise in pressure causes a signiﬁcant change in transmitral Doppler ﬂow pattern (as previously described). There is pseudonormalization of the ratio of ventricular to atrial ﬁlling velocities (E to A ratio) and when atrial pressures are extremely increased, to a frankly restrictive pattern. These changes in relaxation and ﬁlling are associated with changes in distensibility. During compensated DHF, the LV diastolic P-V relationship shifts upward, indicating decreased diastolic distensibility. During the initial development of decompensated DHF (during the phase of “worsening DHF”), LV volume may increase along a similar abnormal diastolic P-V curve (from point A to point B). Later, when acute pulmonary edema develops in decompensated DHF, there may be a marked upward shift in the diastolic P-V relationship (from point B to point C), indicating a further decrease in LV distensibility. Once patients with decompensated

WORSENING DHF

33 A 22 Normal 11

LV pressure (mmHg)

COMPENSATED DHF

LV pressure (mmHg)

Abnormal Diastolic Function in Decompensated Diastolic Heart Failure

0

B

33 A 22

11

0 0

20

40

60

80

100

0

20

40

60

LV volume (ml)

ACUTE PULMONARY EDEMA

POST TREATMENT

LV pressure (mmHg)

B

33

100

C

C LV pressure (mmHg)

80

LV volume (ml)

22

11

0

33 A 22

11

0 0

20

40

60

LV volume (ml)

80

100

0

20

40

60

LV volume (ml)

80

100

Figure 2-13 Left ventricular (LV) diastolic pressure-volume (P-V) relationship in compensated and decompensated diastolic heart failure (DHF). During compensated DHF, the LV diastolic P-V relationship shifts upward, indicating decreased diastolic distensibility. During the development of decompensated DHF initially (during the phase of “worsening DHF”), LV volume may increase along a similar abnormal diastolic P-V curve (from point A to point B). Later, when acute pulmonary edema develops in decompensated DHF, there may be a marked upward shift in the diastolic P-V relationship (from point B to point C), indicating a further decrease in LV distensibility. Once patients with decompensated DHF are adequately treated—for example, with diuretics and nitrates—the LV diastolic P-V relationship moves back to the compensated DHF state (from point C to point A).

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness DHF are adequately treated—for example, with diuretics and nitrates—the LV diastolic P-V relationship moves back to the compensated DHF state (from point C to point A). Decompensated DHF may be caused by both cardiovascular and noncardiovascular factors (or triggers) that act on the already existing structural and functional abnormalities (composing a substrate) to precipitate the development of acute pulmonary edema (Fig. 2-14). The substrate in patients with DHF consists of structural remodeling of the LV chamber and of the constituent cardiomyocytes and extracellular matrix that compose the chamber. These structural changes are associated with signiﬁcant abnormalities in LV diastolic function, including decreased LV distensibility. These changes in LV structure and function form the substrate from which patients develop the clinical syndrome of DHF. There are a number of comorbid conditions that may act as triggers for the development of acute decompensated DHF. These include uncontrolled hypertension, increased salt and water intake, tachyarrhythmias, chronic renal failure, anemia, and coexistent lung disease.1,3,30–36 These comorbidities act upon the substrate to precipitate acute decompensated DHF. It should be noted, however, that in the absence of this substrate, these triggers do not result in DHF. For example, an increase in salt and water

intake in the absence of concentric remodeling or diastolic dysfunction does not result in DHF.

Abnormal Diastolic Function in Diastolic Heart Failure During Exercise While studies consistently show that diastolic function is abnormal in patients with DHF at rest, these abnormalities become even more exaggerated during exercise (see Chapter 17).37–39 Speciﬁcally, patients with DHF are not able to increase LV end diastolic volume, recruit Frank-Starling forces, increase relaxation rate, or increase ﬁlling rate. Consequently, exercise results in a marked increase in diastolic pressure, a limited ability to increase cardiac output, and marked truncation of exercise capacity. These abnormal responses to exercise are made worse by the exaggerated increase in arterial blood pressure that frequently accompanies exercise in patients with DHF. Abnormal diastolic function also plays a role in exercise intolerance suﬀered by patients with SHF, in which systolic dysfunction causes the left ventricle to lose the ability to augment diastolic ﬁlling in response to exercise by the normal mechanism of accentuated elastic recoil and early diastolic suction, previously

LV diastolic pressure (mmHg)

Normal

Diastolic heart failure

30

DHF Normal control

25 20

Decreased distensibility

15 10 5 0 0

20

40

60

80

100

120

LV diastolic volume (ml)

Substrate LV structure LV function

Triggers HTN, ↑ Na2/H2O, Tachy, CRF, ↓ HgB lung disease

Diastolic heart failure

Figure 2-14 Diastolic heart failure (DHF) substrate versus trigger. Patients with DHF have structural remodeling of the left ventricular (LV) chamber and of the constituent cardiomyocytes and extracellular matrix that compose the chamber. These structural changes are associated with significant abnormalities in LV diastolic function, including decreased LV distensibility. These changes in LV structure and function form the substrate from which patients develop the clinical syndrome of DHF. There are a number of comorbid conditions that may trigger the development of acute decompensated DHF. These include uncontrolled hypertension, increased salt and water intake, tachyarrhythmias, chronic renal failure (CRF), anemia, and coexistent lung disease. These comorbidities act upon the substrate to precipitate acute decompensated DHF. It should be noted, however, that in the absence of this substrate, these triggers do not result in DHF. For example, an increase in salt and water intake in the absence of concentric remodeling or diastolic dysfunction does not result in DHF.

21

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness described.18–20 Early diastolic ﬁlling in HF can be increased during exercise by a diﬀerent mechanism: an elevation in LA pressure to create the requisite transmitral gradient rather than the normal decline in early diastolic LV pressure. The increase in LA pressure results in pulmonary congestion with exercise, a hallmark of HF (see Fig. 2-3).

sure, indicating a “paradoxical” increase in diastolic compliance.41 By contrast, during demand ischemia, diastolic compliance falls acutely.41–43 These opposite initial compliance changes with demand and supply ischemia may be explained by diﬀerences in the pressure and volume within the coronary vasculature, by the mechanical eﬀects of the normal myocardium adjacent to the ischemic region, and by tissue metabolic factors.

CLINICAL RELEVANCE

Ischemia/Reperfusion Causing Diastolic Dysfunction

A variety of cardiac diseases can cause the development of abnormal diastolic function, abnormal cardiovascular remodeling, and the development of DHF. The mechanisms by which cardiovascular disease causes these outcomes include (but are not limited to) hemodynamic alterations, nonhomogeneous contraction and relaxation, myocardial ischemia, and LV concentric remodeling and hypertrophy. These mechanisms can act individually to alter diastolic function but often act in concert to cause the development of DHF. For ease of understanding, these mechanisms will ﬁrst be discussed individually.

Ischemic Diastolic Dysfunction Ischemia can cause a reversible impairment of myocyte relaxation and diastolic function. The resultant slowing or failure of myocyte relaxation causes a fraction of actin-myosin cross-bridges to persist and continue to generate tension throughout diastole, especially in early diastole, creating a state of “partial persistent systole.” Two kinds of ischemia can alter diastolic function: demand ischemia, created by an increase in energy utilization that outstrips the necessary supply (such as during exercise or stress), and supply ischemia, created by a decrease in myocardial blood ﬂow without a change in energy utilization (such as a myocardial infarction or coronary artery spasm). The diﬀerences between supply and demand ischemia are transient. After more sustained ischemia of 30 to 60 minutes or longer, both types result in decreased diastolic compliance.

Ischemic diastolic dysfunction can continue during and after reestablishment of normal myocardial blood ﬂow (i.e., reperfusion). Reperfusion after a period of ischemia may result in a phase of post-ischemic diastolic “stunning,” analogous to post-ischemic stunning of contractile function. For example, diastolic dysfunction may be present early after cardiac surgery, after the myocardium has been exposed to cardioplegic arrest, or after thrombolytic or percutaneous treatment of an acute myocardial infarction. In each of these circumstances, reversible diastolic dysfunction follows reperfusion after a period of ischemia despite normal blood ﬂow, with slow recovery to normal levels (Fig. 2-15).44–46 Post-ischemic mechanical dysfunction results in both systolic and diastolic dysfunction, and the latter may be a more sensitive parameter of ischemic injury.41 During reperfusion, LV diastolic chamber stiﬀness is increased.44,45 Over time, diastolic dysfunction resolves, and it is therefore reasonable to refer to this process as post-ischemic diastolic stunning. Recognition of this phenomenon is important because a reduced cardiac output or elevated PCWP in the early postoperative period or early after treatment of acute coronary syndrome may reﬂect an increase in LV diastolic chamber stiﬀness rather than a reduction in contractile function. This distinction can be made readily with echocardiography.

Demand Ischemia During demand ischemia, diastolic dysfunction may be related to myocardial ATP depletion, with a concomitant increase in ADP, resulting in rigor (rigor bond formation).29 Although ischemia is also associated with the persistence of an increased intracellular calcium concentration during diastole, one study found that ischemic diastolic dysfunction was not directly mediated by an increase in calcium concentration and a calcium-activated tension.40 As a result of the rigor, LV pressure decay, as assessed by Tau, is impaired, and the left ventricle is functionally stiﬀer than normal during diastole. Typically demand ischemia occurs during exercise or pharmacologically induced stress; it results from an increase in oxygen demand in the setting of limited coronary ﬂow reserve caused by coronary stenosis and/or ventricular hypertrophy.

Supply Ischemia Supply ischemia results from a marked reduction in coronary ﬂow. The net eﬀect is inadequate coronary perfusion even in the resting state. Acute supply ischemia causes an initial transient downward and rightward shift of the diastolic P-V curve such that end diastolic volume increases relative to end diastolic pres-

Post CABG

20 PCWP (mmHg)

22

Pre CABG 14

9.5

10

10.5

11

11.5

LV end diastolic area

12

12.5

(cm2)

Figure 2-15 Coronary artery bypass graft (CABG) decreases left ventricular (LV) compliance. The relationship between LV end diastolic area, measured by two-dimensional echocardiography, and the pulmonary capillary wedge pressure (PCWP), which reflects LV compliance, before and after CABG. The PCWP and LV diastolic areas were increased with volume loading using isotonic saline. After CABG, the LV diastolic area was smaller at each level of PCWP, as reflected by a leftward shift of the pressure-area relationship; this indicates a reduction in LV compliance. (From McKenney P, et al: Increased left ventricular diastolic chamber stiffness immediately after coronary artery bypass surgery. J Am Coll Cardiol 1994;24:1189.)

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness

Ischemia-Induced Pulmonary Symptoms Ischemia, either spontaneous or during exercise, prevents the normal increase in LV distensibility and, as previously mentioned, can cause a rapid and marked increase in LV diastolic chamber stiﬀness. In the latter setting, LV diastolic pressures quickly increase, resulting in acute pulmonary congestion (“ﬂash” pulmonary edema). This upward shift of the LV diastolic P-V curve is completely reversible with recovery of myocardial perfusion.24 The eﬀects of ischemia explain why many patients with coronary disease have respiratory symptoms with their anginal pain, including wheezing, an inability to take a deep breath, or shortness of breath. Such respiratory symptoms may occur in the absence of anginal pain and are often referred to as anginal equivalents. These symptoms are similar to those of HF, which is not surprising, since the responsible mechanism is an elevation in pulmonary capillary pressure. One study, for example, showed that the acute decrease in LV distensibility and increase in diastolic pressure during angina caused an increase in airway resistance and a reduction in lung compliance.47 A similar symptom complex can occur in patients with concentric LV hypertrophy (LVH), even in the absence of epicardial coronary artery disease.

Left Ventricular Concentric Hypertrophy Widespread use of noninvasive methods of cardiac imaging has led to the recognition that LV diastolic dysfunction and DHF are commonly induced by the myocardial hypertrophy associated with hypertensive, coronary, or valvular heart disease. Resistance to diastolic ﬁlling is usually the result of common structural abnormalities, including concentric LV remodeling, cardiomyocyte hypertrophy, altered structure and composition of the extracellular matrix, and increased ﬁbrillar collagen. All of these hypertrophy-associated changes lead to impaired cellular and myocardial relaxation (see Fig. 2-9). LVH and ischemia have important interactions. For a given degree of ischemia, a greater decline in diastolic function is seen in hypertrophied hearts.9,48 Hearts with concentric LVH are highly susceptible to subendocardial ischemia for several reasons49: ❒

❒

❒

❒

There is some evidence of inadequate coronary growth relative to muscle mass, with a resultant decrease in capillary density.50 The ensuing increase in capillary-to-myocyte oxygen diﬀusion distance renders the hypertrophied myocyte more susceptible to ischemia. The increase in ventricular wall thickness raises the epicardial-endocardial distance. Coronary arterial circulation consists of epicardial vessels that penetrate transmurally, giving rise to mid-myocardial branches that perfuse the thickened LV wall before supplying the subendocardium. Thus, coronary perfusion pressure is dissipated in proportion to LV wall thickness, leaving the subendocardium as the region most vulnerable to ischemia.49 Coronary arterial remodeling accompanies concentric hypertrophy and is manifested by an increase in coronary arterial medial thickness and perivascular ﬁbrosis, which can restrict the extent of coronary arterial vasodilatation. Vascular tone at rest is often abnormally reduced, and coronary ﬂow at rest is increased in the hypertrophied heart.51,52 Enhanced coronary ﬂow is required in the resting state to supply the increased muscle mass. However, since maximal achievable coronary ﬂow is similar to that of normal ventricles, coronary ﬂow reserve is diminished. Endothelial

❒

❒

dysfunction also may contribute to the reduction in coronary reserve, although the response to exogenous nitric oxide is preserved.53,54 Thus, when metabolic demand and the need for oxygen increase, coronary reserve is often inadequate to meet the increased oxygen requirements, and ischemia ensues.52 Increased LV diastolic pressures can cause vascular compression, thereby reducing coronary ﬂow and perfusion of the subendocardial layer.49 The incidence and severity of coronary atherosclerosis is increased in the presence of systemic arterial hypertension, a frequent cause of concentric LVH. Thus, patients with concentric LVH on a hypertensive basis often have signiﬁcant concomitant coronary artery disease.

These factors make the heart with concentric LVH exquisitely sensitive to subendocardial ischemia. The hypertrophied ventricle also cannot relax normally in diastole with exercise. Thus, to produce the necessary increase in ventricular input, there is an increase in LA pressure, rather than the normal reduction in ventricular pressure, which produces a suction eﬀect, as previously described. This can lead to an elevation in pulmonary capillary pressure that is suﬃcient to induce pulmonary congestion. Exercise-induced subendocardial ischemia can produce an “exaggerated” impairment of diastolic relaxation of the hypertrophied myocardium (see Fig. 2-15). These factors often act in concert. For a given degree of ischemia, the functional impairment in relaxation is more severe in the hypertrophied than in the nonhypertrophied heart.9,48 Thus, patients with concentric LVH secondary to chronic hypertension or aortic stenosis are particularly susceptible to ischemic diastolic dysfunction.

Genetic and Infiltrative Diseases Genetic disease processes, such as hypertrophic cardiomyopathy, and inﬁltrative diseases, such as amyloidosis, cause diastolic dysfunction and lead to the development of DHF. These disease processes are discussed in detail in Chapters 21 and 23.

Trigger Mechanisms of Noncardiac Factors in Acute Decompensated Diastolic Heart Failure Patients with DHF are older and have a large number of coexistent, comorbid disease processes, each of which may act on the structural and functional substrate that occurs in patients with DHF and may trigger the development of acute decompensated DHF (see Fig. 2-14). For example, present in patients with DHF may be advanced age, poorly controlled diabetes, chronic renal insuﬃciency, anemia, atrial ﬁbrillation, selected drugs (e.g., glitazones, acidic nonsteroidal anti-inﬂammatory drugs [ANSAIDs], calcium channel blockers), abnormal sodium and water balance, chronic lung disease, increased arterial blood pressure, and increased eﬀective arterial elastance. When present chronically, some of these factors may contribute to development of the structural and functional changes that form the substrate from which DHF develops. For example, diabetes may be associated with increases in advanced glycation endproduct–induced collagen cross-links, in collagen content, and in myocardial stiﬀness. The changes in the structure and function of cardiomyocytes and extracellular matrix that are common to advanced age may make the myocardium more vulnerable to

23

24

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness the eﬀects of hypertension and coronary artery disease, making the development of DHF more frequent. In addition, once the structural and functional substrate of DHF has formed (i.e., concentric remodeling and abnormal diastolic function), the factors previously listed can act on this substrate to precipitate (or trigger) the development of acute decompensated DHF. However, in the absence of the substrate structure/function changes of DHF, these factors by themselves will not result in its development.

FUTURE RESEARCH There are many aspects of the pathophysiology of DHF and acute decompensated DHF that remain to be completely understood. In particular, the cellular and extracellular mechanisms causing the pathophysiologic changes in LV and LA structure and function remain to be completely deﬁned. The independent eﬀects of aging and the relationship between advancing age and the development of diastolic dysfunction and DHF must be addressed, as must also the question of whether diastolic dysfunction is an inevitable consequence of aging or can be avoided by a “successful” aging process, without these abnormalities (particularly as regards diastolic function). We must deﬁne whether and how aging plus disease processes (hypertension, diabetes, etc.) common in an aging population result in DHF. Finally, we must deﬁne the factors that cause the transition from asymptomatic diastolic dysfunction (with or without compensated LVH or concentric remodeling) to symptomatic DHF. In particular, we must deﬁne clinically applicable, noninvasive methods to detect and predict this transition. Only with an increased knowledge and understanding of the pathophysiology of DHF can eﬀective management strategies that target this pathophysiology be developed and successfully applied to patients with DHF to decrease mortality and morbidity of this important cause of congestive heart failure. REFERENCES 1. Quiñones MA, Zile MR, Massie BM, Kass DA, for the Participants of the Dartmouth Diastole Discourses: Chronic heart failure: A report from the Dartmouth Diastole Discourses. Congest Heart Fail 2006;12:162–165. 2. Aurigemma GP, Zile MR, Gaasch WH: Contractile behavior in the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296–304. 3. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355:260–269. 4. Redﬁeld MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 5. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 6. Brucks S, Little WC, Chao T, et al: Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005;95:603–606. 7. Zile MR, Gaasch WH, Carroll JD, et al: Heart failure with a normal ejection fraction. Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001;104:779–782. 8. Zile MR: Heart failure with preserved ejection fraction: Is this diastolic heart failure? J Am Coll Cardiol 2003;41:1519. 9. Aurigemma GP, Gaasch WH: Clinical practice. Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 10. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiﬀness of the left ventricle. N Engl J Med 2004;350:1953–1959.

11. Baicu CF, Zile MR, Aurigemma GP, et al: Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005;111:2306–2312. 12. Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Deﬁnitions and terminology. Prog Cardiovasc Dis 2005;47:307–313. 13. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 14. Yusuf S, Pfeﬀer MA, Swedberg K, et al. and CHARM Investigators and Committees: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781. 15. Oh JK, Hatale L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 16. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular ﬁlling pressure in sinus tachycardia. A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. 17. Ahmen SH, Clark LL, Pennington WR, et al: Matrix metalloproteinases/ tissue inhibitors of metalloproteinases: Relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006;113:2089–2096. 18. Cheng CP, Igarashi Y, Little WC: Mechanism of augmented rate of left ventricular ﬁlling during exercise. Circ Res 1992;70:9–19. 19. Cheng CP, Noda T, Nozawa T, et al: Eﬀect of heart failure on the mechanism of exercise induced augmentation of mitral valve ﬂow. Circ Res 1993;72:795–806. 20. Little WC, Cheng CP: Modulation of diastolic dysfunction in the intact heart. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart: The biology of diastole in health and disease, 2d ed. Boston, Kluwer Academic Publishers, 1994:167–176. 21. Little WC: Diastolic dysfunction beyond distensibility: Adverse eﬀects of ventricular dilatation. Circulation 2005;112:2888–2890. 22. Katz AM: Physiology of the Heart. New York, Raven Press, 1992: 178. 23. Carroll JD, Hess OM, Hirzel HO, et al: Dynamics of left ventricular ﬁlling at rest and during exercise. Circulation 1983;68:59–67. 24. Carroll JD, Hess OM, Hirzel HO, et al: Exercise-induced ischemia: The inﬂuence of altered relaxation on early diastolic pressures. Circulation 1983;67:521–528. 25. Borbély A, van der Velden J, Papp Z, et al: Cardiomyocyte stiﬀness in diastolic heart failure. Circulation 2005;111:774–781. 26. Van Heerebeek L, Borbély A, Niessen HWM, et al: Myocardial structure and function diﬀer in systolic and diastolic heart failure. Circulation 2006;113:1966–1973. 27. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II. Causal mechanisms and treatment. Circulation 2002;105:1503–1508. 28. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344: 17–22. 29. Vinch CS, Aurigemma GP, Hill JC, et al: Usefulness of clinical variables, echocardiography, and levels of brain natriuretic peptide and norepinephrine to distinguish systolic and diastolic causes of acute heart failure. Am J Cardiol 2003;91:1140–1143. 30. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–259. 31. Yancy CW, Lopatin M, Stevenson LW, et al for the ADHERE Scientiﬁc Advisory Committee and Investigators: Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: A report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006;47:76–84. 32. Brucks S, Little WC, Chao T: Relation of anemia to diastolic heart failure and the eﬀect on outcome. Am J Cardiol 2004;93:1055–1057. 33. Fukuta H, Sane DC, Brucks S, et al: Statin therapy may be associated with lower mortality in patients with diastolic heart failure: A preliminary report. Circulation 2005;112:357–363. 34. O’Meara E, Clayton T, McEntegart MB, et al: Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: Results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation 2006;113:986–994.

Chapter 2 • Pathophysiology of Diastolic Heart Failure: Relaxation and Stiffness 35. Zile MR: Treating diastolic heart failure with statins. “Phat” chance for pleiotropic beneﬁts (editorial). Circulation 2005;112:300–303. 36. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure (editorial). Circulation 2006;113:1922–1925. 37. Little WC, Zile MR, Klein A, et al: Eﬀect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol 2006;98:383–385. 38. Warner JG Jr, Metzger DC, Kitzman DW, et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572. 39. Little WC, Wesley-Farrington DJ, Hoyle J, et al: Eﬀect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288–293. 40. Eberli FR, Stromer H, Ferrell MA, et al: Lack of direct role for calcium in ischemic diastolic dysfunction in isolated hearts. Circulation 2000;102:2643–2649. 41. Apstein CS, Grossman W: Opposite initial eﬀects of supply and demand ischemia on left ventricular diastolic compliance: The ischemia-diastolic paradox. J Mol Cell Cardiol 1987;19:119–128. 42. Varma N, Eberli FR, Apstein CS: Increased diastolic chamber stiﬀness during demand ischemia: Response to quick length change diﬀerentiates rigor-activated from calcium-activated tension. Circulation 2000;101: 2185–2192. 43. Varma N, Eberli FR, Apstein CS: Left ventricular diastolic dysfunction during demand ischemia: Rigor underlies increased stiﬀness without calcium-mediated tension. Amelioration by glycolytic substrate. J Am Coll Cardiol 2001;37:2144–2153. 44. McKenney PA, Apstein CS, Mendes LA, et al: Increased left ventricular diastolic chamber stiﬀness immediately after coronary artery bypass surgery. J Am Coll Cardiol 1994;24:1189–1194.

45. McKenney PA, Apstein CS, Mendes LA, et al: Immediate eﬀect of aortic valve replacement for aortic stenosis on left ventricular diastolic chamber stiﬀness. Am J Cardiol 1999;84:914–918. 46. Bolli R: Myocardial “stunning” in man. Circulation 1992;86:1671. 47. Pepine CJ, Wiener L: Relationship of anginal symptoms to lung mechanics during myocardial ischemia. Circulation 1972;46:863– 869. 48. Eberli FR, Apstein CS, Ngoy S, et al: Exacerbation of left ventricular ischemic diastolic dysfunction by pressure-overload hypertrophy. Modiﬁcation by speciﬁc inhibition of cardiac angiotensin converting enzyme. Circ Res 1992;70:931–943. 49. Isayama S: Interplay of hypertrophy and myocardial ischemia. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart: The biology of diastole in health and disease, 2d ed. Boston, Kluwer Academic, 1994:203–212. 50. Tomanek RJ, Wessel TJ, Harrison DG: Capillary growth and geometry during long-term hypertension and myocardial hypertrophy in dogs. Am J Physiol 1991;261:H1011–H1018. 51. Eberli FR, Ritter M, Schwitter J, et al: Coronary reserve in patients with aortic valve disease before and after successful aortic valve replacement. Eur Heart J 1991;12:127–138. 52. Marcus ML, Koyanagi S, Harrison DG, et al: Abnormalities in the coronary circulation that occur as a consequence of cardiac hypertrophy. Am J Med 1983;75:62–66. 53. Ishihara K, Zile MR, Nagatsu M, et al: Coronary blood ﬂow after the regression of pressure-overload left ventricular hypertrophy. Circ Res 1992;71:1472–1481. 54. MacCarthy PA, Shah AM: Impaired endothelium-dependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy. Circulation 2000;101:1854–1860.

25

3

DAVID H. SPODICK, MD

Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY CLINICAL RELEVANCE AND FUTURE RESEARCH ABBREVIATIONS

INTRODUCTION Pericardologists1 were concerned almost exclusively with diastole (for good reasons of pericardial constriction and cardiac tamponade) before the late 1980s, when diastolic dysfunction (DD) started to attract widespread attention among other cardiologists. In many respects, acute and subacute constrictive pericarditis (CP) and cardiac tamponade epitomize DD, usually in the presence of normal systolic cardiac function. Indeed, both often have normal or high ejection fractions (EFs)—a consequence of ventricular underﬁlling with basically normal or compensatorily hyperfunctional myocardium.2 However, the normal pericardium also aﬀects the cardiac ﬁlling dynamics of both normal and diseased hearts, although to a lesser degree.3

PATHOPHYSIOLOGY The normal pericardium becomes more important in dilated hearts and with increased central circulatory volume and less so with hypovolemia and normal responses to other inﬂuences that reduce cardiac size, like head-up tilt (HUT), lower body negative pressure (LBNP), and administration of such agents as nitroprusside and nitroglycerine.3 With the often low compliance of hearts with DD, the inﬂuence on ﬁlling of the normally stiﬀ, lowcompliance pericardium may be either less than normal or additive, but this relationship has not been investigated. In the absence of formal, speciﬁcally targeted investigations of the inﬂuence of the pericardium on DD and diastolic heart failure

(DHF), the current state of knowledge permits only reasonable extensions and hypothesis generation from what we know of pericardial function and behavior during normal cardiac function and to some extent during systolic cardiac impairments. Box 3-1 summarizes the macrophysiology of the normal pericardium, many elements of which—subject to investigation—may aﬀect DD and DHF. Box 3-2 summarizes the many cardiac eﬀects of pericardiectomy or suﬃciently extensive pericardiotomy.4 Patients who have had pericardiectomy for any indication grossly appear to function quite well, although the subject has not been intensively studied in human patients and certainly not compared for individual patients acutely and especially chronically, which would permit a better estimate of the pericardium’s dispensability. In considering the many eﬀects of pericardiectomy and pericardiotomy suﬃciently widespread to remove pericardial mechanical inﬂuence (see Box 32), the apparent benignity of pericardiectomy/otomy is at least superﬁcially surprising because it implies that there are either widespread and adequately compensatory adjustments or that the pericardium is really not indispensable. Nonindispensability would be especially surprising when one considers the items in Box 3-1, as well as the very rich pericardial microphysiology5 (not a subject of this discussion). There is, however, broad and deep experience with experimental pericardiectomy and pericardiotomy (see Box 3-2) in hearts without cardiac disease, which, like the macro functions of the normal pericardium (see Box 3-1), should be considered in evaluating and further investigating DD and DHF. All pericardial investigations must always be considered in the light of the varied investigational protocols, which have deﬁnitely aﬀected experimental results. Thus, it matters quantitatively and even qualitatively whether the experimental subjects are intact and conscious with a closed chest and having recovered from surgery, versus open chest, anesthetized, and/or autonomically blocked experimental subjects, as well as the species of the subjects.3 For example, dog, rabbit, and human pericardial structures diﬀer signiﬁcantly; the canine pericardium is much more anisotropic than the human pericardium.6 Moreover, within the intact pericardium, it matters quantitatively whether the pressure is 27

28

Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure Box 3-1

Macrophysiology of the Normal Pericardium* Mechanical Functions: Promotion of Cardiac Efficiency, Especially during Hemodynamic Overloads I. Relatively inelastic cardiac envelope A. Maintenance of normal ventricular compliance (volume-elasticity relation) B. Defense of the integrity of any Starling curve: Starling mechanism operates uniformly at all intraventricular pressures because presence of pericardium 1. Maintains ventricular function curves. 2. Limits effect of increased left ventricular end diastolic pressure. 3. Supports output responses to: a. Venous inflow loads and atrioventricular valve regurgitation (particularly when acute) b. Rate fluctuations 4. Hydrostatic system (pericardium plus pericardial fluid) distributes hydrostatic forces over epicardial surfaces. a. Favors equality of transmural end diastolic pressure throughout ventricle, therefore uniform stretch of muscle fibers (preload) b. Constantly compensates for changes in gravitational and inertial forces, distributing them evenly around the heart C. Limitation of excessive acute dilation D. Protection against excessive ventriculoatrial regurgitation (atrial support) E. Ventricular interaction: relative pericardial stiffness 1. Provides a mutually restrictive chamber favoring balanced output from right and left ventricles integrated over several cardiac cycles 2. Permits either ventricle to generate greater isovolumic pressure from any volume 3. Reduces ventricular compliance with increased pressure in the opposite ventricle (e.g., limits right ventricular stroke work during increased impedance to left ventricular outflow) F. Maintenance of functionally optimal cardiac (especially left ventricular) shape

II. Provision of closed chamber with slightly subatmospheric pressure in which: A. The level of transmural cardiac pressures will be low, relative to even large increases in “filling pressures” referred to atmospheric pressure. B. Pressure changes aid atrial filling via more negative pericardial pressure during ventricular ejection. C. Diastolic suction can accelerate filling following systole. III. “Feedback” cardiocirculatory regulation via pericardial servomechanisms A. Neuroreceptors detect lung inflation and (via vagus): alter heart rate and blood pressure. B. Mechanoreceptors: Lower blood pressure and contract spleen. IV. Limitation of hypertrophy associated with chronic exercise Membranous Functions I. Reduction of external friction due to heart movements A. Production of pericardial fluid B. Generation of phospholipid surfactants II. Buttressing of thinner portions of the myocardium: Myocardial thickness varies reciprocally with parietal pericardial thickness. A. Atria B. Right ventricle III. Defensive immunologic constituents in pericardial fluid IV. Fibrinolytic activity in mesothelial lining V. Prostacyclin (PGE2, PG12 and eicosanoids) released into pericardial sac in response to stretch, hypoxia and increased myocardial loading/work VI. Synthesis and release of endothelin, increased by angiotensin III stimulation VII. Barrier to inflammation from contiguous structures Ligamentous Function I. Limits undue cardiac displacement II. Modifies pericardial stress/strain by limiting directions of traction of its fibers

*Condensed from Spoclick DH: The pericardium: A comprehensive textbook. New York, Marcel Dekker, 1997.

measured by an open-ended catheter or a ﬂat balloon transducer, with balloons yielding higher levels of pericardial constraint (speciﬁcally radial epicardial stress), especially signiﬁcant at very low eﬀusion volumes.7 Most of the pathophysiologic eﬀects of pericardiectomy or sufﬁciently extensive pericardiotomy must be considered in light of the fact that the pericardium, speciﬁcally the parietal pericardium, constrains the heart, which is immediately recognizable by retraction of the in situ pericardial tissue when it is incised.3 (The visceral pericardium may also have some constraining eﬀect, but this is incompletely investigated.) Indeed, in 1898 Barnard incised the pericardium and observed that the heart herniated through the incision, especially in diastole and more so when he squeezed the abdomen, elevating vena cava pressure.8 Thus it is no surprise that pericardial constraint accounts for about 90% of right atrial (RA) and 80% of right ventricular (RV) cavitary pressure.9 The immediate ﬁlling pressures of the cardiac chambers are their transmural pressures (TMPs): cardiac chamber pressures minus

normally negative—therefore numerically additive—intrapericardial pressure.3 TMPs are created by having an intact pericardium and are approximately equal over both ventricles, although there may be local eﬀects causing small local diﬀerences.10 The right ventricular end diastolic pressure-dimension (RVEDPD) relation, for example, is not ﬂat or zero because of this, and as noted in Box 3-2, at matched left ventricular end-diastolic (LVED) volume, pericardiectomy causes a fundamental alteration in otherwise normal RV, but not left ventricular (LV), ﬁlling.11 Finally, transmural LVED pressure is a more important determinant of LV mechanoreceptor activity than absolute LVED pressure.3,12 Mechanoreceptors are sensitive to changes in ventricular stretch, determined by ventricular volume and TMP; pericardial constraint may attenuate their activity by limiting cardiac distension.3 Whereas, with an intact pericardium, the right ventricle dominates direct ventricular diastolic interaction (ventricular interdependence), after pericardiectomy or suﬃciently extensive

Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure Box 3-2

Pericardiectomy/Pericardiotomy*: Pathophysiologic Effects A. General Considerations 1. Reduced or absent constraint of the cardiac chambers 2. At matched LVEDV, pericardiectomy causes a fundamental alteration in RV but not LV filling. 3. Pericardiectomy shifts LVEDP-V curve to the right. 4. Pericardiectomy decreases RVEDP-V slope. 5. Reduced atrioventricular and ventricular interaction (i.e., parallel interaction, due to pericardium); left ventricle dominates. (With an intact pericardium, the right ventricle dominates.) 6. Decreased suction (less negative pressure) during ventricular systole B. Specific Effects 1. Decreased: a. RA mean pressure b. RA filling rate c. Pulmonary volume overload with intravascular volume loading d. Excess intravascular volume redistribution from pulmonary systemic circulation e. Decreased ventricular isovolumic pressure generation from any volume f. Decreased base to apex intraventricular pressure gradient; filling velocity shifts toward the base g. E/A and E′ h. Decreased LV mechanoreceptor activity12 2. Increased: a. Cardiac chamber transmural pressures b. RV size c. LV stroke volume, SWI and CI due to Frank-Starling response to increased preload d. LA compliance with greater increase in conduit than reservoir function e. LV compliance f. Peak dp/dt g. Early LV filling velocity (A) and filling fraction h. LV end diastolic diameter and volume i. LV early filling rate j. Ventricular series interactions (relative to direct interaction) k. LV mechanoreceptor activity l. Rate of myocardial protein synthesis producing increased LV mass m. Exercise responses i. Maximal O2 consumption ii. Maximal stroke volume and cardiac output iii. LA pressure and SV and LASV iv. LV end diastolic pressure n. Ventricular pressure-volume curves: Ventricular pressure begins its sharp rise later (at a higher cardiac volume) and increases more gradually thereafter. *Pericardiotomy = sufficiently wide incision/excision.

pericardiotomy, the left ventricle dominates the relationship; thus LV isovolumic pressure generation from any LV volume is decreased and, comparably, after pericardiectomy ventricular pressure-volume (P-V) curves show their customary sharp rise later (i.e., at a higher chamber volume) and thereafter also increase more gradually than before pericardiectomy.13

After pericardiectomy, the cardiac chambers operate at diﬀerent TMPs because of the normally slightly negative intrapericardial pressure (unless, subject to investigation, the ambient pleural and pulmonary pressures of the cardiac fossa could substitute for this). With DHF, pericardial inﬂuence would also be subject to investigation to characterize cardiac ﬁlling in relation to the TMPs. Moreover, the force balance aﬀecting cardiac chambers and their corresponding systolic performance is described by the transmural diﬀerence between intracavitary and extramural pressures.14 Indeed, the chamber collapses seen in cardiac tamponade can be attributed to sometimes even negative transmural diastolic pressures (i.e., intrapericardial pressure intermittently suﬃciently higher than subjacent chamber pressures). In pericardial constriction (usually completely obliterative), there can be no truly transmural pressures.2 Ventricular interaction (ventricular interdependence) reﬂects the inﬂuence, particularly the ﬁlling characteristics, of the contralateral ventricle.4 Direct interaction occurs immediately via the ventricular septum, while indirect interaction (series interaction) is by way of the pericardium. For series interaction, an immediate change in one ventricle is not transmitted as directly as through the septum but is transmitted sequentially in subsequent heartbeats. Series and direct interaction inﬂuence P-V relations, pulmonary-cardiac contact pressure, and coronary engorgement. Of these, the P-V relations are the most important to producing LV diastolic pressure. Hypertrophied hearts, which are characterized by DD, especially with ventricular failure, should be a natural subject for further investigation of interaction. Draining a noncompressing hydropericardium, as occurs in heart failure, induces a state analogous to removing the normal pericardial constraint, or at least reducing it considerably, since it has been shown that any size, small to large, of even clinically nontamponading eﬀusions signiﬁcantly exaggerate respiratory eﬀects on cardiac dynamics when measured with appropriate instruments.15 These are a quantitatively small counterpart to the eﬀusions producing cardiac tamponade, which more strongly couple the parietal pericardium to the chamber surfaces, grossly exaggerating ventricular interaction, especially the respiratory eﬀects due to the existence of an intact pericardium, notably pulsus paradoxus.16 A particular advantage of an intact pericardium, which could be investigated in DD and DHF, is the pericardial contribution to diastolic suction. Diastolic suction, speciﬁcally ventricular suction, occurs in early diastole and must exist in normal as well as abnormal hearts.17 The intensity of diastolic suction is proportional to the kinetic energy of the preceding systole. Moreover, diastolic suction is greatest when the heart size is least, after the end of systole, precisely when it is needed for ﬁlling. (Systolic suction may also exist in the atria during reduction of intrapericardial contents by ventricular ejection.3) Presence of the pericardium thus permits the kinetic energy acquired during systole to be applied to ﬁlling. Moreover, diastolic suction is more important at the rapid heart rates common to cardiac failure, which amputate the late to mid-diastolic diastasis interval so that there is less “passive” ﬁlling. In any case, suction must be necessary for even normal cardiac ﬁlling because, although the Frank-Starling relation implies that cardiac output should be determined by venous ﬁlling of the right heart, RA pressure is normally low, and small changes should not aﬀect the entire heart. Indeed, changes in body position and breathing may cause larger changes in pressure.18 This is dramatically seen when excised mammalian hearts in buﬀered solutions continue to empty and reﬁll, where pericar-

29

30

Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure dial absence ensures that there can be no change in extramural pressure. Yet, diastolic suction is directly observed, indeed obvious. In such hearts, an intact pericardium would facilitate or magnify suction. In these isolated hearts, diastolic ﬁlling pressure thus does not uniquely determine ﬁber length and cannot entirely explain the cardiac “output.” In DD, one might predict that decreased myocardial compliance, epitomized by hypertensive hearts, would reduce macrophysiologic pericardial eﬀects by analogy to pericardial eﬀects on the normal right and left ventricles; the normal right ventricle is thinner and far more compliant than the left—especially with LV hypertrophy—and thus much more directly subject to pericardial constraint and to changing intrapericardial pressure. Indeed, normal RV compliance is three to four times LV compliance,19 a relationship predictably aﬀected by DHF but subject to investigation. Another target for investigation in DD and DHF would be the eﬀect of the pericardium in restricting acute chamber dilation (as of the left atrium following papillary muscle rupture with acute mitral regurgitation). Constraint is illustrated in reverse in those cases of “pericardial shock” with severe hypotension immediately after pericardiocentesis, usually in patients with concomitant heart disease who develop acute LV failure after pericardial drainage due to acute LV dilation.20 Indeed, some of these patients also develop acute pulmonary edema. One could assume that the pericardium and pericardial eﬀusion ﬂuid, especially with cardiac tamponade, had resisted ventricular dilation, following which drainage left a lax, nonconstraining, and therefore no longer resisting (constraining) pericardium. The eﬀects of pericardiectomy could also be investigated in DHF on a purely mechanistic basis because pericardiectomy shifts the LVED P-V relationship to the right or down (Box 3-2), while DHF shifts it to the left.21 Some of the major considerations are condensed in Box 3-3. Box 3-3

Selected Major Pericardial Functions Potentially* Applicable to Investigating Diastolic Dysfunction and Diastolic Failure I. Mechanical effects due to mainly the parietal pericardium and minimal in euvolemic individuals with normal hearts A. Decreased by hypovolemia B. Exaggerated by central hypervolemia (and pericardial effusion with or without tamponade) and by cardiac dilation C. Comparative effects in DD/DHF uninvestigated II. Normally, RV and LV volumes are equally restrained by the pericardium. (Though perhaps due to regional pericardial effects, cavitary pressures fall more in RV than LV after pericardiectomy.) Effects with DD/DHF uninvestigated. III. Differences in RV and LV filling partly relate to differences in atrial compliance and ventricular distensibility. (Volume loading and pericardiectomy affect A-V pressure gradient.) Effects in DD/DHF uninvestigated. IV. Nitroglycerine and nitroprusside decrease ventricular diastolic pressures, reflecting loss of pericardial constraint when decreased venous return shrinks cardiac volume. Applications in DD/DHF uninvestigated. *Pending formal, specific investigation.

CLINICAL RELEVANCE AND FUTURE RESEARCH Pericardial pathophysiology as capsulated in Boxes 3-1 and 3-2 applies to investigations of the pericardium and its eﬀect on the normal heart, usually the left ventricle. There are as yet no formal investigations of the role of the pericardium in patients and animal models with DD or DHF. Although one may generate hypotheses (e.g., see Box 3-3) and make reasonable projections from the foregoing data, clinical relevance can emerge only from speciﬁcally designed, controlled investigations tested in appropriate clinical contexts. For example, does the stiﬀness of the normal pericardium, accounting for its normal constraint,13 add to or otherwise modify the reduced compliance of the hypertensive left ventricle with DD or DHF? In some circumstances, structural pericardial modiﬁcations may be a therapeutic option. When pericardiectomy was tried some years ago for dilated cardiomyopathy, it proved to be more detrimental than helpful. The recent development, however, of a pericardial “garment” for the ventricles (e.g., the Acorn mesh) actually compensates for pericardial anisotropy since it is constructed with special ﬁber orientations that oppose the diﬀering directional tensions in the underlying pericardial ﬁbers.22 In addition, there is currently an enlarging ﬁeld of intrapericardial drug and instrumental therapy for investigation in diastolically as well as systolically and rhythmically abnormal hearts.23

ABBREVIATIONS HUT: Head-up tilt LBNP: lower body negative pressure DD: diastolic dysfunction DHF: diastolic heart failure TMP: transmural pressure: cardiac chamber pressures minus normally negative—therefore additive—pericardial pressure (e.g., LVTMP = left ventricular transmural pressure, and so on) PTMP: pericardial transmural pressure: intrapericardial pressure minus pleural pressure LV: left ventricle LA: left atrium RV: right ventricle RA: right atrium EDP: end diastolic intracavitary pressure (e.g., LVEDP = left ventricular end diastolic pressure, and so on) EDPV relation: end diastolic pressure-volume relation EDPD relation: end diastolic pressure-dimension relation Ventricular interaction (interdependence): Eﬀects of physical changes and movements in one ventricle on the other. Direct interaction: septal movement (as during breathing phases) imposed by pericardial constraint (series interaction is the eﬀect via the vasculature and lungs of one ventricle on the other). Pericardium-dependent ventricular interactions are almost entirely diastolic, although systolic and atrioventricular interactions also exist. Suction: ﬁlling of a cardiac chamber because of negative/relatively negative pressure “leading” the direction of blood ﬂow. Ventricular diastolic suction is especially important, especially at small/relatively small chamber/heart volumes. Most suction is facilitated by an intact pericardium. CP: constrictive pericarditis CT: cardiac tamponade EF: ejection fraction

Chapter 3 • Role of Pericardium in Diastolic Dysfunction and Diastolic Heart Failure REFERENCES 1. Seferovic PM, Spodick DH, Maisch B (eds): Pericardiology. Belgrade, Science, 1999. 2. Haﬀty BG, Singh JB, Spodick DH: Tracking left ventricular performance noninvasively: Response of the peak ear pulse derivative during cardiac catheterization. Chest 1983;83:543–546. 3. Spodick DH: Threshold of pericardial constraint: The pericardial reserve volume and auxiliary pericardial functions. J Am Coll Cardiol 1985;6: 296–297. 4. Spodick DH: Pericardial diseases. In Braunwald E, Zipes DP, Libby P (eds) Heart Disease, 6th ed. Philadelphia, WB Saunders, 2001:1823–1866. 5. Spodick DH: Macro and microphysiology and anatomy of the pericardium. Am Heart J 1992;124:1046–1051. 6. Janicki JS, Weber KT: The pericardium and ventricular interaction, distensility, and function. Am J Physiol 1980;238:H494–H503. 7. Tyberg JV, Misbach GA, Glantz SA, et al: A mechanism for shifts in the diastolic left ventricular pressure-volume curve: The role of the pericardium. Euro J Cardiol 1978;7:163–175. 8. Spodick DH: Acute pericarditis. New York, Grune Stratton, 1959:182. 9. Hamilton DR, Dani RS, Semlacher RA, et al: Right atrial and right ventricular transmural pressures in dogs and humans: Eﬀects of the pericardium. Circulation 1994;90:2492–2500. 10. Spadaro J, Bing OHL, Gaasch WH, Weintraub RM: Pericardial modulation of right and left ventricular diastolic interaction. Circ Res 1981; 48:233–238. 11. Gaasch WH, Zile MR: Left ventricular diastolic dysfunction and diastolic heart failure. Annu Rev Med 2004;55:373–394. 12. Wang SY, Sheldon RS, Bergman DW, Tyberg JV: Eﬀects of pericardial constraint on left ventricular mechanoreceptor activity in cats. Circulation 1995;92:3331–3336.

13. Spodick DH: Progress in investigation of eﬀusion and tamponade, immunosuppression, and constriction in pericarditis and pericardial diseases. Curr Op Cardiol 1992;7:476–481. 14. Boltwood CM: Ventricular performance related to transmural ﬁlling pressure in clinical cardiac tamponade. Circulation 1987;75:941–947. 15. Wayne VS, Bishop RL, Spodick DH: Dynamic eﬀects of nontamponading pericardial eﬀusion: Respiratory responses in the absence of pulsus paradoxus. Br Heart J 1984;51:202–204. 16. Spodick DH: Pathophysiology of cardiac tamponade. Chest 1998;113: 1372–1378. 17. Myers RBH, Spodick DH: Constrictive pericarditis: Clinical and pathophysiologic characteristics. Am Heart J 1999;138:219–232. 18. Robinson TF, Factor SM, Sonnenblick EH: The heart as a suction pump. Scient Amer 1981;210:84–98. 19. Belenkie I, Dani R, Smith ER, Tyber JV: The importance of pericardial constraint in experimental pulmonary embolism and volume loading. Am Heart J 1992;123:733. 20. Spodick DH: The pericardium: A comprehensive textbook. New York, Dekker, 1997. 21. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 22. Saavedra WF, Tunin RS, Paolocci N, et al: Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol 2002;39:2069–2076. 23. Spodick DH: Direct therapy for coronary disease, myocardial disease, and severe cardiac arrhythmias. In Spodick DH (ed): Intrapericardial therapeutics and diasgnostics (IPTD). Clin Cardiol 1999;22:I–1, I–42.

31

BRIAN D. HOIT, MD

4 Left Atrial Function: Basic Physiology INTRODUCTION PATHOPHYSIOLOGY Atrial Function in Health Left Atrial Reservoir Function Left Atrial Conduit Function Global Left Atrial Function LEFT ATRIAL FUNCTION IN DISEASE Left Atrial Function and Systolic Left Ventricular Dysfunction

Left Atrial Function and Diastolic Left Ventricular Dysfunction Left Atrial Function in a Model of Atrial Systolic Failure Importance of Left Atrial Functions and Their Interplay in Left Ventricular Systolic Dysfunction FUTURE RESEARCH ACKNOWLEDGMENT

INTRODUCTION A resurgence of interest in atrial function has enhanced our understanding of the atrial contributions to cardiovascular performance in health and disease (see Chapter 13). The reasons for this “renaissance” are multifactorial and include (1) the recognition that atrial function is an important, at times critical, determinant of left ventricular (LV) ﬁlling, (2) the increasing number of drugs, devices, ablative procedures, and surgeries available for the treatment of atrial ﬁbrillation,1–3 (3) the considerable interest in dual- and three-chamber pacemakers that maintain atrioventricular and biventricular synchrony, respectively,4–6 (4) the pathophysiological and clinical relevance of chamber-speciﬁc structural, electrical, and ionic remodeling,7–9 (5) the clinical impact of atrial distensibility and stunning, particularly postcardioversion,10,11 and (6) the important prognostic role of atrial function in heart failure.12,13 Despite this attention, quantifying atrial function is diﬃcult, in part because the atria are geometrically complex. Because of the obliquity of the atrial septum, the right atrium projects anteriorly, inferiorly, and to the right of the left atrium. The broad, triangular, muscular right atrial (RA) appendage protrudes anteriorly, the superior vena cava opens into the dome of the right atrium, and the inferior vena cava opens into its inferior and posterior portion. The body of the left atrium is smaller and thicker than the right atrium. The chamber has been modeled as a sphere, cube, or ellipse. The left atrial (LA) appendage is longer and narrower than the right appendage and contains all the pectinate muscles of the

left atrium. The four pulmonary veins, upper and lower from each lung (the left pair frequently opening via a common channel), enter the posterior aspect of the left atrium.14 The atrial walls consist of two muscular layers, the fascicles of which both originate and terminate at an atrioventricular ring and follow nearly perpendicular courses. Fascicles in the inner layer ascend vertically through a pectinate muscle, change depth and course circumferentially in the outer layer, encircle the atrium, dive into the inner layer, and descend vertically within a pectinate muscle. While some fascicles are intrinsic to one atrium, others are shared. The muscular terminations of the veins are also composed of two layers, the inner longitudinal and the outer circular.15 Ultrastructurally, atrial myocardium diﬀers signiﬁcantly from ventricular myocardium. For example, myocytes are smaller in diameter and have fewer T-tubules and more abundant Golgi apparatus in the atrium than in the ventricle.16 Rates of contraction and relaxation and of conduction velocity and anisotropy diﬀer, as do their respective biophysical underpinnings (i.e., myosin isoform composition and qualitative and quantitative differences in a wide assortment of ion transporters, channels, and gap junctional proteins).17–19 While there are important diﬀerences between left and right atrial structures and functions at various organizational hierarchies, the function of the left atrium at the organ level will be used in this chapter to illustrate the atrial contributions to ventricular ﬁlling. The discussion is drawn largely from studies our group has performed over the past 15 years. 33

34

Chapter 4 • Left Atrial Function: Basic Physiology

PATHOPHYSIOLOGY

Pressure-Volume Relations of the Atrium

Atrial Function in Health

A time-independent representation of the atrial events during the cardiac cycle can be obtained by plotting instantaneous atrial pressure and volume (Fig. 4-1). During ventricular systole, atrial relaxation and descent of the ventricular base lower atrial pressure (the “x” descent) and assist in atrial ﬁlling; the latter results in a “v” wave on the atrial pressure tracing. Thus, during ventricular systole, the atrium operates as a reservoir, storing systemic and pulmonary venous return. When the atrioventricular valves open, blood stored in the atria empties into the ventricles, and atrial pressure falls (the “y” descent), during which time the atria act as conduits for venous blood ﬂow into the ventricles. Atrial contraction, denoted by an “a” wave on the atrial pressure tracing, actively assists ventricular ﬁlling. The resultant P-V loop inscribes a “ﬁgure-eight” that consists of a clockwise “V” loop due to atrial ﬁlling and passive emptying, and a counterclockwise “A” loop due to active atrial contraction. Although Alexander et al. described instantaneous LA P-V relations by a time-varying elastance in the isolated left atrium using computer-simulated LA loading conditions,25 assessment of atrial systolic elastance in vivo was hampered by the lack of an accurate measurement of LA volume with an adequate sampling frequency. Therefore, as a critical initial step, we demonstrated that cast-validated LA volumes could be estimated accurately with high temporal resolution sonomicrometry using two nearly orthogonal atrial dimensions.26,27 The left atrium was assumed to be a general ellipsoid of revolution:

Left Atrial Booster Pump Function

LA pressure (mmHg)

34

v

where SAX is the short or mediolateral axis, and LAX is the long or anteroposterior axis. Coupled with high-ﬁdelity micromanometers, instantaneous P-V loops of the intact left atrium were generated (Fig. 4-2). The maximum slope of the isochronal P-V relation was measured every 10 msec during the “A” loop (from

a

0

MVO

16.0 28

20.5

16.5 ECG

LAed A LAes MVC

V

8.0 6.0

4.0

A BC D 1 sec.

A

LA volume = π/6(SAX)2(LAX),

LA pressure (mmHg)

LA short axis (mm)

40

LA long axis (mm)

The principal role of the left atrium is to modulate LV ﬁlling and cardiovascular performance through the interplay of atrial reservoir, conduit, and booster pump functions. Typically, the importance of the atrial booster pump function (i.e., the augmented ventricular ﬁlling resulting from active atrial contraction) has been estimated by measurements of (1) cardiac output and LV diastolic volume both with and without eﬀective atrial systole,20 (2) relative LV ﬁlling (e.g., early to late [E/A] ﬁlling ratios) using steady-state Doppler echocardiographic transmitral ﬂow or radionuclide angiography,21 and (3) atrial shortening using methods such as two-dimensional echocardiography, angiography, and sonomicrometry.22 Booster pump function is also evaluated echocardiographically by estimating the kinetic energy and force generated with atrial contraction.23,24 However, measurements of atrial systolic function and the importance of the atrial booster pump are dependent on a multiplicity of factors, including the timing of atrial systole, vagal stimulation, the magnitude of venous return (i.e., atrial preload), LV end diastolic pressures (i.e., atrial afterload), and LV systolic reserve. Not surprisingly, despite considerable study, the magnitude and relative importance of the atrial contribution to LV ﬁlling and cardiac output remain controversial. Analogous to end systolic elastance measurements in the left ventricle (where end systolic elastance is calculated as the slope of the ventricular end systolic pressure-volume [P-V] relation), a load-independent index of atrial contraction based on the instantaneous atrial P-V relation has the potential to explain and minimize the discrepancies and confusion that exist in the literature. Accordingly, understanding and deriving atrial elastance require a consideration of the relation between instantaneous atrial pressure and volume.

LA volume (ml)

B

Figure 4-1 A, Analog recording of left atrial (LA) pressure and dimensions in the time domain. The vertical lines indicate times of mitral valve opening (A), end of passive atrial emptying and onset of atrial diastasis (B), atrial end diastole (C), and atrial end systole (D). “a” and “v” represent respective venous pressure waves. B, LA pressure-volume loop from a single beat illustrating the characteristic figure-eight configuration. Arrows indicate direction of loop as a function of time. “A” loop represents active atrial contraction. “V” loop represents passive filling and emptying of the left atrium. MVO, time of mitral valve opening; LAed, left atrial end diastole; Laes, left atrial end systole. (From Hoit BD et al: Circulation 1994;89:1829–1838.)

Chapter 4 • Left Atrial Function: Basic Physiology BASELINE

POST CALCIUM Slope = 3.6

Slope = 5.4

26.6

LA pressure (mmHg)

LA pressure (mmHg)

17.7

35

6.9

6.7 5.7

8.9

5.0

LA volume (ml)

10.1 LA volume (ml)

A Slope 3.6

Slope = 5.4 23

LA pressure (mmHg)

Figure 4-2 A, Five left atrial pressure-volume loops at baseline (left) and after calcium infusion (right). Note the linearity of the end systolic pressure-volume relations, the greater extent of atrial systolic shortening, and the increase in the end systolic pressure-volume slope after calcium infusion (the latter indicating a positive inotropic effect). B, Loops are computersmoothed for clarity. (From Hoit BD et al: Circulation 1994;89:1829–1838.)

LA pressure (mmHg)

18

7

7 6

9 LA volume (ml)

5

10 LA volume (ml)

B

atrial diastasis to atrial end systole) from ﬁve variably loaded beats and were ﬁtted to a time-varying elastance model: E(t) = P(t)/[V(t) − V(o)], where E(t) is time-varying elastance, V(o) is the volume axis intercept, and P(t) and V(t) are instantaneous isochronal pressure and volume, respectively. Loading conditions were altered with either phenylephrine boluses or vena caval occlusions. Time-dependent changes in E(t) and maximal atrial systolic elastance (Emax) were found to be highly linear and sensitive to pharmacologically induced changes in inotropic state. In addition, LA systolic P-V relations using either the non-isochronal maximal P-V ratio (Emax P/V) or end systole (Ees) were shown to be useful estimates of Emax. In addition to assisting the quantitation of ejection phase (i.e., ejection fraction, stroke volume, mean normalized systolic ejection rate [MNSER], and velocity of circumferential shortening [Vcf ]) and load-independent indices of contraction (i.e., Emax, Ees, and Emax P/V), P-V loops of the left atrium oﬀered possibilities for study of atrial energetics in vivo. Speciﬁcally, the planimetered “A” loop P-V area (total mechanical work done by the atrium) minus the “V” loop P-V area (work done on the atrium by pulmonary venous blood ﬂow during ventricular systole) represents the net

atrial mechanical work. In a study using normal, open-chest dogs, A- and V-loop areas were similar and did not change with increased atrial preload, suggesting that booster pump and reservoir functions of the atrium were balanced over a wide range of LA pressures. However, calcium-induced increases in contractility and subsequent volume loading produced signiﬁcant increases in the A- but not the V-loop area, indicating that net atrial mechanical work was greater and load dependent after calcium infusion. Calcium infusion was also associated with a change in the trajectory of the A loop resulting in a decrease in the time from Emax to end systole; thus the atrial A loop, which resembled a right ventricular (RV) P-V loop before, looked like the LV P-V loop after calcium infusion, suggesting an eﬀect of calcium on ventricular input impedance. While atrial P-V loops can be generated in humans using invasive and semi-invasive means,28–31 these methods are cumbersome, time consuming, and diﬃcult to apply. Clearly, there is a need for an objective, noninvasive measurement of atrial myocardial performance and contractility. Measurement of myocardial strain and strain rate, which represent the magnitude and rate of myocardial deformation, are indices that have the potential to overcome these limitations.32

Chapter 4 • Left Atrial Function: Basic Physiology

Left Atrial Reservoir Function Grant et al. estimated that 42% of the LV stroke volume and its associated energy are stored in the left atrium during LV systole.33 The subsequent dissipation of this energy during the reservoir phase acts as a ventricular restorative force during the ensuing LV diastole. Reservoir function is governed by atrial distensibility during ventricular systole (although LA reservoir function has been shown to be related to LA contraction and descent of the LV base during systole34 and to LA systolic shortening and LV end systolic volume35), which is measured rigorously by ﬁtting atrial pressures and dimensions—taken either at the time of mitral valve opening over a range of atrial pressures and volumes or from one of the limbs of the “V” loop in a static P-V loop—to an exponential equation.36,37 Although atrial dimensions and pressures are required for its measurement, the relative reservoir function can be estimated simply with pulmonary vein Doppler (Fig. 4-3). Thus, the proportion of LA inﬂow during ventricular systole provides an index of the reservoir capacity of the atrium.38 In this regard, we showed that LA compliance is an important independent determinant of the pattern of pulmonary venous ﬂow, using an experimental protocol that excluded the LA appendage and produced an isolated decrease in atrial compliance and relative reservoir-to-conduit ﬂow.22 As a consequence, alterations in atrial compliance in various disease stages should be considered when the pattern of pulmonary venous ﬂow is used to estimate LA pressure, assess LV diastolic function, or quantify mitral regurgitation. Suga showed that atrial compliance was a signiﬁcant determinant of cardiac performance in a circulatory analog model.39 Speciﬁcally, decreased atrial compliance was associated with greater phasic and mean atrial pressures but a lower mean level of atrial pressure during ventricular ﬁlling; this resulted in a smaller LV end diastolic volume and decreased venous return. We conﬁrmed earlier mathematical predictions that early LV ﬁlling (i.e., Doppler

mitral E velocity) increases directly with operative atrial compliance.40 Thus it is interesting to speculate that regions of increased distensibility in the left atrium may facilitate early diastolic ﬁlling of the left ventricle. One such region of the left atrium with increased distensibility is the atrial appendage. In isolated canine atria, the slope of the P-V relation for the left atrium without the appendage is signiﬁcantly greater than with the appendage intact.41 We subsequently showed that in the intact dog, the pressure-strain relation is steeper (i.e., more stiﬀ or less distensible) in the body than in the appendage of the left atrium (Fig. 4-4). Atrial systolic shortening and reservoir capacity (measured as the change in dimension during atrial systole, and the maximum minus minimum dimension, respectively) increased in both the body and the appendage during volume infusion and were greater in the appendage than in the body of the left atrium. Thus, for a given increase in LA pressure, there was a greater increase in the end diastolic atrial dimension, with greater utilization of the Frank-Starling mechanism by the appendage than by the body of the left atrium. Moreover, biochemical studies indicate that atrial natriuretic factor is concentrated in the LA appendage,42 which may, by virtue of its increased distensibility, be better suited for the regulation of intravascular volume. In addition, greater distensibility of the appendage than the body of the left atrium would be potentially beneﬁcial in the context of increased LV ﬁlling pressures and decreased global atrial distensibility. It is interesting that relative blood ﬂow to the LA appendage was increased with experimental LA hypertrophy,43 and the appendage-to-nonappendage LA blood ﬂow ratio was increased during severe exercise in dogs, further suggesting that the LA appendage may become functionally important during stress. These data suggest that the substantial contributions of the appendage to overall LA compliance may have important negative implications for routine atrial appendectomy at the time of mitral valve surgery and for the use of percutaneous appendage exclusion devices.44,45

1 sec

J

K

PV Doppler (cm/sec)

40

KVTI

200

0 0

1 sec 40 J

JVTI 0

ECG

K

KVTI

PV flow (ml/min)

JVTI

PV Doppler (cm/sec)

36

Figure 4-3 Representative pulmonary vein (PV) Doppler with flow-probe waveform superimposed (top panel) and a schematic of the pulmonary venous flow velocity (bottom panel). J and K are peak systolic and diastolic velocities; Jvti and Kvti are systolic and diastolic integrals, respectively. The ratio of systolic-to-diastolic velocities (and integrals) represents the relative reservoir-to-conduit function of the left atrium. (From Hoit BD et al: Circulation 1992;86:651–659.)

Chapter 4 • Left Atrial Function: Basic Physiology 20

LA APP

Mean LA pressure (mmHg)

Mean LA pressure (mmHg)

20

10

LA APP

18

*

16 14

*

12 10 8

* 6

0 0.0

0.1

0.2

0.3

0.4

0.5

0.0

0.6

0.2

0.3

0.4

0.5

Natural strain (ln[D/Dmin])

Natural strain (ln[D/Dmin])

A

0.1

B

Figure 4-4 A, Representative mean left atrial (LA) pressure–natural strain relationships for the LA body and appendage from a single dog. Data are fitted to an exponential function. Pressure-strain relationship of appendage is shifted to the right of the body. B, Mean pressure–natural strain data for 12 dogs. Error bars represent SE. Data indicate that the appendage is more distensible than the body of the left atrium. (From Hoit BD, Walsh RA, Am J Physiol 1992;262: H1356–H1360.)

Myocardial strains can be obtained noninvasively using either tissue Doppler imaging (TDI) or 2D speckle imaging. Recently, atrial strain and strain rates (representing the magnitude and rate of myocardial deformation, respectively) during ventricular systole predicted the 9-month atrial ﬁbrillation recurrence rate in patients with lone atrial ﬁbrillation after a successful cardioversion.11 Coupled with an estimate of atrial pressure,46 strain has the potential to estimate atrial distensibility noninvasively.

Left Atrial Conduit Function Atrial conduit function occurs primarily, but not exclusively, during ventricular diastole and represents the volume of blood that passes through the left atrium that cannot be attributed to reservoir or booster pump functions; in a well-characterized model, atrial conduit function accounted for 35 ± 8% of all ﬂow through the atrium.47 A reciprocal relationship exists between conduit and reservoir functions of the left atrium. Indeed, the redistribution of atrial functions was reported as an important compensatory mechanism that facilitates LV ﬁlling in patients with myocardial ischemia, acute myocardial infarction, hypertensive heart disease, and mitral stenosis.48–51 Although it has been postulated that a more distensible atrium reduces atrial conduit ﬂow, we showed that while pericardiectomy decreased the atrial stiﬀness constant (increased distensibility), the relative conduit function, measured as the ratio of ﬂow probedetermined systolic-to-diastolic pulmonary vein ﬂow, actually increased.38 However, it should be noted that the LA reservoir volume (max − min LA volume) and absolute systolic pulmonary venous ﬂow also increased post pericardiectomy. In addition, removal of the pericardium was associated with an increase in the peak early velocity and deceleration time of transmitral diastolic ﬂow, consistent with the increase in LV compliance after pericardiectomy. Thus it is possible that the decreased systolic to diastolic P-V ratio reﬂects a greater change in compliance of the left ventricle than of the atrium. Irrespective of the mechanisms, these data underscore the complexity of pericardial inﬂuences on atrial and ventricular ﬁlling and the multifactorial determinants of P-V relations.

Global Left Atrial Function Although it is clear that atrial reservoir, conduit, and booster pump functions (and their modulation by the pericardium) play important roles in maintaining ventricular ﬁlling, a global measure (i.e., throughout the entire atrial cycle) of atrial function is lacking. A potential candidate property suitable for quantitation is synchrony. Therefore, we correlated time-tissue Doppler velocity curves from the lateral left and right atria and the lateral left atrium and interatrial septum over three cycles every 10 msec to obtain indices of inter- and intra-atrial phase heterogeneity, respectively. The intra-atrial phase heterogeneity index was 0.90 ± 0.06, indicating that the time-velocity curves over the entire cardiac cycle for the septum and lateral LA segments were highly correlated (i.e., in phase). In contrast, the inter-atrial phase index of 0.66 ± 0.10 indicated a greater degree of heterogeneity between the lateral LA and RA segments. These indices may be particularly useful to understand the eﬀect of altered atrial conduction on atrial function and ventricular ﬁlling in various pathological states.

LEFT ATRIAL FUNCTION IN DISEASE Although LV adaptation to chronic hemodynamic loading has been studied extensively, the mechanisms by which the left atrium compensates for sustained increases in pressure and volume are less clear. We considered that adaptation may be due to the addition of contractile units (hypertrophy), an alteration in the molecular composition of the contractile machinery (e.g., protein isoform transitions), or a reduction of atrial systolic stress by structural remodeling. In pathological studies of human atria, increases in the amount of the slow, β-myosin isoform were correlated with the severity and duration of pressure and volume overload. In this context, a switch from the fast (α) to the slow (β) myosin heavy chain (MHC) isoform in the ventricles of small mammals is accompanied by decreased myosin ATPase activity and velocity of contraction, reduced oxygen consumption, and a greater eﬃciency of contraction. Thus, these isoform switches are likely to represent adaptations to the functional requirements

37

38

Chapter 4 • Left Atrial Function: Basic Physiology imposed by sustained hemodynamic loads in a chamber such as the left atrium, which contains predominantly α MHC.

Left Atrial Function and Systolic Left Ventricular Dysfunction Experimental studies that examine atrial adaptation use models of mitral regurgitation,36 myocardial infarction,12 LV diastolic dysfunction,52 and pacing-induced myocardial failure (ventricular and atrial tachypacing53,54). In the ventricular tachypacing model of heart failure, we found a signiﬁcant upregulation of β MHC in the LA body that was associated with LA hypertrophy, increased atrial mechanical work (A-loop area, Fig. 4-5), maintained force generation (Emax and Ees), and decreased velocity of LA contraction. Another important ﬁnding of our study was that atrial MHC isoform switches vary by region. Despite hypertrophy of the appendage, the percent of β MHC did not increase in comparison with controls, suggesting that adaptation to hemodynamic overload includes diﬀerentially determined quantitative (e.g., hypertrophy) and qualitative (e.g., isoform switch) components and that there are fundamental diﬀerences in the atrial response to stress hypertrophy, which occurs in the body, versus “strain” hypertrophy, which occurs in the appendage.

Left Atrial Function and Diastolic Left Ventricular Dysfunction In carefully studied animal models, the improvement in systolic function that occurs after cessation of tachypacing is associated with residual abnormalities of LV isovolumic relaxation and chamber compliance, and in some instances, the development of LV hypertrophy. Since LV diastolic dysfunction represents a source of excess afterload on the left atrium, we examined the gravimetric, myosin biochemical, and functional changes in the left atrium that accompany regression of pacing-induced heart failure. Animals were rapidly paced for 3 weeks to produce heart failure, and hemodynamic and functional studies were performed 3 weeks after pacing cessation.52 We showed that improvement of LV systolic dysfunction was associated with persistent LV

24.0

Left Atrial Function in a Model of Atrial Systolic Failure We examined global and regional LA pump functions after one week of isolated atrial ﬂutter (atrial pacing at 400 bpm) in closedchest, sedated dogs.55 LV function, as assessed by the echocardiographic LV area shortening fraction, was preserved. Global and regional atrial pump functions were determined by mitral and LA appendage waveform analysis, and relative conduit and reservoir functions by pulmonary venous waveform analysis with Doppler velocimetry. We found that after one week of rapid atrial pacing, global and regional atrial booster pump functions (i.e., body and appendage) were impaired, and relative reservoir-to-conduit function of the left atrium was reduced (Fig. 4-6). Similar changes in the absence of atrial hypertrophy were noted in a highly instrumented preparation treated with similar atrial tachypacing for 6 weeks.

Importance of Left Atrial Functions and Their Interplay in Left Ventricular Systolic Dysfunction The redistribution of atrial reservoir and conduit functions and an augmented booster pump function are important compensatory mechanisms that facilitate LV ﬁlling in patients with myocardial ischemia, acute myocardial infarction, and hypertensive heart disease. However, considerably less is known about how these mechanisms operate in the setting of LV dysfunction. Therefore, we tested the hypothesis that in contrast to dogs with a normal left ventricle, cardiac output falls with the loss of atrial

Left atrial pressure (mmHg)

Left atrial pressure (mmHg)

22.4

V

V

A

A

10.0

9.5 5.5

8.4

17.4

Left atrial volume (ml)

A

diastolic dysfunction and normalization of both atrial Ees and net atrial work despite the persistent abnormalities of loaddependent indices of LA systolic function (e.g., ejection fraction, systolic ejection rate). LA stiﬀness and reservoir volumes also remained abnormal. Changes in systolic and diastolic function of the left atrium were accompanied by persistent upregulation of the atrial β MHC isoform and incomplete regression of LA hypertrophy, indicating an apparent dissociation of myosin isoform shifts, myocardial hypertrophy, and atrial work.

21.4 Left atrial volume (ml)

B

Figure 4-5 Left atrial pressure-volume loops from three variably loaded beats in a control dog (A) and in a dog with pacing-induced heart failure (B). The A loop represents active atrial contraction; the V loop represents passive filling and emptying of the left atrium. The increase in A loop area after pacing indicates increased atrial systolic work. Loops are computer-smoothed for clarity. (From Hoit BD et al: Cardiovasc Res 1995;29:469–474.)

Chapter 4 • Left Atrial Function: Basic Physiology Baseline

1 week rap

MV velocity

A A E 80 cm/sec

E

e

a e

40 cm/sec

40 cm/sec a

LAA velocity

Figure 4-6 Doppler waveforms of transmitral (MV, top panel), left atrial appendage (LAA, middle panel), and pulmonary vein (PV, bottom panel) flows at baseline and after one week of rapid atrial pacing (RAP). E, early transmitral diastolic velocity; A, late transmitral diastolic velocity; e, early LAA emptying velocity; a, late LAA emptying velocity; J1 and J2, systolic velocities; K, diastolic PV velocities. The corresponding electrocardiogram is shown in each panel. (From Hoit BD et al: J Am Soc Echo 1997;10:805–810.)

80 cm/sec

J2

40 cm/sec J1

K 40 cm/sec J2

PV velocity

systolic contraction in dogs with concomitant LV dysfunction because atrial compensatory mechanisms fail. Chronic atrial and ventricular dysfunction (both singly and in combination) were modeled with rapid pacing in dogs with radiofrequency atrioventricular nodal ablation and implantation of RA and RV pacing catheters.56 Serial echocardiographic analyses of global and regional LA pump function were estimated from mitral and LA appendage Doppler velocimetry, and relative reservoir and conduit functions of the left atrium were determined from pulmonary venous Doppler. Right heart catheterization studies were performed simultaneously to assess right heart pressures and cardiac output. Isolated atrial systolic failure was produced by 1 week of rapid atrial pacing (400 bpm), and moderate

K

J1

LV dysfunction was produced by 2 weeks of rapid RV pacing (220 bpm). Two weeks of rapid ventricular pacing superimposed on rapid atrial pacing during the second week produced combined LA and LV dysfunction. As previously noted, isolated LV dysfunction increased atrial booster pump and reservoir functions, whereas isolated rapid atrial pacing decreased atrial booster pump and increased the relative conduit function of the left atrium. In contrast, the decreased atrial booster pump function in animals with combined atrial and ventricular dysfunction was incompletely compensated by the redistribution of the reservoir and conduit functions of the left atrium. As a result, cardiac output decreased and right heart pressures increased only after superimposed atrial and ventricular pacing.

39

40

Chapter 4 • Left Atrial Function: Basic Physiology

FUTURE RESEARCH While knowledge of atrial function lags considerably behind that of the ventricle, the chasm is rapidly closing. The studies discussed herein describe the role of atrial function to ventricular ﬁlling in normal physiology and provide a framework for understanding mechanical, energetic, and biochemical mechanisms responsible for atrial adaptation to chronic hemodynamic loading. Important future directions include distinguishing the role of atrial function in early versus late LV systolic dysfunction, investigating the role of matrix metalloproteinases (and other molecules) in structural remodeling of the atria, characterizing the biochemical and molecular biological changes that accompany atrial adaptation and failure, and identifying the relation between structural and electrical remodeling of the left atrium. These goals are likely to be met with the development of novel techniques to evaluate atrial reservoir, conduit, and booster pump functions of the atrium.

ACKNOWLEDGMENT This work was supported in part by a Grant in Aid award from the American Heart Association Ohio Valley Aﬃliate (0355198B). REFERENCES 1. Hersi A, Wyse DG: Management of atrial ﬁbrillation. Curr Probl Cardiol 2005;30:175–233. 2. Marine JE, Dong J, Calkins H: Catheter ablation therapy for atrial ﬁbrillation. Prog Cardiovasc Dis 2005;48:178–192. 3. Gillinov AM, Wolf RK: Surgical ablation of atrial ﬁbrillation. Prog Cardiovasc Dis 2005;48:169–177. 4. Frielingsdorf J, Gerber AE, Hess OM: Importance of maintained atrioventricular synchrony in patients with pacemakers. Eur Heart J 1994;15:1431–1440. 5. McComb JM, Gribbin GM: Eﬀect of pacing mode on morbidity and mortality: Update of clinical pacing trials. Am J Cardiol 1999;83:211D–213D. 6. Vural A, Agacdiken A, Ural D, et al: Eﬀect of cardiac resynchronization therapy on left atrial appendage function and pulmonary venous ﬂow pattern. Int J Cardiol 2005;102:103–109. 7. Nattel S, Shiroshita-Takeshita A, Cardin S, Pelletier P: Mechanisms of atrial remodeling and clinical relevance. Curr Opin Cardiol 2005;20: 21–25. 8. Yue L, Melnyk P, Gaspo R, et al: Molecular mechanisms underlying ionic remodeling in a dog model of atrial ﬁbrillation. Circ Res 1999;84:776–784. 9. Wijﬀels MC, Kirchhof CJ, Dorland R, et al: Electrical remodeling due to atrial ﬁbrillation in chronically instrumented conscious goats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulation 1997;96:3710–3720. 10. Grimm RA, Leung DY, Black IW, Thomas JD: Left atrial appendage “stunning” after spontaneous conversion of atrial ﬁbrillation demonstrated by transesophageal Doppler echocardiography. Am Heart J 1995;130:174–176. 11. Di Salvo G, Caso P, Lo Piccolo R, et al: Atrial myocardial deformation properties predict maintenance of sinus rhythm after external cardioversion of recent-onset lone atrial ﬁbrillation: A color Doppler myocardial imaging and transthoracic and transesophageal echocardiographic study. Circulation 2005;112:387–395. 12. Kono T, Sabbah HN, Rosman H, et al: Left atrial contribution to ventricular ﬁlling during the course of evolving heart failure. Circulation 1992;86:1317–1322. 13. Bruch C, Gotzmann M, Sindermann J, et al: Prognostic value of a restrictive mitral ﬁlling pattern in patients with systolic heart failure and an implantable cardioverter-deﬁbrillator. Am J Cardiol 2006;97:676–680. 14. Strandring S, ed: Gray’s Anatomy, 39th ed. London, Elsevier, 2005.

15. Thomas CE: The muscular architecture of the atria of hog and dog hearts. Am J Anat 1959;104:207–236. 16. McNutt NS, Fawcett DW: The ultrastructure of the cat myocardium. II. Atrial muscle. J Cell Biol 1969;42:46–67. 17. Thomas C, Coker B, Zellner J, et al: Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998;97:1708–1715. 18. Li GR, Lau CP, Shrier A: Heterogeneity of sodium current in atrial vs epicardial ventricular myocytes of adult guinea pig hearts. J Mol Cell Cardiol 2002;34:1185–1194. 19. Tuteja D, Xu D, Timofeyev V, et al: Diﬀerential expression of smallconductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol 2005;289: H2714–H2723. 20. Mitchell JH, Gupta DN, Payne RM: Inﬂuence of atrial systole on eﬀective ventricular stroke volume. Circ Res. 1965;17:11–18. 21. Hoit BD, Rashwan M, Verba J, et al: Instantaneous transmitral ﬂow using Doppler and M-mode echocardiography: Comparison with radionuclide ventriculography. Am Heart J 1989;118:308–314. 22. Hoit BD, Shao Y, Tsai LM, et al: Altered left atrial compliance after atrial appendectomy. Inﬂuence on left atrial and ventricular ﬁlling. Circ Res 1993;72:167–175. 23. Stefanadis C, Dernellis J, Lambrou S, Toutouzas P: Left atrial energy in normal subjects, in patients with symptomatic mitral stenosis, and in patients with advanced heart failure. Am J Cardiol 1998;82:1220– 1223. 24. Manning WJ, Silverman DI, Katz SE, Douglas PS: Atrial ejection force: A noninvasive assessment of atrial systolic function. J Am Coll Cardiol 1993;22:221–225. 25. Alexander J, Sunagawa K, Chang N, Sagawa K: Instantaneous pressurevolume relation of the ejecting canine left atrium. Circ Res 1987;61: 209–219. 26. Hoit BD, Shao Y, McMannis K, et al: Determination of left atrial volume using sonomicrometry: A cast validation study. Am J Physiol 1993;264: H1011–H1016. 27. Hoit BD, Shao Y, Gabel M, Walsh RA: In vivo assessment of left atrial contractile performance in normal and pathological conditions using a timevarying elastance model. Circulation 1994;89:1829–1838. 28. Stefanadis C, Dernellis J, Toutouzas P: Evaluation of the left atrial performance using acoustic quantiﬁcation. Echocardiography 1999;16: 117–125. 29. Stefanadis C, Dernellis J, Stratos C, et al: Assessment of left atrial pressurearea relation in humans by means of retrograde left atrial catheterization and echocardiographic automatic boundary detection: Eﬀects of dobutamine. J Am Coll Cardiol 1998;31:426–436. 30. Dernellis JM, Stefanadis CI, Zacharoulis AA, Toutouzas PK: Left atrial mechanical adaptation to long-standing hemodynamic loads based on pressure-volume relations. Am J Cardiol 1998;81:1138–1143. 31. Tse HF, Hettrick DA, Mehra R, Lau CP: Improved atrial mechanical eﬃciency during alternate- and multiple-site atrial pacing compared with conventional right atrial appendage pacing: Implications for selective site pacing to prevent atrial ﬁbrillation. J Am Coll Cardiol 2006;47:209–212. 32. Pislaru C, Abraham TP, Belohlavek M: Strain and strain rate echocardiography. Curr Opin Cardiol 2002;17:443–454. 33. Grant C, Bunnell IL, Green DG: The reservoir function of the left atrium during ventricular systole. Am J Med 1964;37:36–43. 34. Barbier P, Solomon SB, Schiller NB, Glantz SA: Left atrial relaxation and left ventricular systolic function determine left atrial reservoir function. Circulation 1999;100:427–436. 35. Hoit BD, Shao Y, Gabel M, Walsh RA: Inﬂuence of loading conditions and contractile state on pulmonary venous ﬂow. Validation of Doppler velocimetry. Circulation 1992;86:651–659. 36. Kihara Y, Sasayama S, Miyazaki S: Role of the left atrium in adaptation of the heart to chronic mitral regurgitation in conscious dogs. Circ Res 1988;62:543–553. 37. Hoit BD, Walsh RA: Regional atrial distensibility. Am J Physiol 1992;262: H1356–H1360. 38. Hoit BD, Shao Y, Gabel M, Walsh RA: Inﬂuence of pericardium on left atrial compliance and pulmonary venous ﬂow. Am J Physiol 1993;264: H1781–H1787. 39. Suga H: Importance of atrial compliance in cardiac performance. Circ Res 1974;35:39–43. 40. Hoit BD, LeWinter M, Lew WY: Independent inﬂuence of left atrial pressure on regional peak lengthening rates. Am J Physiol 1990;259: H480–H487.

Chapter 4 • Left Atrial Function: Basic Physiology 41. Davis CA, Rembert JC, Greenﬁeld JC: Compliance of the left atrium with and without left atrium appendage. Am J Physiol 1990;259: H1006–H1008. 42. Hintze TH, McIntyre JJ, Patel MB, et al: Atrial wall function and plasma atriopeptin during volume expansion in conscious dogs. Am J Physiol 1989;256:H713–H719. 43. Bauman RP, Rembert JC, Greenﬁeld JC: Regional atrial blood ﬂow in dogs. J Clin Invest 1989;83:1563–1569. 44. Kamohara K, Fukamachi K, Ootaki Y, et al: A novel device for left atrial appendage exclusion. J Thorac Cardiovasc Surg 2005;130:1639–1644. 45. Ostermayer SH, Reisman M, Kramer PH, et al: Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial ﬁbrillation: Results from the international multi-center feasibility trials. J Am Coll Cardiol 2005;46:9–14. 46. Nagueh SF: Noninvasive evaluation of hemodynamics by Doppler echocardiography. Curr Opin Cardiol 1999;14:217–224. 47. Hitch DC, Nolan SP: Descriptive analysis of instantaneous left atrial volume—with speciﬁc reference to left atrial function. J. Surg Res 1981;30:110–120. 48. Sigwart U, Grbic M, Goy J, Kappenberger L: Left atrial function in acute transient left ventricular ischemia produced during percutaneous transluminal coronary angioplasty of the left anterior descending coronary artery. Am J Cardiol 1990;65:282–286.

49. Matsuda Y, Toma Y, Moritani K, et al: Assessment of left atrial function in patients with hypertensive heart disease. Hypertension 1986;8:779– 785. 50. Matsuda Y, Toma Y, Ogawa H: Importance of left atrial function in patients with myocardial infarction. Circulation 1983;65:566–571. 51. Triposkiadis F, Wooley CF, Boudoulas H: Mitral stenosis: Left atrial dynamics reﬂect altered passive and active emptying. Am Heart J 1990;120:124–132. 52. Hoit BD, Shao Y, Gabel M, et al: Left atrial systolic and diastolic function after cessation of pacing in tachycardia-induced heart failure. Am J Physiol 1997;273:H921–H927. 53. Hoit BD, Shao Y, Gabel M: Left atrial systolic and diastolic function accompanying chronic rapid pacing–induced atrial failure. Am J Physiol 1998;275: H183–H189. 54. Hoit BD, Shao Y, Gabel M, Walsh RA: Left atrial mechanical and biochemical adaptation to pacing induced heart failure. Cardiovasc Res 1995;29:469–474. 55. Hoit BD, Shao Y, Gabel M: Global and regional atrial function after rapid atrial pacing: An echo Doppler study. J Am Soc Echocardiogr 1997;10:805–810. 56. Hoit BD, Gabel M: Inﬂuence of left ventricular dysfunction on the role of atrial contraction: An echocardiographic-hemodynamic study in dogs. J Am Coll Cardiol 2000;36:1713–1719.

41

JAMES D. THOMAS, MD ZORAN B. POPOVIC´, MD

5

Physical Determinants of Diastolic Flow INTRODUCTION PATHOPHYSIOLOGY Mechanical Properties of Left Ventricular Chamber Diastole CLINICAL RELEVANCE Physical Factors Governing Left Ventricular Filling Velocities

Understanding Pulmonary Vein Flow Through Computer Modeling of the Heart Lumped Parameter Model of the Heart and Circulation Understanding Intraventricular Flow FUTURE RESEARCH ABBREVIATIONS

INTRODUCTION Comprehensive assessment of ventricular diastolic function is a complex process. Full elucidation generally requires invasive measurements, such as left ventricular (LV) end diastolic pressure, the time constant of isovolumic LV relaxation (τ), the pressurevolume (P-V) relationship of the ventricle at end diastole, and mean left atrial (LA) pressure. Such invasive measurements are inappropriate for routine clinical purposes, and thus diastolic function is generally assessed using Doppler echocardiography, largely through the observation of transmitral and pulmonary venous ﬂow, supplemented by myocardial velocity and color M-mode Doppler information. In order to intelligently use these noninvasive indices to infer actual diastolic function of the heart, however, it is critical that a conceptual framework be in place that reﬂects the physical and physiological determinants of intracardiac blood ﬂow. In this chapter, we will outline in both basic physical principles and computer simulations the relationship between basic parameters of diastolic function and the intracardiac ﬂow patterns that can be obtained clinically.

PATHOPHYSIOLOGY Mechanical Properties of Left Ventricular Chamber Diastole The major function of the heart in diastole is to let the blood column ﬂow from the antechambers (left atrium and pulmonary

veins) into the left ventricle, while keeping ﬁlling pressures to a minimum. During exercise, this task is compounded by the shortening of time allowed for ﬁlling and the increase of volume needed to get into the left ventricle. Of the various chamber-wall properties that aﬀect this process, we will brieﬂy cover three: chamber stiﬀness, relaxation, and early diastolic suction.

Chamber Stiffness Chamber stiﬀness can be deﬁned as the instantaneous change of pressure for a given volume increment, mathematically the ﬁrst derivative of LV pressure by volume (dP/dV). LV pressure is a complex nonlinear function of LV volume, meaning that stiﬀness changes with diastolic volume. Although the LV P-V relationship was initially considered to be exponential in shape (concave upward),1 more recent work suggests that it is sigmoidal in shape (Fig. 5-1), with a concave downward portion to the left of the usual rising exponential.2,3 This sigmoidal curve can be expressed as: P = A ∗ e(V−Vd0)Kp+ + Pb+ V ≥ Vd0 P = −B ∗ e(Vd0−V)Kp− + Pb− V < Vd0, where Vd0 is the inﬂection point, A and B are the exponential curve multipliers of the upper and lower part, Pb+ and Pb− are pressure oﬀsets of the upper and lower part, while Kp+ and Kp− are the diastolic chamber stiﬀness indices, determining the overall steepness of the end diastolic P-V relationship (EDPVR) above and below the inﬂection volume. Frequently, EDPVR is conceptually simpliﬁed by assuming that Vd0 equals 0,1 and even further 43

Chapter 5 • Physical Determinants of Diastolic Flow 120 LV pressure (mmHg)

44

90 60 30 0 0

50 LVd0

100

150

LV volume (ml) Figure 5-1 Passive pressure-volume (P-V) loop relationships. The thick continuous and thick dotted lines represent the upper and lower part of the sigmoid end diastolic pressure-volume relationship, respectively. The curvature of the upper part is determined by the chamber stiffness index, which can be interpreted as the inverse of the volume needed to increase the steepness of the P-V curve by a factor of 2.72.

simpliﬁed by neglecting Pb+, leaving us with the equation P = AeK×EDV, or in other words ln P = a + K × EDV (see also Chapter 2).1 By diﬀerentiating this equation, we see that end diastolic stiﬀness dP/dV is K × AeK×EDV or K × PEDV. Another parameter of note is the average stiﬀness,4 that is, the stroke volume divided by the LV pressure increment during diastole, a simple overall measure of how stiﬀ the patient’s LV is during diastole over a given (working) set of conditions.5 The fact that myocardial relaxation is a continuous process throughout diastole results in changing relationships between pressure and volume from very stiﬀ end systole P-V relationships to much more compliant EDPVR.

Relaxation Myocardial relaxation occurs because of calcium reuptake at the end of systole, producing a shift downward and rightward, leading to a fall in LV pressure (at a given volume). The rate of pressure decrease during relaxation depends on the velocity of calcium reuptake and on the LV volume: The smaller the volume, the lower the potential for pressure to fall,2 limited by the end diastolic pressure curve shown in Figure 5-1. Rate of calcium reuptake is further modiﬁed by LV lengthening during relaxation, so true relaxation can be measured only during the isovolumic period.6 Several equations have been proposed to describe the rate of isovolumic pressure decay,7 the most general being: P(t) = (Po − Pb) × e−t/τ + Pb, which can be, with some caveats, simpliﬁed to: P(t) = Po × e−t/τ, and further to8,9: τ ≈ IVRT/(ln PAVC − ln PMVO), where IVRT is the isovolumic relaxation time (the time between aortic valve closure and mitral valve opening), and PAVC and PMVO are LV pressure at aortic valve closure (AVC) and mitral valve opening (MVO), respectively, which can be approximated nonin-

vasively by systolic blood pressure and an estimate of LA pressure. Importantly, LV relaxation is a never-ending process that critically aﬀects the end diastolic pressure that the patient achieves, particularly during exercise. Consider Figure 5-2A, showing a series of P-V curves representing successive intervals of τ, and Figure 5-2B, the same curves magniﬁed on diastolic pressures. Note that after 6τ, the ﬁlling curve is virtually indistinguishable from the end diastolic P-V curve, as relaxation is 99.8% complete. When relaxation rate is normal, the end diastolic ﬁlling curve is completely relaxed at normal heart rates (12.5τ, 2C) and almost complete during exercise (5τ, 2D); with delayed relaxation, however, while the EDPV curve is fully relaxed at rest (6.25τ, 2E), it becomes stiﬀ with exercise (3τ, 2F). The combination of relaxation and the EDPVR results in a dynamic P-V relationship, represented by the round dots in Figure 5-2A. Note that in early diastole, LV pressure continues to fall even though volume is increasing, meaning that the instantaneous stiﬀness is actually negative, which some consider diastolic suction. Two other deﬁnitions of “diastolic suction” are also relevant. Consider ventricular ﬁlling from a very low end systolic volume (where the EDPVR is concave downward). If relaxation is very rapid or ﬁlling is delayed (by mitral stenosis or experimentally with a mitral occluder2), then LV pressure can fall below atmospheric pressure.2,10 Alternatively, suction has been used to refer to the small (1 to 3 mmHg) diﬀerences in pressure between the base and the apex, which assist in the low-pressure ﬁlling of the ventricle, particularly with exercise, and which will be discussed later.11

Determinants of Intracardiac Blood Flow In the most general sense, the motion of blood inside the heart, as the motion of any ﬂuid, is determined by the Navier-Stokes equations, a complex set of four multidimensional partial diﬀerential equations, which must be solved simultaneously at every point in space and moment in time: 䉮·v = 0 and

ρ

Dv = −∇P + B + μ∇2 v Dt

These equations appear deceptively simple but contain such complex mathematical concepts that except in the simplest of geometries, they can never be solved either analytically or with powerful supercomputers. Fortunately, considerable simpliﬁcations can be made to these equations that will facilitate a conceptual and computational approach. The most important simpliﬁcation is to take the distribution of blood throughout the heart and replace it with just a few measurements at speciﬁc points inside the heart. For instance, instead of describing pressure in every cubic millimeter inside the left ventricle, we assume that LV pressure can be approximated by an average of these and give a single number for LV pressure, which is precisely how we measure and report LV pressure in practice. Similarly, instead of describing the direction and speed of blood ﬂow at every point within the heart, we focus on points where blood velocity is

Chapter 5 • Physical Determinants of Diastolic Flow

2τ 100 3τ 4τ

50

100

4τ 5τ 6τ 25 Diastole

0 0

150

Volume (ml)

Systole

Systole

50 2τ

2τ

1τ

3τ 4τ 5τ 6τ

25 12.5τ Diastole

Pressure (mmHg)

1τ Pressure (mmHg)

150

B

50

3τ 4τ 5τ 6τ

25 Diastole

0

0 0

100

50

100

50

150

150

Volume (ml)

Volume (ml)

τ = 40 msec, HR = 150, DFP = 200 msec

τ = 40 msec, HR = 75, DFP = 500 msec

C

D

Systole

Systole

50 2τ

1τ

2τ

1τ

3τ 4τ 5τ 6τ

25 Diastole

Pressure (mmHg)

50

Pressure (mmHg)

100

50

Volume (ml)

A

3τ 4τ 5τ 6τ

25 Diastole

0

0 0

100

50

0

150

100

50

150

Volume (ml)

Volume (ml) τ = 80 msec, HR = 75, DFP = 500 msec

E

3τ

5τ 6τ

Diastole

0 50

2τ

1τ

1τ

150

0

Systole

50

Systole

Pressure (mmHg)

Pressure (mmHg)

200

τ = 80 msec, HR = 120, DFP = 240 msec

F

Figure 5-2 Diastolic pressure-volume (P-V) relationships shown as a function of the duration of diastole. Duration of diastole is measured by the multiples of a time constant of relaxation (τ). Panel A shows a series of P-V relationships that occur after successive intervals of τ, while panel B shows the same curves zoomed on diastolic pressures. The combination of relaxation and the end diastolic P-V (EDPV) relationship results in a dynamic diastolic part of the P-V loop represented by the round dots in A. Note that in early diastole, left ventricular pressure continues to fall even though volume is increasing, meaning that the instantaneous stiffness is actually negative, which some consider diastolic suction. When relaxation rate is normal, the end diastolic filling curve is completely relaxed at normal heart rates (arrow 12.5τ, C) and almost complete during exercise (arrow 5τ, D); with delayed relaxation, however, while the EDPV curve is fully relaxed at rest (arrow 6.25τ, E), it becomes stiff with exercise (arrow 3τ, F).

45

46

Chapter 5 • Physical Determinants of Diastolic Flow maximum, such as the tips of the mitral leaﬂets and the pulmonary vein oriﬁces. Finally we assume ﬂuid incompressibility and zero viscosity and heat conduction losses. In this way, the thousands of partial diﬀerential equations that would have to be solved simultaneously throughout the heart are replaced by a few ordinary diﬀerential equations that can be solved quite easily on a personal computer. To understand how these equations can model the ﬂow within the heart, we ﬁrst start by replacing the Navier-Stokes equations with the well-known Bernoulli equation, which applies to ﬂow across discrete points such as valves. Here we present it with its inertial and convective terms (we still omit the viscous term, since it is negligible in almost every intracardiac situation): Δp = M

dv 1 + ρΔ v2 , dt 2

( )

where Δp is the pressure diﬀerence between two points; M is the inertial constant and represents the “eﬀective” mass being accelerated; dv/dt is the instantaneous temporal acceleration of ﬂow through the region; ρ is blood density; and Δ(v2) is the change in the square of velocity from one point to another (with pressure in mmHg and velocity in m/sec, 1/2ρv2 reduces to 4v2 in the simpliﬁed Bernoulli equation). The ﬁrst product is the inertial term of the Bernoulli equation and corresponds to the energy used accelerating and decelerating ﬂow; the second term is the convective term and represents kinetic energy of ﬂow. The eﬀective mass of blood in a narrow oriﬁce is small, and thus M is a negligible quantity in, for example, valve stenosis, but the dominant term when ﬂow is not obstructed, such as in the normal mitral valve. For constant ﬂow through an oriﬁce of minimal diameter D, the inertial constant M varies approximately in proportion to D, while the kinetic term 1/2ρv2 varies inversely to D4. For nonobstructive ﬂow through the body of heart chambers, where pressure changes gradually over a distance, not at a discrete point, we must use the Euler equation, a diﬀerential version of the Bernoulli equation for pressure change along a streamline of ﬂow: ∂p ∂v ⎞ ⎛ ∂v = −ρ ⋅ ⎜ + v ⋅ ⎟ , ⎝ ∂t ∂s ⎠ ∂s where the inertial and convective terms are in the same order as in the Bernoulli equation, but the discrete terms (Δp and Δ(v2)) have been replaced by their spatial derivatives, yielding the rate of pressure change per centimeter of distance along the streamline. To return the total pressure drop between points A and B along the streamline, this equation must be integrated numerically: B ⎛ ∂v ∂v ⎞ Δp = − ρ ⋅ ∫ ⎜ + v ⋅ ⎟ ds. A ⎝ ∂t ∂s ⎠

Figure 5-3 shows schematically how these partial derivatives are summed together to produce the pressure gradient map.12 Another practical fact is that we can obtain the same map by applying the Euler equation to a color Doppler M-mode tracing.

CLINICAL RELEVANCE In this section, we will demonstrate how interaction of solid and ﬂuid mechanics determines intracardiac ﬂow within three speciﬁc

Inertial term Convective term Figure 5-3 Combination of convective (right) and inertial (left) term to produce an intraventricular pressure gradient. (From Thomas JD, Popovic ZB: Intraventricular pressure differences: A new window into cardiac function. Circulation 2005;112:1684–1686.)

regions of the heart: mitral valve, pulmonary vein, and left ventricle.

Physical Factors Governing Left Ventricular Filling Velocities To describe mathematically ﬂow through the mitral valve, we ﬁrst consider a very simpliﬁed construct, consisting of the left ventricle, which has pressure as a function of time pV(t); the left atrium, which has pressure as a function of time (pA(t)); and the mitral valve, which has area AMV and contains a mass of blood M that is accelerating in passing from the left atrium to the left ventricle. To a ﬁrst approximation, M is the blood within a cylinder that can ﬁt inside the narrowest portion of the mitral leaﬂet tips and whose length is approximately the diameter of the valve. In reality, though, since pressure is applied across the mitral valve, the most relevant hydrodynamic concept is the length of this cylinder, termed the mitral inertance, related linearly to the diameter of that structure. We will use this construct to discuss three parameters of transmitral ﬂow: mitral acceleration, peak mitral ﬂow, and mitral deceleration.

Acceleration of Mitral Flow To understand the acceleration of blood across the mitral valve, we apply Newton’s second law of motion: The rate at which an object accelerates is given by the force exerted on that object divided by its mass. In this case, the acceleration would be recorded by Doppler echocardiography as the velocity acceleration detected for mitral inﬂow, while the force is the diﬀerence in pressure on either side of the mitral valve multiplied by the area of the valve13: a=

F ΔpA Δp = ≈ . m ρM ρL

Here we have taken advantage of the fact that valve area appears in both the numerator and the denominator (through the deﬁnition of inertial mass) to simplify the relationship. Clearly the higher the pressure diﬀerence across the valve and the smaller the length of the blood column within the mitral valve, the more rapidly the velocity will accelerate. This is why mitral velocity

Chapter 5 • Physical Determinants of Diastolic Flow increases almost instantaneously in mitral stenosis, which has a very high pressure gradient across the valve and a very small blood mass, due to the small diameter of the mitral oriﬁce. If the blood within the mitral valve were subject to an instantaneously applied pressure diﬀerence (as if the relaxation of the left ventricle occurred suddenly), mitral velocity would start to rise linearly. In the physiological situation, the pressure gradient is not abruptly applied but rather increases gradually (roughly linearly) with time as the ventricle relaxes, resulting in a roughly parabolic mitral velocity acceleration curve.14

Peak E-Wave Velocity and Conservation of Energy Mitral valve acceleration eventually decreases over time because the maximal velocity generated by a pressure diﬀerence is limited by conservation of energy (expressed in the Bernoulli equation). Within the heart, energy in the blood takes on three principal forms: pressure (a form of potential energy), kinetic energy, and heat; the total energy in the system must remain constant. In the left atrium, where blood velocity is low, most of the energy is in the form of pressure, but as it moves toward the mitral valve, its velocity rises and it acquires a kinetic energy (1/2ρv2), which causes the local blood pressure to fall. If no energy losses appear, pressure diﬀerence and velocity are related by the simpliﬁed Bernoulli relation, which becomes roughly Δp = 4v2 when pressure is measured in millimeters of mercury and velocity in meters per second. The velocity reaches the target gradient asymptotically, but this is delayed by the amount of inertance present. Reaching the asymptote can be even further delayed by the gradient not being imposed abruptly but slowly, as seen in a normally relaxing left ventricle.

Deceleration of Mitral Flow Returning to our general model of the mitral valve, once ﬂow has been accelerated to maximal velocity by the pressure diﬀerence across the mitral valve, it begins falling as the pressure diﬀerence between the left atrium and the left ventricle equilibrates. This is analogous to ﬂow between two tanks stopping when the level of water in the two tanks becomes the same. When we speak of the change in pressure with a change in volume, we are dealing with the concept of compliance or its inverse, stiﬀness, the change in pressure for a given change in volume, which is a major determinant of the deceleration of ﬂow across the mitral valve. Since the stiﬀer the ventricle, the more rapidly the pressure equilibrates across the mitral valve to decelerate the ﬂow, we can understand why short deceleration time across the mitral valve is associated with increased ventricular stiﬀness. Note that in this situation, we must consider atrial and ventricular stiﬀness together, since both chambers are involved in determining how quickly pressure equilibrates across the mitral valve. For ventricular stiﬀness SV and atrial stiﬀness SA, the net atrioventricular stiﬀness Sn is simply SA + SV. To obtain a mathematical expression for mitral velocity deceleration rate, we ﬁrst note that for a restrictive mitral valve with area A (i.e., mitral stenosis, though even for a normal mitral valve), the overall principle holds: 1 Δp = ρv2 , 2 which simpliﬁes to 4v2 when Δp is in mmHg and v in m/sec. Diﬀerentiating this yields:

dΔp/dt = ρv dv/dt. But dΔp/dt can also be expressed in terms of ﬂow across the mitral valve (Av) and net atrioventricular stiﬀness: dΔp/dt = −AvSn. Substituting for dΔp/dt yields: ρv dv/dt = −AvSn, or, rearranging, dv/dt = ASn/ρ. Thus, the stiﬀer the ventricle (or atrium) and the larger the valve area, the faster the deceleration. Alternatively, one can represent this as a purely inertial system (with a nonrestrictive oriﬁce), which yields a simple harmonic motion, in which case the velocity across the valve is described roughly by a sine wave: ⎛ t ⎞ v (t ) = v0 sin ⎜ ⎟, ⎝ m k⎠ where v0 is the peak E-wave velocity, m is mitral inertance, and k is the stiﬀness constant of the ventricle. The deceleration time (time for the E wave to fall from its peak to zero velocity) can be solved for as: tdec =

π 2

ρ⋅L 1 ⋅ , A k

where ρ, L, and A are blood viscosity, mitral valve length, and mitral valve area, respectively. Therefore, the stiﬀer the ventricle, the shorter the deceleration time. This is intuitively very understandable: Tighter springs oscillate fast. Note that in this simpliﬁcation, one assumes that active relaxation is complete at the time of interest.13 Modeling of Mitral Valve Flow Up until now, we have been discussing speciﬁc features of the transmitral E wave through signiﬁcant simpliﬁcations that allow closed-form mathematical solutions. To permit more realistic modeling of transmitral ﬂow, however, one needs more general equations that can be solved only numerically. A generalized equation for blood ﬂow through the mitral valve and its interaction with the transmitral gradient is15: 1 dv dt = ⎛ PA − Pv − ρv2 ⎞ M , ⎝ ⎠ 2 where v is velocity, t is time, PA and Pv are instantaneous atrial and ventricular pressures, and M is mitral inertance. Conversely, the impact of mitral ﬂow on LA and LV pressures is expressed through the equations dPA/dt = −Av/CA and dPv/dt = Av/Cv + ∂Pv/∂t, where A is mitral valve area, and CA and CV are atrial and ventricular compliance (inverse of stiﬀness), respectively. By solving these three diﬀerential equations, we can assess how changing the parameters of the equation that represent passive diastolic properties, LV relaxation, mitral inertance, and preload can aﬀect transmitral ﬂow. We start with a preliminary discussion of these interactions before presenting an even more

47

Chapter 5 • Physical Determinants of Diastolic Flow detailed model that includes pulmonary vein ﬂow in addition to transmitral ﬂow. Impact of Relaxation: Changes in relaxation aﬀect the earliest part of the mitral ﬂow (Fig. 5-4A and B). They have a profound eﬀect on the peak values of E-wave velocity. The overall eﬀect of relaxation on the descending phase of the E wave is more complex: When τ is very short, relaxation is essentially complete

by the time of the peak of the E wave, and small changes in τ have little eﬀect on deceleration; on the other hand, if τ is signiﬁcantly longer, the relaxation remains an important aspect of the deceleration phase, and further lengthening of τ will cause a decrease in the deceleration rate (that is, prolongation in deceleration time). Passive Diastolic Properties of the Left Ventricle: Increasing the steepness of the diastolic P-V curve aﬀects

LV RELAXATION CONSTANT (MSEC)

LV RELAXATION CONSTANT (MSEC) 140

20

Velocity (cm/sec)

LV pressure (mmHg)

25

15 10

40

5

60

20 30

100

50

70

90

110

A 16.2 12.3 10.0

D 7.8 6.9 5.8

VTI 13.1 12.7 12.0

60 40

20

40

60

20

0

130

100

200

300

400

500

Time (msec)

A

B LV VOLUME CONSTANT

(CM3)

LV VOLUME CONSTANT (CM3) 140

20 15 40

10

60 90

5

Velocity (cm/sec)

25 LV pressure (mmHg)

E 91 82 73

80

LV volume (cm3)

Vvk 40 60 90

120 100 80

E 58 82 93

A 9.2 12.3 13.7

D 8.4 6.9 4.8

VTI 6.6 12.7 16.3

60 40

40

60

90

20 0

0 30

50

70

90

110

0

130

100

LV volume (cm3)

200

300

400

500

Time (msec)

C

D LA PRESSURE (mmHg)

LA PRESSURE (mmHg) 140

20 5

10

20

15 10 5

Velocity (cm/sec)

25

LAP E A 5 40 4.5 10 82 12.3 20 124 24.1

120 100

20

80 60

D 3.5 6.9 9.6

VTI 6.9 12.7 17.7

10

40

5

20 0

0 30

50

70

90

LV volume

E

TAU 20 40 60

LV relaxation constant (msec)

120

0

0

LV pressure (mmHg)

48

110

130

0

(cm3)

100

200

300

400

500

Time (msec)

F

Figure 5-4 Effect of left ventricular relaxation constant (τ; panels A and B), volume constant (inverse of chamber stiffness index; panels C and D) and left atrial pressure (preload; panels E and F) on a left ventricular pressure volume curve (left panels) and mitral valve velocity profile (right panels). Prolonged relaxation blunts the lower left corner of pressure volume curve and decreases peak mitral valve flow. Increased stiffness (i.e., decreased volume constant) moves lower left corner of the pressure volume loop to the left and upwards, decreases peak mitral valve flow and increases its deceleration rate. Finally, increased left atrial pressure shifts lower right corner of the pressure volume loop to the right while increasing peak mitral valve flow. E, peak velocity of E wave (cm/sec); A, peak acceleration rate of E wave (m/sec2); D, peak deceleration rate of the E wave (m/sec2); VTI, E wave velocity time integral (cm). (From Thomas JD, Weyman AE: Echocardiographic Doppler evaluation of left ventricular diastolic function. Physics and physiology. Circulation 1991;84: 977–990.)

Chapter 5 • Physical Determinants of Diastolic Flow primarily deceleration time, that is, operative chamber stiﬀness (Fig. 5-4C and D). However, a caveat has to be introduced. The ventricular P-V curve (as well as the atrial P-V curve) is exponential in shape. Since operative chamber stiﬀness is equal to the slope of these curves, stiﬀness and mitral deceleration rise when operative chamber volumes increase. This change is indistinguishable from the change that may arise from material properties of the ventricle, leading to a steeper curve at all pressures (that is, a true change in the diastolic properties of the ventricle). Preload Alterations: Preload aﬀects all components of the mitral velocity curve (Fig. 5-4E and F). However, its most prominent eﬀect is on the E wave. For mitral deceleration, the eﬀects depend on the initial position of the P-V curve. If the preload increase does not move the P-V loop too much into the steeper portion of the EDPVR, the eﬀects may be negligible. It is not so in the severely diseased ventricles operating close to the limit of the preload reserve. Mitral Inertance: Mitral inertance aﬀects both acceleration and deceleration of the mitral valve. It changes acceleration of mitral valve inﬂow and leads to ﬂattening of the parabolic curve of velocity rise. Mitral inertance essentially acts by introducing the time lag between the transmitral pressure gradient and the mitral velocity curve: It makes the peak of the velocity curve occur after the peak of the transmitral pressure gradient curve (Fig. 5-5). It also introduces the diﬀerence between the true mitral valve pressure gradient and the pressure gradient calculated from application of the simpliﬁed Bernoulli equation to transmitral velocity (see Fig. 5-5). As it correlates with the mitral valve area, it can be largely neglected in patients with mitral stenosis, but it is an important factor in the nonstenotic valve. We have shown, by using the combination of echocardiography and direct pressure recordings, that the average value of mitral inertance in humans is 3.82 ± 1.22 g/cm2, corresponding to an eﬀective length of the blood column of about 3.6 cm within the mitral valve.16 Future research may allow direct estimation of inertance from echocardiography data alone. Interaction of Ventricular Compliance and Relaxation: Importance of Heart Rate: During early ﬁlling, relaxation is not yet complete. This means that ﬁlling occurs while the dynamic P-V curve continuously shifts downward and toward the right. Thus, as the ventricle ﬁlls, it moves to the steeper part of the EDPVR, which in turn becomes progressively “ﬂatter.” These two

P underestimation Actual ΔP by catheter Calculated ΔP from velocity

Phase lag Figure 5-5 Impact of mitral inertance: Transmitral velocities lag behind transmitral pressure differences. (From Nakatani S et al: Mitral inertance in humans: Critical factor in Doppler estimation of transvalvular pressure gradients. Am J Physiol Heart Circ Physiol 2001;280:H1340–1345.)

trends may oﬀset each other, with the result that diastolic pressures are constant or falling despite an increase in LV volume, giving the impression of negative stiﬀness in early diastole. Figure 5-4A and B show how τ eﬀects mitral valve ﬂow and end diastolic P-V relationships.15 We reiterate here that while τ aﬀects the early part of the diastolic P-V curve, τ has an eﬀect on end diastolic volume only when dramatically prolonged. The situation is diﬀerent during exercise, where shortening of the diastolic interval and the increase of arterial blood pressures produce incomplete relaxation (with a rise in end diastolic pressure) rather than simply delayed relaxation (which has little impact on LV end diastolic pressure).17

Understanding Pulmonary Vein Flow Through Computer Modeling of the Heart Such conceptual thought experiments as those previously discussed can be helpful in understanding general trends in the relationship between invasive parameters and noninvasive measurements, but a more comprehensive approach can be obtained with a computer model that invokes realistic descriptions of chamber and valvular functions. The reason for this is that the ﬂows of blood through diﬀerent parts of the circulatory system are interdependent. A change in a single parameter (e.g., resistance in systemic arterioles) aﬀects ﬂow throughout the system. Thus, changes in pulmonary circulation aﬀect systemic circulation even if not assuming any ventricular-ventricular interactions.

Lumped Parameter Model of the Heart and Circulation Since the mid-1980s, the authors and colleagues have worked to develop models of the heart with increasing complexity, beginning from a very simple isolated model of the mitral valve used to understand the mitral pressure half-time; to models incorporating more realistic diastolic characteristics of the ventricle and atrium; to models that simulated all the cardiac chambers and valves, as well as the peripheral and pulmonary vasculature; to most recently a simulation that links knowledge of basic myocyte and ﬁber function to the gross architecture of the heart. We will use a lumped parameter model to explore some of the determinants of transmitral and pulmonary venous ﬂow inside the heart.3 The lumped parameter approach assumes that blood ﬂow is similar to the ﬂow of a current through an electric circuit, which can be represented at speciﬁc nodes of the circuit (left atrium, left ventricle, aortic valve, etc.). Each of these nodes is represented by a speciﬁc ordinary diﬀerential equation. The principle of the conservation of ﬂow (Kirchoﬀ ’s ﬁrst law) is applied throughout the circuit, and the parameters of the system are obtained by simultaneously solving all diﬀerential equations. Our model consists of 24 coupled diﬀerential equations representing eight diﬀerent chambers (the right atrium and ventricle, pulmonary arteries and veins, left atrium and ventricle, aorta, and systemic veins) as well as the valves and vascular beds connecting them (Fig. 5-6), giving time-varying ﬂows and pressures throughout the model. Figure 5-7 displays normal Doppler velocity tracing of pulmonary vein and transmitral ﬂow recorded in the normal subject by transesophageal echocardiography (left) and a model output of corre-

49

50

Chapter 5 • Physical Determinants of Diastolic Flow Pulmonary capillaries Pulmonary artery

Pulmonary vein

Pulmonic valve

Left atrium

Right ventricle

Tricuspid valve

Mitral valve

Left ventricle

Right atrium

tions have opposite eﬀects. Mitral valve regurgitation (through the parameter MV ERO) has its eﬀect mostly on the systolic waveform, while Kp+ and τ have eﬀect mostly on AR. The results of this sensitivity analysis illustrate the complexities of these relationships, which are not intuitively apparent. In contrast, for the mitral inﬂow, as expected, the greatest inﬂuence was exerted by preload. Importantly, τ showed the opposite eﬀects on E and A waves, in congruence with the E/A ratio being reversed in the setting of impaired relaxation. Table 5-1 should be kept in mind, as very often pulmonary vein ﬂow is used as a surrogate marker of LA function, with S, D, and AR reﬂecting the LA reservoir, conduit, and pump functions, respectively. Our table indicates that for none of these is there a straightforward relationship between the speciﬁc waveform and speciﬁc material parameters of the pulmonary vein ﬂow waveform.

Aortic valve Venae cavae

Systemic capillaries

Aorta

Figure 5-6 A lumped parameter model of the heart. (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)

sponding pulmonary vein and transmitral ﬂow velocities, along with simulated pressure curves. Starting from this normal shape of velocity and pressure tracings, we ﬁrst modeled a delayed relaxation pattern, by increasing τ from 50 to 120 msec. Then, to model restrictive ﬁlling, we shifted the end systolic P-V relationship by 10 ml to the right and decreased contractility from 4.0 to 2.5 mmHg/ml, thus moving the P-V loop toward the steeper part of the EDPVR. The model outputs are displayed in Figure 5-7, along with actual Doppler and pressure tracings of a representative patient with delayed relaxation (panel B) and restrictive ﬁlling (panel C). One can observe a close correspondence between the modeled and actual shapes, with a correlation coeﬃcient approaching 1. Figure 5-8 shows the impact of some of the model parameters on pulmonary vein and mitral valve ﬂow. LA systolic and diastolic function had opposing eﬀects on the S and AR waves of the pulmonary vein, with minimal eﬀect on the D wave (panels A through D). Finally, all waveforms showed strong positive response to preload (panels E and F). Worse LV relaxation decreases the mitral valve E/A ratio and blunts diastolic waves of pulmonary vein ﬂow (panels G and H). These observations are analyzed in depth in Table 5-1, by showing the sensitivities of peak velocity of the three pulmonary vein ﬂow waves and of two mitral inﬂow waves on model parameters. The sensitivities represented here were obtained by calculating a normalized Jacobian matrix, showing the proportional change in an output index for a given incremental change in an input parameter. A sensitivity of 1 means that for each 1% change of a model parameter value, the output variable will change by 1%. A value of 2 indicates a 2% change for a 1% increase. Negative numbers indicate inverse relationships. Because of the highly nonlinear nature of the model, these observations are relevant to only very small increments but do provide an overall sense of the dependency of Doppler indices on hemodynamic parameters. For example, one can readily observe the dramatic eﬀect of preload on all three pulmonary vein ﬂow waves, in particular AR, which increases almost 6-fold the increment in blood volume. Furthermore, one can observe that LA diastolic and systolic func-

Impact of Pulmonary Vein–Left Atrial Pressure Gradient and Left Atrium Size Similar to mitral valve inertance is pulmonary vein inertance. Its eﬀect on pulmonary vein ﬂow is similar to its eﬀect on transmitral ﬂow. Inertance leads to a lag of pulmonary vein ﬂow behind the PV–LA pressure gradient. This is intuitively understandable: the pressure is needed to push the blood column, which then keeps moving because of its kinetic energy.18 Another interesting observation is the impact of the change of LA size, induced by clipping of the LA appendage, on pulmonary vein ﬂow. The only aﬀected pulmonary vein ﬂow wave was the S wave, indicating that LA size aﬀects primarily LA reservoir function.19

Understanding Intraventricular Flow The previous model formulations seem like child’s play when one is confronted with the task of simulating intraventricular ﬂow with its demands for representing pressure and velocity throughout the chamber. Three major phenomena develop simultaneously during ﬁlling: An intraventricular gradient appears at the beginning of LV ﬁlling, the blood column slows after exiting the mitral valve while continuing as laminar ﬂow toward the apex, and ﬁnally vortices start appearing due to propagation of the blood column past the tips of the mitral leaﬂets, while the left ventricle continually changes its size. It is well documented that a small LV base-to-apex pressure gradient develops in early diastole (Fig. 5-9A). We have already discussed that this gradient is of utmost importance for the lowpressure ﬁlling of the ventricle and is commonly termed diastolic “suction.” However, the exact mechanisms causing it are unclear. The most probable mechanisms are isovolumic conformational changes in LV shape that are driven by elastic forces within the myocyte and/or the myocardial interstitium, explored in greater depth below. As blood emerges from the mitral valve, it slows down as the ﬂow stream expands to ﬁll the left ventricle. Interestingly, within the ﬁrst four centimeters of the left ventricle, the velocity of propagation of the blood column is fairly constant, despite the dramatic change of the chamber size, but it is generally less than the actual velocities within the bolus of blood traversing the mitral valve. For example, pulsed-wave Doppler may record a velocity of 100 cm/sec, while the normal propagation velocity will be only 60 or 70 cm/sec, and even lower in diseased hearts, due to the bleeding oﬀ of vortices at the front of the bolus of blood. We and others have shown that in heart disease, the amount of slowing

Chapter 5 • Physical Determinants of Diastolic Flow

50 E

100 0

Δ = –1.53±9.38 cm/sec

A

0.5

Velocity (cm/s)

y = 0.95x r = 0.94 p < 0.0001

Velocity (cm/s)

Velocity (cm/s)

0

0

A

E 100

1.0

0

Time (sec)

0.5

S

60

y = 1.02x r = 0.92 p < 0.0001

D

0 AR –60 0

1.0

0.5

Δ = 0.76±7.69 cm/sec

Velocity (cm/s)

PULMONARY VENOUS FLOW

TRANSMITRAL FLOW

60

S

0 AR –60

1.0

0

Time (sec)

Time (sec)

D

0.5

1.0

Time (sec)

A

0

0.5

A 100

1.0

0

Time (sec)

0.5

A

40

0

1.0

Δ = 3.52±8.65 cm/sec

E

80

Time (sec)

0.3

0

y = 1.02x r = 0.96 p < 0.0001 Δ = –1.54±3.32 AR cm/sec

–40 0

0.5

40 D

S 0

AR

–40

1.0

0

0.5

80

0.6

y = 0.96x r = 0.91 p < 0.0001 Δ = 3.72±11.81 cm/sec

S 0 AR –60

1.0

0

0

20

0 0

1

0

1 Time (sec)

B

0.3

0.6

Time (sec)

y = 1.16x r = 1.0 p < 0.0001 Δ = 1.99±1.61 mmHg

0 0

1

30

0

0.6

0

Time (sec)

Pressure (mmHg)

0

AR

0.6 Time (sec)

LV PRESSURE Pressure (mmHg)

Pressure (mmHg)

Δ = –3.63±11.30 mmHg

D

0

0

LV PRESSURE y = 0.94x r = 0.96 p < 0.0001

S

0.3 0.6

30

Time (sec)

Time (sec)

120

80

Time (sec)

Pressure (mmHg)

0

0.6

LA PRESSURE Pressure (mmHg)

Pressure (mmHg)

Δ = –1.04±1.04 mmHg

0.3

–60

LA PRESSURE y = 0.84x r = 0.97 p < 0.0001

0

Time (sec)

D

Time (sec)

Time (sec)

20

E

100

PULMONARY VENOUS FLOW Velocity (cm/s)

D

Velocity (cm/s)

Velocity (cm/s)

S

A

Time (sec)

PULMONARY VENOUS FLOW 40

Velocity (cm/s)

100

E

y = 0.95x r = 0.92 p < 0.0001

Velocity (cm/s)

A Δ = 0.70±8.35 cm/sec

0

Pressure (mmHg)

E

50

0

0

120

0 0

1

100

y = 0.80x r = 0.99 p < 0.0001 Δ = –5.01±8.69 mmHg

0 0

Time (sec)

0.6 Time (sec)

Pressure (mmHg)

y = 0.99x r = 0.93 p < 0.0001

TRANSMITRAL FLOW Velocity (cm/s)

0

Velocity (cm/s)

Velocity (cm/s)

TRANSMITRAL FLOW

100

0 0

0.6 Time (sec)

C

Figure 5-7 Actual and modeled pressures and filling patterns in a normal subject (A), patient with delayed relaxation (B), and patient with restrictive filling (C). Note similarities between observed and modeled data. (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)

51

Chapter 5 • Physical Determinants of Diastolic Flow TRANSMITRAL FLOW

PULMONARY VEIN 60

A

Velocity (cm/sec)

Velocity (cm/sec)

90 E 60 30 0

S

0.5

0.48* 0.64 AR

1

0

1

B 90

60 A

E

Velocity (cm/sec)

Velocity (cm/sec)

0.5 LA end-systolic elastance (mmHg/ml)

A

60 30 0

30

D

S

0.2* 0.25

0

0.3 AR –30

0

0.5

1

0

LA end-diastolic elastance (mmHg/ml)

0.5

1

LA end-diastolic elastance (mmHg/ml)

C

D 150 E

Velocity (cm/sec)

100 A

100 50 0

S

D

50

3800* 0 4180 –50

4560 AR

–100 0

0.5

1

0

0.5

Preload (ml)

1

Preload (ml)

E

F 60 E

Velocity (cm/sec)

120 A

80 40

D

S 30

0.05* 0

0.10 AR

0.15

–30

0 0

0.5

0

1

LV relaxation time constant (sec)

G

0.32

0

LA end-systolic elastance (mmHg/ml)

Velocity (cm/sec)

D

30

–30 0

Velocity (cm/sec)

52

0.5

1

LV relaxation time constant (sec)

H

Figure 5-8 Simultaneous modeling of pulmonary vein and transmitral velocities using lumped-parameter approach. Increased left atrial systolic elastance (i.e., higher contractility) increases A wave of the transmitral flow and AR wave of the pulmonary vein flow (panels A and B); increased left atrial diastolic elastance (i.e., higher passive stiffness) has the opposite effect (panels C and D); increased preload increases all components of transmitral and pulmonary vein flow (panels E and F); finally, prolongation of ventricular relaxation decreases E and increases A wave velocities of the transmitral flow and decreases diastolic pulmonary vein flow (panels G and H). (From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.)

Chapter 5 • Physical Determinants of Diastolic Flow of the blood column relative to the component velocity (that is, the so-called E/Vp ratio) is related to LV ﬁlling pressures,20,21 though the exact mechanistic relationship between these two phenomena is unclear (Fig. 5-9B). As noted, intraventricular ﬂow during diastole characteristically forms circular eddies lateral to the main ﬂow, which can be seen when the heart is imaged by echocardiography with highfrequency transducers, or after the contrast injection, and can be quantiﬁed by magnetic resonance velocity mapping (Fig. 5-9C).22 Creation of vortices plays a crucial role in mitral valve closure and in the transfer of blood toward the apex and then into the LV outﬂow tract. Again, full elucidation of vortex generation and movement is unclear.

TABLE 5-1 RESULTS OF SENSITIVITY ANALYSIS FOR THE PULMONARY VEIN AND TRANSMITRAL FLOW PULMONARY VEIN FLOW

Parameters Preload LV compliance index LV systolic elastance LV τ LA systolic elastance LA diastolic stiffness Mitral valve area MV ERO

TRANSMITRAL FLOW

S

D

AR

E

A

2.38 –0.45 –0.2 0.05 0.8 –0.79 –0.06 –2.73

2.33 –0.12 0.05 –0.19 –0.14 0.6 0.12 0.17

5.88 –1.15 –0.44 –1.76 0.97 –1.27 –0.16 –0.18

1.53 –0.24 –0.09 –0.33 –0.38 –0.11 0.07 0.32

1.9 –0.04 –0.19 0.16 –0.25 0.97 –1.02 –0.11

Modeling of the Intraventricular Flow by Fluid-Mechanical Computer Modeling of the intraventricular ﬂow is demanding because ventricular motion eﬀects blood ﬂow, but blood ﬂow itself eﬀects ventricular motion. Some simpliﬁcation is possible with compu-

A, atrial wave; AR, atrial reversal wave; D, diastolic wave; E, early wave; ERO, effective regurgitant orifice; LA, left atrial; LV, left ventricular; MV, mitral valve; S, systolic wave. From Thomas JD et al: Physical and physiological determinants of pulmonary venous flow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465.

25

P

ECG

Pressure (mmHg)

20 MVO

15 10

LVP Base LA

LVP Apex 5 0

IVPG

–5

A 30

MV

pw (mmHg)

25 20 15 10

r = 0.80 p < 0.001 y = 5.27x+4.66 SEE = 3.1

5

LV

0 0.5

1

1.5

2

2.5

3

3.5

4

E/vp ratio

B

C

Figure 5-9 Three consecutive early diastolic intraventricular phenomena: A, Intraventricular pressure gradient formation in early diastole; B, relationship between the slowing of the blood column in the early diastole with preload; and C, formation of vortices. (B, From Garcia MJ et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454; C, From Kilner PJ et al: Asymmetric redirection of flow through the heart. Nature 2000;404:759–761.)

53

54

Chapter 5 • Physical Determinants of Diastolic Flow tational ﬂuid dynamics (CFD) models, where LV motion is prescribed based on images from echocardiography or magnetic resonance imaging, but these models lack ﬂuid feedback on the myocardium. Full ﬂuid-structure interaction (FSI) models are being developed in which movement of the blood and muscle is not known a priori but is computed during the simulation on a ∼mm three-dimensional grid at ∼msec intervals, an extraordinary computational challenge. Furthermore, most commercially available software programs allow only small strain deformations (up to 5%) and are inadequate for cardiac modeling, where strains may exceed 50%. Fortunately, large strain solvers recently have been implemented in commercial codes, which enabled several researchers to begin true ﬂuid-solid interaction modeling of LV function.23–25 Although these models have simpliﬁed geometry and muscle properties, they give us insight into the ﬂow propagation in the normal heart. Flow Propagation Inside the Ventricle We will ﬁrst discuss the ﬁlling modeled by an axi-symmetric thin-walled FSI model of the left ventricle containing both LV outﬂow and inﬂow.26 During the rapid ﬁlling phase, a jet starts its propagation through the mitral valve into the ventricular chamber. Driven by this jet, a doughnut-shaped vortex is formed around the jet just downstream from the mitral oriﬁce. During ﬁlling, the vortex ring travels toward the middle of the expanding ventricle, while a weak vortex is formed within the aortic outﬂow tract, which dissipates late during diastasis. After the vortex ring reaches the middle of the ventricle, its anterior part becomes stationary while the posterior part continues forward. During atrial contraction, a new, weaker vortex ring that encompasses a part of the outﬂow tract is formed, while the posterior side of the initial vortex ring continues to move into the posterior apical region of the ventricle. At the end of the ﬁlling, the posterior part of the second vortex ring merges with the ﬁrst one, forming a large vortex in the posterior apex (Fig. 5-10). Effect of Ventricular Dilation on Flow A fascinating conundrum in echocardiography is the possibility of having very high velocities of mitral valve inﬂow, while the ﬂow propagation velocity (velocity of the blood column inside the left ventricle) may be several times slower. Baccani et al. created a simple CFD simulation of this problem in dilated cardiomyopathy.27 They showed that LV dilation slows down ﬂow propagation velocity. Furthermore, they have shown that this is associated with the initial vortex staying attached to the mitral valve (Fig. 5-11). Pressure Propagation Inside the Ventricle Flow and velocity propagation, though tightly linked, are separate phenomena. To analyze this relationship, we developed a two-dimensional axi-symmetric thick-walled FSI model. The ﬂuid domain was represented by 6321 triangular elements, while the solid domain was represented by 1206 bricklike quadrilateral elements. The time-varying pressure at the mitral valve opening was generated by the numerical simulations of the lumped parameter model. The ﬂuid domain was represented by incompressible Navier-Stokes equations. The LV wall was given time-varying stiﬀness properties, with strains calculated using a large strain deformation code. Finally, the decrease in stiﬀness of the wall during ventricular relaxation was modeled as an exponential decay from systolic stiﬀness to diastolic stiﬀness.28,29 The baseline ventricular ﬁlling pattern is illustrated in Figure 5-12, showing the E wave entering the cavity, with formation of

Figure 5-10 Computer modeling of vortices during left ventricular filling. During the rapid filling phase, initial inflow through the mitral valve forms a doughnut-shaped vortex downstream from the mitral orifice. This vortex ring then travels toward the middle of the expanding ventricle, while a weak vortex of brief duration is formed within the aortic outflow tract. After the initial vortex ring reaches the middle of the ventricle, its anterior part becomes stationary while the posterior part continues forward. During the atrial contraction, a new, weaker vortex ring that encompasses a part of the outflow tract is formed, while the posterior side of the initial vortex ring continues to move into the posterior apical region of the ventricle. In the end of the filling, the posterior part of the second vortex ring merges with the first, forming a large vortex in the posterior apex. (From Cheng Y et al: Fluid-structure coupled CFD simulation of the left ventricular flow during filling phase. Ann Biomed Eng 2005;33:567–576.)

a vortex oﬀ the tips of the mitral valve that propagates beside the E wave into the ventricle. The ventricle expands under the inﬂuence of decreased elasticity and increased strain due to LV ﬁlling. As the relaxation ﬁnishes after about 200 msec, the E wave loses strength, and velocity slowly decreases as the expansion of the ventricle ceases. After the E wave ends, atrial pressure increases and the A wave enters the ventricular cavity, forming another vortex oﬀ the mitral valve. As the A wave propagates toward the apex, this vortex is taken up by the ﬁrst vortex that is still present. By now, ventricular stresses have signiﬁcantly increased, raising LV pressure and slowing down ﬁlling. The ﬁlling behavior described here corresponds with clinically observed behavior. Using this ﬂuid-structure interaction model, we have investigated the inﬂuence of changes in relaxation (τ) and end diastolic stiﬀness. In Figure 5-12, color Doppler M-mode images are shown from four diﬀerent conditions: (A-B) baseline, (C-D) shorter τ, (E-F) longer τ, and (G-H) increased ventricular diastolic stiﬀness. At baseline, the E and A waves are roughly balanced (equal color-mapped peak velocities). Intraventricular pressure gradients (IVPGs) are slightly above normal due to the

Chapter 5 • Physical Determinants of Diastolic Flow 0

0.02

1

0.02

0.01

0.5

0.04

0

z

0 0.01

0.06

0.02

0.08

–0.5 0.08

0.06

0.04

0.02

0

0

0.2

0.4

0.6

0.8

1

–1

t

0 0.02 0.03 0

z

Figure 5-11 Impact of ventricular dilation on flow. Images represent a computer model of left ventricular flow in mid-diastole. In a normal ventricle (upper left panel), the proximal vortex becomes unattached and freely moves toward the apex, enabling prompt filling of the ventricle, as evidenced by high flow propagation velocity (upper right panel). In contrast, left ventricular dilation prohibits the movement of vortices toward the apex (lower left panel), and slows down flow propagation velocity (lower right panel). (From Baccani B et al: Fluid dynamics of the left ventricular filling in dilated cardiomyopathy. J Biomech 2002;35:665–671.)

0.06 0.02

mild mitral stenosis inherent in the model. With shorter τ, the E-wave velocity, Vp, and IVPG increase, while a longer τ produces the classic appearance of delayed relaxation (i.e., low E velocity, slow propagation, large A wave, and reduced IVPG).29–32 Because of the mild mitral stenosis, E-wave deceleration time is prolonged; for very large time constants, the E wave is no longer separated from the A wave.29 With a stiﬀer ventricle, velocities and IVPG are reduced, reﬂecting lower stroke volume, the expected behavior when atrial pressure is held at baseline so no pseudonormalization will occur. The A wave is particularly blunted, reﬂecting ineﬀective ﬁlling of the stiﬀ ventricle.31,33 As support for these ﬁndings, we have recently shown that in humans, IVPG in the elderly becomes blunted with worsened relaxation.9 In addition, elderly people with preserved ventricular compliance (i.e., a less stiﬀ ventricle), still had worsened IVPGs, reﬂecting the dependence of IVPGs on intact relaxation, without an impact of compliance.

Insights from Experimental Studies Currently, no model can predict the impact of structural changes of LV shape on ﬂow propagation within the LV. In that situation, we are left with some experimental studies. We will discuss brieﬂy some of them. Presence of Ischemia Acute ischemia delays apical ﬁlling34,35 and is associated with the loss of IVPGs.36,37 Beppu et al. described the altered apical blood ﬂow pattern in dogs with apical akinesis after coronary ligation.38 Ischemia decreases the maximal distance of mitral ﬂow into the ventricle during diastole, with blood ﬂow in the region of the infarction becoming either static or eddied.38,39

0.09 0

0.2

0.4

0.6

0.8

1

Distorted Left Ventricular Geometry In a recent sheep study, myocardial aneurysm was induced by the ligation of coronary arteries subtending the LV apex.40 Flow propagation velocity abruptly decreased when blood ﬂow column entered LV aneurysms and the point of this deceleration coincided with the edge of the aneurysm (Fig. 5-13). The infarct size correlated with the distance from the apex to the point of the deceleration of ﬂow propagation. However, no point of abrupt decrease was detected when myocardial infarct was induced by circumﬂex occlusion. Also, signiﬁcantly, the presence of breakpoint coincided with loss of the IVPG. In a clinical study that is congruent with these ﬁndings, we have shown that removal of the aneurysm by infarct exclusion surgery improves IVPGs.41 These data show that in order for ﬂow to enter the heart cavity, heart walls have to be compliant. Effect of Isovolumic Processes During the isovolumic period of LV relaxation, the left ventricle changes its shape in the absence of any change of volume. The most dramatic aspect of this is that the left ventricle untwists, a process that is linked to the elastic elements of the ventricle that induce early LV suction. Untwisting is a necessary successor to systolic torsion (twist). Systolic torsion and diastolic untwisting occur because myocardial ﬁbers form a leftward helix in the subepicardium.42 The contraction of these ﬁbers rotates the base and the apex of the left ventricle clockwise and counterclockwise, respectively. However, unlike systolic torsion that increases proportional to systolic volume change, untwisting is a phenomenon that peaks prior to the opening of the mitral valve.11,43 The reason this occurs is that systolic torsion builds potential energy within the elastic elements of the heart.44 With relaxation, energy is released, and elastic elements promptly restore the original, untwisted LV shape. It is no surprise that untwisting is inversely

55

Chapter 5 • Physical Determinants of Diastolic Flow A LV

2

VP

5

1

4

0.6

MV

0

LA

–1 0

0.1

0.2

0.3 0.4 Time (s)

0.5

0.6

0.7

1

0.2

0

1

4

3

0.8

2

0.6

1

0.4

1

0

0.2

0

0.3 0.4 Time (s)

0.5

0.6

0.7

Distance (cm)

4

0.2

0

4

3

0.8

2

0.6

1

0.4

1

0

0.2

0

0.5

0.6

0.7

Distance (cm)

1

0.3 0.4 Time (s)

0

4

3

0.8

2

0.6

1

0.4

1

0

0.2

0

0.5

0.6

0.7

0

Distance (cm)

1

0.3 0.4 Time (s)

6

2 0

0.1

0.2

0.3 0.4 Time (s)

0.5

0.6

0.7

–2 10

F

8 6

2 0

0.1

0.2

0.3 0.4 Time (s)

0.5

0.6

0.7

–2 10

H 8 6

3 4 2

–1 0

2 0

0.1

0.2

0.3 0.4 Time (s)

0.5

0.6

0.7

Relative pressure (mmHg)

4

Velocity (m/s)

5

0.2

8

–1 0

1.2

0.1

10

4

5

–1 0

–2

2

6

G

0.7

3

1.4

6

0.6

Relative pressure (mmHg)

4

Velocity (m/s)

5

0.2

0.5

D

–1 0

1.2

0.1

0.3 0.4 Time (s)

4

5

–1 0

0.2

2

6

E

0.1

3

1.4

6

0

Relative pressure (mmHg)

5 Velocity (m/s)

1.2

0.1

2

–1 0

5

–1 0

6 4

6

C

8

2

0.4

0

10

B

3

1.4

6

Distance (cm)

1.2

0.8

3

1

Distance (cm)

6

Velocity (m/s)

4

1.4

Relative pressure (mmHg)

E-wave

5 Distance (cm)

A-wave

Distance (cm)

6

Distance (cm)

56

–2

Figure 5-12 Modeling of fluid-structure interaction showing influence of changes in relaxation (τ) and end diastolic stiffness. Pseudo–M-mode images of time-velocity (left panels) and time-pressure data from four different conditions: A and B, baseline; C and D, shorter τ; E and F, longer τ; and G and H, increased ventricular diastolic stiffness. At baseline, the E and A waves are roughly balanced (equal color-mapped peak velocities). IVPGs are slightly above normal due to the mild mitral stenosis inherent in the model. With shorter τ, the E-wave velocity, Vp, and IVPG increase, while longer τ produces the classic appearance of delayed relaxation (low E velocity, slow propagation, large A-wave and reduced IVPG). Because of the mild mitral stenosis, E-wave deceleration time is prolonged and for very large time constants no longer fully separated from the A wave. With a stiffer ventricle, velocities and IVPG are reduced, reflecting lower stroke volume, the expected behavior when atrial pressure is held at baseline to prevent pseudonormalization. The A wave is particularly blunted, reflecting ineffective filling of the stiff ventricle.

Chapter 5 • Physical Determinants of Diastolic Flow

7 IVPG (mmHg)

: r2 = 0.99 5 3 1 –1 4 Normal

2

0

Apex-to-base distance (cm)

Apex (A) A-D (23 mm) IVPG (mmHg)

Abrupt decrease in propagation velocity (D)

related to τ, and its magnitude may be used as a surrogate measure of relaxation. Events during early diastole in a normal left ventricle can be summarized in the following way. Relaxation leads to prompt LV untwisting, the peak of which coincides with mitral valve opening; this is immediately followed by peak early mitral annulus velocity; ﬁnally, formation of the IVPG facilitates early LV ﬁlling. We have shown a strong correlation between untwisting and IVPG at rest and during exercise.11 Furthermore, we have shown that essentially the same slope of untwisting-IVPG relationship exists in patients with severe hypertrophic cardiomyopathy (Fig. 5-14). This indicates that untwisting and the IVPG are tightly coupled and that either untwisting is necessary to produce the IVPG or that some strong third factor binds them, expressed simultaneously by untwisting and by the IVPG. Thus, it seems that three major factors determine ﬂow propagation and IVPGs: chamber dilation, worsened relaxation, and loss of compliance.

: r2 = 0.97 : r2 = 0.67

4 3 2 1 0 –1 4

2

4

p < 0.00001 Normal exercise p < 0.00001

2 Normal rest

HCM exercise P = NS

HCM rest P = NS 0 0

FUTURE RESEARCH The number of ﬂow-based diastolic parameters that are proposed to be helpful in clinical practice is staggering. Still, more and more indices are proposed every year. This review of the physics behind diastolic ﬂows aims to elucidate common underlying processes that are manifested through various diastolic parameters. In this manner, we are trying to bring another “Rosetta stone” to the cardiology community.45 In the remainder of this book, many of these indices will be shown in application to various diseases of

0

LV aneurysm

Peak IVPG (mmHg)

Figure 5-13 Effect of apical aneurysm on intraventricular flow propagation. Flow propagation velocity decreases abruptly when blood enters the aneurysm. This sudden deceleration coincides with the loss of intraventricular pressure gradient. (From Asada-Kamiguchi J et al: Intraventricular pressure gradients in left ventricular aneurysms determined by color M-mode Doppler method: An animal study. J Am Soc Echocardiogr 2006;19:1112–1118.)

5

–5 Peak untwisting velocity (rad/s)

Figure 5-14 Relationship between left ventricular untwisting and intraventricular pressure gradients (IVPGs) at rest (open markers) and during exercise (closed markers). Normal subjects are marked by squares, while hypertrophic cardiomyopathy patients are marked by triangles. While the same slope of untwisting-IVPG relationship exists in normal hearts and in those with severe hypertrophic cardiomyopathy, hearts of patients with hypertrophic cardiomyopathy cannot generate the increase of untwisting during the exercise, leading to smaller IVPG increase. (From in Notomi Y et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533.)

57

58

Chapter 5 • Physical Determinants of Diastolic Flow diastolic function; it is hoped that by keeping these physical principles in mind, the reader will better be able to assess diastolic dysfunction clinically. Despite numerous published studies, our current understanding of physical properties is limited. One ﬁeld that is largely undeﬁned is the modeling of structural-ﬂuid relationships within the left ventricle, which is a structure so complex that to accurately calculate mechanical events during diastole, one needs several days even with the use of the most powerful supercomputers. Therefore, until computer processing power is increased by an order of magnitude, we will lack the ability to answer such seemingly simple questions as: Is torsion necessary to LV contraction? and What happens to end diastolic pressure if we eliminate an increase in the IVPG during diastole? To paraphrase Sir Isaac Newton, we are still like children playing on the seashore and diverting ourselves now and then, ﬁnding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lies all undiscovered before us.

ABBREVIATIONS A: atrial AR: atrial reversal CFD: computational ﬂuid dynamics D: diastolic E: early EDPVR: end diastolic pressure-volume relationships FSI: ﬂuid-structure interactions IVPG: intraventricular pressure gradient LA: left atrium LV: left ventricular MV: mitral valve P-V: pressure-volume PV: pulmonary vein(s) S: systolic Vp: ﬂow propagation velocity τ: time constant of isovolumic pressure decay (Tau) t: time REFERENCES 1. Glantz SA, Parmley WW: Factors which aﬀect the diastolic P-V curve. Circ Res 1978;42:171–180. 2. Nikolic S, Yellin EL, Tamura K, et al: Passive properties of canine left ventricle: Diastolic stiﬀness and restoring forces. Circ Res 1988;62: 1210–1222. 3. Thomas JD, Zhou J, Greenberg N, et al: Physical and physiological determinants of pulmonary venous ﬂow: Numerical analysis. Am J Physiol 1997;272:H2453–2465. 4. Ohno M, Cheng CP, Little WC: Mechanism of altered patterns of left ventricular ﬁlling during the development of congestive heart failure. Circulation 1994;89:2241–2250. 5. Matsubara H, Nakatani S, Nagata S, et al: Salutary eﬀect of disopyramide on left ventricular diastolic function in hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 1995;26:768–775. 6. Nikolic S, Yellin EL, Tamura K, et al: Eﬀect of early diastolic loading on myocardial relaxation in the intact canine left ventricle. Circ Res 1990;66: 1217–1226. 7. Senzaki H, Fetics B, Chen CH, Kass DA: Comparison of ventricular pressure relaxation assessments in human heart failure: Quantitative inﬂuence on load and drug sensitivity analysis. J Am Coll Cardiol 1999;34: 1529–1536. 8. Scalia GM, Greenberg NL, McCarthy PM, et al: Noninvasive assessment of the ventricular relaxation time constant (t) in humans by Doppler echocardiography. Circulation 1997;95:151–155.

9. Popovic ZB, Prasad A, Garcia MJ, et al: Relationship between diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and ﬁtness. Am J Physiol Heart Circ Physiol 2005. 10. Nikolic SD, Yellin EL, Dahm M, et al: Relationship between diastolic shape (eccentricity) and passive elastic properties in canine left ventricle. Am J Physiol 1990;259:H457–H463. 11. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533. 12. Thomas JD, Popovic ZB: Intraventricular pressure diﬀerences: A new window into cardiac function. Circulation 2005;112:1684–1686. 13. Thomas JD, Weyman AE: Echocardiographic Doppler evaluation of left ventricular diastolic function. Physics and physiology. Circulation 1991;84:977–990. 14. Courtois M, Kovacs SJ Jr, Ludbrook PA: Transmitral pressure-ﬂow velocity relation: Importance of regional pressure gradients in the left ventricle during diastole. Circulation 1988;78:661–671. 15. Thomas JD, Newell JB, Choong CY, Weyman AE: Physical and physiological determinants of transmitral velocity: Numerical analysis. Am J Physiol 1991;260:H1718–H1731. 16. Nakatani S, Firstenberg MS, Greenberg NL, et al: Mitral inertance in humans: Critical factor in Doppler estimation of transvalvular pressure gradients. Am J Physiol Heart Circ Physiol 2001;280:H1340–H1345. 17. Hay I, Rich J, Ferber P, et al: Role of impaired myocardial relaxation in the production of elevated left ventricular ﬁlling pressure. Am J Physiol Heart Circ Physiol 2005;288:H1203–H1208. 18. Firstenberg MS, Greenberg NL, Smedira NG, et al: Doppler echo evaluation of pulmonary venous–left atrial pressure gradients: Human and numerical model studies. Am J Physiol Heart Circ Physiol 2000;279: H594–H600. 19. Kamohara K, Fukamachi K, Ootaki Y, et al: Evaluation of a novel device for left atrial appendage exclusion: The second-generation atrial exclusion device. J Thorac Cardiovasc Surg 2006;132:340–346. 20. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular ﬁlling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 21. Firstenberg MS, Vandervoort PM, Greenberg NL, et al: Noninvasive estimation of transmitral pressure drop across the normal mitral valve in humans: Importance of convective and inertial forces during left ventricular ﬁlling. J Am Coll Cardiol 2000;36:1942–1949. 22. Kilner PJ, Yang GZ, Wilkes AJ, et al: Asymmetric redirection of ﬂow through the heart. Nature 2000;404:759–761. 23. Vierendeels JA, Dick E, Verdonck PR: Hydrodynamics of color M-mode Doppler ﬂow wave propagation velocity V(p): A computer study. J Am Soc Echocardiogr 2002;15:219–224. 24. Vierendeels JA, Riemslagh K, Dick E, Verdonck PR: Computer simulation of intraventricular ﬂow and pressure gradients during diastole. J Biomech Eng 2000;122:667–674. 25. Verdonck P, Vierendeels J, Riemslagh K, Dick E: Left-ventricular pressure gradients: A computer-model simulation. Med Biol Eng Comput 1999;37:511–516. 26. Cheng Y, Oertel H, Schenkel T: Fluid-structure coupled CFD simulation of the left ventricular ﬂow during ﬁlling phase. Ann Biomed Eng 2005;33:567–576. 27. Baccani B, Domenichini F, Pedrizzetti G, Tonti G: Fluid dynamics of the left ventricular ﬁlling in dilated cardiomyopathy. J Biomech 2002;35: 665–671. 28. Mirsky I: Assessment of diastolic function: Suggested methods and future considerations. Circulation 1984;69:836–841. 29. Thomas JD, Zhou J, Greenberg N, et al: Physical and physiological determinants of pulmonary venous ﬂow: Numerical analysis. Am J Physiol 1997;272:H2453–H2465. 30. Lemmon JD, Yoganathan AP: Computational modeling of left heart diastolic function: Examination of ventricular dysfunction. J Biomech Eng 2000;122:297–303. 31. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular ﬁlling ﬂow propagation by color M-mode Doppler echocardiography [see comments]. J Am Coll Cardiol 1996;27:365–371. 32. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler ﬂow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 2000;35: 201–208. 33. Appleton CP, Hatle LK, Popp RL: Relation of transmitral ﬂow velocity patterns to left ventricular diastolic function: New insights from a combined

Chapter 5 • Physical Determinants of Diastolic Flow

34. 35. 36. 37. 38.

39.

hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. Stugaard M, Smiseth OA, Risoe C, Ihlen H: Intraventricular early diastolic ﬁlling during acute myocardial ischemia. Circulation 1993;88:2705– 2713. Steine K: Mechanisms of retarded apical ﬁlling in acute ischemic left ventricular failure. Circulation 1999;99:2048–2054. Steine K, Stugaard M, Smiseth OA: Mechanisms of retarded apical ﬁlling in acute ischemic left ventricular failure. Circulation 1999;99:2048– 2054. Steine K, Flogstad T, Stugaard M, Smiseth OA: Early diastolic intraventricular ﬁlling pattern in acute myocardial infarction by color M-mode Doppler echocardiography. J Am Soc Echocardiogr 1998;11:119–125. Beppu S, Izumi S, Miyatake K, et al: Abnormal blood pathways in left ventricular cavity in acute myocardial infarction. Experimental observations with special reference to regional wall motion abnormality and hemostasis. Circulation 1988;78:157–164. Delemarre BJ, Visser CA, Bot H, Dunning AJ: Prediction of apical thrombus formation in acute myocardial infarction based on left ventricular spatial ﬂow pattern. J Am Coll Cardiol 1990;15:355–360.

40. Asada-Kamiguchi J, Jones M, Greenberg NL, et al: Intraventricular pressure gradients in left ventricular aneurysms determined by color M-mode Doppler method: An animal study. J Am Soc Echocardiogr 2006;19: 1112–1118. 41. Firstenberg MS, Smedira NG, Greenberg NL, et al: Relationship between early diastolic intraventricular pressure gradients, an index of elastic recoil, and improvements in systolic and diastolic function. Circulation 2001;104: I330–I335. 42. Ingels NB Jr, Hansen DE, Daughters GT 2nd, et al: Relation between longitudinal, circumferential, and oblique shortening and torsional deformation in the left ventricle of the transplanted human heart. Circ Res 1989;64: 915–927. 43. Gibbons Kroeker CA, Ter Keurs HE, Knudtson ML, et al: An optical device to measure the dynamics of apex rotation of the left ventricle. Am J Physiol 1993;265:H1444–H1449. 44. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 2000;87:235–240. 45. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 1997;30:8–18.

59

HIDEKATSU FUKUTA, MD, PhD WILLIAM C. LITTLE, MD

6

General Principles, Clinical Definition, and Epidemiology INTRODUCTION PATHOPHYSIOLOGY Systolic Performance Diastolic Performance Definition of Systolic and Diastolic Heart Failure Terminology CLINICAL APPLICATIONS Diagnosis of Diastolic Heart Failure Timing of Ejection Fraction Measurement

Is Measurement of Diastolic Function Necessary? Prognostic Utility of Doppler Echocardiography Practical Recommendations EPIDEMIOLOGY Epidemiology of Diastolic Dysfunction Epidemiology of Diastolic Heart Failure CONCLUSIONS AND FUTURE RESEARCH

INTRODUCTION Heart failure (HF) is deﬁned as the pathological state in which the heart is unable to pump blood at a rate required by the metabolizing tissues or can do so only with an elevated ﬁlling pressure. Inability of the heart to pump blood suﬃciently to meet the needs of the body’s tissues may be due to the inability of the left ventricle to ﬁll (diastolic performance) or eject blood (systolic performance) or both. Thus, consideration of the systolic and diastolic performance of the left ventricle provides a conceptual basis to classify and understand the pathophysiology of HF.

PATHOPHYSIOLOGY Systolic Performance Left ventricular (LV) systolic performance is the ability of the left ventricle to empty, which can be quantiﬁed as an emptying frac-

tion, or an ejection fraction (EF): a ratio of stroke volume-to-end diastolic volume. Thus, LV systolic dysfunction is deﬁned as a decreased EF. The EF can be obtained by determining the LV volume by use of two-dimensional echocardiography with or without contrast, radionuclide ventriculography, or magnetic resonance imaging. The EF has been used as an index of myocardial contractile performance. However, it is inﬂuenced not only by myocardial contractility but also by LV afterload.1 Furthermore, in the presence of a left-sided valvular regurgitation (mitral or aortic regurgitation) or a left-to-right shunt (ventricular septal defect or patent ductus arteriosus), the LV stroke volume may be high, while the forward stroke volume (stroke volume minus regurgitant volume or shunt volume) is lower. Thus, the eﬀective EF is deﬁned as the forward stroke volume divided by end diastolic volume.2 The eﬀective EF is a useful means to quantify systolic function, for two reasons: First, the eﬀective EF represents the functional emptying of the left ventricle that contributes to cardiac 63

Chapter 6 • General Principles, Clinical Definition, and Epidemiology output. Second, the eﬀective EF is relatively independent of LV end diastolic volume over the clinically relevant range. An operational deﬁnition of systolic dysfunction is an eﬀective EF of less than 0.50.2 When deﬁned in this manner, systolic dysfunction results from impaired myocardial function, increased LV afterload, structural abnormalities of the left ventricle, or a combination thereof.2

Diastolic Performance For the left ventricle to function eﬀectively as a pump, it must be able not only to eject but also to ﬁll, which is its diastolic function. Diastolic function conventionally has been assessed on the basis of the LV end diastolic pressure-volume (P-V) relation (see Chapter 7).3 A shift of the curve upward and to the left has been considered to be the hallmark of diastolic dysfunction (Fig. 6-1, curve A). In this situation, each LV end diastolic volume is associated with a high end diastolic pressure, and thus the left ventricle is less distensible. Decreased LV distensibility is caused by aging, systemic hypertension, and hypertrophic or restrictive cardiomyopathy.2 Diastolic function also has been assessed based on LV ﬁlling patterns by use of Doppler echocardiography.4,5 In the absence of mitral stenosis, three patterns of LV ﬁlling indicate progressive impairment of diastolic function: (1) reduced early diastolic ﬁlling with a compensatory increase in importance of atrial ﬁlling (impaired relaxation); (2) most ﬁlling early in diastole but with rapid deceleration of mitral ﬂow (pseudonormalization); and (3) almost all ﬁlling of the left ventricle occurring very early in diastole in association with very rapid deceleration of mitral ﬂow (restrictive ﬁlling) (Fig. 6-2).6 These Doppler LV ﬁlling patterns, however, are inﬂuenced not only by LV diastolic properties but also by left atrial (LA) pressure. In contrast, tissue Doppler measurement of mitral annular velocity and color M-mode measurement of the velocity of propagation of mitral inﬂow to the apex appear to be less load sensitive. The peak early diastolic mitral annular velocity (EM) provides a relatively load insensitive measure of LV relaxation.7 EM is decreased with increasing severity of diastolic dysfunction.8,9 The color M-mode imaging performed from the apex provides a temporal and spatial map of the velocities of blood ﬂow in early diastole along the long axis of the left ventricle. The velocity of

LV end diastolic pressure

64

A Normal

B

ΔP ΔV

LV end diastolic volume Figure 6-1 A shift of the curve to A indicates that a higher left ventricular (LV) pressure will be required to distend the LV to a similar volume, indicating that the ventricle is less distensible. The slope of the LV end diastolic pressure-volume relation indicates the passive chamber stiffness. Since the relation is exponential in shape, the slope (ΔP/ΔV) increases as the end diastolic pressure increases. (Data from Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890.)

propagation of mitral inﬂow to the apex (VP) is reduced in conditions with impaired LV relaxation.9 A pseudonormalized LV ﬁlling pattern can be distinguished from a normal ﬁlling pattern by demonstrating reduced EM and VP. Furthermore, since early diastolic mitral inﬂow velocity (E) becomes higher and relaxation-related parameters (EM and Vp) remain reduced as ﬁlling pressure increases, the E/EM and E/VP can estimate LV ﬁlling pressure with a reasonable accuracy over a wide range of an EF.10–12 Last, color M-mode imaging provides a noninvasive measurement of the diastolic intraventricular pressure gradient between the apex and the base during early diastole.13 Finally, analysis of pulmonary venous ﬂow patterns provides useful information on LV compliance and LA pressure.14 With increase in LV end diastolic pressure, the reversal velocity of pulmonary venous atrial ﬂow increases, and duration increases longer than that of mitral late diastolic velocity. With decrease in LV compliance and increase in mean LA pressure, the systolic component of pulmonary venous ﬂow decreases and the diastolic component of pulmonary venous ﬂow increases. Table 6-1 and Figure 6-2 show stages of diastolic dysfunction incorporatingpulmonary venous ﬂow, tissue Doppler, and color M-mode indices.9

Definition of Systolic and Diastolic Heart Failure When the HF is associated with a reduced EF, the pathological state may be called systolic HF. In contrast, when the HF is associated with diastolic dysfunction in the absence of a reduced EF, the pathological state may be called diastolic HF. It is important to recognize that the HF, whether it results from systolic or diastolic dysfunction, is a clinical syndrome and that both systolic HF and diastolic HF are heterogeneous disorders. Patients with systolic HF have abnormalities of diastolic function,2,3 and those with diastolic HF may have abnormalities of systolic contractile function that are not detected by measurement of an EF.15

Terminology Diastolic Dysfunction and Diastolic Heart Failure The term diastolic dysfunction is used to describe abnormal mechanical (diastolic) properties of the ventricle and includes decreased LV distensibility, delayed relaxation, and abnormal ﬁlling, regardless of whether the EF is normal or reduced and whether the patient is symptomatic or asymptomatic. In contrast, the term diastolic HF is used to describe patients with the symptoms and signs of HF and a normal EF and diastolic dysfunction.

Diastolic Heart Failure and Heart Failure with Normal Ejection Fraction There are many clinical conditions that cause HF with a normal EF. These include diastolic dysfunction, valvular diseases, pericardial diseases, and intracardiac mass; among them, diastolic dysfunction is the most common cause of HF with a normal EF. Diastolic HF is associated with LV diastolic abnormalities. It is important to recognize that although patients with diastolic HF have diastolic dysfunction, frequently they also have systolic contractile abnormalities (despite the normal EF). In addition, comorbidities such as hypertension, anemia, and renal dysfunction are commonly seen in patients with diastolic HF and may contribute to the development of HF.

Chapter 6 • General Principles, Clinical Definition, and Epidemiology Normal

Impaired relaxation

E

E

Pseudonormal

Restrictive E

E Mitral inflow velocity

A

A

A A

D S

S

D

D

D

Figure 6-2 Transmitral inflow velocity, pulmonary vein flow velocity, mitral annular velocity, and color M-mode imaging in stages of diastolic dysfunction. E, early diastolic mitral inflow velocity; A, late diastolic mitral inflow velocity; S, systolic pulmonary vein velocity; D, diastolic pulmonary vein velocity; SM, systolic mitral annular velocity; EM, early diastolic mitral annular velocity; AM, late diastolic mitral annular velocity; and Vp, velocity of propagation of mitral inflow to the apex. (Data from Fukuta H, Little WC: Diastolic versus systolic heart failure. In Smiseth OA, Tendera M (eds): Diastolic Heart Failure. London, Springer, 2007.)

S

S

Pulmonary vein velocity SM

SM

SM

SM

Mitral annular velocity EM EM Color M-mode imaging

AM

AM

EM

AM

EM

AM

VP

TABLE 6-1 STAGES OF DIASTOLIC DYSFUNCTION PARAMETER

NORMAL (YOUNG)

NORMAL (ADULT)

DELAYED RELAXATION

PSEUDONORMAL FILLING RESTRICTIVE FILLING

E/A DT (msec) IVRT (msec) S/D AR (cm/sec) Vp (cm/sec) Em (cm/sec)

>1 <220 <100 <1 <35 >55 >10

>1 <220 <100 ≥1 <35 >45 >8

<1 >220 >100 ≥1 <35 <45 <8

1–2 150–200 60–100 <1 ≥35 <45 <8

>2 <150 <60 <1 ≥25* <45 <8

*Unless atrial mechanical failure is present. AR, pulmonary venous peak atrial contraction reversed velocity; DT, early left ventricular filling deceleration time; E/A, early-to-atrial left ventricular filling ratio; Em, peak early diastolic myocardial velocity; IVRT, isovolumic relaxation time; S/D, systolic-to-diastolic pulmonary venous flow ratio; Vp, color M-mode flow propagation velocity. From Garcia MJ et al: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.

Comparison of Pathophysiology in Systolic and Diastolic Heart Failure Table 6-2 shows the comparison of LV structural and functional characteristics in systolic and diastolic HF (see Chapter 2). Systolic HF and diastolic HF have several similarities in LV structural and functional characteristics, including increased LV mass and increased LV end diastolic pressure. The most signiﬁcant diﬀerence between the two forms of HF is in LV geometry and LV function: Systolic HF is characterized by LV dilatation, eccentric LV hypertrophy, and abnormal systolic and diastolic function, whereas diastolic HF is characterized by concentric LV hypertrophy, a normal EF, and abnormal diastolic function. Thus, the pathophysiology of systolic HF is dependent predominantly on progressive LV dilatation and abnormal systolic function. On the

other hand, the pathophysiology of diastolic HF is dependent predominantly on concentric LV hypertrophy and abnormal diastolic function.

CLINICAL APPLICATIONS Diagnosis of Diastolic Heart Failure A distinction between systolic and diastolic HF is important because these two forms have diﬀerent pathophysiologies and thus might potentially require diﬀerent therapeutic approaches.5 Nevertheless, clinical symptoms and signs are similar in systolic and diastolic HF (Table 6-3).16,17 This may be because systolic HF is often accompanied by diastolic dysfunction, by which

65

66

Chapter 6 • General Principles, Clinical Definition, and Epidemiology TABLE 6-2

TABLE 6-3

COMPARISON OF LEFT VENTRICULAR (LV) STRUCTURAL AND FUNCTIONAL FEATURES BETWEEN SYSTOLIC AND DIASTOLIC HEART FAILURE (HF)

RPREVALENCE OF SPECIFIC SYMPTOMS AND SIGNS IN SYSTOLIC AND DIASTOLIC HEART FAILURE (HF)

CHARACTERISTICS Remodeling LV end diastolic volume LV end systolic volume LV mass Relative wall thickness Cardiomyocyte Extra cellular matrix collagen Diastolic properties LV end diastolic pressure Relaxation time constant Filling rate Chamber stiffness Myocardial stiffness Systolic properties Performance Stroke volume Stroke work Function Ejection fraction Ejection rate PRSW Contractility Positive dp/dt Ees FS vs. stress Preload reserve Ea Arterial-ventricular coupling (Ea/Ees)

SYSTOLIC HF

DIASTOLIC HF

↑ ↑ ↑ eccentric ↓ ↑ length ↓

N N ↑ concentric ↑ ↑ diameter ↑

↑↑ ↑ ↓ N–↓ N–↑

↑↑ ↑↑ ↓↓ ↑ ↑

↓ ↓

N–↓ N

↓ ↓ ↓

N N N

↓ ↓ ↓ Exhausted ↓ ↓

N N–↑ N Limited ↑ N

Ea, effective arterial elastance; EEs, end systolic elastance; FS, fractional shortening; PRSW, preload-recruitable stroke work. Data from Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Definitions and terminology. Prog Cardiovasc Dis 2005;47:307–313.

symptoms and signs related to pulmonary congestion are commonly observed.2 Thus, clinical history and physical examination do not provide useful information in discriminating between systolic and diastolic HF. Several criteria have been proposed for the diagnosis of diastolic HF.18,19 In summary, for the diagnosis of diastolic HF to be made, the following evidence is required: ❒ ❒ ❒

clinical evidence of HF, normal systolic function (LV EF >0.50), and objective evidence of impaired LV relaxation or LV passive stiﬀness.

If strictly applied, the deﬁnition of diastolic HF would include patients with acute mitral or aortic regurgitation, mechanical causes of diastolic dysfunction (mitral stenosis or constrictive pericarditis), right-sided HF, intracardiac mass, or congenital heart diseases; these conditions could be avoided by additional echocardiographic screening.5

Timing of Ejection Fraction Measurement Vasan and Levy criteria require a normal EF within 72 hours of an episode of pulmonary congestion to make a deﬁnite diagnosis of diastolic HF.19 It is possible, however, that the acute pulmonary

Symptoms Dyspnea on exertion Paroxysmal nocturnal dyspnea Orthopnea Physical examination Jugular venous distension Rales Displaced apical impulse S3 S4 Hepatomegaly Edema Chest radiograph Cardiomegaly Pulmonary venous hypertension

SYSTOLIC HF (%)

DIASTOLIC HF (%)

96 50 73

85 55 60

46 70 60 65 66 16 40

35 72 50 45 45 15 30

96 80

90 75

From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure. Part I: Diagnosis, prognosis, and measurement of diastolic function. Circulation 2002;105:1387–1393.

congestion may be due to transient systolic dysfunction or acute mitral regurgitation produced by hypertension and/or myocardial ischemia that had resolved by the time the LV EF was measured. To address this issue, Gandhi et al. used Doppler echocardiography to evaluate LV EF, regional wall motion, and mitral regurgitation in 38 patients both during an acute episode of hypertensive pulmonary edema and 24 to 72 hours later, after treatment and resolution of the hypertension and pulmonary congestion.20 They found that LV EF and regional wall motion were similar, both during the acute episode of hypertensive pulmonary edema and after resolution of the congestion and control of blood pressure (Fig. 6-3).21 No patient had severe mitral regurgitation during the acute episode. They also found that 50% of the patients had an EF equal to or greater than 0.50 during their presentation with acute pulmonary edema and that 88% of the patients with an EF equal to or greater than 0.50 after treatment had an EF equal to or greater than 0.50 during the acute episode, and all of these patients had an EF of at least 0.43. Thus, they concluded that the EF obtained 1–3 days after the acute presentation of patients with hypertensive pulmonary edema accurately identiﬁed patients with a preserved EF during acute presentation. This study suggests that measuring the EF within 72 hours of an acute episode of pulmonary congestion is suﬃcient to meet the diagnostic criteria proposed by Vasan and Levy. However, measurements of diastolic ﬁlling could have changed within the 72-hour period.

Is Measurement of Diastolic Function Necessary? Recognizing the diﬃculties inherent in the clinical assessment of LV diastolic performance, Zile et al. tested the hypothesis that measurements of LV relaxation and passive stiﬀness were not necessary to make the diagnosis of diastolic HF.22 They studied 47 patients with a history of HF, a normal LV EF (>0.50), and at least mild LV hypertrophy (LV mass ≥125 g/m2) or concentric LV remodeling (LV chamber dimension <55 mm combined with LV wall thickness ≥11 mm and relative wall thickness ≥0.45).

Chapter 6 • General Principles, Clinical Definition, and Epidemiology LV EJECTION FRACTION SYSTOLIC BLOOD PRESSURE 0.9 260 0.8 240 0.7

220

0.6

mmHg

200

198 0.5

180

0.50

0.50

0.4

160 140

138

0.3 0.2

120 100

0.1 During acute pulmonary oedema

After treatment

During acute pulmonary oedema

After treatment

Figure 6-3 The systolic arterial pressure of patients at presentation with hypertensive acute pulmonary edema and after treatment 24–72 hours later. Despite the substantial difference in blood pressure, the left ventricular (LV) ejection fraction was similar on admission with acute pulmonary edema and after treatment. (From Little WC: Hypertensive pulmonary oedema is due to diastolic dysfunction. Eur Heart J 2001; 22:1961–1964.)

DIASTOLIC FUNCTION 1.0

Normal

EF = 0.4–0.5

Grade 1

Fraction alive

Fraction alive

1.0

EJECTION FRACTION

0.9 Grade 2 0.8

0.9 EF >0.5

0.8

EF <0.4

Grade 3 p = 0.19

p = 0.0077

0.7 0

250

500

750

1000

0.7 1250

Time (days)

0

250

500

750

1000

1250

Time (days)

Figure 6-4 Kaplan-Meier survival curves for 104 heart failure (HF) patients with an ejection fraction (EF) less than 0.50 and 102 HF patients with an EF equal to or greater than 0.50. Progressively more severe diastolic dysfunction is strongly associated with decreased survival. The EF does not significantly affect survival. For stages of diastolic dysfunction, see Table 6-1 and Figure 6-2. (Data from Brucks S et al: Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005;95:603–606.)

The authors then assessed LV diastolic function during cardiac catheterization and found that all the patients had evidence of abnormalities of LV relaxation and passive stiﬀness.22,23 Thus, they concluded that objective evidence of abnormalities of LV relaxation or distensibility during cardiac catheterization was unnecessary to make the diagnosis of diastolic HF if there was evidence of LV hypertrophy or concentric remodeling.

Prognostic Utility of Doppler Echocardiography Noninvasive assessment of diastolic dysfunction using Doppler echocardiography provides useful information on the severity of HF and prognosis.15,24–27 Speciﬁcally, Brucks et al. examined the association of systolic and diastolic function with severity of HF assessed by plasma B-type natriuretic peptide levels and prognosis in 104 HF patients with an EF less than 0.50 and in 102 HF patients with an EF equal to or greater than 0.50.15 They found that an increasing grade of diastolic dysfunction but not a reduced EF was associated with increased plasma B-type natriuretic

peptide levels. They also found that greater diastolic dysfunction but not a reduced EF was associated with worse 2-year survival (Fig. 6-4). When analysis was limited to HF patients with an EF less than 0.50, both reduced EF and the greater diastolic dysfunction were associated with worse survival. Rihal et al. examined the association of systolic and diastolic function with HF symptoms and 3-year survival in 102 patients with dilated cardiomyopathy and an EF of 0.23 ± 0.08.25 They found that markers of diastolic dysfunction, including short deceleration time and increased peak early diastolic LV inﬂow velocity, were more strongly associated with symptoms than was reduced EF. They also found that the short (<130 msec) deceleration time had incremental prognostic value to the reduced (<0.25) EF. Similarly, Wang et al. showed that the reduced (<3 cm/sec) EM was a powerful predictor for 4-year mortality and provided incremental prognostic value to other clinical risk factors and Doppler echocardiographic variables in 182 HF patients with an EF less than 0.50.26 Recently, Troughton et al. showed in the ADEPT study that the newer diastolic indices of E/EM and E/VP

67

Chapter 6 • General Principles, Clinical Definition, and Epidemiology provide independent prediction of clinical outcomes in systolic HF (EF <35%) that are equal or additive to conventional markers including, EF and E deceleration time.28 These observations suggest that diastolic dysfunction is associated with the severity of HF and prognosis independent of the EF. Thus, although measurement of diastolic function may not be necessary for the diagnosis of diastolic HF, its measurement with Doppler echocardiography is critical for risk stratiﬁcation in all HF patients.

Practical Recommendations If patients have clinical evidence of HF, the EF should be measured within 72 hours of an acute episode of pulmonary congestion. If the EF is less than or equal to 0.50, the diagnosis of systolic HF can be made. If the EF is greater than 0.50 and there is evidence of LV hypertrophy or concentric remodeling, the diagnosis of diastolic HF can be suggested. In the absence of LV hypertrophy or concentric remodeling, the diagnosis of diastolic HF may be supported by the presence of left atrial enlargement.29 When the diagnosis of diastolic HF needs conﬁrmation, Doppler echocardiography or cardiac catheterization provides a deﬁnitive diagnosis. Furthermore, assessment of diastolic function using Doppler echocardiography, particularly with tissue Doppler imaging, provides useful information on the severity of HF and prognosis regardless of the EF. Thus, it is important to evaluate both systolic and diastolic functions not only for making a deﬁnitive diagnosis of diastolic HF but also for identifying high-risk patients.

[SD] age, 51 [14] years) in Augsburg, Germany.31 The prevalence of diastolic abnormalities in the setting of a preserved EF (≥0.45), as deﬁned by the European Study Group on Diastolic Heart Failure (i.e., normal isovolumic relaxation time, 92–105 msec; normal ratio of early-to-late LV ﬁlling [E/A ratio], 1:0.5, depending on age), was 11.1%. The prevalence of diastolic dysfunction, deﬁned as diastolic abnormalities with LA enlargement or treatment with diuretics, was 3.1%. Of the subjects with diastolic abnormalities, only 2.3% had an EF less than 0.45. Independent predictors for diastolic abnormalities or diastolic dysfunction included hypertension, LV hypertrophy, myocardial infarction, obesity (body mass index ≥27.3), diabetes, ratio of fat mass-tofat-free mass greater than 0.70, and male gender. Smoking and low-density-lipoprotein cholesterol levels were not predictors for diastolic abnormalities or dysfunction. Importantly, in the absence of these risk factors, diastolic abnormalities and diastolic dysfunction were rare even in the subjects older than 50 years of age (4.6% and 1.2%, respectively). The prevalence of diastolic abnormalities is lower in the study by Fischer et al.31 than in the study by Redﬁeld et al.30 This may be due to the diﬀerence in age between cohorts studied and the diagnostic criteria for diastolic dysfunction using Doppler echocardiography. These observations suggest that diastolic dysfunction is more common than systolic dysfunction in community-dwelling patients and that risk factors for diastolic dysfunction are similar to those for systolic dysfunction. Thus, treatment of these risk factors may reduce the prevalence of both diastolic and systolic dysfunction, thereby reducing the incidence of overt HF.

Prognosis of Diastolic Dysfunction EPIDEMIOLOGY For assessment of the prevalence and prognosis of diseases, large unselected subjects should be evaluated at a given time and followed prospectively. Thus, in this section, we review populationbased cohort studies reporting the frequency of diastolic dysfunction and/or HF with normal EF in the community.

Epidemiology of Diastolic Dysfunction

Three studies have shown that diastolic dysfunction is associated with increased morbidity and mortality in the community. In the Cardiovascular Health Study,32 standard Doppler echocardiographic variables, including the Doppler E/A ratio, were measured in 2671 participants who were free of coronary artery disease, chronic HF, or atrial ﬁbrillation. Both high (>1.5) and low (<0.7) E/A ratios were predictive of the incidence of HF during a mean follow-up of 5.2 years (Fig. 6-5). After adjustment for covariates including age, blood pressure, stress-corrected LV systolic function, and LV mass, the predictive value of both high

Prevalence of Diastolic Dysfunction Two studies have shown that diastolic dysfunction assessed by Doppler echocardiography is more common than systolic dysfunction in the community. Speciﬁcally, Redﬁeld et al. investigated the prevalence of diastolic dysfunction assessed by comprehensive tissue Doppler imaging in 2042 randomly sampled subjects aged 45 years and older (mean [SD] age, 63 [11] years) in Olmsted County, Minnesota.30 Overall, 28% had diastolic dysfunction (20.8%, mild; 6.6%, moderate; 0.7%, severe), whereas 6% had an EF less than or equal to 0.50 and 2% had an EF less than or equal to 0.40. An EF of 0.50 or less was present in 1.4% of participants with normal, 10.5% with mild, 19.5% with moderate, and 61.5% with severe diastolic dysfunction. The prevalence of diastolic dysfunction increased with age. Diastolic dysfunction was equally common in men and women and more common in participants with hypertension, diabetes, coronary artery disease, and obesity. Similarly, Fischer et al. investigated the prevalence of diastolic dysfunction assessed by standard Doppler echocardiography in 1274 randomly sampled subjects aged 25 years or older (mean

16 14 % with incident CHF

68

12 10 8 6 4 2 0 < 0.7

0.7–1.5

> 1.5

Doppler E/A ratio Figure 6-5 Unadjusted incident congestive heart failure (CHF) rates by Doppler E/A ratio. Incident CHF is higher at the extreme values of this ratio. (From Aurigemma GP et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Study. J Am Coll Cardiol 2001;37:1042–1048.)

Chapter 6 • General Principles, Clinical Definition, and Epidemiology and low E/A ratios remained signiﬁcant (adjusted hazard ratios [HRs] [95% CI] of high and low E/A ratios, 3.50 [1.80–6.80] and 1.88 [1.33–2.68], respectively). Similarly, in the Strong Heart Study,33 the prognostic value of high and low E/A ratios was investigated in 3008 American Indian participants. Both high (>1.5) and low (<0.6) E/A ratios were predictive of all-cause and cardiac mortality during a mean follow-up of 3 years (Fig. 6-6). After adjustment for age, sex, body mass index, systolic blood pressure, cholesterol level, hypertension, diabetes, coronary artery disease, smoking, LV hypertrophy, and low (<0.40) EF, high E/A ratio was an independent predictor for all-cause and cardiac mortality (adjusted HRs [95% CI] for all-cause and cardiac death, 1.73 [0.99–3.03] and 2.8 [1.19– 6.75], respectively). However, low E/A ratio was not an independent predictor for either all-cause or cardiac mortality (adjusted HRs [95% CI] for all-cause and cardiac death, 1.2 [0.8–1.6] and 1.2 [0.7–2.1], respectively). Finally, in the study by Redﬁeld et al.,30 the prognostic value of diastolic dysfunction assessed by comprehensive tissue Doppler imaging was investigated. Both mild and moderate or severe diastolic dysfunctions were predictive of all-cause death during a median of 3.5 person-years of follow-up (Fig. 6-7). After adjustment for age, sex, and EF, both mild and moderate or 25 20 15 10 5 0 All-cause death

Cardiac death

Figure 6-6 Incidence of all-cause and cardiac death among participants with E/A less than 0.6 (blue bars), 0.6 to 1.5 (purple bars), and greater than 1.5 (green bars). (From Bella JN et al: Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: The Strong Heart Study. Circulation 2002;105:1928–1933.)

69

severe diastolic dysfunction were independent predictors for death (adjusted HRs [95% CI] of mild and moderate or severe diastolic dysfunction, 8.31 [3.00–23.1] and 10.2 [3.28–31.0], respectively). These observations suggest that diastolic dysfunction, particularly of moderate or severe degree, is a powerful predictor for increased morbidity and mortality in the community. Regression of LV hypertrophy by antihypertensive agents has been shown to improve LV diastolic ﬁlling.34 The impact of these interventions on clinical outcomes requires further studies.

Epidemiology of Diastolic Heart Failure Reported frequency of diastolic HF in overt HF and that of diastolic HF in the community vary widely.35 This may be due to the diﬀerence in diagnostic criteria for diastolic HF between studies. Thus, in this section, we review community-based cohort studies that used the Framingham criteria for a diagnosis of HF and 0.50 for separating a normal EF from a reduced EF.

Prevalence of Diastolic Heart Failure Four studies have shown that nearly half of patients with HF have a normal EF. Speciﬁcally, Senni et al.36 evaluated all patients receiving ﬁrst diagnosis of HF in Olmsted County, Minnesota, in 1991 (n = 216), of whom 137 had an assessment of EF within 3 weeks before or after the diagnosis of HF. In these patients, 59 (43%) had a normal EF (≥0.50) and 78 (57%) had a reduced EF (<0.50). Compared with HF patients with a reduced EF, those with a normal EF were older and more likely to be female and less likely to have had prior myocardial infarction and left bundle branch block. Similarly, Vasan et al.37 evaluated the echocardiograms of 73 Framingham Heart Study subjects with HF. They found that 37 (51%) had a normal EF (≥0.50) and 36 (49%) had a reduced EF (<0.50). Compared with HF patients with a reduced EF, those with a normal EF were more likely to be female and less likely to have had prior myocardial infarction. These studies, however, did not enumerate the base population. Thus, the prevalence of diastolic HF in the community cannot be estimated from these studies. Two other studies have reported both the frequency of a normal EF in overt HF and the prevalence of HF with a normal EF in

25

Diastolic function Moderate or severe dysfunction Mild dysfunction Normal

Mortality (%)

20 15

Log rank p <.001

10 5

Figure 6-7 Kaplan-Meier survival curves for participants with normal diastolic function versus subjects with mild or moderate or severe diastolic dysfunction. Progressively more severe diastolic dysfunction is strongly associated with decreased survival. For stages of diastolic dysfunction, see Table 6-1 and Figure 6-2. (Data from Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202.)

0 0

1

2

3

4

5

885 246 94

404 122 39

38 8 5

Year No. at risk Normal Mild Moderate or severe

1277 371 131

1277 366 129

1275 361 126

Chapter 6 • General Principles, Clinical Definition, and Epidemiology the community. In the study by Redﬁeld et al.,30 the prevalence of HF was 2.2%. They also found that among the HF patients, 44% had an EF greater than 0.50 and 56% had an EF equal to or less than 0.50. Similarly, Cortina et al. assessed the prevalence of HF in 391 randomly selected subjects aged 40 years or older (mean [SD] age, 60 [13] years) in Asturias, northern Spain.38 They found that the prevalence of HF was 5% and that among the HF patients, 59% had an EF greater than or equal to 0.50 and 41% had an EF less than 0.50. These studies, however, have the limitation that the EF was not determined at the onset of HF. Taken together, these observations suggest that the prevalence of diastolic HF is similar to that of systolic HF and that the prevalence of diastolic HF in adult and elderly populations may be 1%–3%. These studies also suggest that patients with diastolic HF are older and more likely to be female than those with systolic HF.

Prognosis of Diastolic Heart Failure Two studies have shown that both patients with a normal EF and those with a reduced EF have poor prognosis. Speciﬁcally, in the study by Senni et al.,36 the prognosis of patients with a new diagnosis of HF was worse than age- and gender-matched controls. Survival of HF patients was 86 ± 2% at 3 months, 76 ± 3% at 1 year, and 35 ± 3% at 5 years. There was no signiﬁcant diﬀerence in unadjusted survival between HF patients with an EF greater than or equal to 0.50 and those with an EF less than 0.50 (Fig. 6-8). After adjustment for age, sex, functional class, and coronary artery disease, survival did not signiﬁcantly diﬀer between the two groups (adjusted HR of normal EF vs. reduced EF, 0.8, p = 0.37). In the study by Vasan et al.,37 during a median follow-up of 6.2 years, HF patients with a reduced EF (<0.50) had signiﬁcantly higher annual mortality than age- and gender-matched cases (18.9% vs. 4.1%; adjusted HR [95% CI], 4.31 [1.98–9.36]). Similarly, HF patients with a normal EF (≥0.50) had signiﬁcantly higher annual mortality than age- and gender-matched cases (8.7% vs. 3.0%; adjusted HR [95% CI], 4.06 [1.61–10.3]).

1.0 0.8 Survival

70

0.6 0.4 Expected EF < 50% EF ≥ 50%

0.2

p = 0.279

0.0 0

1

2

3

4

6

5

Years EF < 50% EF ≥ 50%

78 59

58 44

51 35

44 32

36 29

16 15

Figure 6-8 Survival of heart failure patients with an ejection fraction (EF) of equal to or greater than 50% and less than 50%. (Data from Senni M et al: Congestive heart failure in the community: A study of all incident cases in Olmsted County, Minnesota in 1991. Circulation 1998;98:2282–2289.)

Importantly, survival (adjusted for age, sex, and other covariates, including diabetes, smoking, and blood pressure) did not signiﬁcantly diﬀer between HF patients with a normal EF and those with a reduced EF (adjusted HR [95% CI] of normal EF vs. reduced EF, 0.65 [0.31–1.35], p = 0.25). These observations suggest that both patients with diastolic HF and those with systolic HF have poor prognosis and that the mortality diﬀerence between the two groups may be minimal.

CONCLUSIONS AND FUTURE RESEARCH Diastolic function can noninvasively be assessed by Doppler echocardiography. Diastolic dysfunction assessed by Doppler echocardiography is more common than systolic dysfunction in the community and is associated with increased morbidity and mortality. Risk factors for diastolic dysfunction are similar to those for systolic dysfunction and include hypertension, LV hypertrophy, myocardial infarction, diabetes, and obesity. Thus, treating these risk factors may reduce the prevalence of both systolic and diastolic dysfunction and may ultimately reduce the incidence of overt HF. A diagnosis of diastolic HF can be made by clinical evidence of HF in the setting of a normal EF, and objective evidence of diastolic dysfunction and abnormal biomarkers can help conﬁrm the diagnosis (Fig. 6-9). However, assessment of diastolic function using Doppler echocardiography provides useful information on the severity of HF and prognosis regardless of the EF. Thus, it is important to evaluate both systolic and diastolic function not only for making a deﬁnite diagnosis of diastolic HF but also for identifying high-risk patients. Diastolic HF and systolic HF are similarly prevalent in the community, and both patients with diastolic HF and those with systolic HF have a poor prognosis.39,40 Patients with diastolic HF are older and more likely to be female than those with systolic HF. Thus, given the aging population, the public health burden of diastolic HF is substantial. Nevertheless at the present time, there is no known therapy for the improvement of survival in diastolic HF, thus emphasizing the urgent need for the establishment of optimal treatment for this condition. Although evidence has accumulated for the contribution of diastolic abnormalities to diastolic HF, the pathophysiology of diastolic HF remains to be fully understood. 1. What causes the transition of asymptomatic diastolic dysfunction to overt diastolic HF? 2. Does mild contractile dysfunction, which is not detected by measurement of an EF, contribute to diastolic HF? 3. Do systemic factors including neurohumoral activation and renal dysfunction contribute to diastolic HF? 4. What are the common causes of death in patients with diastolic HF? 5. Despite the similarities in the clinical manifestations of HF, why are the dramatic diﬀerences in the type of LV remodeling seen in diastolic HF and systolic HF? A better understanding of the pathophysiology of diastolic HF will provide a rationale for the development of the plausible therapeutic strategies for the disorder.

Chapter 6 • General Principles, Clinical Definition, and Epidemiology HOW TO DIAGNOSE HFNEF Symptoms or signs of heart failure

Normal or mildly reduced left ventricular systolic function LVEF >50% and LVEDVI <97 ml/m2

Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness Figure 6-9 Diagnostic flow chart showing how to diagnose heart failure with normal ejection fraction (HFNEF) in a patient suspeted of HFNEF, diastolic heart failure. LVEDVI, left ventricular enddiastolic volume index; mPCW, mean pulmonary capillary wedge pressure; LVEDP, left ventricular end-diastolic pressure; τ, time constant of left ventricular relaxation; b, time constant of left ventricular chamber stiffness; TD, tissue Doppler; E, early mitral valve flow velocity; E′, early TD lengthening velocity; NTproBNP, N-terminal-pro brain natriuretic peptide; BNP, brain natriuretic peptide; E/A, ratio of early (E) to late (A) mitral valve flow velocity; DT, deceleration time; LVMI, left ventricular mass index; LAVI, left atrial volume index; Ard, duration of reverse pulmonary vein atrial systole flow; Ad, duration of mitral valve atrial wave flow. (From Paulus WJ, Tschope C, Sanderson JE, et al: How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28(21):2686.)

Invasive Hemodynamic measurements mPCW >12 mmHg or LVEDP >16 mmHg or τ >48 msec or b >0.27

REFERENCES 1. Kass DA, Maughan WL: From “Emax” to pressure-volume relations: A broader view. Circulation 1988;77:1203–1212. 2. Little WC, Applegate RJ: Congestive heart failure: Systolic and diastolic function. J Cardiothor Vasc Anesthesia 1993;7:2–5. 3. Little WC: Diastolic dysfunction beyond distensibility: Adverse eﬀects of ventricular dilatation. Circulation 2005;112:2888–2890. 4. Little WC, Warner JG Jr., Rankin KM, et al: Evaluation of left ventricular diastolic function from the the pattern of left ventricular ﬁlling. Clin Cardiol 1998;21:5–9. 5. Oh JK, Hatle L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 6. Fukuta H, Little WC: Diastolic versus systolic heart failure. In Smiseth OA, Tendera M (eds): Diastolic Heart Failure. London, Springer, 2007. 7. Hasegawa H, Little WC, Ohno M, et al: Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol 2003;41: 1590–1597. 8. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 9. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.

TD E/E' >15

15 > E/E' > 8

Biomarkers NT-proBNP >220 pg/ml or BNP >200 pg/ml

Biomarkers NT-proBNP >220 pg/ml or BNP >200 pg/ml

Echo–bloodflow doppler E/A>50 yr <0.5 and DT>50 yr >280 msec or Ard–Ad >30 msec or LAVI >40 ml/m2 or LVMI >122 g/m2 ( ); >149 g/m2 ( ) or Atrial fibrillation

TD E/E' >8

HFNEF

10. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527– 1533. 11. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular ﬁlling pressure in sinus tachycardia. Circulation 1998;98:1644– 1650. 12. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular ﬁlling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 13. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol 2001;280:H2507–H2515. 14. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246–270. 15. Brucks S, Little WC, Chao T, et al: Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol 2005;95:603–606. 16. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 17. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure. Part I: Diagnosis, prognosis, and measurement of diastolic function. Circulation 2002;105:1387–1393.

71

72

Chapter 6 • General Principles, Clinical Definition, and Epidemiology 18. European Study Group on Diastolic Heart Failure. How to diagnose heart failure. Eur Heart J 1998;20:990–1003. 19. Vasan RS, Levy D: Deﬁning diastolic heart failure: A call for standardized diagnostic criteria. Circulation 2000;101:2118–2121. 20. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17–22. 21. Little WC: Hypertensive pulmonary oedema is due to diastolic dysfunction. Eur Heart J 2001;22:1961–1964. 22. Zile MR, Gaasch WH, Carroll JD, et al: Heart failure with a normal ejection fraction: Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001;104:779–782. 23. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiﬀness of the left ventricle. N Engl J Med 2004;350:1953–1959. 24. Vanoverschelde JL, Raphael DA, Robert AR, et al: Left ventricular ﬁlling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 25. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy: Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 26. Wang M, Yip G, Yu CM, et al: Independent and incremental prognostic value of early mitral annulus velocity in patients with impaired left ventricular systolic function. J Am Coll Cardiol 2005;45:272–277. 27. Dokainish H, Zoghbi WA, Lakkis NM, et al: Incremental predictive power of B-type natriuretic peptide and tissue Doppler echocardiography in the prognosis of patients with congestive heart failure. J Am Coll Cardiol 2005;45:1223–1226. 28. Troughton RW, Prior DL, Frampton CM, et al: Usefulness of tissue doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT Study). Am J Cardiol 2005;96:257–262. 29. Yturralde RF, Gaasch WH: Diagnostic criteria for diastolic heart failure. Prog Cardiovasc Dis 2005;47:314–319.

30. Redﬁeld MM, Jacobsen SJ, Burnett JC Jr., et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 31. Fischer M, Baessler A, Hense HW, et al: Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample. Eur Heart J 2003;24: 320–328. 32. Aurigemma GP, Gottdiener JS, Shemanski L, et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The cardiovascular study. J Am Coll Cardiol 2001;37:1042–1048. 33. Bella JN, Palmieri V, Roman MJ, et al: Mitral ratio of peak early to late diastolic ﬁlling velocity as a predictor of mortality in middle-aged and elderly adults: The Strong Heart Study. Circulation 2002;105:1928–1933. 34. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular ﬁlling after one year of antihypertensive treatment: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071–1076. 35. Owan TE, Redﬁeld MM: Epidemiology of diastolic heart failure. Prog Card Dis 2005;47:320–332. 36. Senni M, Tribouilloy CM, Rodeheﬀer RJ, et al: Congestive heart failure in the community: A study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–2289. 37. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999; 33:1948–1955. 38. Cortina A, Reguero J, Segovia E, et al: Prevalence of heart failure in Asturias (a region in the north of Spain). Am J Cardiol 2001;87:1417– 1419. 39. Bursi F, Weston SA, Redﬁeld MM, et al: Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–2216. 40. Bhatia RS, Tu JV, Lee DS, et al: Outcomes of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;335: 260–269.

JAMES B. SEWARD, MD KRISHNASWAMY CHANDRASEKARAN, MD MARTIN OSRANEK, MD, MSc KANIZ FATEMA, MBBS, PhD TERESA S. M. TSANG, MD

7

Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction INTRODUCTION PATHOPHYSIOLOGY Clinical Diastolic Dysfunction Pressure and Volume INVASIVE VERSUS NONINVASIVE ASSESSMENT Systolic Function Diastolic Function STATE-OF-THE-ART INVASIVE AND NONINVASIVE PHYSIOLOGY Myocardial Relaxation Ventricular Stiffness Filling Pressures Comprehensive Diastolic Function Assessment NORMAL DIASTOLIC MYOCARDIAL PHYSIOLOGY Temporal-Spatial Pressure and Flow: Suction of Blood into the Left Ventricle Left Atrial Pressure and Left Ventricular Suction

CLINICAL RELEVANCE Epidemic of Diastolic Heart Failure Myocardial Disease and Diastolic Dysfunction Arterial Stiffening and Diastolic Dysfunction Physiologic Coupling of the Cardiovascular System Forward Dysfunction: End-Organ and Microvascular Damage Vascular Stiffening: Summary CLUSTERING OF CARDIOVASCULAR RISK Diastolic Heart Failure With Normal Ejection Fraction and Systolic Heart Failure: Pathophysiologic Subgroups FUTURE RESEARCH GLOSSARY ABBREVIATIONS

73

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

INTRODUCTION In the era of classical cardiovascular (CV) medicine (ending around the year 2000), CV function was validated predominantly by invasive means.1,2 Classic studies established the end systolic and end diastolic pressure-volume relationships as a meaningful and useful way of characterizing intrinsic ventricular pump properties.3 These concepts then evolved such that they could be applied to basic and clinical research. In the present era of CV intervention (projected to last until approximately 2020), CV imaging and molecular science are emphasized. Mathematical modeling and further clariﬁcation of diastolic function through the use of invasive and noninvasive technologies is evolving.2,4 Around 2020, CV medicine is envisioned to evolve toward an “era of CV disease prevention.”5 Prevention will emphasize system physiology complemented by mathematical probability. A portfolio of physiologic models will be used as surrogate expressions of disease, and primary prevention of disease will be based on the intensity or burden of a physiologic or molecular/chemical risk model. Information acquisition will move from invasive to noninvasive. Research and clinical physiologic approaches2,6,7 are currently evolving from invasive to noninvasive means to elucidate fundamental CV physiology.4,8,9 Clinical physiology is no longer limited to catheterization, and the noninvasive echocardiologist can be redeﬁned as an “echophysiologist.” This chapter attempts to relate classical invasive physiology to the current evolution toward Doppler echocardiographic physiology. It is increasingly recognized and emphasized that contraction (systolic function) is dependent on relaxation (diastolic function). It is important to appreciate the two distinct, although intimately interrelated, aspects of the assessment of cardiac properties: (1) of the ventricle as a hemodynamic pump and (2) of the intrinsic properties of the cardiac muscle.3 Systolic and diastolic ventricular properties are dependent on systolic and diastolic myocardial properties, as well as muscle mass, chamber architecture, and chamber geometry. Pressure-volume constructs are used to directly assess ventricular properties.

PATHOPHYSIOLOGY Cardiac dysfunction, with or without systolic dysfunction, is associated with diastolic dysfunction (i.e., elevation of ﬁlling pressure). Cardiac dysfunction can be broadly viewed as a derivative of altered cardiac geometry and cardiomyocyte dysfunction or altered extracardiac loading, which is most commonly attributed to arterial stiﬀening. Once the sentinel cardiac or arterial perturbation is initiated, the dysfunctional state is propagated throughout the contiguous CV system (arteries, pump, and reservoir), becomes cyclical and self-perpetuating, and accounts for the clustering of a portfolio of common adverse events (e.g., heart failure [HF], atrial ﬁbrillation, stroke, cognitive dysfunction).

Clinical Diastolic Dysfunction Diastolic dysfunction refers to abnormal mechanical relaxation (diastolic) properties of the ventricle, which are present in the majority of patients with congestive heart failure (CHF). The term diastolic heart failure (DHF) is conventionally used to

describe patients with CHF symptoms and normal systolic contractility (i.e., normal ejection fraction [EF]), although a preferred term would be HF associated with preserved systolic function. Thus, the distinction between DHF and diastolic dysfunction is merely the presence of CHF symptoms. The CHF symptom complex associated with systolic HF (SHF) or DHF is most strongly correlated with the elevation of ﬁlling pressure. In order for the left ventricle to function as an eﬀective pump, it must be able to empty and ﬁll without requiring abnormal elevation of left atrial (LA) pressure. Atrial pressure is directly related to the ability of the left atrium to expel its contents into the ventricle during diastole. Thus, the principal determinant of risk and symptoms of CHF is the increased pressure reﬂected backward into the left atrium and pulmonary veins during diastolic ﬁlling of the ventricle.10 The stroke volume must be able to increase in response to stress, such as exercise, without any appreciable increase in LA pressure (Fig. 7-1).6 Drugs that produce a sustained decrease in ventricular ﬁlling pressures enhance eﬀort tolerance, breathing capacity, and HF outcome.11

Pressure and Volume Diastolic function conventionally has been assessed on the basis of the left ventricular (LV) diastolic pressure-volume relationship and an upward shift of the curve or increase in LV end diastolic pressure (LVEDP) (Figs. 7-2 and 7-3).6,7 The LV end diastolic pressure-volume relationship is the most important means of characterizing global ﬁlling properties. The pressure-volume loop (see Fig. 7-2) depicts the amount of diastolic ﬁlling (ml of blood) relative to a speciﬁed ﬁlling pressure (mmHg) and is therefore a key physiologic determinant of preload.13 Any delay or impedance

200 Exercise

150 LV pressure (mmHg)

74

Rest

100

50

0

20

28

36

44

52

LV volume (ml) Figure 7-1 Left ventricular (LV) pressure-volume loops at rest and during exercise. Each loop was generated by averaging the data obtained during a 15-second recording of simultaneous pressure and volume, spanning several respiratory cycles. During exercise, the early diastolic portion of the LV pressure-volume loop is shifted downward (arrow) so that the early diastolic LV pressure is lower during exercise than at rest. (From Cheng CP et al: Mechanism of augmented rate of left ventricular filling during exercise. Circ Res 1992;70:9–19. Used with permission.)

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 160 160

Ejection

120

Isovolumic relaxation

Isovolumic contraction

80

Pressure (mmHg)

120 Pressure (mmHg)

ESPVR

End systole

End diastole

20

40

A

60

80

100

120

0

140

B

Volume (ml)

EDPVR

0

0 0

Ees

40

40 Filling

80

20 Vo

40

60

80

100

120

140

Volume (ml)

160

Pressure (mmHg)

120

80

40

0 0

C

20

40

60

80

100

120

140

Volume (ml)

of myocardial relaxation will increase the ﬁlling pressure, which will be reﬂected backward into the left atrium and pulmonary veins. The end diastolic pressure-volume relationship is intrinsically nonlinear (see Fig. 7-3), a characteristic attributed to the diﬀerent types of structural ﬁbers being stretched in diﬀerent pressurevolume ranges.14 In the low pressure-volume range, with only a small increase in pressure for a given increment in volume, the stretch of compliant elastin ﬁbers and of the myocytes with sarcomeric titin molecules15 is believed to account for stiﬀness. As volume is increased to a higher range, pressure rises more steeply as slack lengths of collagen ﬁbers and titin are exceeded and stretch is more strongly resisted by these stiﬀ elements. Therefore, chamber stiﬀness increases as end diastolic pressure or volume increases.3 With diastolic dysfunction, any abnormal increase in diastolic ﬁlling pressure corresponds to a less distensible or less compliant ventricle during the ﬁlling phase of the cardiac cycle. Consequently, a “stiﬀ ” ventricle is less able to increase its stroke volume without further elevation of LA pressure. Pressure reﬂected backward through the open mitral valve into the atrium and pulmonary veins can cause shortness of breath, elevation of pulmonary

Figure 7-2 The hemodynamic events occurring during the cardiac cycle are displayed by plotting instantaneous pressure versus volume. A, A normal pressure-volume loop. The four phases of the cardiac cycle are displayed on the pressure-volume loop, which is constructed by plotting instantaneous pressure and volume. The loop repeats with each cardiac cycle and shows how the heart transitions from its end diastolic state to the end systolic state and back. B, Decrease in filling pressure (preload). With a constant contractile state and afterload resistance, a progressive reduction in ventricular filling pressure causes the loops to shift toward lower volumes at both end systole and end diastole. When the resulting end systolic pressure-volume points are connected, a reasonably linear end systolic pressure-volume relationship (ESPVR) is obtained. The linear ESPVR is characterized by a slope (Ees, ventricular elastance) and a volume axis intercept (Vo). EDVPR denotes end diastolic pressure-volume relationship. C, Increased afterload (blood pressure). When afterload resistance is increased at a constant preload, the loops get narrower and longer, and under ideal conditions the end systolic pressure-volume points fall on the same ESPVR as obtained with preload reduction. (From Burkhoff D et al: Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: A guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 2005;289:501–512.)

venous pressure, secondary pulmonary hypertension, and decrease in clinical exercise capacity.15–18

INVASIVE VERSUS NONINVASIVE ASSESSMENT Systolic Function Cardiac function assessment traditionally has focused on decreased contractility and the measure of EF. The noninvasive measure of systolic function, EF, is almost exclusively used in clinical trials and medical practice. Although EF is clinically considered an important index of LV systolic function, it is not exclusively governed by LV properties. Rather, EF is determined by the interaction of arterial and ventricular properties.20–23 A normal EF suggests that contractility and arterial stiﬀness are well matched. EF is very load dependent and normally increases up to 30% during stress.24 EF is thus limited by many factors, including marked preload dependence25 and low reproducibility when measured by diﬀerent imaging modalities.26 Furthermore, EF greater than 45% does not contribute to assessment of CV risks in patients with HF.27 In patients with CHF and elevated ﬁlling pressure, diastolic dysfunction correlates better with B-type natriuretic peptde concentration and mortality than with EF or LV volume.12,26

75

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction

A Normal

LV end diastolic pressure

76

B

ΔP

ΔP ΔV

ΔP

ΔV

ΔV

LV end diastolic volume Figure 7-3 Left ventricular (LV) end diastolic pressure-volume curves showing the relationship between end diastolic volume and pressure. Stiffness, at different points on the curve, is reflected as the change in pressure (ΔP) divided by the change in volume (ΔV). During normal LV filling, the myocardium must efficiently relax in order to prevent resistance to atrial emptying and elevation of atrial pressure. As the left ventricle relaxes, the diastolic volume and pressure increase. The ventricular filling pressure is reflected backward into the left atrium. Flow ultimately stops or transiently reverses when the atrial and ventricular pressures equilibrate. Normal atrial emptying thus must occur without requiring significant elevation of left atrial pressure. In this early period of diastole more than two thirds of the LV stroke volume normally enters the left ventricle. The severity of heart failure and prognosis are related to the severity of filling abnormalities regardless of the ejection fraction.12 A shift of the curve upward and to the left is considered the hallmark of diastolic dysfunction (curve A). A “stiff ” left ventricle in early diastole disturbs the normal suction gradient between the left ventricle and the left atrium (see Fig. 7-6C). The LV pressure increases rapidly, thus impeding the normal filling of the ventricle. Pressure is reflected backward into the left atrium, increasing atrial wall stress and pulmonary venous pressure. This pressure-volume curve is typical for isolated diastolic dysfunction with preserved ejection fraction and delayed relaxation, elevated diastolic pressure, and near-normal ventricular volume. In a heart with abnormal geometry, as found in dilated, ischemic, or hypertrophic cardiomyopathy, the LV end diastolic pressure-volume curve is shifted to the right (curve B). Decreased diastolic suction (see Fig. 7-6B) is disturbed because of abnormal chamber geometry, which is commonly associated with uncoordinated wall motion or impaired myocardial contractility. The disturbed LV suction forces the left ventricle and left atrium to function at a higher filling pressure, decreasing ventricular filling and increasing atrial and pulmonary venous pressure. (From Little WC: Diastolic dysfunction beyond distensibility: Adverse effects of ventricular dilatation. Circulation 2005;112:2888–2890.)

Diastolic Function Although the invasive research “testing ground” has made important contributions to the understanding of pressure-volume relationships and diastolic physiology,3,10 only recently has assessment of diastolic function been extensively incorporated into clinical practice. Assessment of diastolic function was neglected because there was no reliable noninvasive method to assess diastolic dysfunction, and invasive conﬁrmation of elevated ﬁlling pressure was deemed impractical if not unethical. Invasive monitoring through a pulmonary artery catheter or implantable transducer can provide continuous data. Pulmonary artery catheters, however, appear to contribute to morbidity and mortality29 and contribute little to clinical assessment.30 Even when LV cardiac catheterization is performed, the principal measure of diastolic function is LVEDP, which measures only the load-dependent ﬁlling pressure and reﬂects conditional physiologic circumstances only at the time of data acquisition. With the advent of noninvasive Doppler echocardiography, clinical assessment of diastolic function has become increasingly attainable and validated. However, early impediments to clinical use of Doppler echocardiographic diastolic function assessment became apparent. The ﬁrst measures of diastolic function, which relied on mitral and pulmonary vein ﬂow, were load dependent—similar to EF and LVEDP—and changed dynamically even during the examination. Because of the dynamic nature of these physiologic events, measures of diastolic function were limited for use in the assessment of long-term morbidity and mortality.

STATE-OF-THE-ART INVASIVE AND NONINVASIVE PHYSIOLOGY Diastolic function assessment by both invasive2 and noninvasive means is plagued by ambiguities surrounding the dynamic nature, indirectness, and diﬃculty of reproducibly measuring everchanging diastolic function. Dynamic measures include: 1. Decrease in pressure during the period of isovolumic relaxation (invasive: time constants of relaxation; noninvasive: deceleration time and longitudinal ﬁber relaxation) 2. Passive and active chamber stiﬀness or, its inverse, compliance (invasive: elastance; noninvasive: diastolic grade and LA volume) 3. End diastolic pressure (invasive: LVEDP; noninvasive: Doppler E/E′ ratio, end diastolic mitral versus pulmonary vein Doppler ﬂow) (Table 7-1)

Myocardial Relaxation Invasive Assessment Pressure relaxation can be measured invasively by placing a micromanometer catheter into the left ventricle. The rate of pressure decrease, which begins during the isovolumic period, is inﬂuenced by several physiologic factors2: 1. Capacity and rapidity with which the sarcoplasmic reticulum and sarcolemmal Na+/Ca2+ exchanger restores cellular Ca2+ levels to low diastolic levels

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction TABLE 7-1 DIASTOLIC FUNCTION ASSESSMENT BY INVASIVE AND NONINVASIVE MEANS METHOD Functional parameter Myocardial relaxation Ventricular and arterial stiffness

Invasive Mathematical models of pressure-volume loops2 Analysis of viscoelastic properties2: simultaneous measurement of pressure, volume, and flow Vascular: pulse pressure, central blood pressure

Filling pressure

Left ventricular end diastolic pressure40

2. Extent of elastic recoil (suction) within the heart caused by compression by myocyte contraction during the prior systole and history of prior systolic ejection, which is largely determined by the aortic input impedance (stiﬀness) 3. Other chamber-level factors, such as dyscoordination and heterogeneity Isovolumic pressure relaxation traditionally starts when pressure decay is maximal, generally occurring shortly after aortic valve closure, and extends to a point when LV pressure decreases just below a threshold equal to the end diastolic pressure plus 5 mmHg. Recorded pressure-time curves can be mathematically analyzed to extract the rate of pressure decrease.2 However, the type of model used to describe relaxation can have marked inﬂuences on the apparent changes with drug and chamber-loading interventions.2 Model-dependent analysis of relaxation is commonly fraught with systematic deviations from the real data, particularly with depressed cardiac function.30 Some diseases, including hypertrophic cardiomyopathy, are characterized by regional heterogeneity of loading and material properties, which result in nonuniform relaxation. Diseases with a complex process of pressure decrease, such as hypertrophic cardiomyopathy, in general cannot be easily expressed in a single time constant.

Noninvasive Assessment Diastolic dysfunction is associated with substantial abnormalities of active relaxation and passive stiﬀness of the ventricle.31 Doppler transmitral velocity deceleration time (DT) and tissue Doppler early diastolic mitral annular velocity (E′) are commonly used noninvasive indices of myocardial relaxation. DT ﬂuctuates with the dynamic changes in ventricular loading pressure, whereas E′ is relatively load independent. DT is useful for estimating intensity32,33 or “grade” of dysfunction34 at the time of the examination. Tissue Doppler E′ velocity is touted as less load dependent and can distinguish pseudonormal from normal ﬁlling patterns. The pseudonormal ﬁlling pattern is commonly encountered when using mitral inﬂow Doppler to characterize diastolic function grade.32 Active (e.g., Ca2+-dependent) and passive (e.g., ﬁbrosis) structural mechanisms regulate the rates of ventricular pressure decay and early diastolic ventricular ﬁlling.35 Active relaxation represents the speed of transition from the contracted state (systole) to the relaxed state (diastole) and is strongly related to the uptake of calcium for the contracted myocyte. Passive relaxation is most strongly related to myocardial compliance and the eﬀects of tissue ﬁbrosis. Load-dependent measures reﬂect the dynamic physio-

Noninvasive ultrasonography Tissue Doppler annular velocity, E′31–33 Measures of “stiffness”9,34–36: effective arterial elastance (Ea), end systolic elastance (Ees); Doppler-derived diastolic dysfunction. Vascular stiffness37–39: pulse wave velocity, augmentation index Doppler E/E′31,41–45: acute load-dependent filling pressure Left atrial volume46–48: chronic average increase in filling pressure

logic state of ﬁlling pressure under the conditions existing at the time of the examination as well as the likelihood of a favorable response to a therapeutic manipulation (modiﬁability).32,36–40 The tissue Doppler E′ velocity reﬂects the relaxation velocity of the myocardium and expresses both passive and active myocardial relaxation.31 Variations in long-axis shortening have relatively little eﬀect on the EF or stroke volume. Most of the stroke volume is produced by shortening of the minor axis dimension,41 which explains why either decreased diastolic (E′) or decreased systolic annular tissue Doppler can be observed in the presence of a normal EF.

Ventricular Stiffness Invasive Assessment Ideally, to analyze the viscoelastic properties of the ventricle, one should take simultaneous measurements of chamber pressure, volume, and ﬂow. Passive elastic properties are those that relate a change in pressure to a given change in volume, whereas viscous properties are those that relate change in pressure to the rate of change in volume or ﬂow. As opposed to noninvasive Doppler, no invasive methods are readily applicable for measuring ﬂow rates of ﬁlling in the human heart. Therefore, most analyses must obtain ﬂow data from the derivative of volume.2 The invasive measurement of pressure uses a high-ﬁdelity micromanometer catheter. Measurement of volume is more challenging, with investigators commonly using various imaging-based methods to construct a volume-time curve. This approach is labor intensive, typically yielding a limited number of samplings of volumes during the diastolic period, and is subject to various sources of noise given the extensive processing required.2 A notable alternative is intracardiac electrical impedance, which can serve as a continuous measure of chamber volume.42–45 The association between diastolic pressure and volume from a single cardiac cycle does not necessarily follow a simple mathematic relationship.2 Only limited ﬁlling property data can be obtained from a single cardiac cycle. Various solutions have been used to overcome these limitations. After a diastolic pressurevolume curve is obtained, these data are typically subjected to a mathematical curve-ﬁtting process to extract parameters of chamber or muscle stiﬀness. As with relaxation analysis, there are important limitations of such ﬁtting when applied to a diastolic curve, owing to the nature of the mathematics.2 Unless the diastolic data are perfectly monoexponential, which is rarely the case, simply evaluating the same curve or restricting analysis to slightly

77

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction loading ampliﬁcation associated with age.48,55 Diastolic HF with preserved EF appears to be best correlated with increased ventricular-arterial stiﬀness. Relaxation of the “stiﬀ ” ventricular myocardium is delayed when the ventricle is exposed to increased systolic pressure during ejection (i.e., increased afterload).58 Diastolic dysfunction, as reﬂected in increased ﬁlling pressure, is directly related to greater prolongation of diastolic relaxation and increased ventricular-vascular stiﬀening.55,59 A major hemodynamic consequence of arterial stiﬀening is widening of the arterial pulse pressure, which also increases cyclic changes in arterial ﬂow. Increased arterial stiﬀness increases systolic pressure and decreases diastolic pressure. Coronary perfusion occurs principally during diastole; thus, in persons with stiﬀ conduit vessels and lower diastolic pressure, coronary microvascular perfusion is adversely aﬀected.60 Impaired myocyte relaxation of the subendocardial longitudinal ﬁbers is an ageassociated ﬁnding. Reduced myocardial relaxation is best measured as a decrease in tissue Doppler E′ velocity. Structural remodeling and functional disturbances are essential to the development of diastolic dysfunction and HF, but acute or subacute decompensation with CHF generally requires a precipitant, or “trigger.”61 The stiﬀ arterial system is particularly sensitive to acute dysfunction, as occurs with excessive sodium intake, hypertension, atrial ﬁbrillation, myocardial infarction, or marked bradycardia (prolonged diastasis). High arterial pulsatility is noted to have detrimental eﬀects on blood ﬂow regulation62 and contributes to adverse mechanical forces, which aﬀect vascular tone, atherogenesis, angiogenesis, hemostasis, and microvascular autoregulation.

diﬀerent ranges of volume and pressure can inﬂuence the derived parameters. Ultimately, derived stiﬀness parameters must be viewed cautiously, particularly if the data themselves do not clearly follow an exponential rise waveform.2 Even if directly measured by invasive pressures and volumes, the relationship between the two variables during ﬁlling does not necessarily provide information solely related to the cardiac chamber.

Noninvasive Assessment Limited success has been achieved in replicating pressure-volume loops by noninvasive Doppler echocardiography.8,46,47 However, several noninvasive studies have identiﬁed a relationship between limitation of exercise capacity, increased CV stiﬀness,48–51 and DHF.52,53 Noninvasive Doppler echocardiographic assessment of “stiﬀness” appears to be an excellent means of expressing ventricular and arterial stiﬀening.9,54 Eﬀective arterial elastance (Ea), which reﬂects vascular stiﬀening, and end systolic elastance (Ees), which reﬂects ventricular stiﬀening, can be calculated noninvasively9,54 and validated against invasive assessment (Fig. 7-4).21,46,54–56 Ea, Ees, and diastolic stiﬀness increase with age and correlate with one another.21 Normally, there is an inverse relationship between Ees and Ea. As arterial compliance decreases (increased stiﬀness), ventricular compliance would be expected to increase (decreased stiﬀness).55 In order for EF to increase during exercise, the coupling ratio of Ea and Ees must decrease. However, with aging, the increase in exercise EF becomes blunted,23,57 suggesting ageassociated diﬀerences in the coupling ratio (Ea/Ees) and its components. Both arterial and ventricular stiﬀness tend to increase to a similar degree—Ea/Ees remains constant despite an increase in arterial stiﬀness (see Fig. 7-4). Thus, ventricular stiﬀness tends to increase with age. As ventricular and arterial stiﬀness increase, the system becomes more pressure labile and sensitive to loading conditions.21 This physiologic change is most evident with aging, as reﬂected in increased systolic and pulse pressure after age 50 to 60 years. These changes explain decreased exertional capacity and pressure-

Invasive Assessment LVEDP is the most common measure of diastolic dysfunction recorded during clinical cardiac catheterization. Increased ﬁlling pressure is not a requisite of diastolic dysfunction but is a universal

Elderly

150

180

Ea

Ees Ees

Filling Pressures

Ea

100

50

Systolic pressure (mmHg)

Young

LV pressure (mmHg)

78

0

150 120

90

Young

60 0

A

Elderly

50

100

LV volume (ml)

0

50

40

100

LV volume (ml)

B

60

80

100 120

LV EDV

Figure 7-4 Graphs showing the relationship between left ventricular (LV) pressure and volume. A, Pressure-volume loops from a 19-year-old man (Young) and an 87-year-old woman (Elderly) show increases in ventricular elastance or stiffness (Ees, solid line) that match increases in arterial elastance or stiffness (Ea, dashed line). Ea and Ees are normally equal in absolute magnitude, which yields optimal and efficient matching of the heart and artery. However, the elderly patient shows marked increases in both Ea and Ees (arterial and ventricular stiffening). The change in loop shape in the elderly patient reflects stiff arteries with a wider pulse pressure. B, As is shown by plotting systolic pressure versus LV end diastolic volume (EDV), the diastolic pressure-volume relationship also becomes steeper in the elderly patient. Ea, Ees, and diastolic stiffness increase with age and correlate with one another.22 Patients with decreased arterial compliance (Ea) show increased ventricular stiffness (Ees), which has important implications for blood pressure lability and loading sensitivity. These findings help explain heart failure with preserved ejection fraction.68,69 (From Kass DA: Ventricular arterial stiffening: Integrating the pathophysiology. Hypertension 2005 Jul;46:185–193.)

feature of both systolic and diastolic dysfunction.63 Increased ﬁlling pressure is not speciﬁcally representative of either systolic or diastolic dysfunction64 but is a potent marker of evolution toward overt CHF and hospitalization.65 Diastolic ﬁlling pressure reﬂects the load-dependent changes in chamber stiﬀness, with diastolic dysfunction uniformly occurring before or coincident with overt systolic dysfunction.63 The decrease in cyclic adenosine monophosphate needed to impair diastolic relaxation is much smaller than is required to impair contractility. Abnormal diastolic dysfunction is thus an earlier and more sensitive marker of a deﬁcient energy state in HF than are abnormalities of systolic performance.66 For example, if EF is greater than 45%, it does not further contribute to assessment of CV risk in patients with HF.26 The principal determinant of HF risk is the inability of the ventricle to properly ﬁll during diastole (i.e., inability to “prime the pump”).

Noninvasive Assessment The easiest and most reproducible noninvasive measure of ﬁlling pressure elevation is the ratio of early diastolic transmitral inﬂow velocity (E) to E′ (Doppler E/E′ ratio).32,36,37,67–69 The E/E′ ratio has been well correlated with invasive measures of LV ﬁlling pressure and pulmonary capillary wedge pressure.36,67,68 The ratio depicts the relationship between dynamic changes in LA pressure and LV compliance. As LA pressure increases, E increases, depicting the increased pressure gradient between atrium and ventricle. Conversely, myocardial relaxation, as depicted by tissue Doppler E′ velocity of the mitral annulus, is unchanging and relatively unaﬀected by loading dynamics.31 The E/E′ ratio, which is load dependent, reﬂects ﬁlling pressure at the time of the recording. An E/E′ ratio greater than 10 is highly sensitive (92%) and speciﬁc (80%) for the prediction of pulmonary wedge pressure greater than 15 mmHg.37,70 Filling pressure is dynamic; thus, it is common to record a normal ﬁlling pressure at rest and an elevated ﬁlling pressure with exercise. E/E′ should be viewed as a measure of the intensity of the ﬁlling pressure abnormality at the time of recording. Increased LA size reﬂects the average burden of volume or pressure overload or both. Atrial volume index is the preferred means of expressing atrial size because the atria enlarge asymmetrically and in direct relationship to the body surface area. Atrial enlargement because of abnormal pressure overload is substantiated by the coexistence of abnormal tissue relaxation (i.e., low E′ velocity) (Fig. 7-5); conversely, atrial enlargement because of benign volume overload is associated with a normal Doppler E′ velocity. LA volume index increases slowly and changes little with acute pressure or volume overload.71,72 Indexing LA volume to body surface area accounts for plasma volume throughout life.73–75 LA volume index best reﬂects “chronicity,” or average ﬁlling pressure, and the E/E′ ratio best reﬂects the “intensity” of ﬁlling pressure elevation at the time of the recording.76–78 For example, persons with chronic, yet intermittent, elevation of ﬁlling pressure (increased LA volume index and abnormal E′) can have a normal E/E′ at rest and an abnormal E/E′ with exertion. Clinical outcome is more strongly related to the average burden of ﬁlling pressure elevation as reﬂected in the atrial volume79 and not the resting grade of diastolic dysfunction.34

Comprehensive Diastolic Function Assessment The pressure-volume loop and tissue Doppler echocardiography both demonstrate the close link between systolic and diastolic

Average LA filling pressure (mmHg)

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 30 25 20 15

Atrial volume and pressure begin to exceed the LA and pulmonary vein reservoir capacity

10 5

Normal

LA enlargement

0 16

28

40

LA volume index (ml/m2) Figure 7-5 Graph showing the relationship of left atrial (LA) size (LA volume index) to average filling pressure. Pressure overload of the left atrium is present if the medial mitral annular tissue Doppler E′ velocity falls below 10 cm/sec (i.e., abnormal myocardial relaxation) and the atrial volume exceeds 28 ml/m2 (i.e., increased atrial wall tension). The cumulative burden of increased volume and/or pressure overload is related to the magnitude of atrial enlargement. The atrial volume remodels slowly and best reflects burden. Filling pressure at the time of examination (intensity) is best reflected in the E/E′ ratio, whereas atrial enlargement due to pressure overload reflects the chronicity or average burden of increased LA filling pressure. Conversely, atrial enlargement with a normal E′ velocity is consistent with “benign” isolated atrial volume overload, as seen in athletes, chronic disease, and anemia.

function.3,80 Patients with compensated systolic dysfunction have lesser degrees of diastolic dysfunction. Conversely, patients with overt CHF have higher grades of diastolic dysfunction.81 Diastolic dysfunction82,83 is not a part of “normative aging” but an age-related risk associated with the development of increased total CV risk, including increased HF, atrial ﬁbrillation, and mortality,63,84 independent of age and sex.85 As advances in noninvasive methods continue to evolve,86–88 reliance on invasive methods will continue to decrease.2 The invasive examination remains the physiologic testing ground for understanding instantaneous physiology. However, the Doppler echocardiographic examination, although not ideal, is now the gold standard for clinical assessment of diastolic function and physiologic CV burden, in addition to complementing CV research.68,89

NORMAL DIASTOLIC MYOCARDIAL PHYSIOLOGY During LV contraction, potential energy is normally stored as the myocytes are compressed and the elastic elements in the LV wall are compressed and twisted.6,90,91 Relaxation of the myocardial contraction allows this potential energy to be released as the elastic elements recoil.6,92 The release of wall tension (potential energy) is normally rapid enough to cause the LV pressure to decrease despite an increase in LV volume (see Fig. 7-1).93 Although there is a relative decrease in early diastolic enhanced LV relaxation and elastic recoil from tachycardia and adrenergic stimulation during exercise,94–97 LA pressure does not increase to an abnormal level.98–101 Neither an increase in atrial pressure nor more vigorous atrial contraction contributes to the increased mitral valve pressure gradient and resulting increase in dV/dtmax that occurs during exercise.93 The intraventricular pressure gradient is greater in normal subjects than in patients with HF.102,103

79

80

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction In order for LV contraction to release the store of elastic potential energy, LV volume must decrease below a critical value during contraction. The minimum end systolic volume required to generate suction equals the equilibrium volume, the volume of the fully relaxed ventricle at zero pressure.97 If either the equilibrium volume decreases or the end systolic volume increases, the ventricle will be unable to release potential energy capable of suctioning blood into the ventricle.91,97,104 Other determinants of suction are the time constant of LV relaxation105 and the degree of largescale LV torsion and twist.91

Temporal-Spatial Pressure and Flow: Suction of Blood into the Left Ventricle Peak ﬂow across the mitral valve normally equals or exceeds the peak ﬂow rate across the aortic valve. The rapid movement of blood from the left atrium into the left ventricle in early diastole is due to a pressure gradient from the left atrium all the way to the LV apex (Fig. 7-6A).102 Ventricular ﬁlling is thus primed by a rapidly developing pressure envelope extending between the left atrium (highest pressure) and the LV apex (lowest pressure).106 As a consequence of the early diastolic intraventricular gradient between the left atrium and ventricular apex, blood is virtually “sucked” into the left ventricle. Suction is initiated during isovolumic ventricular relaxation and continues during early rapid ﬁlling.105 The lower the early diastolic LV pressure, the greater the suction, which allows the heart to function at lower LA pressure.95,107 Diastolic suction contributes to ﬁlling more than one order of magnitude greater than does passive atrial decompression.105

A

B

Left Atrial Pressure and Left Ventricular Suction The ability to dynamically decrease early LV ﬁlling pressure is particularly important in response to stress, which allows an increase in LV stroke volume without an appreciable increase in LA pressure.95,97,106,108–114 Diastolic intraventricular pressure gradients are the result of the interaction of inertial (local) and convective forces caused by unsteady intracardiac ﬂow and pressure distribution.102 Inertial forces are caused by the impulse (potential pressure) developed by myocardial restoring forces related to the inotropic state (LV contraction and the creation of potential energy).97,115 Convective deceleration is determined by spatialtemporal ﬁlling ﬂow velocity and, most particularly, the presence of a normal cone-shaped ventricular geometry (see Fig. 7-6A).116 When the mitral valve opens and blood is normally sucked into the left ventricle, the gradient between that ventricle and the left atrium begins to decrease, and ﬂow ultimately stops or transiently reverses when these pressures equilibrate. Under normal circumstances, relaxation is completed during rapid ﬁlling as the LV pressure attains its near minimum.58,117 More than two thirds of the LV stroke volume normally enters the left ventricle during this earliest phase of diastole. The time of pressure deceleration is determined by normal vigorous suction (active force) or by “stiﬀ ” noncompliant LV muscle (passive force) associated with disease states.118–120 The normal response to stress is an increase in the gradient between the left atrium and the LV apex.102 βadrenergic stimulation increases contractility, myocardial restoring forces, and the resulting enhanced ventricular suction.97,110,115 Increased diastolic suction facilitates rapid ﬁlling and lowers minimum LV pressure.108,113 Enhanced diastolic suction acts as a

C

Figure 7-6 Diagrams of diastolic left ventricular (LV) filling. The relative spacing and shape of the dots reflect pressure (widely spaced = low pressure) and velocity (elongated = fast). A, In the normal heart, recoil of elastic elements produces a pressure gradient from the LV apex (lowest pressure) to the left atrium (higher pressure). This results in acceleration (suction) of blood out of the left atrium, which produces rapid diastolic filling that quickly propagates to the LV apex. The release of diastolic wall tension (potential energy) is normally rapid enough to cause the LV pressure to decrease despite an increase in LV volume.97 B, Dilated, ischemic, and hypertrophic cardiomyopathy typically contribute to heart failure. The normal intraventricular diastolic pressure gradient, which sucks blood from the left atrium into the left ventricle, is disturbed. The dilated, hypocontractile, or geometrically abnormal left ventricle produces a lower intraventricular pressure gradient in early diastole as a result of decreased elastic recoil and increased convective deceleration (i.e., decreased blood velocity with respect to distance). The pressure envelope in early diastole becomes dispersed, decreasing the pressure gradient between the left atrium and the left ventricle.106 The left atrium enlarges in response to increased filling pressure. Early forward flow from the pulmonary veins is commonly replaced by flow and pressure reversal in late diastole (arrows). C, Heart failure with preserved systolic function and a normal-sized left ventricle more commonly occurs in older persons, often in the absence of apparent clinical CV disease. The increased filling pressure (often due to arterial-ventricular stiffening) is transmitted backward from the aorta to the left ventricle, impeding the efficient transit of blood from the left atrium to the left ventricle. The increased filling pressure is transmitted backward to the left atrium causing LA enlargement and increased pulmonary venous pressure.34 Early forward flow from the pulmonary veins (large arrows) is commonly replaced by reversal of flow and pressure into the pulmonary veins (small arrows) in late diastole.

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction compensatory mechanism to maintain low pulmonary venous and arterial pressure in situations of increased contractility.102 The gradient between the left atrium and the LV apex is determined by inertial acceleration (elastic recoil) and convective deceleration (chamber geometry) of blood.102 Inertial acceleration is the change in velocity with respect to time, and convective deceleration is proportional to the decrease in velocity with respect to distance.121 Convective deceleration is increased when the distance or architecture of the left ventricle is altered and intraventricular blood ﬂow is diverted away from the longitudinal axis of the left ventricle. An increase in convective deceleration caused by altered ventricular geometry thus decreases the normal gradient between the left atrium and the LV apex (see Fig. 7-6). Late in diastole, atrial contraction produces a second LA-to-LV pressure gradient that again propels blood into the left ventricle. After atrial systole, as the left atrium relaxes, its pressure drops below LV pressure, which initiates closure of the mitral valve. The onset of ventricular systole produces a rapid increase in LV pressure that seals the mitral valve and ends diastole.

CLINICAL RELEVANCE A thorough understanding of normal and abnormal myocardial physiology is vital to the determination of cause and eﬀect. CHF and the clustering of associated risk factors cannot be assumed to represent cause and eﬀect. Although risk factors modify and enhance the severity of the physiologic condition, most risk events, such as CHF, atrial ﬁbrillation, and stroke, are best viewed as consequences and not causes. In particular, age-associated CV disease appears to have a common physiologic basis, which best accounts for the clustering of common adverse events.83,85,122

Epidemic of Diastolic Heart Failure As the world’s population has increased, the average life expectancy has also increased by approximately 3 months per year since 1840.123,124 This fact best accounts for the existence of an artifactual age-associated global epidemic of CV risk.5,125,126 HF is the most common indication for hospitalization of older persons. However, it is also well known that at least 50% of patients with CHF have a normal EF,127–131 and two studies report that more than 70% of older patients with symptomatic HF have a normal EF and ﬁt the diagnosis of DHF.131,132 In addition, more than half of patients with CHF are relatively asymptomatic, which contributes to a substantial underestimation of the true incidence of HF, particularly in older persons. However, patients with HF and preserved EF (i.e., DHF) have exercise intolerance,19 shortness of breath on exertion, episodes of pulmonary edema requiring hospitalization, and increased mortality, similar to patients with SHF.52,53,133–135 In general, mortality with CHF is approximately 50% at 5 years.136 Patients with DHF tend to be older and more likely to have a history of hypertension, atrial ﬁbrillation, and fewer symptoms, whereas patients with SHF are more likely to have a longer history of CHF, ventricular arrhythmias, and clinical manifestations of coronary artery disease.131 Clinical and research emphasis is increasingly placed on the physiology of cardiac dysfunction and not merely systolic contractility (i.e., EF). State-of-the-art noninvasive Doppler echocardiographic physiology has become the standard of clinical and investigative assessment of CV function. Thus, any discussion of CV function must incorporate the strengths and unique attri-

butes of invasive and noninvasive cardiac and vascular physiology used in the assessment and understanding of diastolic and systolic function. Symptoms of CHF are strongly related to the elevation of ﬁlling pressure, which accounts for breathlessness, exercise intolerance, and reduced quality of life.133,137–139 CV dysfunction leading to elevation of ﬁlling pressure and the clustering of adverse events can be broadly grouped as a consequence of either altered cardiomyocyte function accompanied by distorted ventricular geometry81,140 or abnormal cardiac loading, which most commonly begins as a consequence of extracardiac stiﬀening of the conduit arterial system (see Fig. 7-2).54,81,133,137,140–142 Diastolic disorders from cardiomyocyte dysfunction include dilated cardiomyopathy, hypertrophic cardiomyopathy, and ischemic heart disease. Diastolic disorders beginning with increased pressure loading are most commonly ascribed to increased pulse pressure and central systolic blood pressure (i.e., hypertension).141,143–145 Energy-dependent myocardial relaxation (diastolic function) is metabolically more vulnerable than systolic contraction. Resistance to ventricular ﬁlling reﬂects pressure backward into the atria and the pulmonary veins during diastole when the atria and ventricles are directly exposed to each other. As the volume in the atrium and pulmonary vein increases, their combined reservoir capacity is ultimately exceeded. The dynamics of the left atrium and pulmonary veins undergo a transition from physiologic volume overload to abnormal pressure overload (see Fig. 7-5). The transition from a state of benign atrial volume overload to pressure overload is commonly slow and intermittent. The transition to a pressure overload state is clinically more apparent with stress intolerance and acute congestive symptoms after a stressful trigger (e.g., illness, surgery, infarction). Stress-induced increase in atrial pressure accounts for breathlessness and exercise intolerance. Sustained increase in pulmonary venous pressure accounts for symptoms ascribed to the syndrome of CHF.

Myocardial Disease and Diastolic Dysfunction Abnormal suction of blood into the left ventricle has been replicated with various HF models,91,108 such as myocardial ischemia114,146,147 and hypertrophic cardiomyopathy (see Fig. 7-6B).148 Any condition that interferes with normal regional systolic function might be expected to modify the pattern of the normal early diastolic intraventricular pressure gradients.147 With LV muscle disease, the end diastolic pressure-volume curve is shifted substantially to the right, and the diastolic pressure curve is shifted upward, reﬂecting the increase in ﬁlling pressure (see Fig. 7-3B).6 Abnormal LV ﬁlling dynamics are seen, along with increased LA pressure and inability to increase stroke volume without abnormal elevation of LA pressure. In patients with dilated cardiomyopathy, the normal pressure gradient from the left atrium to the LV apex is substantially decreased.102 Hypertrophic cardiomyopathy is a myocardial disease with abnormal ventricular geometry and preserved systolic function and is also accompanied predominantly by abnormal diastolic function. Diastolic suction is disturbed because of abnormal changes in chamber geometry, which are commonly associated with uncoordinated wall motion or impaired myocardial contractility. The decreased capacity to generate suction contributes to the abnormal increase in ﬁlling pressure.102 Limited suction response to stress causes LV ﬁlling pressure to increase disproportionately and causes exercise-related shortness of breath.102 Decreased

81

82

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction suction shifts the pressure-volume curve toward a higher minimum diastolic pressure (see Fig. 7-3B). With dobutamineinduced stress, the gradient between the left atrium and the LV apex can be demonstrated to be impaired.102 Altered geometry of the ventricle impairs inertial acceleration (decreased global elastic recoil) and enhances convective deceleration. Myocardial disease, associated with impaired elastic recoil and enhanced convective deceleration, is proportional to the magnitude of altered LV geometry.118 Cardiomyopathic ventricles show abnormal suction at baseline and have a limited ability to recruit suction when undergoing inotropic stimulation.102 The minimum diastolic pressure of the failing heart increases during exercise.108 Although the increase in ﬁlling pressure accounts for the symptoms of CHF (i.e., increased ﬁlling pressure and decreased EF), it is not directly related to the hemodynamic cause of decreased cardiac output and distorted LV geometry. Thus, simply decreasing ﬁlling pressure will decrease symptoms but will fall short of eliminating the primary problem. Lasting clinical improvement requires reversal of the LV remodeling and return of the cardiac output and renal perfusion to near-normal values to prevent relapse of ﬂuid retention and subsequent clinical deterioration.139

Arterial Stiffening and Diastolic Dysfunction Widening of the arterial pulse is common to aging and generally reﬂects the stiﬀening or senescence of the conduit arteries49,54,149–151 and a dominant hemodynamic risk for cardiac dysfunction.141,152–154 In response to an increase in preload volume, the increase in systolic and diastolic blood pressure is exaggerated, which accounts for the shortness of breath, exercise intolerance, and hypertensive pulmonary edema seen in patients with DHF.53 The blood vessels are coupled in tandem with the ventricle (pump), which undergoes simultaneous systolic and diastolic stiﬀening (see Figs. 7-3 and 7-6C).21,55 Combined stiﬀening alters how the heart-arterial system interacts at rest, but particularly under stress by exertional demands,54 and is particularly evident in patients with CHF and preserved EF, smaller-than-normal end diastolic volume,31 and normal ventricular geometry.55 Delayed active and passive relaxation of the stiﬀ left ventricle in early diastole disturbs the normal suction gradient between the left ventricle and the left atrium. HF with preserved EF and a normalsized and -shaped left ventricle more commonly occurs in older persons, women,151,155–157 and obese persons81,133,137,140,142 and is associated with a lower rate of myocardial infarction.158 Vascular stiﬀness aﬀects CV reserve, coronary and peripheral ﬂow regulation, endothelial function, and mechanical signaling and causes blood pressure lability and diastolic dysfunction. Ageassociated ventricular systolic and diastolic stiﬀness occurs even in the absence of other CV disease and is thought to be the dominant cause of age-related HF with preserved EF.9,49,55,151,159,160 Stiﬀening of arterial-ventricular function is referred to as coupling disease and is considered to be the principal contributor to the epidemic of age-associated CV adverse events such as HF, atrial ﬁbrillation, stroke, and cognitive dysfunction.54

Physiologic Coupling of the Cardiovascular System Reservoir, Pump, and Arteries The concept of “continuity disease” has been proposed to describe the relationship and shared physiology between the arteries and the rest of the CV system.54 The CV system is best viewed as a

contiguous system, analogous to a conventional water pump. The heart is a pump delivering pulsatile ﬂow to the arterial system. The arterial and capillary vascular system is an extensive hydraulic ﬁlter, which converts pulsatile ﬂow to continuous ﬂow at the end organ. The atria and veins act as a distensible reservoir that stores blood during ventricular contraction and ﬁlls the ventricle during diastole, thus initiating the conversion of continuous ﬂow back to pulsatile ﬂow. Any abnormality that interferes with eﬃcient forward-directed ﬂow initiates deterioration in the forward and backward directions to the adjoining components of the contiguous system. The age-associated epidemic of HF appears to be principally related to an increase in arterial stiﬀness. Increased arterial stiﬀness aﬀects the ventricle (reverse direction) and distal arterial bed (forward direction). The concept of coupling disease54 can be expanded to include the interdependence of the whole CV system (i.e., arteries, pump, and reservoir).

Arterial-Ventricular Coupling It is necessary to address the interaction of the whole CV system as a discipline in order to understand the vascular and cardiac regulatory mechanisms associated with the contiguous relationship of ventricular and arterial function.57 The interaction of ventricular and arterial properties, or coupling, is an important and largely underappreciated determinant of cardiac performance.19–22,161 Elastance is the change in pressure for a given change in volume of the ventricle. Arterial elastance (Ea) indexed to body surface (EaI) represents a steady-state arterial property that characterizes the functional properties of the arterial system (see Fig. 7-4).20 Ea is a lumped parameter that accounts for aortic impedance, peripheral resistance, and arterial compliance. Ea is equal to the LV end systolic pressure divided by the stroke volume. Ea shares common units with elastance measures of ventricular function (Ees or Ees indexed to body surface [EesI]); their ratio (EaI/EesI), an index of arterial-ventricular coupling,20 is inversely related to EF.162 In healthy subjects free of CV disease, EF increases by up to 30% during exercise.23 However, in order for the EF to increase during exercise, the coupling ratio, EaI/EesI, must decrease (Fig. 7-7).19 Studies show that with aging, the normal increase in EF during exercise (i.e., EF reserve) becomes blunted,23,57 suggesting ageassociated diﬀerences in the shift of coupling ratio and its components during exercise. Suboptimal vascular-ventricular coupling helps explain the age-associated blunting of maximal exercise EF and its underlying mechanisms.19

Stiffening Stiﬀening of any component of the CV system signals the dysfunctional state to contiguous (i.e., coupled) systems. Stiﬀening within the CV system is accompanied by changes that do not require renal disease or cardiac hypertrophy to be present.21 Patients with low arterial compliance (e.g., increased stiﬀness; Ea) have increased ventricular stiﬀening (Ees),55 which has important implications regarding blood pressure lability and loading sensitivity. To maintain optimal interaction with the stiﬀened arterial system, the LV itself must also develop greater systolic stiﬀness.21,163–166 Arterial-ventricular stiﬀening alters the way in which the CV system responds to stress demands and changes in volume and pressure loading.54 The physiologic changes of increased stiﬀness are associated with decreased exertional capacity, which contributes to the clinical complex of CHF with preserved systolic EF.48

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 90

0.7

85

0.6

<40 yr

0.5

75

>60 yr

Eal/Eesl

EF (%)

80

70

0.3

65

0.2

60

A

Sit

50% max

Max

B

<40 yr

Supine

Sit

50% max

Max

30 >60 yr <40 yr >60 yr

2.8 2.6

<40 yr

2.4

25

<40 yr

20 Eesl

3.0

Eal

>60 yr

0.1 Supine

3.2

2.2

15

<40 yr

10

>60 yr

5

2.0 1.8

C

0.4

0 Supine

Sit

50% max

Max

D

Supine

Sit

50% max

Max

Figure 7-7 Comparison of ejection fraction (EF), ventricular-vascular coupling index (EaI/EesI), arterial elastance index (EaI), and ventricular elastance index (EesI) by analysis of variance. Men aged <40 years (red circles) and >60 years (yellow squares) and women aged <40 years (blue circles) and >60 years (green squares) were compared at rest (Supine Sit) and at half-maximal (50% max) and maximal (Max) exercise capacities. A, The EF is augmented with exercise in both age groups and sexes. B, Correspondingly, the EaI/EesI (i.e., the inverse of EF) decreases in both age groups and sexes. In both men and women, the decrease in EaI/EesI ratio at maximal exercise is greater (improved function) in younger than in older subjects. C, At maximal exercise, EaI is greater in older women (stiffer arteries) than in younger women, even though heart rate, which is a determinant of EaI, is greater at peak exercise in younger versus older women. In contrast, there is no difference in the EaI between the two age groups in men, even though heart rate is also significantly higher in younger than in older men at peak exercise. D, EesI increases with exercise in both age groups and sexes. At maximal exercise, EesI is greater (better) in younger men than in older men and is slightly greater in younger women than in older women. These results show that EF increase in older persons is blunted and associated with less corresponding decrease in the ventricular-vascular index with exercise. With aging, women show a smaller decrease in both arterial (Ea) and ventricular (Ees) elastance than men. However, both men and women show similar blunting in EF augmentation and decrease in EaI/EesI ratio with aging. Increased stiffness (lower compliance) of the ventricular myocardium accounts for age-associated delay in myocardial relaxation, increased filling pressure, and atrial enlargement, which contribute to the onset of adverse cardiovascular events. (From Najjar SS et al: Age and gender affect ventricularvascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611–617.)

Diastole and Stiffness Cardiac relaxation is delayed when the heart (pump) is exposed to increased systolic pressure during ejection (i.e., increased afterload), as occurs with vascular stiﬀening or enhanced systemic resistance.54,58 Ejecting into a stiﬀ thoracic aorta decreases total compliance and substantially increases pulse pressure.167 Arterialventricular stiﬀening changes the mechanical forces to which the endothelial cells and arterial smooth muscles are exposed. These mechanical forces have key roles in regulating wall tone, atherogenesis, angiogenesis, and other features of vascular hemostasis. Cardiac maladaptations such as hypertrophy and increased ventricular Ees make the net eﬀects of vascular stiﬀening even worse, particularly from the standpoint of net CV reserve, blood pressure regulation, and blood volume distribution.54 Coupling between altered systems helps explain the cause-and-eﬀect physiologic manifestations observed in many CV disease states.143 Severe cardiac dysfunction can occur in spite of normal LV contractility (i.e., EF) and geometry.168 In patients with LV diastolic dysfunction and preserved EF caused by arterial stiﬀening, the abnormal increase in LV ﬁlling

pressure is directly related to the primary hemodynamic abnormality. In these patients, an absolute change in LV ﬁlling pressure and cardiac output are potent predictors of clinical outcome. Intravascular volume depletion should be avoided, and therapy should concentrate on blood pressure reduction with vasodilators that aﬀect the renin-angiotensin-aldosterone system and sympathetic nervous system.138,139

Forward Dysfunction: End-Organ and Microvascular Damage End-Organ Pulsatility A complex network of small arteries and arterioles represents the resistance vasculature. Increased vascular capillary resistance may result from decreased lumen diameter, a longer vessel length, or rarefaction (decreased number of vessels connected in parallel).144,149 High resistance at the capillary level decreases both pulsatile ﬂow and steady ﬂow, resulting in a steady blood ﬂow through resistance vessels and tissue. Arterial pulsations, which

83

84

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction cannot enter the high-resistance vessels, are reﬂected backward and summate with the pressure of the approaching waves. The distribution of these phenomena is not identical along the arterial tree and diﬀers according to age, anatomy, and physiology of the vascular bed in question.144 In elderly people, increased vascular stiﬀness and higher systolic blood pressure and pulse pressure increase arterial pulsatility closer to the end organ, which favors end-organ damage, particularly in the heart, brain, and kidneys.144 Pressure pulsatility has major eﬀects on microvascular structure and function. Deleterious eﬀects on vascular reactivity and end-organ function are ampliﬁed in the setting of increased arterial stiﬀness and elevated pulse pressure. Reduced regional vascular resistance can diminish the decrease in pressure in the precapillary arterioles and expose the capillaries to potentially harmful levels of pressure pulsatility.169 If changes in the relationship between mean arterial pressure and ﬂow involve microvascular structural remodeling or rarefaction, as opposed to a reversible change in microvascular tone, impaired responsiveness to metabolic demand may result, causing altered autoregulatory ﬂow modulation.170

artery pulsations are normally transmitted through the pulmonary capillaries to the left atrium.15,16,178 The notable feature of the kidney and brain, compared with the heart, is that they are continually and passively perfused at high-volume ﬂow throughout both systole and diastole,145 whereas the heart is perfused principally during diastole. The vascular capillary resistance in these organs is very low, so that in comparison with other vascular beds, resistance is closer to input and characteristic impedance. Wave reﬂections from the brain and kidney are very low, and pulsatile pressure and ﬂow extend well into these organs, similar to the lungs.15,16 The brain and kidneys thus literally “throb” with each beat of the heart.145 Whereas other organs are protected by relatively intense vasoconstriction upstream, the brain and kidneys are susceptible to inﬂuences upstream that can increase ﬂuctuations in ﬂow and pressure and contribute to age-associated end-organ or microvascular damage.179–181 As with the lungs, exposure of the small vessels of the brain and kidneys to highly pulsatile pressure and ﬂow can explain microvascular damage151 and the resulting cognitive and renal dysfunction commonly encountered in the aging population.145

Heart and Coronary Perfusion

Vascular Stiffening: Summary

Coronary circulation is autoregulated but with two particularities.144,171 First, because of nearly exclusive coronary perfusion during diastole, perfusion pressures are determined by diastolic blood pressure and not mean arterial pressure. Flow into the coronary arteries during systole is caused entirely by passive distention of the epicardial arteries.172 Second, as arterial stiﬀness increases in association with systolic hypertension, atherosclerosis, or both, aortic branches with decreased lumen diameter and shorter height cause the arterial pressure reﬂections to arrive in the aortic root in late systole, rather than in diastole. The consequence is systolic pressure summation closer to the aortic valve, which impairs diastolic coronary perfusion.21,151,161,173 Age-associated increase in arterial vascular stiﬀness thus contributes to decreased coronary perfusion and secondary myocardial dysfunction, which begins as an abnormality in diastolic function (elevation of ﬁlling pressure).36 The ensuing alteration in myocardial relaxation causes a measurable increase in ventricular stiﬀness (decreases active and passive relaxation), initiating a cascade of physiologic and structural changes, which lower the threshold for the occurrence of adverse CV events.

Age-associated vascular stiﬀening increases systolic blood pressure and pulse pressure. Pulsatile forces acting on large and small arteries, down to the microvessels, contribute substantially to increased CV risk and selective end-organ damage in addition to diastolic dysfunction.179,182

Brain and Kidney Mean arterial blood pressure normally decreases by less than 1 mmHg between the ascending aorta and a peripheral artery such as the cerebral and renal arteries.145,174,175 Exposure of small vessels to highly pulsatile arterial pressure and ﬂow can explain microvascular damage and can result in stroke and cognitive dysfunction,145,176 as well as renal insuﬃciency.177 Normally pulsatile arterial energy is restricted to the major arteries and is absorbed in these vessels as a consequence of blood and arterial wall elastance. However, the renal, brain, lung, and coronary beds are different from all other vascular beds.145 The brain and myocardium receive (relatively) torrential ﬂow at rest to sustain sensitive brain cells and maintain cardiac function, respectively. The heart pulsates because it ﬁlls and empties, but the brain and kidneys also pulsate because of the high pulsatile ﬂow into and within these organs. The lungs also pulsate in a similar manner, and pulmonary

Reverse Continuity Disease (Aorta to Coronary Artery, Ventricle, and Atrial Reservoir) The age-associated increase in arterial stiﬀness is not explained on the basis of vascular disease such as atherosclerosis, which is commonly encountered in older persons; instead, the most unifying feature is that of major conduit vessels becoming larger and physiologically stiﬀer.144 Stiﬀening of the vascular system causes an increase in systolic blood pressure due to reﬂected pulse waves.144 Antegrade energy is “reﬂected” backward, with the incident and reﬂected waves summating. Summated pressure progressively increases the afterload in the aortic root, coronary arteries, ventricle, and atrial reservoir.

Coronary Perfusion A stiﬀ aorta causes pressure reﬂections to arrive more rapidly and reach the aortic root in late systole, instead of in diastole as they normally do, thus impairing coronary perfusion. The coronary ischemia causes altered Ca2+ regulation, which appears to have a fundamental role in diverse age-associated diseases and associated increased cardiac stiﬀness.57,183 With age, mitochondrial sequestration of Ca2+ decreases, release of Ca2+ from stores is greatly enhanced, and extrusion of intracellular Ca2+ is diminished. These changes delay the myocyte transition from a contracted to a relaxed state. Thus, when the atrioventricular valve opens, the atrium is confronted with a variable degree of increased ventricular myocardial stiﬀness and ﬁlling pressure. After age 50, aortic diastolic blood pressure and coronary artery perfusion tend to decrease, whereas systolic blood pressure and pulse pressure increase.184 For example, increased central pulse pressure is superior to peripheral pulse pressure in the pre-

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction diction of myocardial infarction.182 Conduit arterial physiology and morphology have strong relationships to age-associated decrease in coronary perfusion, which in turn can account for the delay in myocyte relaxation and increase in ﬁlling pressure.

ture (rarefaction) and surrounding tissue (tissue ﬁbrosis). Endorgan perfusion is particularly vulnerable to diastolic hypotension and volume depletion. The natural history of CV dysfunction “forward continuity disease” revolves around end-organ damage, which is most evident in the heart, kidney, and brain.

Ventricular and Atrial Reservoir Stiffness Age- or disease-associated increase in vascular stiﬀening and arterial afterload cause ventricular systolic and diastolic stiﬀening. The induced cascade of altered ﬁlling dynamics is typiﬁed by abnormal myocardial relaxation and increased ﬁlling pressure. The atrial appendage and pulmonary veins are normally three to four times more distensible than the body of the atrium.185,186 Distensibility of the atrium plays a major role in normal cardiac function. Increased atrial distensibility beneﬁts cardiac hemodynamics and increasing cardiac output187 through augmented atrial reservoir function.188 An increase in atrial distensibility prevents an increase in atrial pressure.189 Thus, a highly compliant left atrium, with large reservoir capacity, low pressure during atrial ﬁlling, and relatively high mean atrial pressure during ventricular ﬁlling, best maintains ventricular hemodynamics.187 A stiﬀ ventricle and increased ﬁlling pressure is reﬂected backward into the atrial reservoir. During ventricular diastole, the atrium and ventricle are directly exposed to each other, and any increase in ﬁlling pressure is reﬂected backward, causing atrial and pulmonary vein walls to become stretched. The normal reservoir capacity and distensibility of the atrium and pulmonary veins can become exceeded.190 Atrial pressure overload causes atrial myocyte stretch, upregulation of the local renin-angiotensin system, cell death, and collagen deposition.78,88,191–193 A stiﬀ, noncompliant atrial reservoir has decreased capacity to store blood during ventricular systole and is unable to increase output on demand. In older persons, incremental increase of atrial volume more commonly represents the burden of pressure overload caused by the inability of a stiﬀ ventricle to eﬃciently receive blood during diastole.78,194

Pulmonary Venous Stiffness and Pulmonary Artery Pressure Increase The symptom of breathlessness is caused by backward transition of the increased atrial pressure into the pulmonary veins, capillaries, and arteries.15,16 Dyspnea is typically caused by an increase in either pulmonary interstitial ﬂuid17 or physiologic dead space.18 The stiﬀ hypertrophied LV, coupled with increased LA and pulmonary venous pressures, produces shortness of breath.17,18 As the resistance to forward ﬂow increases, variable resting or exerciseinduced pulmonary artery hypertension develops.

Forward Continuity Disease (Aorta to Arteries, Arterioles, and Capillaries) Increased conduit stiﬀness is characterized by increased central systolic pressure and decreased diastolic pressure. The systolic pressure is augmented by pressure waves reﬂected from the periphery. The increased pulsatile pressure is transmitted into the arteries. The brain and kidney, which are not protected by an extensive compliant precapillary arterial bed, are particularly vulnerable to pressure-induced microvascular damage and perfusion deﬁcits. In response to increased systolic pressure, the microvessels increase their intima at the expense of the lumen (i.e., the intima-to-lumen ratio increases) and the normal autoregulatory function of the microvasculature. Increased pressure damages the microvascula-

CLUSTERING OF CARDIOVASCULAR RISK Is is apparent that CV dysfunction potentiates the development of adverse CV events. Heart failure (cause: altered myocardial geometry and/or ventricular stiﬀening), atrial ﬁbrillation (cause: atrial stretch, cell death, ﬁbrosis, and electrical heterogeneity), cognitive and renal dysfunction (cause: microvascular end-organ damage), and stroke (cause: atrial stretch/dysfunction, reduced circulating nitroso products, increased thrombosis) all “cluster” around age- and disease-associated CV dysfunction. Today, CV investigators are much closer to a physiologic understanding of a common causal relationship among these diverse yet interrelated, commonly age-associated, adverse CV events.

Diastolic Heart Failure with Normal Ejection Fraction and Systolic Heart Failure: Pathophysiologic Subgroups Although HF with normal EF is commonly thought to be the result of a single hemodynamic mechanism, data indicate that subgroups exist with distinctly diﬀerent underlying pathophysiologies.159,195 Diastolic dysfunction refers to mechanical and functional abnormalities present during relaxation and ﬁlling, which is usually associated with concentric hypertrophy. DHF refers to clinical syndromes in which patients with HF have little or no ventricular dilation, dominant diastolic dysfunction, and preserved EF. Systolic dysfunction refers to the decreased ability of the ventricle to develop tension and shorten, which generally leads to eccentric hypertrophy. The mechanisms leading to HF with normal EF diﬀer among patient subgroups. Subjects with preserved EF fall into two distinct subgroups: those who are nonhypertensive (e.g., idiopathic hypertrophic cardiomyopathy, inﬁltrative diseases) and those who are hypertensive.159 Subjects in the nonhypertensive group have an upward or leftward shift of the end diastolic pressure-volume curve, indicative of passive diastolic dysfunction and the classical paradigm of DHF. The LV chamber is normal or smaller than normal and hypertrophied. The hypertensive group also has an increase in LV mass and in LV end diastolic volume and a normal or even rightward shift in the end diastolic pressure-volume relationship. Within the hypertensive subgroup of patients, some have signiﬁcantly higher than normal values of ventricular and arterial elastance. The rightward shift of the pressure-volume curve may not always be the predominant factor contributing to HF in patients with hypertension. The extracardiac factors, including renal dysfunction, obesity, and anemia, among others, are speculated to account for the volume overload state. Plasma volume overload may be an important factor contributing to HF.159 SHF is the clinical syndrome in which patients with HF have distorted ventricular geometry, ventricular enlargement, and reduced EF. Diastolic dysfunction, which is closely related to elevation of ﬁlling pressure, is found in patients with both DHF and SHF and relates most closely to symptoms of breathlessness and exercise intolerance196 but does not accurately reﬂect the underlying pathophysiology or HF phenotype.195,197 DHF and SHF

85

86

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction share many clinical and hemodynamic features but are increasingly recognized to be caused by diﬀerent pathophysiologic mechanisms.195,197 LV systolic performance (stroke work), function (EF), and contractility (dP/dt, stress vs. shortening and ventricular elastance) are not signiﬁcantly diﬀerent in patients with DHF and in normal controls.168 SHF is characterized by eccentric hypertrophy, progressive LV dilation, and abnormal systolic properties. DHF exhibits concentric hypertrophy, normal or reduced LV volume, concentric remodeling, and abnormal diastolic function (i.e., reduced LV long-axis shortening,198 decreased tissue Doppler myocardial systolic velocity,199 disturbed ventriculoarterial coupling,55 slow LV relaxation, and high LV stiﬀness31). However, DHF and elevation of ﬁlling pressure also occur in patients with SHF in whom diastolic abnormalities correlate better with symptoms than with LV EF.196 The most striking diﬀerence between SHF and DHF is the tendency of the end diastolic volume to increase in SHF. Cardiomyocyte diameter is larger in DHF, and collagen volume is larger in DHF but increases similarly in SHF and DHF as ﬁbrosis progresses.195 The excess cardiomyocyte hypertrophy in DHF is strongly related to a history of arterial hypertension, which in one study was present in 73% of DHF patients and only 13% of SHF patients.195 This distinction, which can be attributed to activation of diﬀerent proliferative signaling mechanisms, has important implications, because therapy that improves prognosis of SHF may not slow progression in DHF.197 Evidence suggests that cardiomyocytes in SHF and DHF express diﬀerent gene products. Van Heerebeek et al.195 described an abnormal distribution of titin isoforms in the hearts of patients with these two clinical syndromes. Titin is a huge cytoskeletal protein found in the cardiomyocyte. Mammalian hearts contain either or both of two titin isoforms, N2BA and N2B.200 A key diﬀerence is that the N2B isoform is stiﬀer than the N2BA isoform. N2B tends to predominate in stiﬀer ventricles, whereas N2BA occurs in more compliant hearts. The less stiﬀ N2BA isoform has been reported in human dilated cardiomyopathy,201 and the stiﬀer N2B is more prominent in DHF with high diastolic stiﬀness.195 The cardiomyocyte stiﬀness observed in DHF could be attributed to the titin isoform shift. The myocardial structure and function diﬀer in SHF and DHF because of distinct cardiomyocyte abnormalities. Given the profound diﬀerences in LV volume, mass geometry, and systolic properties in patients with SHF and DHF, long-term treatment will likely be fundamentally diﬀerent.168 Elevated ﬁlling pressure, common to both SHF and DHF, best accounts for symptoms, rather than the fundamental pathologic abnormality causing the symptoms. Thus, ﬂuid manipulation and alleviation of breathlessness may not adequately address the problem, which may account for the high incidence of rehospitalization of HF patients. In patients with SHF, therapies that reverse eccentric remodeling (i.e., reverse remodeling) by decreasing LV volume and restoring LV EF result in decreased morbidity and mortality.202,203 Treatment of DHF should be directed at reversing the cellular and extracellular mechanisms that lead to concentric remodeling, ﬁbrosis, and abnormal diastolic function.168 A reversal of collagen turnover—decreasing its synthesis while increasing its degradation—would appear to accompany pharmacologic inhibition of angiotensin II, through the use of angiotensin-converting enzyme inhibition and antagonism of its AT1 receptor.204 Because a high percentage of patients with DHF have diabetes mellitus, collagen cross-links formed by advanced-glycation end products205 could also contribute to increased myocardial stiﬀness.

FUTURE RESEARCH Diastolic function assessment by invasive2 and/or noninvasive means is plagued by ambiguities surrounding the dynamic nature, lack of directness, and diﬃculty of reproducibly measuring everchanging diastolic function. Advances in noninvasive methods continue to erode the need for invasive validation. The invasive examination remains the physiologic “testing ground” for understanding instantaneous physiology. However, the Doppler echocardiographic examination is now the gold standard for clinical assessment of dynamic and chronic manifestations of diastolic function. Energy-dependent diastolic relaxation is more vulnerable to dysfunction than is systolic contraction. Thus, diastolic dysfunction is expectedly found with both systolic and diastolic cardiac dysfunction. Understanding of the complexities and redundancies of the CV system is being translated into clinical practice. Forward and reverse coupling, CV stiﬀness, risk factor clustering, elastance, distensibility, and other terms are becoming incorporated into the vernacular of the “echophysiologist.” The future of CV medicine hinges on the acquisition and understanding of the physiologic model(s) of disease. Filling pressure, myocyte contraction and relaxation, and spatial-temporal event recording are increasingly viewed as the keys to determining systolic and diastolic function and the development of primary prevention and physiologic treatment scenarios.

GLOSSARY Terms Clustering: Common risk factors attributed to cause diastolic dysfunction cluster around one another, which suggests the existence of a common underlying physiologic perturbation. Continuity disease: Dysfunction in one component of the cardiovascular system (arteries, ventricle, or atria) is transmitted to an adjoining system(s) Forward continuity: Example: Arterial stiﬀening causes contiguous stiﬀening of the distal arterial, arteriolar, and microvascular systems. Reverse continuity: Example: Arterial stiﬀening causes contiguous stiﬀening of coronary, ventricular, atrial, and pulmonary venous functions. Coupling disease: Stiﬀening of the contiguous arterial-ventricular system function Echophysiologist: A diagnostician who uses noninvasive ultrasonography to assess and model physiologic function. Stiﬀening: Increased rigidity; decreased compliance and elastance

ABBREVIATIONS CHF, congestive heart failure CV, cardiovascular

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction DHF, diastolic heart failure DT, deceleration time E, early diastolic transmitral inﬂow velocity E′, early diastolic mitral annular velocity Ea, eﬀective arterial elastance EaI, eﬀective arterial elastance index Ees, end systolic elastance EesI, end systolic elastance index EF, ejection fraction HF, heart failure LA, left atrial LV, left ventricular LVEDP, LV end diastolic pressure SHF, systolic heart failure REFERENCES 1. Baim DS, Grossman W: Grossman’s cardiac catheterization, angiography, and intervention, 5th ed. Philadelphia, Lippincott, Williams & Wilkins, 1996. 2. Kass DA. Assessment of diastolic dysfunction: Invasive modalities. Cardiol Clin 2000;18:571–586. 3. Burkhoﬀ D, Mirsky I, Suga H: Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: A guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 2005;289: 501–512. 4. Fox JM, Maurer MS: Ventriculovascular coupling in systolic and diastolic heart failure. Curr Heart Fail Rep 2005;2:204–211. 5. Braunwald E: The Simon Dack lecture. Cardiology: The past, the present, and the future. J Am Coll Cardiol 2003;42:2031–2041. 6. Little WC: Diastolic dysfunction beyond distensibility: Adverse eﬀects of ventricular dilatation. Circulation 2005;112:2888–2890. 7. Grossman W: Diastolic dysfunction in congestive heart failure. N Engl J Med 1991;325:1557–1564. 8. Klotz S, Hay I, Dickstein ML, et al: Single beat estimation of the end-diastolic pressure-volume relationship: A novel method with the potential for noninvasive application. Am J Physiol Heart Circ Physiol 2006 Jan 20. 9. Redﬁeld MM, Jacobsen SJ, Borlaug BA, et al: Age- and gender-related ventricular-vascular stiﬀening: A community-based study. Circulation 2005 Oct 11;112:2254–2262. 10. Packer M: How should we judge the eﬃcacy of drug therapy in patients with chronic congestive heart failure? The insights of six blind men. J Am Coll Cardiol 1987;9:433–438. 11. Packer M: Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure. Circulation 1990;81 Suppl: III78–III86. 12. Jacob R, Kissling G: Ventricular pressure-volume relations as the primary basis for evaluation of cardiac mechanics: Return to Frank’s diagram. Basic Res Cardiol 1989;84:227–246. 13. Diamond G, Forrester JS, Hargis J, et al: Diastolic pressure-volume relationship in the canine left ventricle. Circ Res 1971;29:267–275. 14. Labeit S, Kolmerer B: Titins: Giant proteins in charge of muscle ultrastructure and elasticity. Science 1995;270:293–296. 15. Bergel DH, Milnor WR: Pulmonary vascular impedance in the dog. Circ Res 1965;16:401–415. 16. Milnor WR, Conti CR, Lewis KB, et al: Pulmonary arterial pulse wave velocity and impedance in man. Circ Res 1969;25:637–649. 17. Myers J, Froelicher VF: Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991;115:377–386. 18. Sullivan MJ, Higginbotham MB, Cobb FR: Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 1988;77:552–559. 19. Najjar SS, Schulman SP, Gerstenblith G, et al: Age and gender aﬀect ventricular-vascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611–617. 20. Sunagawa K, Maughan WL, Burkhoﬀ D, et al: Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245: H773–H780. 21. Chen CH, Nakayama M, Nevo E, et al: Coupled systolic-ventricular and vascular stiﬀening with age: Implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221–1227.

22. Saba PS, Roman MJ, Ganau A, et al: Relationship of eﬀective arterial elastance to demographic and arterial characteristics in normotensive and hypertensive adults. J Hypertens 1995;13:971–977. 23. Fleg JL, O’Connor F, Gerstenblith G, et al: Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 1995;78:890–900. 24. Kumar A, Anel R, Bunnell E, et al: Preload-independent mechanisms contribute to increased stroke volume following large volume saline infusion in normal volunteers: A prospective interventional study. Crit Care 2004 Jun;8: R128–R136. 25. Bellenger NG, Burgess MI, Ray SG, et al: Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance: Are they interchangeable? Eur Heart J 2000;21:1387–1396. 26. Solomon SD, Anavekar N, Skali H, et al: Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators. Inﬂuence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation 2005 Dec 13;112:3738–3744. 27. Lim TK, Ashraﬁan H, Dwivedi G, et al: Increased left atrial volume index is an independent predictor of raised serum natriuretic peptide in patients with suspected heart failure but normal left ventricular ejection fraction: Implication for diagnosis of diastolic heart failure. Eur J Heart Fail 2006 Jan;8:38–45. 28. Connors AF Jr, Speroﬀ T, Dawson NV, et al: SUPPORT Investigators. The eﬀectiveness of right heart catheterization in the initial care of critically ill patients. JAMA 1996;276:889–897. 29. U.S. Department of Health and Human Services. National Institutes of Health. No increase in deaths or hospitalizations for heart failure patients who have a pulmonary artery catheter [updated 2004 Nov 9; cited 2006 Apr 26]. Available from: http://www.nhlbi.nih.gov/new/press/04–11–09.htm. 30. Senzaki H, Fetics B, Chen CH, et al: Comparison of ventricular pressure relaxation assessments in human heart failure: Quantitative inﬂuence on load and drug sensitivity analysis. J Am Coll Cardiol 1999;34:1529– 1536. 31. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure: Abnormalities in active relaxation and passive stiﬀness of the left ventricle. N Engl J Med 2004;350:1953–1959. 32. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527–1533. 33. Rivas-Gotz C, Manolios M, Thohan V, et al: Impact of left ventricular ejection fraction on estimation of left ventricular ﬁlling pressures using tissue Doppler and ﬂow propagation velocity. Am J Cardiol 2003;91:780–784. 34. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 35. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure. Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 36. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular ﬁlling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 37. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular ﬁlling pressure in sinus tachycardia: A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. 38. Sohn DW, Kim YJ, Park YB, et al: Clinical validity of measuring time difference between onset of mitral inﬂow and onset of early diastolic mitral annulus velocity in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 2004;43:2097–2101. 39. Diwan A, McCulloch M, Lawrie GM, et al: Doppler estimation of left ventricular ﬁlling pressures in patients with mitral valve disease. Circulation 2005 Jun 21;111:3281–3289. Epub 2005 Jun 13. Erratum in: Circulation 2005;112:e76. 40. Temporelli PL, Giannuzzi P, Nicolosi GL, et al: GISSI-3 Echo Substudy Investigators. Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: Results of the GISSI-3 Echo Substudy. J Am Coll Cardiol 2004;43:1646–1653. 41. Lewis RP, Sandler H: Relationship between changes in left ventricular dimensions and the ejection fraction in man. Circulation 1971;44: 548–557. 42. Baan J, van der Velde ET, de Bruin HG, et al: Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 1984;70:812–823.

87

88

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 43. Burkhoﬀ D, van der Velde E, Kass D, et al: Accuracy of volume measurement by conductance catheter in isolated, ejecting canine hearts. Circulation 1985;72:440–447. 44. Kass DA: Clinical evaluation of left heart function by conductance catheter technique. Eur Heart J 1992;13 Suppl E:57–64. 45. Kass DA, Yamazaki T, Burkhoﬀ D, et al: Determination of left ventricular end-systolic pressure-volume relationships by the conductance (volume) catheter technique. Circulation 1986;73:586–595. 46. Chen CH, Fetics B, Nevo E, et al: Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol 2001;38:2028–2034. 47. Senzaki H, Chen CH, Kass DA: Single-beat estimation of end-systolic pressure-volume relation in humans: A new method with the potential for noninvasive application. Circulation 1996;94:2497–2506. 48. Hundley WG, Kitzman DW, Morgan TM, et al: Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802. 49. Vaitkevicius PV, Fleg JL, Engel JH, et al: Eﬀects of age and aerobic capacity on arterial stiﬀness in healthy adults. Circulation 1993;88:1456– 1462. 50. Lakatta EG: Cardiovascular aging research: The next horizons. J Am Geriatr Soc 1999;47:613–625. 51. Chen CH, Nakayama M, Talbot M, et al: Verapamil acutely reduces ventricular-vascular stiﬀening and improves aerobic exercise performance in elderly individuals. J Am Coll Cardiol 1999;33:1602–1609. 52. Kitzman DW, Higginbotham MB, Cobb FR, et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072. 53. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344:17–22. 54. Kass DA: Ventricular arterial stiﬀening: Integrating the pathophysiology. Hypertension 2005 Jul;46:185–193. 55. Kawaguchi M, Hay I, Fetics B, et al: Combined ventricular systolic and arterial stiﬀening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720. 56. Kelly RP, Ting CT, Yang TM, et al: Eﬀective arterial elastance as index of arterial vascular load in humans. Circulation 1992;86:513–521. 57. Lakatta EG: Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993;73:413–467. 58. Leite-Moreira AF, Correia-Pinto J, Gillebert TC: Afterload induced changes in myocardial relaxation: A mechanism for diastolic dysfunction. Cardiovasc Res 1999;43:344–353. 59. Takimoto E, Soergel DG, Janssen PM, et al: Frequency- and afterloaddependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites. Circ Res 2004 Mar 5;94:496–504. 60. Davies JE, Whinnett ZI, Francis DP, et al: Evidence of a dominant backward-propagating “suction” wave responsibe for diastolic coronary ﬁlling in humans, attenuated in left ventricular hypertrophy. Circulation 2006 Apr 11;113:1768–1778. 61. Aurigemma GP, Zile MR, Gaasch WH: Contractile behavior of the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296–304. 62. Kass DA, Saeki A, Tunin RS, et al: Adverse inﬂuence of systemic vascular stiﬀening on cardiac dysfunction and adaptation to acute coronary occlusion. Circulation 1996;93:1533–1541. 63. Aurigemma GP, Gaasch WH: Clinical practice: Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 64. Redﬁeld MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 65. Verdecchia P, Angeli F, Gattobigio R, et al: Asymptomatic left ventricular systolic dysfunction in essential hypertension: Prevalence, determinants, and prognostic value. Hypertension 2005 Mar;45:412–418. 66. Katz AM: Role of the basic sciences in the practice of cardiology. J Mol Cell Cardiol 1987;19:3–17. 67. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 68. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal non-invasive assessment of left ventricular ﬁlling pressures: A comparison of tissue

69. 70. 71.

72. 73. 74. 75. 76. 77. 78.

79. 80. 81. 82. 83. 84. 85. 86.

87. 88. 89.

90. 91. 92.

Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004 May 25;109:2432– 2439. Dokainish H, Zoghbi WA, Lakkis NM, et al: Comparative accuracy of Btype natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure. Am J Cardiol 2004;93:1130–1135. Agricola E, Galderisi M, Oppizzi M, et al: Doppler tissue imaging: A reliable method for estimation of left ventricular ﬁlling pressure in patients with mitral regurgitation. Am Heart J 2005;150:610–615. Barberato SH, Mantilla DE, Misocami MA, et al: Eﬀect of preload reduction by hemodialysis on left atrial volume and echocardiographic Doppler parameters in patients with end-stage renal disease. Am J Cardiol 2004;94:1208–1210. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284–1289. Messerli FH: Cardiovascular eﬀects of obesity and hypertension. Lancet 1982;1:1165–1168. De Divitiis O, Fazio S, Petitto M, et al: Obesity and cardiac function. Circulation 1981;64:477–482. Wang TJ, Parise H, Levy D, et al: Obesity and the risk of new-onset atrial ﬁbrillation. JAMA 2004;292:2471–2477. Tsang TS, Barnes ME, Gersh BJ, et al: Prediction of risk for ﬁrst age-related cardiovascular events in an elderly population: The incremental value of echocardiography. J Am Coll Cardiol 2003;42:1199–1205. Douglas PS: The left atrium: A biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol 2003;42:1206– 1207. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular ﬁlling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease: Additional value of analyzing left atrial size, left atrial ejection fraction and the diﬀerence in duration of pulmonary venous and mitral ﬂow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial ﬁbrillation and congestive heart failure in patients ≥65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54–58. Robinson TF, Factor SM, Sonnenblick EH: The heart as a suction pump. Sci Am 1986;254:84–91. Yip GW, Ho PP, Woo KS, et al: Comparison of frequencies of left ventricular systolic and diastolic heart failure in Chinese living in Hong Kong. Am J Cardiol 1999;84:563–567. Gerstenblith G, Frederiksen J, Yin FC, et al: Echocardiographic assessment of a normal adult aging population. Circulation 1977;56:273–278. Fleg JL, Shapiro EP, O’Connor F, et al: Left ventricular diastolic ﬁlling performance in older male athletes. JAMA 1995;273:1371–1375. Tsang TS, Gersh BJ, Appleton CP, et al: Left ventricular diastolic dysfunction as a predictor of the ﬁrst diagnosed nonvalvular atrial ﬁbrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636–1644. Tsang TS, Barnes ME, Bailey KR, et al: Left atrial volume: Important risk marker of incident atrial ﬁbrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467–475. Appleton CP, Hatle LK, Popp RL: Relation of transmitral ﬂow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. Nishimura RA, Abel MD, Hatle LK, et al: Assessment of diastolic function of the heart: Background and current applications of Doppler echocardiography. Part II. Clinical studies. Mayo Clin Proc 1989;64:181–204. Rossvoll O, Hatle LK: Pulmonary venous ﬂow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696. Redﬁeld MM, Rodeheﬀer RJ, Jacobsen SJ, et al: Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: A community-based study. Circulation 2004 Jun 29;109:3176– 3181. Sengupta PP, Khandheria BK, Korinek J, et al: Apex-to-base dispersion in regional timing of left ventricular shortening and lengthening. J Am Coll Cardiol 2006 Jan 3;47:163–172. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 2000;87:235– 240. Brutsaert DL, Sys SU, Gillebert TC: Diastolic failure: Pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318–325. Erratum in: J Am Coll Cardiol 1993;22:1272.

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 93. Cheng CP, Freeman GL, Santamore WP, et al: Eﬀect of loading conditions, contractile state, and heart rate on early diastolic left ventricular ﬁlling in conscious dogs. Circ Res 1990;66:814–823. 94. Yellin EL, Nikolic S, Frater RW: Left ventricular ﬁlling dynamics and diastolic function. Prog Cardiovasc Dis 1990;32:247–271. 95. Yellin EL, Hori M, Yoran C, et al: Left ventricular relaxation in the ﬁlling and nonﬁlling intact canine heart. Am J Physiol 1986;250:H620– H629. 96. Gilbert JC, Glantz SA: Determinants of left ventricular ﬁlling and of the diastolic pressure-volume relation. Circ Res 1989;64:827– 852. 97. Nikolic S, Yellin EL, Tamura K, et al: Passive properties of canine left ventricle: Diastolic stiﬀness and restoring forces. Circ Res 1988;62:1210–1222. Erratum in: Circ Res 1988;62:1059. 98. Vatner SF, Pagani M: Cardiovascular adjustments to exercise: Hemodynamics and mechanisms. Prog Cardiovasc Dis 1976;19:91–108. 99. Poliner LR, Dehmer GJ, Lewis SE, et al: Left ventricular performance in normal subjects: A comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528–534. 100. Higginbotham MB, Morris KG, Williams RS, et al: Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986;58:281–291. 101. Nonogi H, Hess OM, Ritter M, et al: Diastolic properties of the normal left ventricle during supine exercise. Br Heart J 1988;60:30–38. 102. Yotti R, Bermejo J, Antoranz JC, et al: A noninvasive method for assessing impaired diastolic suction in patients with dilated cardiomyopathy. Circulation 2005;112:2921–2929. 103. Rovner A, Greenberg NL, Thomas JD, et al: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005 Nov;289:H2081– H2088. 104. Solomon SB, Nikolic SD, Glantz SA, et al: Left ventricular diastolic function of remodeled myocardium in dogs with pacing-induced heart failure. Am J Physiol 1998;274:H945–H954. 105. Wang Z, Jalali F, Sun YH, et al: Assessment of left ventricular diastolic suction in dogs using wave-intensity analysis. Am J Physiol Heart Circ Physiol 2005 Apr;288;H1641–H1651. Erratum in: Am J Physiol Heart Circ Physiol 2005;288:H3017. 106. Courtois M, Kovacs SJ Jr, Ludbrook PA: Transmitral pressure-ﬂow velocity relation: Importance of regional pressure gradients in the left ventricle during diastole. Circulation 1988;78:661–671. 107. Sabbah HN, Stein PD: Pressure-diameter relations during early diastole in dogs: Incompatibility with the concept of passive left ventricular ﬁlling. Circ Res 1981;48:357–365. 108. Cheng CP, Noda T, Nozawa T, et al: Eﬀect of heart failure on the mechanism of exercise-induced augmentation of mitral valve ﬂow. Circ Res 1993;72:795–806. 109. Katz LN: The role played by the ventricular relaxation process in ﬁlling the ventricle. Am J Physiol 1930;95:542–553. 110. Bell SP, Fabian J, LeWinter MM: Eﬀects of dobutamine on left ventricular restoring forces. Am J Physiol 1998;275:H190–H194. 111. Ling D, Rankin JS, Edwards CH II, et al: Regional diastolic mechanics of the left ventricle in the conscious dog. Am J Physiol 1979;236: H323–H330. 112. Falsetti HL, Verani MS, Chen CJ, et al: Regional pressure diﬀerences in the left ventricle. Cathet Cardiovasc Diagn 1980;6:123–134. 113. Nikolic SD, Feneley MP, Pajaro OE, et al: Origin of regional pressure gradients in the left ventricle during early diastole. Am J Physiol 1995;268: H550–H557. 114. Firstenberg MS, Smedira NG, Greenberg NL, et al: Relationship between early diastolic intraventricular pressure gradients, an index of elastic recoil, and improvements in systolic and diastolic function. Circulation 2001;104 Suppl 1:I330–I335. 115. Udelson JE, Bacharach SL, Cannon RO III, et al: Minimum left ventricular pressure during beta-adrenergic stimulation in human subjects: Evidence for elastic recoil and diastolic “suction” in the normal heart. Circulation 1990;82:1174–1182. 116. Pasipoularides A, Shu M, Shah A, et al: RV instantaneous intraventricular diastolic pressure and velocity distributions in normal and volume overload awake dog disease models. Am J Physiol Heart Circ Physiol 2003 Nov;285: H1956–1965. Erratum in: Am J Physiol Heart Circ Physiol 2004;287: H2367. 117. Weisfeldt ML, Frederiksen JW, Yin FC, et al: Evidence of incomplete left ventricular relaxation in the dog: Prediction from the time constant for isovolumic pressure fall. J Clin Invest 1978;62:1296–1302.

118. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiﬀness from the time for deceleration of early left ventricular ﬁlling. Circulation 1995;92:1933–1939. 119. Marino P, Faggian G, Bertolini P, et al: Early mitral deceleration and left atrial stiﬀness. Am J Physiol Heart Circ Physiol 2004 Sep;287: H1172–H1178. 120. Lisauskas JB, Singh J, Bowman AW et al: Chamber properties from transmitral ﬂow: Prediction of average and passive left ventricular diastolic stiﬀness. J Appl Physiol 2001;91:154–162. 121. Thomas JD, Popovic ZB: Intraventricular pressure diﬀerences: A new window into cardiac function. Circulation 2005;112:1684–1686. 122. Vita JA, Keaney JF Jr, Larson MG, et al: Brachial artery vasodilator function and systemic inﬂammation in the Framingham Oﬀspring Study. Circulation 2004 Dec 7;110:3604–3609. 123. Hadler NM: A ripe old age. Arch Intern Med 2003;163:1261–1262. 124. Oeppen J, Vaupel JW: Demography: Broken limits to life expectancy. Science 2002;296:1029–1031. 125. Braunwald E: Shattuck lecture. Cardiovascular medicine at the turn of the millennium: Triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360–1369. 126. Rich MW: Heart failure in the 21st century: A cardiogeriatric syndrome. J Gerontol A Biol Sci Med Sci 2001;56:M88–M96. 127. Gottdiener JS, McClelland RL, Marshall R, et al: Outcome of congestive heart failure in elderly persons: Inﬂuence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med 2002;137:631–639. 128. Senni M, Tribouilloy CM, Rodeheﬀer RJ, et al: Congestive heart failure in the community: A study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–2289. 129. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33:1948–1955. 130. Kitzman DW, Gardin JM, Gottdiener JS, et al: Cardiovascular Health Study Research Group. Importance of heart failure with preserved systolic function in patients ≥65 years of age. Am J Cardiol 2001;87:413–419. 131. Kelly RV, Tan WA, Cho H, et al: Prevalence of symptomatic diastolic heart failure in patients hospitalized with cerebral or peripheral vascular disease. Congest Heart Fail 2005;11:256–261. 132. Vasan RS, Benjamin EJ, Levy D: Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol 1995;26:1565–1574. 133. Smith GL, Masoudi FA, Vaccarino V, et al: Outcomes in heart failure patients with preserved ejection fraction: Mortality, readmission, and functional decline. J Am Coll Cardiol 2003;41:1510–1518. 134. Senni M, Redﬁeld MM: Heart failure with preserved systolic function: A diﬀerent natural history? J Am Coll Cardiol 2001;38:1277–1282. 135. McAlister FA, Teo KK, Taher M, et al: Insights into the contemporary epidemiology and outpatient management of congestive heart failure. Am Heart J 1999;138:87–94. 136. Kupari M, Lindroos M, Iivanainen AM, et al: Congestive heart failure in old age: Prevalence, mechanisms and 4-year prognosis in the Helsinki Ageing Study. J Intern Med 1997;241:387–394. 137. Jaarsma T, Halfens R, Abu-Saad HH, et al: Quality of life in older patients with systolic and diastolic heart failure. Eur J Heart Fail 1999;1:151– 160. 138. Stevenson LW: Are hemodynamic goals viable in tailoring heart failure therapy? Hemodynamic goals are relevant. Circulation 2006;113: 1020–1027. 139. Le Jemtel TH, Alt EU: Are hemodynamic goals viable in tailoring heart failure therapy? Hemodynamic goals are outdated. Circulation 2006;113:1027–1032. 140. Tsutsui H, Tsuchihashi M, Takeshita A: Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function. Am J Cardiol 2001;88:530–533. 141. Safar ME: Pulse pressure, arterial stiﬀness, and cardiovascular risk. Curr Opin Cardiol 2000;15:258–263. 142. Philbin EF, Rocco TA Jr, Lindenmuth NW, et al: Systolic versus diastolic heart failure in community practice: Clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors. Am J Med 2000;109: 605–613. 143. Safar ME, Thomas F, Blacher J, et al: Metabolic syndrome and agerelated progression of aortic stiﬀness. J Am Coll Cardiol 2006 Jan 3;47: 72–75. 144. Safar ME: Peripheral pulse pressure, large arteries, and microvessels. Hypertension 2004 Aug;44:121–122.

89

90

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 145. O’Rourke MF, Safar ME: Relationship between aortic stiﬀening and microvascular disease in brain and kidney: Cause and logic of therapy. Hypertension 2005 Jul;46:200–204. 146. Bell SP, Fabian J, Watkins MW, et al: Decrease in forces responsible for diastolic suction during acute coronary occlusion. Circulation 1997;96: 2348–2352. 147. Courtois M, Kovacs SJ, Ludbrook PA: Physiological early diastolic intraventricular pressure gradient is lost during acute myocardial ischemia. Circulation 1990;81:1688–1696. 148. Rovner A, Smith R, Greenberg NL, et al: Improvement in diastolic intraventricular pressure gradients in patients with HOCM after ethanol septal reduction. Am J Physiol Heart Circ Physiol 2003 Dec;285:H2494– H2499. 149. Nichols WW, O’Rourke MF: McDonald’s blood ﬂow in arteries: Theoretical, experimental and clinical principles, 5th ed. London, Hodder Arnold, 2005. 150. Kelly R, Hayward C, Avolio A, et al: Noninvasive determination of agerelated changes in the human arterial pulse. Circulation 1989;80:1652– 1659. 151. Mitchell GF, Parise H, Benjamin EJ, et al: Changes in arterial stiﬀness and wave reﬂection with advancing age in healthy men and women: The Framingham Heart Study. Hypertension 2004 Jun;43:1239– 1245. 152. Asmar R, Rudnichi A, Blacher J, et al: Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertens 2001;14:91–97. 153. Miura K, Dyer AR, Greenland P, et al: Chicago Heart Association. Pulse pressure compared with other blood pressure indexes in the prediction of 25-year cardiovascular and all-cause mortality rates: The Chicago Heart Association Detection Project in Industry Study. Hypertension 2001;38: 232–237. 154. Haider AW, Larson MG, Franklin SS, et al. for Framingham Heart Study: Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003;138:10–16. 155. Smulyan H, Asmar RG, Rudnicki A, et al: Comparative eﬀects of aging in men and women on the properties of the arterial tree. J Am Coll Cardiol 2001;37:1374–1380. 156. Gatzka CD, Kingwell BA, Cameron JD, et al: ANBO2 Investigators, Australian comparative outcome trial of angiotensin-converting enzyme inhibitor- and diuretic-based treatment of hypertension in the elderly. Gender diﬀerences in the timing of arterial wave reﬂection beyond diﬀerences in body height. J Hypertens 2001;19:2197–2203. 157. Hayward CS, Kelly RP: Gender-related diﬀerences in the central arterial pressure waveform. J Am Coll Cardiol 1997;30:1863–1871. 158. Yancy CW, Lopatin M, Stevenson LW, et al: ADHERE Scientiﬁc Advisory Committee and Investigators. Clinical presentation, management, and inhospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: A report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006 Jan 3;47:76–84. 159. Maurer MS, King DL, El-Khoury Rumbarger L, et al: Left heart failure with a normal ejection fraction: Identiﬁcation of diﬀerent pathophysiologic mechanisms. J Card Fail 2005;11:177–187. 160. Avolio AP, Deng FQ, Li WQ, et al: Eﬀects of aging on arterial distensibility in populations with high and low prevalence of hypertension: Comparison between urban and rural communities in China. Circulation 1985;71: 202–210. 161. Kass DA: Age-related changes in ventricular-arterial coupling: Pathophysiologic implications. Heart Fail Rev 2002;7:51–62. 162. Cohen-Solal A, Caviezel B, Laperche T, et al: Eﬀects of aging on left ventricular-arterial coupling in man: Assessment by means of arterial eﬀective and left ventricular elastances. J Hum Hypertens 1996;10:111– 116. 163. Little WC, Cheng CP: Left ventricular-arterial coupling in conscious dogs. Am J Physiol 1991;261:H70–H76. 164. Burkhoﬀ D, de Tombe PP, Hunter WC, et al: Contractile strength and mechanical eﬃciency of left ventricle are enhanced by physiological afterload. Am J Physiol 1991;260:H569–H578. 165. Van der Velde ET, Burkhoﬀ D, Steendijk P, et al: Nonlinearity and load sensitivity of end-systolic pressure-volume relation of canine left ventricle in vivo. Circulation 1991;83:315–327. 166. Saba PS, Ganau A, Devereux RB, et al: Impact of arterial elastance as a measure of vascular load on left ventricular geometry in hypertension. J Hypertens 1999;17:1007–1015.

167. Saeki A, Recchia F, Kass DA: Systolic ﬂow augmentation in hearts ejecting into a model of stiﬀ aging vasculature: Inﬂuence on myocardial perfusiondemand balance. Circ Res 1995;76:132–141. 168. Baicu CF, Zile MR, Aurigemma GP, et al: Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005 May 10;111:2306–2312. 169. Loutzenhiser R, Bidani A, Chilton L: Renal myogenic response: Kinetic attributes and physiological role. Circ Res 2002;90:1316–1324. 170. Mitchell GF, Vita JA, Larson MG, et al: Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiﬀness: The Framingham Heart Study. Circulation 2005 Dec 13;112:3722–3728. 171. Hoﬀman JI: A critical view of coronary reserve. Circulation 1987;75: I6–I11. 172. Douglas JE, Greenﬁeld JC Jr: Epicardial coronary artery compliance in the dog. Circ Res 1970;27:921–929. 173. Lakatta EG, Levy D: Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises. Part I. Aging arteries: A “set up” for vascular disease. Circulation 2003;107:139–146. 174. Pauca AL, Wallenhaupt SL, Kon ND, et al: Does radial artery pressure accurately reﬂect aortic pressure? Chest 1992;102:1193– 1198. 175. Pauca AL, O’Rourke MF, Kon ND: Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension 2001;38:932–937. 176. Laurent S, Katsahian S, Fassot C, et al: Aortic stiﬀness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003 May;34:1203–1206. 177. Safar ME, London GM, Plante GE: Arterial stiﬀness and kidney function. Hypertension 2004 Feb;43:163–168. 178. Smiseth OA, Thompson CR, Lohavanichbutr K, et al: The pulmonary venous systolic ﬂow pulse: Its origin and relationship to left arterial pressure. J Am Coll Cardiol 1999;34:802–809. 179. Rizzoni D, Porteri E, Boari GE, et al: Prognostic signiﬁcance of small-artery structure in hypertension. Circulation 2003 Nov 4;108:2230– 2235. 180. Schoﬁeld I, Malik R, Izzard A, et al: Vascular structural and functional changes in type 2 diabetes mellitus: Evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation 2002;106:3037– 3043. 181. Verhave JC, Fesler P, du Cailar G, et al: Elevated pulse pressure is associated with low renal function in elderly patients with isolated systolic hypertension. Hypertension 2005 Apr;45:586–591. 182. Safar ME, Levy BI, Struijker-Boudier H: Current perspectives on arterial stiﬀness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003;107:2864–2869. 183. Apstein CS, Morgan JP: Cellular mechanisms underlying left ventricular diastolic dysfunction. In Gaasch WH, LeWinter MM (eds): Left ventricular diastolic dysfunction and heart failure. Philadelphia, Lea & Febiger, 1994:3–24. 184. Rizzoni D, Palombo C, Porteri E, et al: Relationships between coronary ﬂow vasodilator capacity and small artery remodelling in hypertensive patients. J Hypertens 2003;21:625–631. 185. Goto M, Arakawa M, Suzuki T, et al: A quantitative analysis of reservoir function of the human pulmonary “venous” system for the left ventricle. Jpn Circ J 1986;50:222–231. 186. Hoit BD, Walsh RA: Regional atrial distensibility. Am J Physiol 1992;262: H1356–H1360. 187. Suga H: Importance of atrial compliance in cardiac performance. Circ Res. 1974;35:39–43. 188. Nagano T, Arakawa M, Tanaka T, et al: Diastolic compliance of the left atrium in man: A determinant of preload of the left ventricle. Heart Vessels 1989;5:25–32. 189. Kihara Y, Sasayama S, Miyazaki S, et al: Role of the left atrium in adaptation of the heart to chronic mitral regurgitation in conscious dogs. Circ Res 1988;62:543–553. 190. Davis CA III, Rembert JC, Greenﬁeld JC Jr: Compliance of left atrium with and without left atrium appendage. Am J Physiol 1990;259: H1006–H1008. 191. Basnight MA, Gonzalez MS, Kershenovich SC, et al: Pulmonary venous ﬂow velocity: Relation to hemodynamics, mitral ﬂow velocity and left atrial volume, and ejection fraction. J Am Soc Echocardiogr. 1991;4:547– 558. 192. Little WC, Downes TR: Clinical evaluation of left ventricular diastolic performance. Prog Cardiovasc Dis 1990;32:273–290.

Chapter 7 • Invasive Physiology: Clinical Cardiovascular Pathophysiology and Diastolic Dysfunction 193. Matsuda Y, Toma Y, Matsuzaki M, et al: Change of left atrial systolic pressure waveform in relation to left ventricular end-diastolic pressure. Circulation 1990;82:1659–1667. 194. Simek CL, Feldman MD, Haber HL, et al: Relationship between left ventricular wall thickness and left atrial size: Comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8: 37–47. 195. Van Heerebeek L, Borbely A, Niessen HW, et al: Myocardial structure and function diﬀer in systolic and diastolic heart failure. Circulation 2006 Apr 25;113:1966–1973. 196. Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004 Mar 2;109:972–977. 197. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure. Circulation 2006;113:1922–1925. 198. Yip G, Wang M, Zhang Y, et al: Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redeﬁnition? Heart 2002;87:121–125.

199. Yu CM, Lin H, Yang H, et al: Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation 2002;105:1195–1201. 200. LeWinter MM: Titin isoforms in heart failure: Are there beneﬁts to supersizing? Circulation 2004;110:109–111. 201. Nagueh SF, Shah G, Wu Y, et al: Altered titin expression, myocardial stiﬀness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 2004 Jul 13;110:155–162. 202. Konstam MA, Udelson JE, Anand IS, et al: Ventricular remodeling in heart failure: A credible surrogate endpoint. J Card Fail 2003;9:350–353. 203. Udelson JE, Patten RD, Konstam MA: New concepts in post-infarction ventricular remodeling. Rev Cardiovasc Med 2003;4 Suppl 3:S3–S12. 204. Weber KT: Are myocardial ﬁbrosis and diastolic dysfunction reversible in hypertensive heart disease? Congest Heart Fail 2005;11:322–324. 205. Herrmann KL, McCulloch AD, Omens JH: Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy. Am J Physiol Heart Circ Physiol 2003;284:H1277–H1284.

91

SRIKANTH SOLA, MD

8

Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging INTRODUCTION PRINCIPLES OF MAGNETIC RESONANCE IMAGING Physics of Magnetic Resonance Imaging Basic Imaging Sequences CLINICAL RELEVANCE Hypertropic Cardiomyopathy Hypertension and Aortic Stenosis Coronary Artery Disease

Dilated Cardiomyopathy Constrictive Pericarditis Restrictive Cardiomyopathy Cardiac Amyloidosis Cardiac Sarcoidosis Hemochromatosis LIMITATIONS OF CARDIAC MAGNETIC RESONANCE IMAGING FUTURE RESEARCH

INTRODUCTION Recent advances in image acquisition techniques and scanner hardware have allowed magnetic resonance imaging (MRI) to become a useful tool in the noninvasive assessment of cardiovascular diseases. In addition to high-resolution anatomical images, cardiovascular magnetic resonance (CMR) provides quantitative assessment of ventricular function, myocardial perfusion, viability, and shunt ﬂow and measurements of valvular velocities and gradients.1–3 In addition, coronary, pulmonary, and systemic vasculatures can be assessed with contrast-enhanced magnetic resonance angiography (MRA) without the use of ionizing radiation or nephrotoxic contrast agents. CMR’s comprehensive ability to image the heart also makes it a useful tool in the evaluation of diastolic function.

PRINCIPLES OF MAGNETIC RESONANCE IMAGING Physics of Magnetic Resonance Imaging All atoms have nuclei that are composed of one or more protons. These protons have a small positive electric charge and spin at a rapid rate. The rapid spinning motion of a positively charged proton produces a very small but measurable magnetic ﬁeld that in a sense is like a tiny bar magnet. Normally, the magnetic ﬁelds of these protons are randomly oriented throughout the body. When placed within an MRI scanner, the protons within the body will align themselves with the external magnetic ﬁeld of the scanner, just like a compass would align itself with Earth’s magnetic ﬁeld. By applying speciﬁc radiofrequency (RF) waves, some of these protons will change their alignment (“resonate”) to a more 93

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging

RV LV

RV LV

LV Liver

Liver

Liver

A

C

B

Basic Imaging Sequences MRI depends on using gradient coils within the scanner to send RF pulses in speciﬁc patterns to stimulate the 1H protons within the body. As these protons relax, they emit signals that are detected by receiver coils placed over the surface of the body. Pulse sequences are combinations of diﬀerent types of RF pulses that are placed together to create images with speciﬁc characteristics. Combinations of diﬀerent pulse sequences can be used to evaluate parameters that deﬁne both global and regional diastolic functions. These parameters include: ﬂow mapping of the mitral valve, pulmonary vein, and tricuspid valve; global and regional rotation; translation and radial motion; peak ﬁlling rate (PFR) and timeto-peak ﬁlling rate (TPFR) of contrast; and phosphorus-31 magnetic resonance (31P-MR) spectroscopy to measure myocardial energy content. The most common types of pulse sequences relevant to diastolic function are the following.

Spin Echo or “Black Blood” Images These pulse sequences are designed so that ﬂowing blood produces no signal and appears black (Fig. 8-1A). However, because of the time required to stimulate and then saturate the signal emitted from the ﬂowing blood, spin echo pulse sequences produce still images. Spin echo sequences can be “weighted” to highlight diﬀerent relaxation properties of the protons, resulting in T1 (T1w) or T2 (T2w) weighted images. Although spin echo sequences are not used speciﬁcally to evaluate cardiac diastolic function, they do provide good tissue contrast and anatomical detail, making them useful for visualizing morphology.

A

140

MVC

AVC

AVO

excited state. As these protons relax and return to their original alignment, they give oﬀ an RF signal that can be measured and used to generate a clinical image. Since hydrogen (1H) is the most abundant atom in the body capable of generating a clinically useful image, 1H protons form the basis of clinical MRI.

MVO

Figure 8-1 Hypertrophic obstructive cardiomyopathy. A, Short axis spin echo image. Moving blood is black, whereas myocardium and fat have intermediate and high signal intensities, respectively. Note the prominent interventricular septum (arrow). The right ventricle is not well seen on this image. B, GRE still-frame image at the same level. Blood is bright (white) on this image. C, DE-MRI image at the same level. Note the area of hyperenhanced (bright) myocardium in the inferoseptal wall (arrow) near the right ventricular (RV) insertion point, which represents scarred or fibrotic tissue. LV, left ventricle.

B

C

D

E

F

130 LV cavity volume (ml)

94

120 110 100 90 80 70 60 50 0

100

200

300

400

500

600

700

Time (msec) A: Ejection B: Isovolumic relaxation C: Early filling D: Diastasis E: Atrial contraction F : Isovolumic contraction Figure 8-2 Volume-time curve of the left ventricle during the cardiac cycle in a 27-year-old healthy volunteer. Cine MRI, using a GrE (balanced steadystate-free precession) technique, was used to generate a stack of short axis images encompassing the left ventricle. Planimetry of the left ventricular (LV) endocardial border of each short axis image creates a time-volume curve. The onset of ejection (A), characterized by decrease in LV volume, coincides with aortic valve opening (AVO). At aortic valve closure (AVC), the minimal LV volume is obtained. The difference in volume between AVO and AVC represents the stroke volume (SV). The time period between AVC and mitral valve opening (MVO) is the isovolumic relaxation (B). At the moment of MVO, ventricular filling starts. This is characterized by an early, fast-filling phase (C), a period with nearly no filling (diastasis, D), and a final phase of filling caused by atrial contraction (E). The last part (i.e., isovolumic contraction) starts with mitral valve closure (MVC) and ends with AVO. (From Bogaert J: Cardiac function. In Bogaert J et al (eds): Clinical Cardiac MRI. Springer-Verlag, 2005:99–141.)

Gradient Echo or “White Blood” Images These pulse sequences are fast enough to “catch” the signal coming from excited blood so that blood appears white (Fig. 8-1B). Gradient echo (GRE) sequences produce cine images with good temporal resolution (typically 20–30 fps; up to 70 fps for perfusion imaging). GRE sequences are used for evaluating cardiac function as well as turbulent ﬂow due to valvular disease or intracardiac shunts.

GRE sequences yield accurate and highly reproducible measurements of ventricular volumes and indices of cardiac systolic function without the need for geometric assumptions.4,5 From the contours describing the endocardial and epicardial borders of the myocardium, time-volume curves can be derived that assess global diastolic function (Fig. 8-2). The peak ﬁlling rate (PFR) from

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging these curves describes the maximum change in cm2 per second during the rapid ﬁlling phase of ventricular systole, whereas time to PFR is measured between end systole and the point at which PFR occurs. Both PFR and time to PFR are typically prolonged when diastolic function is impaired.6,7

Phase Velocity or Phase Contrast Imaging As hydrogen nuclei move through a magnetic ﬁeld, they shift their particular phase (the manner in which protons rotate about a particular axis) in a way that is proportional to their velocity. Phase-contrast MRI (PC-MRI), which is somewhat analogous to pulsed-wave Doppler echocardiography, takes advantage of this change in phase with velocity to measure the velocity of blood moving through an area of interest. Clinically, PC-MRI is used to calculate transvalvular velocities as well as gradients, regurgitant volumes, and ratios of pulmonary-to-systemic blood ﬂows (Qp/Qs). Flow mapping of mitral and tricuspid valve inﬂow

95

using PC-MRI allows accurate assessment of peak velocities and volume ﬂow of early (E) and late or atrial (A) ﬁlling waves (Fig. 8-3), showing good correlation with Doppler-derived data.8–10 Similar techniques are also used to map pulmonary and caval venous ﬂow (Fig. 8-4).11 More recently, PC-MRI measurements of tissue velocities have been used to quantify myocardial velocities, enabling calculation of local strain. Strain rate can also be quantiﬁed for regions of myocardium as well as for each myocardial voxel.12

Myocardial Tagging A unique feature of CMR is that it allows the myocardium to be magnetically labeled with a rectangular or radial grid that acts as a marker of myocardial deformation during contraction (Fig. 8-5) and also shows abnormal myocardial tagging. The creation of tags requires the application of speciﬁc RF pre-pulses in one or more planes perpendicular to the imaging plane, prior to the application 30

35 E

25

30 20

20

Velocity cm/sec

Velocity cm/sec

25 A

15 10

15

S

D

10 5 0

5

–5

0

–10

A

–15

–5 0

100

200

300

400

500

600

85 170 255 340 425 510 595 680 765 850 935 Time (msec)

A

Time (msec)

A

0

700 30

25

A 25 20 Velocity cm/sec

Velocity cm/sec

20 15 10 E 5

D 15 S 10 5 0 A –5

0

–10 0 0

B

100

200

300

400

500

600

700

Time (msec)

Figure 8-3 A, Mitral inflow pattern using PC-MRI in a 24-year-old healthy subject, depicting normal E/A ratio. B, Severe myocardial relaxation disturbance leading to reversal of the E/A ratio. The early filling velocities are strongly decreased (E), whereas the late-filling velocities are increased (A). (From Bogaert J: Cardiac Function. In Bogaert J et al (eds): Clinical Cardiac MRI. Springer-Verlag, 2005:99–141.)

B

85 170 255 340 425 510 595 680 765 850 935 Time (msec)

Figure 8-4 Venous flow patterns using PC-MRI in a 39-year-old healthy subject through the inferior vena cava (A) and pulmonary vein (B). In the inferior vena cava, the systolic (S) forward-flow velocity is slightly larger than the diastolic (D) flow. Line A represents the reversed flow caused by atrial contraction. In the pulmonary vein (B), diastolic forward-flow velocities slightly exceed systolic forward-flow velocities. (From Bogaert J: Cardiac Function. In Bogaert J et al (eds): Clinical Cardiac MRI. Springer-Verlag, 2005:99–141.)

96

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging of RF pulses that are used for cine (bright blood) imaging.13 The tagging pre-pulses cause the tissue in the tag planes to be “saturated” so that they appear as hypointense or black lines compared with the normal surrounding tissue. By measuring tag displacement and deformation during the cardiac cycle, myocardial deformation can be analyzed, which serves as the basis for strain and strain rate analysis using CMR (Fig. 8-6).14–16 Images can be obtained every 20 msec, allowing very high temporal resolution.17 Clinically, myocardial tagging is used in the evaluation of diastolic function, of abnormal myocardial deformation in patients with hypertrophic cardiomyopathy (HCM) or complex congenital heart disease, and of pericardial motion in patients with suspected constrictive pericarditis and in the diﬀerentiation of solid structures (e.g., muscular tissue from tumor or thrombus).18–20 Diﬀerent myocardial tagging techniques are currently available that allow

RV

LV

B

A

Delayed Hyperenhancement In areas where the myocardium is scarred or ﬁbrotic, there is delayed “wash-in” and “wash-out” of MRI contrast agents. These ﬁbrotic or scarred areas show up as bright or “hyperenhanced” areas of myocardium when “delayed” images are taken, typically 10–15 minutes after injection of gadolinium-DTPA (diethylenetriamine penta-acetic acid) (see Fig. 8-1C). A special inversion signal given prior to the main pulse sequence is used to “null” the signal from the normal myocardium so that it can be more easily distinguished from abnormal, hyperenhanced myocardium. Speciﬁc patterns of hyperenhancement correspond with certain cardiovascular diseases and can be used to distinguish ischemic from non-ischemic cardiomyopathy, as well as to diﬀerentiate among diﬀerent forms of inﬁltrative cardiomyopathies (Fig. 8-7).

Magnetic Resonance Spectroscopy

RV LV

evaluation of myocardial deformation in both two-dimensions and three-dimensions.21

Figure 8-5 Myocardial tagging in a healthy individual demonstrating normal patterns of myocardial deformation between end diastole (A) and end systole (B).

Besides 1H, other magnetic nuclei in the human body, such as 23 Na, 13C, 19F, and 31P, can also generate MRI signals, though normally with much less intensity and under much more technically demanding conditions. 31P-MR spectroscopy provides a proﬁle of regional adenosine triphosphate (ATP) and phosphocreatine (PCr) contents and thus an estimate of energy status and viability A-wave (SRA) E-wave (SRE)

E-wave (SRE)

A-wave (SRA)

1.5

1.5 Strain rate (1/sec)

Strain rate (1/sec)

1.0 1.0 0.5 0 –0.5

0.5 0 –0.5 –1.0

–1.0

–1.5

Peak systolic strain rate (SRS)

Peak systolic strain rate (SRS)

5

5 0 Strain (%)

Strain (%)

0 –5 –10

–10 –15

–15

–20

–20 0

A

–5

200

400

600 Time (msec)

800

1000

0

1200

B

200

400

600

800

1000

1200

Time (msec)

Figure 8-6 A, Representative strain rate (upper) and strain (lower) profiles from a healthy subject. Profiles were measured using tagged GrE images from the anterior wall segment of a short axis slice at a midventricular level. The markers on the strain and strain rate traces represent the time resolution (54 msec). B, Strain rate (upper) and strain (lower) from a person with left ventricular hypertrophy. Note the depressed SRE lower than 1.0 s−1 and the intact systolic function. (From Edvardsen T et al: Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging—the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2006;151:109–114.)

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging HYPERENHANCEMENT PATTERNS Ischemic

A. Subendocardial infarct

Non-ischemic

A. Mid-wall HE

• Idiopathic dilated • Hypertrophic cardiomyopathy cardiomyopathy • Myocarditis • Right ventricular pressure overload (e.g. congenital heart disease, pulmonary HTN)

• Sarcoidosis • Myocarditis • Anderson-Fabry • Chagas disease

B. Epicardial HE B. Transmural infarct

• Sarcoidosis, myocarditis, Anderson-Fabry, Chagas disease

C. Global endocardial HE Figure 8-7 Hyperenhancement (HE) patterns seen in common clinical conditions. If hyperenhancement is present, the endocardium should be involved in patients with ischemic disease. Isolated midwall or epicardial hyperenhancement strongly suggests a non-ischemic etiology. (From Shah et al, in Edelman RR et al (eds): Clinical Magnetic Resonance Imaging, 3rd ed. Elsevier, 2005.)

of the myocardium.22 Myocardial relaxation is an active, energydependent process, and changes in the ratio of myocardial PCr and ATP levels (PCr/ATP) by 31P-MR spectroscopy are seen in abnormal diastolic function.23 On a cellular level, these abnormalities in PCr/ATP ratios are thought to result in impaired Ca2+ sequestration, leading to impaired relaxation in cardiac myocytes.

CLINICAL RELEVANCE This section reviews the role of CMR in evaluating diastolic function in a spectrum of cardiac disorders, including HCM, ischemic heart disease, constrictive pericarditis, and restrictive cardiomyopathies.

Hypertrophic Cardiomyopathy The characteristic ﬁnding of HCM is an inappropriate myocardial hypertrophy in the absence of an obvious cause, such as aortic stenosis or hypertension. Although transthoracic echocardiography is the primary imaging modality in HCM, CMR is an excellent alternative in the diagnosis and follow-up of patients. The array of MRI sequences used in the evaluation of HCM includes spin echo MRI, GRE MRI, PC-MRI, MRI tagging, delayed enhancement (DE), and MR spectroscopy. A combination of these sequences is used to identify the presence and severity of

• Amyloidosis, systemic sclerosis, post cardiac transplantation

hypertrophied myocardium,24–26 to distinguish diﬀerent forms of HCM,27,28 to diﬀerentiate obstructive from nonobstructive forms of the disease,29 and to deﬁne prognosis.30,31 Diastolic dysfunction is thought to be one of the major pathophysiological mechanisms in patients with HCM,32 frequently leading to diastolic heart failure. These diagnostic abnormalities can be evaluated using cine tagging, DE, PC-MRI, and MRI spectroscopy sequences. The eﬀect of myocardial hypertrophy on regional and global left ventricular (LV) and right ventricular (RV) function can be precisely characterized by MRI. Global systolic function in HCM is often increased with high ejection fractions and low end systolic volumes. In the hypertrophied myocardium, however, cine tagging sequences demonstrate reduced or absent systolic wall thickening, which is related to muscle disorganization (Fig. 8-8).33 Strain analysis in these same regions show that systolic myocardial strains are invariably decreased, with reduced longitudinal and circumferential shortening.34,35 Three-dimensional CMR tagging demonstrates speciﬁc patterns of myocardial deformation among the diﬀerent forms of HCM, although all forms have abnormally small circumferential curvatures in hypertrophied segments.36,37 Abnormal DE of the myocardium after imaging by gadolinium-DTPA is found in approximately 80% of patients with HCM.38,39 Invariably, the enhancement occurs in the hypertrophied regions, with a mean volume of enhancement of 8% to 11% of LV mass. The pattern of enhancement is usually patchy

97

98

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging data demonstrate a delay and prolongation of diastolic untwisting, as well as a reduction in regional strain in patients with LV hypertrophy in comparison with normals.48,49 RV LV

A

Coronary Artery Disease

B

Figure 8-8 Abnormal myocardial deformation in hypertrophied myocardium in patients with hypertrophic cardiomyopathy. Short axis view of the heart during diastole (A) and systole (B). Note the decreased pattern of deformation in the hypertrophied anteroseptal wall of the left ventricle (arrow) compared with the normal surrounding areas of myocardium during systole.

with multiple foci, predominantly involving the middle third of the ventricular wall, especially near the insertion points of the RV free walls onto the interventricular septum (see Fig. 8-1C).37 This pattern of enhancement is distinct from the predominantly subendocardial distribution of hyperenhancement seen in patients with coronary artery disease. Histologically, these abnormally enhanced areas of myocardium are thought to represent scarred myocardium due to microinfarction or are in relation to myocardial disarray and consequent interstitial expansion.40 In a highly select group of patients with HCM, the degree of myocardial enhancement was associated with progressive disease and increased risk for sudden cardiac death.36 It has been proposed that the degree of diastolic dysfunction is linked to the extent of myocardial ﬁbrosis quantiﬁed by DE-MRI.41 Impaired myocardial relaxation can be identiﬁed using GRE-derived time-volume curves of the left ventricle, which demonstrate prolonged time-to-peak rapid ﬁlling and time-to-peak wall thickness thinning rates. In 31 patients with HCM, regional prolongation of time-to-peak wall thinning rate was detected in segments with extensive myocardial ﬁbrosis and decreased perfusion.42 Other MRI techniques, such as 31P-MR spectroscopy, demonstrate abnormal myocardial high-energy phosphate metabolites in both symptomatic43 and asymptomatic patients44 with HCM. Lower myocardial energy content is thought to contribute to relaxation abnormalities in hypertrophied hearts. Finally, PCMRI of ﬂow patterns in the caval and pulmonary veins, as well as the diastolic inﬂow in the tricuspid/mitral valves, can be used to evaluate diastolic function, similar to echocardiography.

Resting impairment of diastolic function is common in ischemic heart disease. Such diastolic dysfunction precedes systolic dysfunction and occurs as the earliest sign of myocardial ischemia. Diastolic ﬁlling patterns in ischemic heart disease are often complex, reﬂecting regional heterogeneity of myocardial function due to diﬀerent degrees of ischemia, infarction, postinfarction remodeling, and myocardial stunning and hibernation. Three-dimensional tagging by CMR is well suited to assess these regional changes in diastolic function. In a model of postinfarction LV remodeling, a reduction of regional strains was observed in both the infarcted region and, to a lesser extent, the remote regions.50 Diastolic untwisting tended to be nonuniform, delayed, and prolonged in areas of both infarcted and hibernating myocardium.51 Similar changes were seen in an animal model of transmural ischemia,52 with restoration of the normal untwisting motion after reperfusion. PC-MRI can be used to evaluate regional diastolic function by quantifying tissue velocities in patients with previous myocardial infarction. PC-MRI measurements of mitral valve inﬂow after myocardial infarction demonstrate the typical changes in transvalvular ﬂow patterns and closely correlate with Doppler echocardiography.53

Dilated Cardiomyopathy While the diagnosis of dilated cardiomyopathy can be easily made with transthoracic echocardiography, CMR can provide a comprehensive evaluation of cardiac function, myocardial stress perfusion, and viability. CMR has been shown to reliably discriminate between ischemic and non-ischemic causes of cardiomyopathy, and CMR remains the gold standard for the evaluation of LV and RV volumes, masses, ejection fractions, and viabilities.54,55 Diastolic dysfunction is common in dilated cardiomyopathy, and its severity is related to prognosis. The same CMR techniques previously described can be used for the comprehensive evaluation of both systolic and diastolic function in these patients— GRE-based time-volume curves for analysis of global diastolic function; PC-MRI to determine inﬂow curves as well as tissue velocities; myocardial tagging to evaluate strain and, more recently, ventricular dyssynchrony; and 31P-MR spectroscopy to determine PCr/ATP ratios as a measure of myocardial energy content.

Hypertension and Aortic Stenosis Chronic pressure overload in systemic hypertension and aortic stenosis leads to hypertrophy of the left ventricle, with the addition of new sarcomeres in parallel to existing ones to normalize wall tension.45 Hypertrophy, coupled with a variable degree of altered passive elastic properties of the myocardium, leads to diastolic dysfunction. In LV hypertrophy, changes in ventricular time-volume curves, including prolonged TPFR, early-to-late ﬁlling ratio, and early ﬁlling percentage measured from GRE sequences, can be demonstrated before changes in the classical mitral Doppler pattern.46 Other early changes include a decreased PCr/ATP ratio on 31P-MR spectroscopy, even before the development of evident LV hypertrophy.22 Later in hypertrophy, PCMRI demonstrates typical changes in mitral valve inﬂow that are similar to the classical mitral Doppler patterns.47 CMR-tagged

Constrictive Pericarditis The pericardium is well characterized by CMR because of its excellent contrast resolution and multiplanar imaging capability. Typically, T1- and T2-weighted spin echo, GRE, and tagged cine sequences are used in patients with suspected pericardial disease to evaluate cardiac function and morphology, pericardial thickness and tethering, and the presence of ventricular interdependence. In patients with acute pericarditis, T2-weighted spin echo or DE images after administration of gadolinium-DTPA can be used to detect pericardial inﬂammation and edema.56 On T1-weighted spin echo images, the normal pericardium is most easily identiﬁed over the right ventricle and appears as a thin band of low signal intensity between the high signal intensities of the external pericardial fat and the internal epicardial fat

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging (Fig. 8-9). The low signal intensity of the pericardium on CMR images is attributable to the ﬁbrous, low proton density component of the pericardium in combination with a small quantity of pericardial ﬂuid.57 The normal pericardial thickness is approximately 2 mm, although thicknesses of up to 4 mm are not necessarily abnormal. The appearance of pericardial eﬀusions may vary depending on the protein and cellular content of the eﬀusion; transudative pericardial eﬀusions appear dark on T1-weighted spin echo images and bright on T2-weighted images due to their high water content. Exudative eﬀusions, which have relatively lower water content, have the opposite appearance.58 In patients with pericardial eﬀusions, GRE sequences are useful to distinguish the pericardium from pericardial ﬂuid. The latter typically has a bright appearance on GRE sequences. Characteristic ﬁndings of constrictive pericarditis by CMR are described in Box 8-1. The classical CMR ﬁnding in patients with constrictive pericarditis is tethering or adhesion of the parietal pericardium to the visceral pericardium/epicardial surfaces.59 This ﬁnding is best appreciated on cine tagged sequences and diﬀers markedly from the normal free sliding motion of the parietal pericardium over the visceral pericardium/epicardium in normal individuals (Fig. 8-10). Other techniques, such as freebreathing cine GRE sequences, can be used to evaluate ventricular interdependence. In patients with constrictive pericarditis, the interventricular septum can be seen to shift toward the left ventricle during inspiration, whereas the opposite motion occurs with expiration. The characteristic septal shift is often most prominent on the ﬁrst heart beat that follows the beginning of inspiration. PC-MRI, while useful for evaluating ﬂow patterns across the cavae and atrioventricular valves, is less useful in evaluating peri-

cardial constriction due to its inability to diﬀerentiate respiratory changes in ﬂow patterns. Although a normal-thickness pericardium does not necessarily exclude constriction,60 irregular thickening of the pericardium is seen in up to 80% of individuals with constrictive pericarditis. A pericardial thickness of 5–6 mm has a high speciﬁcity for constrictive pericarditis. Pericardial thickening is often not generalized, and focal pericardial thickening in strategic locations such as the atrioventricular grooves can give rise to a full clinical picture of constrictive pericarditis even when the morphological abnormalities are not that impressive. In patients with extensive ﬁbrosis or calciﬁcation, the pericardium will have low signal intensity (black) on T1-weighted and T2-weighted spin echo images. However, the extent of pericardial calciﬁcation or ﬁbrosis is often better depicted by computed tomography, due to the signal loss of calciﬁed tissues by MRI.

Restrictive Cardiomyopathy Diastolic dysfunction and restrictive ﬁlling patterns are common to all of the restrictive cardiomyopathies. By CMR, the abnormal diastolic function is evident on cine tagged images, PC-MRI, ventricular time-volume curves, and 31P-MR spectroscopy using the techniques we have described. Although it is often not feasible to diﬀerentiate among diﬀerent restrictive cardiomyopathies on Box 8-1

Characteristic Findings of Constrictive Pericarditis by Cardiovascular Magnetic Resonance (CMR) • • • • • • •

A

B

Figure 8-9 Normal pericardium in a healthy individual, four-chamber view. A, The pericardium appears as a thin band of low signal intensity (black) on a spin echo image. B, The pericardium appears as a band of intermediate signal intensity (grey) on a GRE image.

• • • •

Pericardial tethering Pericardial calcification Increased pericardial thickness (>4 mm) Tubular or conical narrowing of one or both ventricles Enlargement of one or both atria Dilatation of the vena cava and hepatic vein Abnormal flow across the vena cava and atrioventricular valves on phase-contrast sequences of magnetic resonance imaging Diastolic restraint Abnormal diastolic motion Pericardial effusion (in patients with effusive-constrictive pericarditis) Pleural effusion

RV LV RA LA

A

B

C

Figure 8-10 Characteristic CMR findings in a patient with constrictive pericarditis. A, Four-chamber GRE image depicting the common tubular-shaped deformity of the ventricles and atrial dilatation. Note the thickened fibrous pericardium over the right ventricular free wall (arrows) and the darker area of calcified pericardium over the lateral wall of the left ventricle (arrowheads). B, C, Diastolic and systolic still frame from cine tagged four-chamber images shows the characteristic tethering of the pericardium to the epicardial surface during diastole. RV, right ventricle. RA, right atrium. LV, left ventricle. LA, left atrium.

99

100

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging the basis of diastolic ﬁlling patterns alone, CMR can help to identify the etiology of restrictive cardiomyopathy based on its functional and morphological characteristics.

Cardiac Amyloidosis Cardiac involvement is common in certain forms of systemic amyloidosis and is a major determinant of treatment options and prognosis. Several CMR ﬁndings have been described in cardiac amyloidosis, but the most characteristic feature of this disorder is a diﬀuse pattern of hyperenhancment on DE-MRI images that occurs in a noncoronary distribution (Fig. 8-11). Maceira et al. evaluated 29 patients by CMR who had biopsy-proven systemic amyloidosis and were considered to have cardiac amyloidosis on the basis of the presence of morphological and diastolic ﬁlling changes on echocardiography. They found a global subendocardial pattern of hyperenhancment in 20 of the 29 patients (69%) by CMR.61 In addition, the distribution of gadolinium-DTPA within both the myocardium and the LV blood pool was abnormally prolonged, with a modest correlation between T1 relaxation times of gadolinium-DTPA and diastolic function (r = −0.42, p = 0.025). Morphologically, the inﬁltration by amyloid protein results in a homogeneously increased thickness of ventricular and atrial walls, with occasional involvement of the papillary muscles and valve leaﬂets. Ventricular cavity size is usually normal or decreased, but the atria are usually enlarged due to the diastolic dysfunction, valvular dysfunction from amyloid deposition, or both. Approximately 5% to 15% of patients develop asymmetric septal hypertrophy in combination with a systolic anterior motion of the mitral valve in a pattern that may mimic HCM.62 Pleural and pericardial eﬀusions are not infrequent. Systolic function is usually preserved or mildly impaired until late in the disease.

Cardiac Sarcoidosis Myocardial involvement of sarcoidosis is present at autopsy in 20% to 30% of patients with this disease, although clinical involvement is evident in only 5%. GRE sequences may demonstrate normal or impaired LV systolic function, often with regional wall motion abnormalities, depending on the degree of sarcoid involvement of the heart. In the early stages of sarcoidosis, the myocardium may demonstrate patchy areas of high signal intensity on T2-weighted black blood images due to localized inﬂammation, along with focal, patchy areas of hyperenhancement (i.e. bright) that occur in a noncoronary distribution. The latter corresponds to areas of noncaseating granulomas that are the typical histological ﬁndings of sarcoidosis. These areas of hyperenhancement are also seen in more chronic cases of cardiac sarcoidosis, along with ventricular wall thinning and aneurysms, most commonly along the basal anteroseptal wall (Fig. 8-12).

Hemochromatosis Initially, myocardial iron overload in patients with primary or secondary hemochromatosis is asymptomatic. There is a mild increase in LV wall thickness and end diastolic chamber diameter. Diastolic dysfunction usually precedes systolic dysfunction and is characterized by a restrictive ﬁlling pattern.63,64 Global systolic abnormalities do not occur until the iron concentration reaches a critical level, but then there is often a rapid deterioration in systolic function. At the time of diagnosis, these patients typically have a dilated cardiomyopathy on GRE sequences, as well as evidence of abnormal myocardial deformation on cine tagged images. In addition, both the myocardium and the liver appear dark on T2-weighted spin echo sequences due to loss of signal as a result of iron accumulation in these tissues (Fig. 8-13).

LIMITATIONS OF CARDIAC MAGNETIC RESONANCE IMAGING

RV RA LV LA

Figure 8-11 Four-chamber delayed hyperenhancement image in a patient with amyloidosis. The diffuse pattern of hyperenhancement in the left ventricle is characteristic of amyloidosis and distinguishes this condition from other causes of hyperenhancement, such as ischemic heart disease, hypertrophic cardiomyopathy, and sarcoidosis.

Despite its increasing robustness, important limitations still remain in CMR imaging. The electromagnetic forces created by the MRI scanner can induce important thermal and nonthermal eﬀects in some patients. Therefore, the presence of contraindications to MRI must be identiﬁed before the patient enters the scanner (Table 8-1). Pacemakers and deﬁbrillators are increasingly common in the cardiac population, although these devices should pose less of a hazard as experience in CMR imaging of these patients increases and new, MRI-compatible devices become available. Nonferromagnetic metallic devices, such as mechanical heart valves, sternal wires, and retained (nonlooped) pacing wires after cardiac surgery, are safe to image, although they are often a source of image artifact. Patient cooperation is critical to successful cardiac imaging. Patient movement during image acquisition can result in degraded image quality, and uncooperative patients may require oral or intravenous sedation to prevent unwanted motion artifacts. Multiple breath holds of 10–15 seconds each are often utilized in adults to limit cardiac motion caused by respiration. Children and adult patients who are unable to hold their breaths can still be imaged successfully, although acquisition times are often increased to preserve image quality. As previously noted, clinically available PC-MRI sequences are unable to distinguish respiratory variation in ﬂow patterns across the systemic veins or atrioventricular

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging

LV

LV

B

A

Figure 8-12 Two-chamber (A) and midventricular short axis (B) delayed hyperenhancement images of a patient with cardiac sarcoidosis. Note the typical patchy pattern of hyperenhancement that occurs in a noncoronary distribution. Cine GrE images (not shown) demonstrated reduced systolic function with regional wall motion abnormalities.

RV

LV

RV LV

Figure 8-13 Secondary hemochromatosis in a patient with iron overload due to recurrent blood transfusions for hereditary anemia. A, Short axis GrE image demonstrates the characteristic low signal over the liver due to accumulation of iron particles. B, Axial T2-weighted spin echo image demonstrates the abnormally low signal intensity of the myocardium due to iron accumulation within myocardial tissue.

RA LA

Liver

A

B

TABLE 8-1 CONTRAINDICATIONS TO MAGNETIC RESONANCE IMAGING (MRI) CONCERN ABSOLUTE CONTRAINDICATIONS Cerebral aneurysm clips Implanted neural stimulator; cochlear implant; implanted insulin or other drug pump Cardiac pacemaker or defibrillator

Ocular foreign body; metal shrapnel or bullet fragment Temporary pacemaker wires or pulmonary artery catheters RELATIVE CONTRAINDICATIONS Hearing aids Pregnancy Claustrophobia

May become displaced by the strong external magnetic field of the scanner, causing severe local injury. Aneurysm clips that are “nonferromagnetic” or “weakly ferromagnetic” are safe to image. Most implantable devices employ a strong internal magnet or electronic circuitry that can be damaged by the strong external magnetic field of the scanner. Pacemakers/defibrillators are important contraindications to MRI due to the potential for device malfunction. Small studies suggest that some non–pacer-dependent patients with pacemakers can be imaged, although the devices must be interrogated and potentially reprogrammed before and after imaging. MRIcompatible devices are in development. Metallic foreign objects within the body can become displaced by the strong external magnetic field of the scanner, causing severe local tissue injury. Wires and catheters contain metallic tips that may become heated during MRI, causing local tissue damage. Same concerns as cochlear implants; must be removed prior to entering the scanner. Considerable evidence suggests that exposure to MRI is safe. However, exposure during the first trimester, particularly to MRI contrast agents, should be avoided. Some claustrophobic patients may have difficulty within the confines of an MRI scanner. Oral anxiolytics (e.g., alprazolam) may be useful in such patients.

101

102

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging valves. Arrhythmias are problematic due to image degradation and make velocity assessment and ﬂow quantiﬁcation by PCMRI unreliable.

FUTURE RESEARCH Several exciting applications in CMR are under development, including real-time sequences that allow comprehensive, highresolution images of the heart without the need for breath holding, as well as real-time PC-MRI evaluation of ﬂow. Other applications include improved software analytical tools for tagged cine MRI sequences, allowing for easier quantiﬁcation of strain and strain rate data. Newer therapeutic applications are also being developed, which include speciﬁc MRI-compatible catheters for electrophysiology studies/ablation, as well as interventional cardiology-related procedures, which may change the way that interventional cardiology procedures are practiced in the future. REFERENCES 1. Lima JA, Desai M: Cardiovascular magnetic resonance imaging: Current and emerging applications. J Am Coll Cardiol 2004;44:1164–1171. 2. Pennell DJ, Sechtem UP, Higgins CB, et al: Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. Eur J Cardiol 2004;25:1940–1965. 3. Hundley W, Gregory L, Hong F, et al: Assessment of left-to-right intracardiac shunting by velocity-encoded, phase-diﬀerence magnetic resonance imaging: A comparison with oximetric and indicator dilution techniques. Circulation 1995;91:2955–2960. 4. Grothues F, Smith GC, Moon JCC, et al: Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29–34. 5. Pujadas S, Reddy GP, Weber O, et al: Imaging assessment of cardiac function. J Magn Reson Imaging 2004;19:789–799. 6. Suzuki JI, Caputo GR, Masui T, et al: Assessment of right ventricular diastolic and systolic function in patients with dilated cardiomyopathy using cine magnetic resonance imaging. Am Heart J 1991;122:1035–1040. 7. Fujita N, Hartiala J, O’Sullivan M, et al: Assessment of left ventricular diastolic function in dilated cardiomyopathy with cine magnetic resonance imaging: Eﬀect of an angiotensin converting enzyme inhibitor, benazepril. Am Heart J 1993;125:171–178. 8. Hartiala JJ, Mostbeck GH, Foster E, et al: Velocity-encoded cine MRI in the evaluation of left ventricular diastolic function. Measurement of mitral valve and pulmonary vein ﬂow velocity and ﬂow volume across the mitral valve. Am Heart J 1993;125:1056–1066. 9. Kayser HWM, Stoel BC, van der Wall EE, et al: MR velocity mapping of tricuspid ﬂow: Correction for through-plane motion. J Magn Reson Imaging 1997;7:669–673. 10. Mohiaddin RH, Gatehouse PD, Henien M, et al: Cine MR Fourier velocimetry of blood ﬂow through cardiac valves: Comparison with Doppler echocardiography. J Magn Reson Imaging 1997;7:657–663. 11. White RD, Hardy PA, Van Dyke CE, et al: Diastolic dysfunction: Dynamic MRI velocity-mapping of related ﬂow pattern in the superior vena cava. J Magn Reson Imaging 1993;3:65. 12. Wedeen VJ: Magnetic resonance imaging of myocardial kinematics: Technique to detect, localize, and quantify strain rates of the active human myocardium. Magn Reson Med 1992;27:52–67. 13. Zerhouni EA, Parish DM, Rogers WJ, et al: Human heart: Tagging with MR imaging—a new method for noninvasive assessment of myocardial motion. Radiology 1988;169:59–63. 14. Edvardsen T, Rosen BD, Pan L, et al: Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging: The Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2006;151:109–114. 15. Young AA, Axel L: Three-dimensional motion and deformation of the heart wall: Estimation with spatial modulation of magnetization—a model-based approach. Radiology 1992;185:241–247. 16. Young AA, Axel L, Dougherty L, et al: Validation of tagging with MR imaging to estimate material deformation. Radiology 1993;188:101–108.

17. Fischer SE, McKinnon GC, Scheidegger MB, et al: True myocardial motion tracking. Magn Reson Med 1994;31:401–1413. 18. Hatabu H, Gefter WB, Axel L: MR imaging with spatial modulation of magnetization in the evaluation of chronic central pulmonary thromboemboli. Radiology 1994;190:791–796. 19. Naito H, Arisawa J, Harada K, et al: Assessment of right ventricular regional contraction and comparison with the left ventricle in normal humans: A cine magnetic resonance study with presaturation myocardial tagging. Br Heart J 1995;74:186–191. 20. Kojima S, Yamada N, Goto Y: Diagnosis of constrictive pericarditis by tagged cine magnetic resonance imaging. N Engl J Med 1999;341: 373–374. 21. Ryf S, Spiegel MA, Gerber M, Boesiger P: Myocardial tagging with 3DCSPAMM. J Magn Reson Imaging 2002;16:320–325. 22. Friedrich J, Apstein CS, Ingwall JS: 31P nuclear magnetic resonance spectroscopic imaging of regions of remodeled myocardium in the infarcted rat heart. Circulation 1995;92:3527–3538. 23. Lamb HJ, Beyerbacht HP, van der Laarse A, et al: Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 1999;99:2261–2267. 24. Posma JL, Blanksma PK, van der Wall EE, et al: Assessment of quantitative hypertrophy scores in hypertrophic cardiomyopathy: Magnetic resonance imaging versus echocardiography. Am Heart J 1996;132:1020–1027. 25. Devlin AM, Moore NR, Ostman-Smith I: A comparison of MRI and echocardiography in hypertrophic cardiomyopathy. Br J Radiol 1999;72: 258–264. 26. Pons-Llado G, Carreras F, Borras X, et al: Comparison of morphologic assessment of hypertrophic cardiomyopathy by magnetic resonance versus echocardiographic imaging. Am J Cardiol 1997;79:1651–1656. 27. Moon JC, Fisher NG, McKenna WJ, Pennell DJ: Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart 2004;90:645–649. 28. Rickers C, Wilke NM, Jerosch-Herold M, et al: Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation 2005;112:855–861. 29. Park JH, Kim YM, Chung JW, et al: MR imaging of hypertrophic cardiomyopathy. Radiology 185;441–446. 30. Spirito P, Bellone P, Harris KM, et al: Magnitude of left ventricular hypertrophy predicts the risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000;342:1778–1785. 31. Elliott PM, Poloniecki J, Dickie S, et al: Sudden death in hypertrophic cardiomyopathy: Identiﬁcation of high risk patients. J Am Coll Cardiol 2000;36:2212–2218. 32. Steward S, Mason D, Braunwald E: Impaired rate of left ventricular ﬁlling in idiopathic hypertrophic subaortic stenosis and valvular aortic stenosis. Circulation 1968;37:8–14. 33. Arrive L, Assayag P, Russ G, et al: MRI and cine MRI of asymmetric septal hypertrophy. J Comput Assist Tomogr 1994;18:376–382. 34. Kramer CM, Reichek N, Ferrari VA, et al: Regional heterogeneity of function in hypertrophic cardiomyopathy. Circulation 1994;90:186–194. 35. Maier SE, Fischer SE, McKinnon GC, et al: Evaluation of left ventricular segmental wall motion in hypertrophic cardiomyopathy with myocardial tagging. Circulation 1992;86:1919–1928. 36. Young AA, Kramer CM, Ferrari VA, et al: Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy. Circulation 1994;90: 854–867. 37. Petrank YF, Dong SJ, Tyberg J, et al: Regional diﬀerences in shape and load in normal and diseased hearts studied by three dimensional tagged magnetic resonance imaging. Int J Card Imaging 1999;l15:309–321. 38. Moon JCC, McKenna WJ, McCrohon JA, et al: Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol 2003;41:1561–1567. 39. Choudhury L, Marhold H, Wagner A, et al: Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:2156–2164. 40. Kim RJ, Judd RM: Gadolinium-enhanced magnetic resonance imaging in hypertrophic cardiomyopathy. In vivo imaging of the pathologic substrate for premature cardiac death? (editorial comment). J Am Coll Cardiol 2003;41:1568–1572. 41. Motoyasu M, Sukuma H, Uemura S, et al: Correlation between hyperenhancement on delayed contrast enhanced MRI and diastolic function in hypertrophic cardiomyopathy. J Cardiovasc Magn Reson 2004;6:245. 42. Yamanari H, Kakishita M, Fujimoto Y, et al: Regional myocardial perfusion abnormalities and regional myocardial early diastolic dysfunction in patients with hypertrophic cardiomyopathy. Heart Vessels 1997;12:192–198.

Chapter 8 • Evaluation of Diastolic Function by Cardiovascular Magnetic Resonance Imaging 43. DeRoos A, Doornbos J, Luyten PR, et al: Cardiac metabolism in patients with dilated and hypertrophic cardiomyopathy: Assessment with protondecoupled P-31 MR spectroscopy. J Magn Reson Imaging 1992;2: 711–719. 44. Jung WI, Sieverding L, Breuer J, et al: 31P NMR spectroscopy detects metabolic abnormalities in asymptomatic patients with hypertrophic cardiomyopathy. Circulation 1998;97:2536–2542. 45. Stuber M, Scheidegger MB, Fischer SE, et al: Alterations in the local myocardial motion pattern in patients suﬀering from pressure overload due to aortic stenosis. Circulation 1999;100:361–368. 46. Hartiala JJ, Foster E, Fujita N, et al: Evaluation of left atrial contribution to left ventricular ﬁlling in aortic stenosis by velocity-encoded cine MRI. Am Heart J 1994;127:593–600. 47. Kudelka AM, Turner DA, Liebson PR, et al: Comparison of cine magnetic resonance imaging and Doppler echocardiography for evaluation of left ventricular diastolic function. Am J Cardiol 1997;80:384–386. 48. Nagel E, Stuber M, Burkhard B, et al: Cardiac rotation and relaxation in patients with aortic valve stenosis. Eur Heart J 2000;21:582–589. 49. Edvardsen T, Rosen BD, Pan L, et al: Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging—the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2006;151:109–114. 50. Bogaert J, Bosmans H, Maes A, et al: Remote myocardial dysfunction after acute anterior myocardial infarction: Impact of left ventricular shape on regional function. J Am Coll Cardiol 2000;35:1525–1534. 51. Nagel E, Stuber M, Lakatos M, et al: Cardiac rotation and relaxation after anterolateral myocardial infarction. Coron Artery Dis 2000;10:261–267. 52. Kroeker CA, Tyberg JV, Beyar R: Eﬀects of ischemia on left ventricular apex rotation. An experimental study in anesthetized dogs. Circulation 1995; 92:3539–3548. 53. Karwatowski SP, Brecker SJD, Yang GZ, et al: Mitral valve ﬂow measured with cine MR velocity mapping in patients with ischemic heart disease:

54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64.

Comparison with Doppler echocardiography. J Magn Reson Imaging 1995;5:89–92. Benjelloun H, Cranney GB, Kirk KA, et al: Interstudy reproducibility of biplane cine nuclear magnetic resonance measurements of left ventricular function. Am J Cardiol 1991;67:1413–1420. Bottini PB, Carr AA, Prisant LM, et al: Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens 1995;8:221–228. Bogaert J, Taylor AM, Van Kerkhove F, et al: Use of the inversion-recovery contrast-enhanced MRI technique for cardiac imaging: Spectrum of diseases. Am J Roentgenol 182:609–615. White CS: MR evaluation of the pericardium. Top Magn Reson Imaging 1995;7:258–266. Watanabe A, Hara Y, Hamada M, et al: A case of eﬀusive-constrictive pericarditis: An eﬃcacy of Gd-DTPA enhanced magnetic resonance imaging to detect a pericardial thickening. Magn Reson Imaging 1998;16:347–350. Kojima S, Yamada N, Goto Y: Diagnosis of constrictive pericarditis by tagged cine magnetic resonance imaging. N Engl J Med 1999;341: 373–374. Talreja DR, Edwards WD, Danielson GK, et al: Constrictive pericarditis in 26 patients with histologically normal pericardial thickness. Circulation 2003;108:1852–1857. Maceira AM, Joshi J, Prasad SK, et al: Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–193. Siqueira-Filho AG, Cunha CLP, Tajik AJ, et al: M-mode and twodimensional echocardiographic features in cardiac amyloidosis. Circulation 63:188–196. Benson L, Liu P, Olivieri N, et al: Left ventricular function in young adults with thalassemia. Circulation 1989;80:274. Liu P, Stone J, Collins A, et al: Is there a predictable relationship between ventricular function and myocardial iron levels in patients with hemachromatosis? Circulation 1993;88:183.

103

MANUEL D. CERQUEIRA, MD

9

Evaluation of Diastolic Function by Radionuclide Techniques INTRODUCTION PATHOPHYSIOLOGY Basic Principles of Radionuclide Assessment of Diastolic Function Equilibrium Radionuclide Angiocardiography Methods in Diastolic Assessment First Pass Radionuclide Angiography

Coronary Artery Disease Heart Failure Hypertrophic Cardiomyopathy Hypertension Aging LIMITATIONS FUTURE RESEARCH

CLINICAL RELEVANCE

INTRODUCTION For over 30 years, in the diagnosis and management of patients with known or suspected heart disease, nuclear cardiology procedures have made extensive use of radioactive tracers that can be injected as a bolus and tracked during ﬁrst pass through the vascular system, attached to red blood cells and in equilibrium within the vascular space or as myocardial perfusion tracers that deﬁne the endocardial borders of the left ventricle.1 First pass radionuclide angiography (FPRNA) and equilibrium radionuclide angiocardiography (ERNA) have been the most commonly used techniques capable of assessing global and regional systolic and diastolic function at rest and following supine or upright exercise. They were used extensively in the 1970s and 1980s. The advantages of these modalities over other cardiac tests available at that time included counts based on true three-dimensional measurements (independent of geometric assumptions), high accuracy, reproducibility, and absolute quantitation. However, such accurate measurements of diastolic function were diﬃcult to perform using the standard methods of acquisition, and processing in clinical practice and eﬀorts to achieve greater accuracy and reproducibility were time consuming, computer intensive, and not practical in most clinical settings.2 Echocardiography provides

similar information on diastolic function and is portable and highly ﬂexible, which oﬀers practical advantages. In addition, echocardiography provides assessment of valves, wall thickness, left ventricular (LV) mass, chamber pressures, ﬂow dynamics, and the integrity of the pericardium from the same study, which makes it much more valuable for patient evaluation and management. For these reasons, echocardiography has been the most practical method for the assessment of diastolic function. Due to practical and economic factors, FPRNA and ERNA techniques are rarely performed in general clinical practice, and even less for evaluation of diastolic function. However, many of the concepts and methods developed for diastolic function analysis for FPRNA and ERNA in the 70s and 80s may be applicable today to the information available from the 8 million radionuclide myocardial perfusion imaging studies performed annually in the United States. Early radionuclide perfusion imaging did not allow the assessment of systolic or diastolic ventricular function. In the mid-1990s, several methods for assessment of systolic ventricular function using 8 time frames in the heart cycle were developed, and recently this technique has been modiﬁed to allow greater temporal sampling through 16 time frames, which can be used for the evaluation of diastolic function.3,4 This may provide incremental 105

106

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques information to the assessment of perfusion and systolic function. In some circumstances, diastolic dysfunction may identify preclinical abnormalities in the absence of alterations of systolic function. Given the current limited utilization of FPRNA and ERNA for assessment of diastolic function, this review will focus on the concepts and methods that have been found to be useful in the past and will then look at the opportunities for obtaining diastolic information from radionuclide myocardial perfusion studies that are currently being performed in such large numbers.

PATHOPHYSIOLOGY Basic Principles of Radionuclide Assessment of Diastolic Function All radionuclide approaches for assessing systolic and diastolic LV function require the generation of a curve plotting the changes in radioactivity, which is proportional to changes in LV volume over time, as shown in Figure 9-1. From this time-activity curve (TAC), the ﬁrst derivative, which measures the change in volume over time, is derived and used to calculate the most rapid changes in ejection and ﬁlling and the time when the maximal rate occurs. The typical ranges of normal values for these diastolic parameters in humans are shown in Box 9-1.5 The left side of the curve prior to end systole (ES) in Figure 9-1 provides information on the systolic function of the ventricle as expressed by the rate of ejection, measured as end diastolic

Box 9-1

Important Radionuclide Parameters of Diastolic Function and Normal Values 1. Peak filling rate (PFR) (>2.5 end diastolic volumes/ second) 2. Time to peak filling rate (TPFR) (<180 msec) 3. Filling fraction (% of stroke volume at one third, one half, or two thirds of diastole) 4. E/A ratio, 1 : 40

Atrial systole

Volume EDV/sec

ED

ED

Diastasis

PER

PFR ES IR

Time (msec) Figure 9-1 The relationship between left ventricular volume over time and the derived systolic and diastolic parameters. ED, end diastole; EDV, end diastolic volume; PER, peak ejection rate; ES, end systole; IR, isovolumic relaxation; PFR, peak filling rate.

volumes per second (EDV/sec), and the time at which this peak ejection occurs, expressed as time to peak ﬁlling rate (TPFR). For ventricles with muscle damage or inﬁltration, pericardial abnormalities, or ischemia, the rate of emptying is decreased and there is prolongation of the time when the peak emptying rate is achieved. Diastole is represented to the right of end systole in Figure 9-1 and is a much more complicated process, which consists of four distinct phases: 1. 2. 3. 4.

Isovolumic relaxation Peak ﬁlling rate (PFR) Diastasis Atrial systole

Isovolumic relaxation starts at end systole, is an energydependent process, has a short duration (usually <50 msec), and ends when pressures in the left ventricle fall below the left atrial (LA) pressure, the mitral valve opens, and rapid ﬁlling begins. PFR represents the most rapid ventricular ﬁlling and is normalized to EDV/sec, which is normally greater than 2.5. Generally, it has been shown to be rapid in young and healthy hearts but declines in the elderly, even in the absence of pathology.6,7 TPFR is an important measure of diastolic function and is less than 180 milliseconds in normal ventricles. There have also been attempts to look at the percent of stroke volume ﬁlling that occurs during the rapid ﬁlling phase as an indicator of disease. Generally, more than 69% of the stroke volume should ﬁll during the rapid ﬁlling portion. Following rapid ﬁlling, there is a separate phase, diastasis, with minimal changes in volume, which is followed by atrial systole. At slower heart rates, a distinct atrial component can be identiﬁed and the peak measured to calculate an E/A ratio similar to that obtained by echocardiography. For nuclear techniques, a ratio of less than 1 : 4 is normal but increases with age. At faster heart rates, the duration of diastasis decreases and the rapid ventricular ﬁlling and atrial systolic portions of the TAC merge, making it diﬃcult to calculate ratios and assess the relative contribution of the two phases. This chapter will focus on disorders of diastolic function resulting from abnormalities of the myocardium and ischemia and not address abnormalities resulting from valvular or pericardial disease. Caution must be used in applying these normal value ranges to a particular patient, as the method of acquisition and processing, as well as patient-speciﬁc parameters, will result in great variability in the values independent of any changes caused by cardiac pathology. As shown above, factors such as age, heart rate, systolic function (ejection fraction [EF]), end diastolic volume, adrenergic state, and medications will alter these parameters in the absence of pathology.2 Given the inﬂuence of these multiple factors on the derived diastolic values, it is easy to see that single or even multiple variables may not accurately identify the presence or absence of pathology in a given individual. Figure 9-2 is a schematic representation of a normal TAC in the presence of diastolic dysfunction, shown as the dashed line. With decreased relaxation, the rate of ﬁlling, expressed as EDV/sec, decreases and the TPFR is delayed and shifted to the left. Under such circumstances, the contribution of atrial systole may be increased and the E/A ratio shifted to a greater reliance on atrial ﬁlling. In patients with very stiﬀ ventricles, such as in hypertrophic cardiomyopathy (HCM) or diminished systolic ventricular function, the loss of the atrial contribution to ﬁlling caused by rhythms other than sinus can rapidly lead to pulmonary edema.

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques Atrial systole

ED

ED

Diastolic function

Volume EDV/sec

Normal Diastasis

Abnormal

PFR

PER ES IR

Time (msec) Figure 9-2 Schematic of normal and abnormal diastolic function timeactivity curves. The blue line shows that PFR has a flatter slope and is shifted to the right, indicating a delay in filling in comparison with the normal curve. ED, end diastole; EDV, end diastolic volume; PER, peak ejection rate; ES, end systole; IR, isovolumic relaxation; PFR, peak filling rate. Box 9-2

Basics of Equilibrium Radionuclide Angiocardiography (ERNA) Acquisition for Diastolic Function Analysis 1. 20–30 millicuries Tc-99m labeled red blood cells 2. Labeling methods a. In vivo: fastest and least expensive but lowest binding efficiency b. Modified in vivo/in vitro: compromise with good labeling efficiency c. In vitro: longest time and expense but best labeling efficiency 3. Planar or single photon emission computed tomography (SPECT) 4. Positioning: Best septal separation, left anterior oblique (LAO) 5. Arrhythmia rejection: ±10% of mean R-R interval and drop postpremature beat 6. Temporal resolution: <50 milliseconds or 16–32 frames/cycle 7. Acquisition a. Frame mode: simplest and least data intensive b. List mode: optimal but adds considerable processing time and data storage c. Forward-backward with buffered beat: compromise

Equilibrium Radionuclide Angiocardiography Methods in Diastolic Assessment Data Acquisition Important variables for performing diastolic function analysis using ERNA are listed in Box 9-2. Technetium (Tc)-99m pertechnetate is the radioisotope of choice and is attached to the patient’s own red blood cells using one of three possible labeling methods, which vary in the time to perform labeling, expense, and labeling eﬃciency.1 Both planar and single photon emission computed tomography (SPECT) methods of acquisition are available, but nearly all studies are performed using planar techniques, with the patient positioned in the left anterior oblique (LAO) view, which

Figure 9-3 Left anterior oblique planar equilibrium radionuclide angiocardiogram at end diastole (ED) and end systole (ES) in a patient with normal systolic and diastolic function. The time-activity curves for analysis are obtained from sequential definition of the edges of the left ventricle.

allows the best separation of the right and left ventricles for independent and accurate volume measurements in each chamber.8,9 An example of a typical LAO view is shown in Figure 9-3. The labeled red blood cells circulate in the vascular space, and the patient’s electrocardiographic (ECG) signal is used to set the timing for acquisition of each heart beat at individual time points, which may vary from 10 to 150 msec, depending on heart rate and the preset parameters. Information for each time point for each beat (usually >400 beats are acquired) is summed so that the ﬁnal TAC is an average rather than information from a single beat or a small number of beats, as is provided by other modalities. For this reason, this technique may be more representative of overall function than are other methods, due to the large number of beats averaged. Unlike systolic function analysis, where changes in heart rate and arrhythmias have relatively little inﬂuence on the time to end systole and EF, diastolic parameters are markedly aﬀected by heart rate variability during acquisition and processing. To avoid volume and ﬁlling inconsistencies due to heart rate variability and arrhythmias from such a large number of beats, the R-R interval is sampled prior to acquisition and the parameters set up to reject individual beats that vary by ±10% of the mean R-R. Since the beat following a rejected beat has a longer ﬁlling period and will add variability to the measurements due to diﬀerences in end diastolic volume and EF, it is also rejected. There are three computer methods used to acquire ERNA studies: frame, list, and buﬀered beat acquisition. Frame mode is the simplest method. It samples the R-R interval prior to acquisition, determines the number of time frames for each beat, and puts data into the appropriate time frame in real time for each beat using the set parameters until a new ECG gating signal identiﬁes the beginning of a new contraction. Once a beat has been added to the particular time bin, it cannot be removed. If there is an early beat, a new ECG trigger resets the acquisition so that the time bins toward the end of the heart cycle will have fewer beats contributing counts. The TAC generated from this method of acquisition suﬀers from count dropoﬀ in the terminal frame(s) due to heart rate variability; and although accurate for EF measurements, these curves cannot be analyzed for diastolic parameters using harmonic analysis. Although this is not the best method, it is universally used because of its simplicity and the small storage size of the retained data. List mode acquisition is the best method. It retains the X,Y spatial distribution of the radiotracer for every millisecond of acquisition, along with the ECG trigger signal so that the data set

107

108

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques can be reformatted into any timing interval and use the appropriate arrhythmia rejection during postprocessing. It provides maximal ﬂexibility relative to heart rate variability, but unfortunately at the expense of prolonged processing time and massive data storage. This technique was used exclusively for all studies performed by the group at the U.S. National Institutes of Health.10 A hybrid method, the buﬀered beat approach, is an attempt to provide realistic ﬂexibility for heart rate variability while keeping data size to a manageable limit. It uses a temporary memory buﬀer to examine each beat and the ECG gating signal with regard to the set baseline parameters and makes an instant decision to keep or reject the beat.6,7 An additional feature of this method is a forward-backward curve generation technique to avoid discontinuities or count dropoﬀ in the last several frames, which precludes harmonic analysis of the TAC.

Data Analysis For analysis of diastolic indices, there needs to be adequate temporal sampling of LV volume to capture the ﬁne detail required to detect minor or subtle alterations in diastolic ﬁlling. The actual sampling interval will vary with heart rate. To achieve a temporal resolution under 50 msec usually requires 16–32 frames per heart cycle with frame mode or buﬀered beat. At slow heart rates, more frames are required than at faster heart rates. The processed images are ﬁltered to reduce statistical noise, the edges of the left ventricle are deﬁned using manual or automated edge detection software, and background subtraction is performed. The radioactive counts within these boundaries represent the total volume in the ventricle and are used to produce a TAC. A TAC from a frame mode of 16 time intervals acquired from a clinical study is shown in Figure 9-4. All the ﬁne detail shown schematically in Figure 9-1 is retained in this curve, which does not have any dropoﬀ in counts in the terminal frames that may be seen in the presence of even minor sinus arrhythmias but is much more pronounced in the presence of atrial or ventricular arrhythmias. Figure 9-5 is from a study with 32 frame intervals. In comparison with the 16-frame study shown in Figure 9-4, the higher temporal

resolution results in even more detail during the diastolic ﬁlling period. Once the TAC has been generated, there are two general methods of diastolic function analysis: digital ﬁltering and mathematical curve ﬁtting.10 With digital ﬁltering or harmonic analysis, three to ﬁve harmonics are applied to smooth noise in the TAC, and the ﬁrst derivative is taken to deﬁne the point at which the greatest change in volume is present; this change and the time at which it occurs represents the PFR and TPFR. An example is shown in Figure 9-6. An absolute requirement for harmonic analysis is that the EDV from the TAC start and end at the same volume point. Figure 9-7 shows an example of count dropoﬀ due to arrhythmias in a study acquired by frame mode. In the presence of count dropoﬀ, error is introduced into the derived values from harmonic analysis. Discontinuity occurs in the terminal frames with frame mode acquisition, and for this reason, list or buﬀered beat acquisition with forward and backward reconstruction of the TAC is required to use harmonic methods of analysis. Diastolic function values derived using a mathematical curve ﬁtting technique generally take the available data and apply a third-order polynomial equation to derive PFR and TPFR from the slope changes in the TAC. This method is less susceptible to discontinuities in the TAC. The basic concepts of diastolic function analysis for ERNA were developed and performed in the late 1970s and early 1980s, when the technical requirements were recognized and observed. Currently, most software packages on nuclear cardiology workstations are capable of generating diastolic function values from any

70000

A 20000

50000 40000 Count (count)

Count (count)

60000

30000 20000 10000

15000

10000

5000

0 0

50

150

250

350

450

0

550

0

100

300

500

700

900

1100

Time (msec) Figure 9-4 A 16 time interval frame mode time-activity curve from the study in Figure 9-3. The individual time points and triangles and the fitted curve are shown. All the fine diastolic detail shown in the schematics for Figures 9-1 and 9-2 can be seen in this curve, even though the 16 time intervals provide less temporal sampling than a 24- or 32-frame study.

B

Time (msec)

Figure 9-5 An equilibrium radionuclide angiocardiogram, shown in representative end diastole and end systole for the actual study and with the 32 time frame derived curve. With 32 frames, finer detail can be seen for all four phases of diastole.

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 8.00e4

FITTING RESULTS ED PER

Figure 9-6 The graph shows the third harmonic fitted curve superimposed by the first derivative curve with the peak ejection rate and peak filling rate. To the right is the print-out of all the variables that can be derived from the data. ED, end diastole; PER, peak ejection rate; ES, end systole; PFR, peak filling rate.

(dv/dt ⫻ 10) : (count)

6.00e4

ES

4.00e4 2.00e4 0 –2.00e4 –4.00e4 –6.00e4

Item EDC (count) ESC (count) TES (msec) TPE (msec) PER(/SV) (%/sec) TPE/T (%) 1/3EF(/SV) (%) 1/3ER(/SV) (%/sec) TPF (msec) PFR(/SV) (%/sec) TPF/TF (%) 1/3FF(/SV) (%) 1/3FR(/SV) (%/sec) 1/2FF(/SV) (%)

Value 64162 36386 202 92 718.8 15.5 31.7 471.4 94 637.2 24.0 59.8 460.2 11.2

–8.00e4 0

50 100 150 200 250 300 350 400 450 500 550 Time (msec)

Box 9-3

30000 25000

Basics of First Pass Radionuclide Angiography (FPRNA) Acquisition for Diastolic Function Analysis

20000 Counts

PFR

15000 10000 5000 0 0

100

200

300

400

500

600

700

800

Time (msec) Figure 9-7 Time-activity curve from a 32-frame study showing terminal frame dropoff in the last two frames due to an arrhythmia.

TAC obtained from ERNA or ECG gated SPECT studies. A typical print-out of results is shown in the right-hand panel of Figure 9-5. Unfortunately, details such as the accuracy of the ECG gating mechanism, the presence or absence of count dropoﬀ in the terminal frames, information density, and temporal resolution are ignored. These systems are capable of generating values for diastolic function indices but are not used clinically.

First Pass Radionuclide Angiography Data Acquisition A method for diastolic radionuclide analysis involves FPRNA. At one time this technique was being performed with equal frequency to myocardial perfusion imaging and ERNA for detection of coronary artery disease (CAD) and systolic function assessment. Today it is rarely performed. First pass techniques for assessment of diastolic function require administration of a compact intravenous (IV) bolus of radioactivity and use of a very high temporal resolution and high count rate camera system to follow the radioactivity as it traverses the right and left ventricles. Serial gated images at 25–50 msec of temporal resolution are acquired, and the resultant TACs allow systolic and diastolic function analysis of the

1. Radiopharmaceutical a. 10–30 millicuries of Tc-99m sulfur colloid, DTPA b. Bolus injection of Tc-99m sestamibi or tetrofosmin in conjunction with perfusion, given rapidly in small volume c. Total dose injected adjusted for count rate capabilities of camera 2. Injection site a. Antecubital vein or external jugular with minimum of 18-gauge IV cannula 3. Camera types a. Multicrystal preferred due to high count rates b. Single crystal must be capable of 150,000 counts/sec 4. Temporal resolution: Usually 25 msec 5. Acquire images in anterior position

right and left ventricles at rest or following exercise or pharmacologic stress. There was a dramatic decline in the use of this technique in the 1980s and 1990s due to a lack of high count rate multicrystal camera systems, which are optimal for the technique. Performing FPRNA studies with a conventional single crystal gamma camera system is not optimal due to the low count rate. The basic requirements for performing studies are shown in Box 9-3 and will be discussed in the following section. Any Tc-99m radiolabeled compound can be used for bolus administration. When assessment is to be made at rest and following stress on one day, an agent that is cleared by the kidneys (Tc-99m DMSO or DTPA) can be given ﬁrst, followed by an agent that is cleared by the liver (Tc-99m sulfur colloid) or a heart perfusion tracer (Tc-99m tetrofosmin or sestamibi), so that there is no interference during the second study from the initial dose. The total dose administered can be lower when a multicrystal camera is used, but with a single crystal camera that is not capable of high count rates, 25–30 millicuries are required. The total dose must be given as a tight IV bolus over 2 or 3 seconds, which requires at least an 18-gauge IV in the antecubital fossa or the external jugular. If such venous access is not available, the study should not be attempted.

109

110

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques Anterior images are acquired with the patient supine or upright with the chest directly on the camera head. Exercise is best performed on a bicycle, which allows the chest to be relatively stationary and the images free of motion artifacts. Studies have been acquired during treadmill exercise, but this requires placement of external radioactive markers that can be used to correct for motion. Since only eight to ten beats can be used to analyze right ventricular (RV) or LV function without having bolus overlap in the chambers, heart rate variability or arrhythmias will further limit the number of beats that can be processed and will result in sampling bias or overlap of tracer activity in more than one chamber. These sampling limitations may result in poor study quality and limit the conclusions that can be reached. Echocardiography, computed tomography (CT) ventriculography, and cardiac magnetic resonance have similar sampling limitations. ERNA, which averages more than 400 beats, provides a more robust assessment of overall function. Depending on the count rate capabilities, diastolic and systolic parameters can be acquired from a single beat, or beats can be summed using ECG gating to give higher information density and allow better edge detection. Conventional gamma camera acquisition provides low counts and generally requires gating and summing of multiple beats for accurate results.

Data Analysis From a single beat or summed beats, the data are Fourier ﬁltered using a third- to ﬁfth-order harmonic with appropriate background subtraction, and the ﬁrst derivative of the resultant TAC is used to measure ﬁlling rates and the time to peak ﬁlling. This technique remains the most accurate for assessment of RV function and for the detection of pulmonary hypertension.

CLINICAL RELEVANCE Radionuclide methods for diastolic function analysis have been performed predominantly on a research basis in speciﬁc patient populations and are not used on a day-to-day basis in general clinical cardiology practice. This is due, in part, to the lack of appropriate equipment, diﬃculty in accurately performing the measurements, and variability in the measurements due to factors other than cardiac pathology, such as age-related changes and the eﬀects of medications. This variability makes it diﬃcult to measure diastolic parameters in a given patient and meaningfully apply the values for purposes of diagnosis, management, or monitoring of therapy. Is the abnormal value due to the patient’s age, systolic function, myocardial stiﬀness, ischemia, or other variables? Even with all of these limitations, the technique has been useful in certain disease states and clinical scenarios, as listed in Box 9-4. These will be discussed in detail.

Coronary Artery Disease Diagnosis Although CAD diagnosis using radionuclide methods is usually performed by measuring myocardial perfusion or changes in systolic function at baseline and following stress, analysis of diastolic function alone or in conjunction with these other measures provides an accurate diagnosis5 based on the induction of LV ischemia, which causes a transient increase in myocardial “stiﬀness”

Box 9-4

Clinical Patient Populations Evaluated Using Radionuclide Diastolic Function Analysis 1. Coronary artery disease (CAD) a. Diagnosis of CAD b. Monitoring therapy 2. Heart failure a. Normal systolic function b. Abnormal systolic function 3. Hypertrophic cardiomyopathy 4. Hypertension 5. Aging

and a decrease in relaxation reﬂected in a decreased PFR and an increased TPFR. These are usually measurements of global changes, but regional analysis can also be performed in an attempt to increase sensitivity by measuring the small changes that may not be detected by a global ﬁlling value or time.11 Using ERNA, Bonow et al. found a very high percentage of abnormal diastolic function in the resting state in patients with documented CAD.12 In 231 patients with chronic CAD, PFR and TPFR were abnormal in 91%, in 85% of those without Q waves, and in 82% of patients with normal resting LV EFs, no resting regional wall motion abnormalities, and no Q waves. These ﬁndings suggest a high rate of abnormalities in patients with CAD at rest independent of LV systolic function or previous myocardial infarction. Using FPRNA, Reduto et al. performed rest and bicycle exercise measurements of PFR and of PFR in the ﬁrst third of diastole in 32 normal and 68 CAD patients.13 In comparison with normals, patients with CAD had a lower PFR overall and a lower PFR in the ﬁrst third of diastole during exercise. Although the CAD patients also had an abnormal EF response to exercise, diastolic parameters were more sensitive for detection of disease. It has also been shown among patients with CAD and with normal LV systolic function at rest that impaired LV ﬁlling and regional asynchrony predict a greater degree of exercise-induced ischemia, suggesting a greater extent of jeopardized myocardium.14,15 Despite the documented eﬃcacy of diastolic function analysis for CAD diagnosis, it is not being used in the practice of cardiology today due to the limitations previously listed. With the potential for deriving similar information from 16-frame ECG gated perfusion studies, the technique may provide ancillary information beyond perfusion that may have a role for diagnosis and monitoring. This needs to be validated.

Monitoring Treatment of Coronary Artery Disease Once a diagnosis of CAD has been made, diastolic function analysis has also been used to document the response to treatment. Bonow et al. documented improvement in abnormal diastolic function following revascularization.16 Again, diastolic abnormalities were present in the resting state and did not require stress to provoke dysfunction. In a study of only 25 patients with singlevessel CAD, all had abnormal resting diastolic dysfunction despite normal systolic function. With exercise, 23 of the 25 developed a drop in EF, indicating the development of ischemia. Following percutaneous transluminal coronary angioplasty, resting diastolic function normalized in all patients; and with exercise, EF

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques increased. These ﬁndings suggest that resting diastolic dysfunction is a very sensitive indicator of signiﬁcant CAD, even in the absence of systolic abnormalities, and that following successful revascularization, resting diastolic dysfunction improves.

Heart Failure

normal contribution to ventricular ﬁlling in these abnormal ventricles. However, at this stage of our understanding of the etiology and management of HCM, it is accepted that diastolic dysfunction is present and that there is no need to document its existence independently of the results available from echocardiography, which is an essential test in HCM.

Normal Systolic Function Patients with clinical symptoms of congestive heart failure generally have abnormal systolic function, but as many as 30% to 40% of these patients may have normal systolic function and their symptoms are on the basis of diastolic dysfunction.17,18 Common causes of diastolic dysfunction include increased resistance to ventricular inﬂow caused by constrictive and restrictive pericardial disease, hypertrophy, scarring due to infarction, and volume overloading. Two other causes include impaired myocardial relaxation due to ischemia or cardiomyopathies and increased resistance to atrial emptying in patients with mitral stenosis. Although radionuclide methods may be useful for detection of diastolic abnormalities in these groups, the information provided is less useful than that provided by echocardiography, which should be the ﬁrst diagnostic test performed. Soufer was able to show in 58 patients with congestive heart failure and normal systolic function that 38% had a reduction in PFR below 2.5 EDV/sec, and an additional 24% had probable diastolic dysfunction with values of 2.5–3.0 EDV/sec. The etiology was CAD and hypertension in the majority of patients.

Abnormal Systolic Function Although it has been shown using ECG techniques that patients with heart failure and abnormal systolic function also have diastolic abnormalities, radionuclide methods have not been investigated in this population.19,20 In these patients, diagnostic abnormalities were associated with worse symptoms and increased event rate. Due to complex hemodynamics, neurohumoral factors, arrhythmias, and medications, the values for diastolic indices are diﬃcult to measure and interpret. For these reasons, radionuclide methods have limited application.

Hypertrophic Cardiomyopathy Patients with HCM have been extensively evaluated in terms of diagnosis and management using radionuclide techniques because of the interest and expertise of the group at the National Institutes of Health.21–26 The major abnormalities in HCM patients include prolonged isovolumic relaxation caused by myocardial ischemia and intracellular calcium overloading, as well as delayed rapid ventricular ﬁlling and a greater dependence on the atrial contribution to ﬁlling. In addition to documenting these abnormalities, radionuclide techniques have been used to monitor the eﬀects of treatment. The calcium blockers verapamil and nifedipine have been shown to improve LV relaxation and ﬁlling with IV administration and with long-term oral administration. In addition to improving hemodynamic parameters, there are also clinical improvements in exercise tolerance and heart failure symptoms.21,22 It was shown that the early and late improvement in symptoms with verapamil was related to the extent of improvement in diastolic ﬁlling. These ﬁndings also explain why HCM patients can go into severe heart failure when they are not in sinus rhythm and lose atrial contraction, which makes a larger than

Hypertension In the presence of hypertension, there are alterations in diastolic function independent of alterations in systolic function or the presence of CAD that can be measured by radionuclide methods.27,28 Cuocolo et al. evaluated 41 essential hypertensive patients without CAD at rest and with exercise by ERNA.27 With exercise, 22 patients had an appropriate increase in EF and 19 had a drop in EF. In the patients with a drop in EF, resting PFR and TPFR were reduced. This suggests that resting diastolic function detects early changes in myocardial function at rest in patients with essential hypertension that predict an abnormal response during stress. These changes were not directly related to previously identiﬁed modiﬁers of diastolic parameters such as age, heart rate, and the extent and severity of hypertension. Abnormalities were directly related to myocardial mass. The acute eﬀects of verapamil on diastolic function in hypertensive patients have also been studied in the cardiac catheterization laboratory. Patients had resting diastolic abnormalities that improved with the acute administration of verapamil.29 These studies suggest that diastolic function analysis may be used for preclinical detection of myocardial dysfunction in patients with hypertension.

Aging There are age-related changes in ventricular relaxation and ﬁlling that are independent of the increasing prevalence of hypertension, CAD, increased LV mass, and altered response to catecholamines and that suggest that there are primary eﬀects of aging on diastolic function.7,30,31 It has been documented by many methods that with increasing age, there is a decrease in PFR and TPFR and an increase in the atrial component of diastole. The etiology of these changes is multifactorial but may be reversed, in part, through exercise training and with the use of calcium blockers.7,30 It is also possible that ﬁbrosis or protein deposition within the myocardium may mediate the abnormalities.32 Documentation of these abnormalities is most useful when diastolic radionuclide parameters are being used to diagnose ischemia, in order not to confuse age-related changes with the presence of CAD. Adjusting for age is critical.

LIMITATIONS Despite the extensive literature on the use of radionuclide methods for analysis of diastolic function, the technique is not being used in clinical settings due to several factors. These include the lack of clinical utilization of these techniques for diagnosis of CAD and systolic function and the absence of special gamma cameras that optimize performance of the measurements. Such measurements were diﬃcult to perform using the standard methods of acquisition and processing in clinical practice, and eﬀorts to achieve greater accuracy and reproducibility were time consum-

111

112

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques ing, computer intensive, and not practical in most clinical settings.2 In addition, techniques such as echocardiography and cardiovascular magnetic resonance provide similar information on diastolic function and much more information on heart valves, wall thickness, LV mass, chamber pressures, ﬂow dynamics, and the integrity of the pericardium. This additional information makes these techniques much more valuable for patient evaluation and management. Other studies have brought into question the value of measuring relaxation rates and time intervals. Studies have shown that despite the improvement in these parameters with the use of calcium channel blockers, there may be an increase in LV end diastolic pressure as well as an overall prolongation of the time constant of relaxation.2

FUTURE RESEARCH Given the widespread use of ECG gated SPECT perfusion imaging and the relative lack of utilization of ERNA and FPRNA, the ability to assess diastolic function analysis from perfusion data would allow screening of diastolic dysfunction in a larger patient population during the assessment for obstructive CAD. In order to correctly perform diastolic function analysis from gated SPECT perfusion images, there are limitations to overcome. These include the low temporal resolution, failure to perform optimal arrhythmia rejection, and poor edge detection due to the low information density contained in the perfusion data. Despite these limitations, there are several groups that have shown the feasibility of such an approach.3,9,33–36 Unlike ERNA and FPRNA, in which the injected radioactivity remains in the intravascular space, Tc-99m perfusion agents are cleared by the liver and empty into the gastrointestinal tract. This means that a smaller percentage of the injected dose is actually in the myocardium when imaging is performed and that the counts are low, mandating that the time intervals for each beat be relatively long to achieve adequate information density in each frame. Increasing the imaging time will improve counts but decrease quality, as patients are likely to move. Most studies are acquired for 8 time frames. If the heart rate is 60 beats/minute, each time frame will be 125 msec, which does not allow suﬃcient temporal resolution to adequately separate out the various components of diastole. If 16 frames are used, each frame will have a temporal resolution of 63 msec and half the counts, but adequate edge deﬁnition can still be performed.3 The other problem that requires resolution is getting a TAC without terminal frame count dropout. Currently, arrhythmia rejection for ECG gated perfusion SPECT uses ±50% of the mean R-R interval to avoid compromising the perfusion study, which would either drop beats and lower total counts or prolong the acquisition time to achieve adequate counts. Some of the newer camera/workstation systems allow multiple acquisition windows so that arrhythmia rejection can be performed on one set of data while a separate window can be used for the perfusion data without arrhythmia rejection. Additional time is not added to the acquisition. If arrhythmias are present, the ECG gated data set will still be compromised, and quality control needs to be performed. The ﬁnal hurdle is getting appropriate edge deﬁnition from the available algorithms to accurately track the endocardial borders of the ventricle. Existing software packages have been shown to handle the lower counts in 16-frame acquisition.3 Deﬁnition of

the mitral valve plane at the base of the heart is also diﬃcult, as the transition from the left atrium, which has little uptake, to the myocardium in the area of the valves and membranous septum is diﬃcult to identify. Failure to clearly delineate this separation will result in error in the volume of the cavity and the resultant TAC. Using this approach in ECG gated SPECT studies, normal value ranges were developed for PFR (2.62 ± 0.46 and −2 SD <1.71 EDV/s) and TPFR (164.6 ± 21.7 and −2 SD >216.7 msec) in 90 patients without CAD or hypertension. PFR had signiﬁcant correlations with age, EDV, and EF, but TPFR did not. This suggests that TPFR may be a more robust measurement by this technique, as it is independent of these other factors that inﬂuence PFR. These normal ranges were then applied to a validation set of patients and showed similar results. From the combined populations, normal threshold values for PFR of greater than 1.70 EDV/sec and for TPFR under 208 msec were established.3 These results need to be validated in a larger population.

REFERENCES 1. Cerqueira M: Nuclear Cardiology. Boston, Blackwell Scientiﬁc, 1994. 2. Arrighi JA, Soufer R: Left ventricular diastolic function: Physiology, methods of assessment, and clinical signiﬁcance. J Nucl Cardiol 1995;2: 525–543. 3. Akincioglu C, Berman DS, Nishina H, et al: Assessment of diastolic function using 16-frame 99mTc-sestamibi gated myocardial perfusion SPECT: Normal values. J Nucl Med 2005;46:1102–1108. 4. Germano G, Kiat H, Kavanagh PB, et al: Automatic quantiﬁcation of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;36:2138–2147. 5. Bonow RO: Radionuclide angiographic evaluation of left ventricular diastolic function. Circulation 1991;84:I208–I215. 6. Johannessen KA, Cerqueira M, Veith RC, Stratton JR: The relation between radionuclide angiography and Doppler echocardiography during contractile changes with infusions of epinephrine. Int J Cardiol 1991;33: 149–157. 7. Levy WC, Cerqueira MD, Abrass IB, et al: Endurance exercise training augments diastolic ﬁlling at rest and during exercise in healthy young and older men. Circulation 1993;88:116–126. 8. Updated imaging guidelines for nuclear cardiology procedures, part 1. J Nucl Cardiol 2001;8:G5–G58. 9. Higuchi T, Taki J, Nakajima K, et al: Left ventricular ejection and ﬁlling rate measurement based on the automatic edge detection method of ECG-gated blood pool single-photon emission tomography. Ann Nucl Med 2004;18:507–511. 10. Bacharach SL, Green MV, Borer JS: Instrumentation and data processing in cardiovascular nuclear medicine: Evaluation of ventricular function. Semin Nucl Med 1979;9:257–274. 11. Bonow RO, Vitale DF, Bacharach SL, et al: Asynchronous left ventricular regional function and impaired global diastolic ﬁlling in patients with coronary artery disease: Reversal after coronary angioplasty. Circulation 1985;71:297–307. 12. Bonow RO, Bacharach SL, Green MV, et al: Impaired left ventricular diastolic ﬁlling in patients with coronary artery disease: Assessment with radionuclide angiography. Circulation 1981;64:315–323. 13. Reduto LA, Wickemeyer WJ, Young JB, et al: Left ventricular diastolic performance at rest and during exercise in patients with coronary artery disease. Assessment with ﬁrst-pass radionuclide angiography. Circulation 1981;63:1228–1237. 14. Perrone-Filardi P, Bacharach SL, Dilsizian V, Bonow RO: Eﬀects of regional systolic asynchrony on left ventricular global diastolic function in patients with coronary artery disease. J Am Coll Cardiol 1992;19:739– 744. 15. Perrone-Filardi P, Bacharach SL, Dilsizian V, Bonow RO: Impaired left ventricular ﬁlling and regional diastolic asynchrony at rest in coronary artery disease and relation to exercise-induced myocardial ischemia. Am J Cardiol 1991;67:356–360.

Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 16. Bonow RO, Kent KM, Rosing DR, et al: Improved left ventricular diastolic ﬁlling in patients with coronary artery disease after percutaneous transluminal coronary angioplasty. Circulation 1982;66:1159–1167. 17. Soufer R, Wohlgelernter D, Vita NA, et al: Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985;55: 1032–1036. 18. Watanabe J, Levine MJ, Bellotto F, et al: Eﬀects of coronary venous pressure on left ventricular diastolic distensibility. Circ Res 1990;67:923–932. 19. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 20. Shen WF, Tribouilloy C, Rey JL, et al: Prognostic signiﬁcance of Dopplerderived left ventricular diastolic ﬁlling variables in dilated cardiomyopathy. Am Heart J 1992;124:1524–1533. 21. Bonow RO, Dilsizian V, Rosing DR, et al: Verapamil-induced improvement in left ventricular diastolic ﬁlling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term eﬀects. Circulation 1985;72:853–864. 22. Bonow RO, Rosing DR, Bacharach SL, et al: Eﬀects of verapamil on left ventricular systolic function and diastolic ﬁlling in patients with hypertrophic cardiomyopathy. Circulation 1981;64:787–796. 23. Bonow RO, Vitale DF, Maron BJ, et al: Regional left ventricular asynchrony and impaired global left ventricular ﬁlling in hypertrophic cardiomyopathy: Eﬀect of verapamil. J Am Coll Cardiol 1987;9:1108–1116. 24. Cannon RO 3rd, Rosing DR, Maron BJ, et al: Myocardial ischemia in patients with hypertrophic cardiomyopathy: Contribution of inadequate vasodilator reserve and elevated left ventricular ﬁlling pressures. Circulation 1985;71:234–243. 25. Maron BJ, Bonow RO, Cannon RO 3rd, et al: Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (2). N Engl J Med 1987;316:844–852. 26. Maron BJ, Spirito P, Green KJ, et al: Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in patients

27. 28. 29. 30. 31. 32. 33. 34.

35. 36.

with hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:733– 742. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic ﬁlling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. Inouye I, Massie B, Loge D, et al: Abnormal left ventricular ﬁlling: An early ﬁnding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120–126. Brush JE Jr, Udelson JE, Bacharach SL, et al: Comparative eﬀects of verapamil and nitroprusside on left ventricular function in patients with hypertension. J Am Coll Cardiol 1989;14:515–522. Arrighi JA, Dilsizian V, Perrone-Filardi P, et al: Improvement of the agerelated impairment in left ventricular diastolic ﬁlling with verapamil in the normal human heart. Circulation 1994;90:213–219. Bonow RO, Vitale DF, Bacharach SL, et al: Eﬀects of aging on asynchronous left ventricular regional function and global ventricular ﬁlling in normal human subjects. J Am Coll Cardiol 1988;11:50–58. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. Kikkawa M, Nakamura T, Sakamoto K, et al: Assessment of left ventricular diastolic function from quantitative electrocardiographic-gated 99mTctetrofosmin myocardial SPET. Eur J Nucl Med 2001;28:593–601. Kumita S, Cho K, Nakajo H, et al: Assessment of left ventricular diastolic function with electrocardiography-gated myocardial perfusion SPECT: Comparison with multigated equilibrium radionuclide angiography. J Nucl Cardiol 2001;8:568–574. Higuchi T, Nakajima K, Taki J, et al: Assessment of left ventricular systolic and diastolic function based on the edge detection method with myocardial ECG-gated SPET. Eur J Nucl Med 2001;28:1512–1516. Sakamoto K, Nakamura T, Zen K, et al: Identiﬁcation of exercise-induced left ventricular systolic and diastolic dysfunction using gated SPECT in patients with coronary artery disease. J Nucl Cardiol 2004;11:152– 158.

113

10

CHRISTOPHER P. APPLETON, MD

Evaluation of Diastolic Function by TwoDimensional and Doppler Assessment of Left Ventricular Filling Including Pulmonary Venous Flow INTRODUCTION LEFT VENTRICULAR FILLING: A HISTORICAL PERSPECTIVE RELATION BETWEEN DIASTOLIC PROPERTIES AND LEFT VENTRICULAR FILLING PATTERNS EXERCISE AND LEFT VENTRICULAR DIASTOLIC FUNCTION DOPPLER MITRAL FLOW VELOCITY PATTERNS Changes in Mitral Flow Velocity Patterns with Aging and Disease States Left Ventricular Filling and Changing Cardiac Loading Conditions Grading the Degree of Left Ventricular Diastolic Dysfunction by Mitral Flow Velocity Alone Grading the Degree of Left Ventricular Diastolic Dysfunction in Epidemiology Studies

PULMONARY VENOUS FLOW VELOCITY Relation of Mitral to Pulmonary Venous A-Wave Duration CLINICAL APPLICATIONS: INTERPRETATION OF INDIVIDUAL MITRAL FLOW VELOCITY VARIABLES Left Ventricular Isovolumic Relaxation Time Left Ventricular Intracavitary Flow During Isovolumic Relaxation Time Mitral Time-Velocity Integral Peak Mitral E-Wave Velocity Mitral Deceleration Time Mitral Flow Velocity at the Start of Atrial Contraction Peak Mitral A-Wave Velocity Mitral A-Wave Duration Mitral Peak E/A Wave Velocity Ratio

115

116

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling ANCILLARY DATA THAT HELP THE INTERPRETATION OF MITRAL FLOW VELOCITY PATTERNS M-Mode and Two-Dimensional Echocardiography Tricuspid Flow Velocity Mitral Annular Velocities in Tissue Doppler Imaging and Relation to Left Ventricular Filling Pulmonary Artery Pressures PERFORMING AN ECHO-DOPPLER EVALUATION OF LEFT VENTRICULAR DIASTOLIC FUNCTION MITRAL FLOW VELOCITY PATTERNS: INTERPRETIVE CHALLENGES Mitral E/A Ratio Less Than 1

Mitral Regurgitation and Stenosis Sinus Tachycardia: Effect on Left Ventricular Filling Uncommon Mitral Valve Velocity Patterns Increased Mitral Respiratory Flow Velocity Variation Atrial Flutter and Fibrillation Diastolic Mitral and Tricuspid Regurgitation RIGHT VENTRICULAR DIASTOLIC FUNCTION USING LEFT VENTRICULAR FILLING PATTERNS FOR PATIENT MANAGEMENT FUTURE RESEARCH

INTRODUCTION The cardiac cycle is continuous. The ﬁlling of the ventricle (diastole) is followed by ventricular contraction (systole) to provide an adequate cardiac output during both rest and exercise to meet the body’s metabolic demands. Systole and diastole aﬀect each other in an intimate manner to accomplish this goal. The normal elastic recoil after left ventricular (LV) contraction aids early ﬁlling of the ventricle, with the late diastolic atrial contraction ensuring that the myocardial sarcomeres are adequately stretched to optimize contractile force. Exercise tests the health of this integrated system by shortening the time for ﬁlling and myocardial perfusion, and a normally functioning cardiac electrical system is also needed for optimal performance. The “new” epidemiology of LV diastolic dysfunction has been discussed in Chapter 6 of this volume. Diastolic heart failure is now recognized as a major national health problem, especially in the elderly, who have a high incidence of LV hypertrophy (LVH). These patients present with symptomatic heart failure despite a normal LV ejection fraction (LVEF) and have morbidity and mortality that is nearly equal to that of patients with reduced systolic function. Diastolic heart failure patients are also at risk for ﬁrst-onset atrial ﬁbrillation and a higher incidence of stroke. Although LVEF is normal in diastolic heart failure, ventricular contractile mechanics have been altered in a way that lengthens the isovolumic contraction and relaxation period so that the period for diastolic ﬁlling becomes shorter and may be inadequate. In both systolic and diastolic heart failure, the degree of diastolic dysfunction is a powerful predictor of prognosis. Despite this new appreciation of the importance of both systole and diastole in maintaining normal cardiovascular physiology, the role of LV diastolic function in health and disease is incompletely understood and underappreciated by many primary care physicians and cardiologists. As discussed in Chapter 2, diastole is a complex phenomenon with many determinants that are diﬃcult to study individually and several phases that encompass both the relaxation and the ﬁlling of the ventricle. Physical examination, echocardiography (ECG), chest radiographs, and laboratory studies are unreliable in diagnosing diastolic heart failure in most individuals, and invasive measurements of LV diastolic properties and pressures are impractical in clinical practice. Therefore, at present, assessing the type and degree of LV diastolic dysfunction relies on evaluating the pattern of LV ﬁlling. Although this can be accomplished by radionuclide and computed tomography

(CT) angiographic and magnetic resonance imaging (MRI) techniques, cardiac ultrasound is currently the method of choice because of its noninvasive and portable nature. Evaluating LV ﬁlling by two-dimensional anatomic ﬁndings, Doppler ﬂow, and tissue Doppler imaging (TDI) have emerged as powerful clinical techniques to predict adverse cardiovascular events such as newonset atrial ﬁbrillation and heart failure, as well as mortality regardless of LVEF. The purpose of this chapter will be to describe the various LV ﬁlling patterns encountered in clinical practice, and what these patterns and their measurable variables reveal about LV diastolic function. In cases of possible ambiguity, ancillary variables such as left atrial (LA) volume, pulmonary venous (PV) ﬂow velocity, and TDI that help in interpreting mitral ﬂow velocity patterns will be discussed.

LEFT VENTRICULAR FILLING: A HISTORICAL PERSPECTIVE In 100 bc, Galen proposed that the heart is ﬁlled by dilation of the right ventricle. Sixteen hundred years later, in 1628, William Harvey described the heart as a central pump in a circulatory system with both arteries and veins. Logically, most cases of heart failure were ascribed to damage or weakening of the heart muscle and a decrease in pumping function. Diastole was considered simply the interval in which the cardiac chambers ﬁlled passively between each pumping cycle and therefore was largely ignored. Gradually, evidence emerged that abnormalities of ventricular ﬁlling could cause symptoms and that diastolic and systolic functions were interrelated. About 1915, Wiggers described the phases of the entire cardiac cycle, and the Frank-Starling mechanism was described, whereby LV end diastolic volume helps regulate forward stroke volume on a beat-to-beat basis. In 1930, Katz recognized the role of LV relaxation in the ﬁlling of the ventricle, suggesting that the normal heart acts like a “suction” pump, a concept proven 60 years later.1 A limitation in cardiac ﬁlling, not pumping function, with resultant reduced cardiac output was recognized as the cardinal feature of constrictive pericarditis, further emphasizing that disorders of ﬁlling could also cause cardiac symptoms and disease. In the 1960s, the study of ventricular biomechanics accelerated. Although most research continued to focus on LV contractile function, cardiac diseases with thickened and noncompliant

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

RELATION BETWEEN DIASTOLIC PROPERTIES AND LEFT VENTRICULAR FILLING PATTERNS The numerous factors that aﬀect LV diastolic properties and the ﬁlling of the left ventricle are described in Chapter 5 of this volume. Although the interaction of these factors is complex, their sum reﬂects the diastolic transmitral pressure gradient, which

Transmitral pressure gradient

LV TMPG Elastic recoil LV relaxation LV-LA compliance Mitral valve LA pressure Viscoelasticity LV pressure LV-RV interaction Atrial contractility Electrical system Pericardial constraint

LA

LV filling Mitral flow velocity

ventricles with good pumping function, such as restrictive2 and hypertrophic3 cardiomyopathies, were described. Angiographic diﬀerences in LV ﬁlling patterns between normals and patients with various heart diseases were reported even when the LVEFs were similar,4 and these phenomena were subsequently studied by M-mode echocardiography.5,6 At the same time, the importance of LV systolic function in determining diastolic restoring forces and rate of LV relaxation was appreciated. Our current view that systole and diastole are an intertwined continuum, with each part aﬀecting all others, gradually began to emerge. In the mid-1980s, echocardiographic studies showed that 20% to 40% of elderly patients with heart failure had a normal LVEF and, therefore, presumably “isolated” diastolic dysfunction.7,8 However, diﬃculties in quantitating individual LV diastolic properties9 caused the clinical study of LV diastolic dysfunction to proceed slowly. LV ﬁlling patterns were analyzed by digitized M-mode,10 angiographic,11 and radionuclide12 methods. In 1982, pulsed wave (PW) Doppler study of mitral ﬂow velocities to study LV ﬁlling was ﬁrst reported.13,14 Doppler ultrasound, a noninvasive technique that could determine dynamic changes in LV ﬁlling after interventions and over time, revolutionized the study of LV diastolic function. Age-related changes in LV ﬁlling were quickly described,15–18 followed by the description of three basic abnormal mitral ﬂow ﬁlling patterns that were correlated to LV diastolic variables and ﬁlling pressures.19 The three abnormal mitral ﬁlling patterns were found to be independent of disease type19 and to have clinical signiﬁcance and prognostic value regardless of cardiac disease type,20–23 suggesting that diﬀerent pathology altered the same basic diastolic properties. PV ﬂow velocity helped assess the ﬁlling of the left atrium, and variables were found to aid the interpretation of LV ﬁlling patterns and pressures.24–27 Using the two ﬂow velocities, a “natural history” of LV ﬁlling in normals and with disease patterns was described.24–27 Manipulation of preload and afterload demonstrated the dynamic nature of LV ﬁlling patterns in response to changes in loading conditions,28–30 and these changes also had prognostic signiﬁcance in patients with cardiac disease.31,32 Additional Doppler methods followed, such as TDI of mitral annular motion (MAM) and the rate of color Doppler mitral inﬂow propagation (Vp), and modelbased image processing continued to improve diagnostic accuracy and advance the new ﬁeld of “diastology.”33–46 These continue to enhance our basic knowledge regarding clinical observations. Although all echo-Doppler variables have limitations in interpreting diastolic function, the aggregate sum of the twodimensional echo and Doppler ﬁndings provides us a powerful and practical way to noninvasively assess LV diastolic function and to objectively follow serial changes after medical intervention or with disease progression.47–49 These methods are powerful prognostic tools in asymptomatic50 as well as symptomatic patients with various diseases, like dilated21,51 and restrictive31 cardiomyopathies. As a result, the clinical syndrome of diastolic heart failure is now more readily recognized, and studies on improved diagnosis and the best treatment strategies for such patients are under way.

Figure 10-1 Determinants of LV filling. In sum, they affect the transmitral pressure gradient, which determines the LV filling pattern. When LV pressure falls below LA pressure, a positive pressure gradient occurs and early diastolic filling begins (hatching). Pressure in the ventricle rises and then briefly exceeds LA pressure, which decelerates mitral flow velocity. A positive pressure gradient occurs again at atrial contraction and results in flow in late diastole, just before systole begins. (Modified from Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–46, ix.)

ultimately determines mitral inﬂow and the LV ﬁlling pattern, as shown in Figure 10-1.49 Positive gradients in diastole result in ﬂow across the mitral valve, while negative gradients decelerate or stop ﬂow.52–54 The diﬀerent LA and LV pressures that are determined by LV diastolic properties and ﬁlling are shown in Figure 10-2. Understanding that LV end diastolic pressure (LVEDP) can be elevated before mean LA pressure is increased is essential to understanding and interpreting diastolic function. Two key diastolic properties, the rate of LV relaxation (diastolic pressure fall) and of LV compliance (throughout all of diastole), are especially important in understanding pressures and LV ﬁlling.55 Normal LV contraction and relaxation are vigorous and rapid, resulting in diastolic elastic recoil that augments early diastolic ﬁlling through a suction eﬀect (chamber volume increasing while pressure is initially still decreasing).38,56,57 This promotes an early mitral valve opening and helps maximize the diastolic ﬁlling period and myocardial perfusion. Rapid ejection and a predominance of early diastolic ﬁlling leaves a period of diastasis before atrial contraction as a reserve that can help maintain adequate ﬁlling when exercise shortens cardiac cycle length. The ﬁrst hemodynamic abnormality seen in nearly all cardiac diseases is a slower rate of LV relaxation.14,52,55,58,59 This is commonly associated with hypertension or LVH.60 Both systole and diastole are aﬀected, even if the LVEF remains normal. In systole, the LV isovolumic contraction and ejection times become prolonged. In diastole, the slower fall in LV pressure causes the mitral valve to open later and the early diastolic transmitral pressure gradient and proportion of ﬁlling to decline.55 The diastasis period often disappears, and a greater

117

118

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling LV

LA

LV + LA

LV

LV V-wave LV A-wave

LA

LV EDP

LV RFW

A-wave Mean LAP

LA TMPG

LV pre-A

LVmin

A

B

C

Figure 10-2 The left atrial (LA) and left ventricular (LV) pressures that are influenced by LV diastolic properties are shown. The transmitral pressure gradient (TMPG, C) determines the LV filling pattern, while other hemodynamic variables relate to mitral and other echo-Doppler flow velocity variables. LV pressure falls after aortic valve closure, and its rate of decline and minimum LV pressure (LVmin, A) reflects the rate of LV relaxation and elastic recoil. As blood fills the left ventricle, there is a rapid increase in pressure from the rapid filling wave (RFW), which decelerates blood inflow. Low-level filling causes pressure to increase slowly in mid-diastole, and then an increase in pressure is seen in both chambers with atrial contraction (A wave). The first diastolic abnormality seen in nearly all cardiac diseases is a slower rate of LV relaxation. As LV compliance decreases, an abnormal increase in LV pressure is initially confined to late diastole and is seen as an increased LV A-wave pressure rise and LV end diastolic pressure (LV EDP). When LV compliance is further reduced, filling of the ventricle causes an increase in pressure throughout the diastolic filling period, which is manifest as an increase in mean LA pressure (B) and its surrogate LV preA pressure. In these cases, LV EDP is obligatorily elevated. (From Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix.)

proportion of ﬁlling at atrial contraction is needed to reach an optimal end diastolic volume. These changes can markedly alter the length of the diastolic ﬁlling period and resting LV ﬁlling pattern, as shown in the two individuals in Figure 10-3. One is normal and one has hypertensive heart disease with LVH. Both have identical heart rates and LVEFs. At this stage, if LV compliance is reduced, the abnormal increase in pressure is seen initially only in late diastole at the time of atrial contraction, and mean LA pressure remains normal, so that patients are usually asymptomatic.47,49,61,62 A comparison of the durations of mitral and PV ﬂow velocities at atrial contraction indicates this earliest abnormality of ventricular compliance and hemodynamics.63–66 With more advanced disease, LV relaxation remains abnormal, but a decrease in LV compliance occurs throughout diastole, which increases mean LA pressure and size and begins to result in symptomatic heart failure. The increased LA pressure will oppose the eﬀect of a slower rate of LV relaxation, causing an earlier mitral valve opening and a higher transmitral pressure gradient,52,67 so that the LV ﬁlling pattern appears more “normal.” However, in this case the increase in early diastolic LV ﬁlling is caused by increased driving pressure rather than suction created by normal ventricular elastic recoil. Patients with this “pseudonormal” LV ﬁlling19 begin to have heart failure symptoms and show moderate functional limitation.48,49,68,69 With a severe decrease in LV compliance, the marked elevation in LA pressure causes early diastolic ﬁlling to predominate, while the left atrium fails and provides little additional late diastolic ﬁlling. This third and most abnormal LV ﬁlling pattern is termed “restrictive.”70 Patients with restrictive ﬁlling patterns also have impaired LV relaxation, but the severe decrease in LV compliance results in a marked elevation of LA pressure, which promotes a rapid initial ﬂow of blood into the ventricle in early diastole. However, the increased proportion of early ﬁlling has an abrupt, premature termination due to a rapid increase in LV pressure with only minimal ﬁlling occurring at atrial contraction. The

reduced atrial contribution indicates that LA systolic failure is present due to the chronic pressure overload. Patients with this pattern are markedly symptomatic, demonstrate a severe functional impairment, and have a poor prognosis.21,31,51 Because both the rate of LV relaxation and LA pressures may have many diﬀerent values that are not necessarily related, many diﬀerent transmitral gradient proﬁles and LV ﬁlling patterns are possible.49,67 As a result, a similar-appearing LV ﬁlling pattern may occur with diﬀerent combinations of these two key diastolic properties, with clinically signiﬁcant diﬀerences in LV ﬁlling pressures. In these instances, the degree of abnormality of LV relaxation and compliance is indicated by anatomic abnormalities such as reduced LVEF, LVH, LA enlargement or altered PV ﬂow, and annular TDI velocities.49

EXERCISE AND LEFT VENTRICULAR DIASTOLIC FUNCTION An increase in heart rate, as with exercise, is the heart’s diastolic “stress test.” As heart rate increases, diastolic ﬁlling time shortens. In normal individuals, several adaptations help keep early and late diastolic ﬁlling separated, a coordination of the electrical and mechanical systems that provide for increased ﬁlling and cardiac output without an elevation of diastolic pressures.71,72 Most importantly the P-R interval shortens.73 At the same time, faster heart rates trigger the Treppe (or “staircase”) eﬀect, which increases LV contractility and rate of relaxation. LVEF increases and LV end systolic volume decreases. The overall eﬀect is an earlier mitral valve opening, increased elastic recoil, and a larger early diastolic transmitral pressure gradient.71 LV contractility is also increased by sympathetic tone, while systemic vascular resistance falls with muscular vasodilation. Impaired relaxation may reduce the cardiac output achieved by reducing the diastolic ﬁlling time below that needed for optimal LV ﬁlling74 and myocardial perfusion. A premature fusion of early

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling NORMAL

Figure 10-3 The effect of impaired left ventricular (LV) relaxation on LV diastolic filling time (DFT) and LV filling patterns. A, Echocardiography (ECG), pulsed wave (PW) Doppler of mitral flow velocity and highfidelity LV pressure recordings are shown in two individuals at rest. Both individuals have heart rates of 75 bpm and a normal LV ejection fraction. In the normal subject (left), LV pressure increases and decreases rapidly so that the diastolic filling time (DFT) is longer than systole (SYS), with a period of diastasis in mid-diastole. In contrast, with impaired LV relaxation (right), longer isovolumic contraction and relaxation times result in the DFT being longer than systole. As a result, the LV filling pattern is markedly altered to reach the same end diastolic volume, with less filling in early diastole, the disappearance of a diastasis period, and a larger contribution of filling at atrial contraction. B, The effect of increased heart rates on diastolic filling time. LV pressure (LVP) is shown in the same two individuals at rest and with exercise. At a heart rate of 125 bpm compared with the normal subject (left), the DFT with impaired LV relaxation (right) is markedly abbreviated, and only 25% as long as systole, making it difficult to maintain adequate LV filling. The result is a reduced LV end diastolic volume, blunted cardiac output, and reduced functional aerobic capacity.

IMPAIRED LV RELAXATION

LV filling pattern

LV filling pattern

HR 75

HR 75

DFT SYS

DFT SYS

A HR 75

HR 125

HR 75

HR 125

LVP

DFT

DFT Exercise

DFT

DFT Exercise

B

and late diastolic ﬁlling often occurs (see Fig. 10-3) with an inability to increase LV end diastolic volume.72,74 LV and LA ﬁlling and PV ﬂow increase with atrial contraction of an incompletely relaxed left ventricle. Patients are aﬀected by reduced aerobic capacity and may complain of abnormal exertional dyspnea. Those with pseudonormal and restrictive ﬁlling patterns have a signiﬁcant decrease in exercise capacity. However, in these individuals, it is the increase in mean LA pressure and pulmonary congestion due to reduced LV compliance that limits exercise rather than a blunted increase in LV end diastolic volume.

DOPPLER MITRAL FLOW VELOCITY PATTERNS Because of their noninvasive nature and ease of use, echo-Doppler techniques have become the accepted clinical standard for assessing LV diastolic function. LV ﬁlling is assessed with both continuous wave (CW) and PW Doppler techniques. Figure 10-4 shows mitral ﬂow velocity obtained with the PW Doppler technique and the variables that are measured.75 These include: LV isovolumic relaxation time (IVRT); peak mitral ﬂow velocity in early diastole (E wave) and at atrial contraction (A wave); the mitral deceleration time (DT); the E-wave velocity just before atrial contraction (E at A), also sometimes referred to as preA velocity; and the duration of mitral A-wave velocity (Adur). An E-at-A wave velocity of more than 20 cm/sec results in a peak A-wave velocity that is larger than it would have been at a slower heart rate, when mitral ﬂow velocity has time to drop to a lower level

before atrial contraction.73 In these cases, the E/A wave ratio may be reduced compared with values obtained at a slower heart rate, so that more reliance on other echo-Doppler variables is needed when interpreting the “fused” LV ﬁlling pattern.

Changes in Mitral Flow Velocity Patterns with Aging and Disease States Elastic recoil and rapid LV relaxation in adolescents and young adults result in a predominance of early diastolic ﬁlling (E wave) with much less ﬁlling (10%–15%) due to atrial contraction. With normal aging, LVEF changes little, but LV relaxation slows in most individuals. The slower relaxation appears to be due largely to a gradual increase in systolic blood pressure and LV mass (hypertrophy). The result is reduced LV ﬁlling in early diastole and increased ﬁlling at atrial contraction.16–18 In most individuals, the peak E- and A-wave velocities become approximately equal during the sixth and seventh decade of life, with atrial ﬁlling contributing up to 35% to 40% of LV diastolic stroke volume. In individuals who maintain lower blood pressures and have no increase in LV mass, the age-related changes of decreasing E/A ratio in asymptomatic “normal” patients used in most reference studies are less pronounced, and normal E-wave predominance can occasionally be seen into the seventh decade of life. In these individuals, normal two-dimensional ﬁndings, LA size, and annular TDI variables conﬁrm that diastolic function is normal. Normal age-related values for mitral variables are listed in Table 10-1.

119

120

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

E

E

A

A

LV RV

Sample volume

Ac RA

E at A

LA

Ac

0 LV IVRT

Mdt

Adur

Mdt

LV IVRT

Adur

Figure 10-4 Mitral flow velocity variables. These are obtained with PW Doppler by placing a 1–2 mm sample volume between the mitral leaflet tips as shown. Variables measured include peak E- and A-wave velocities, as well as the E-wave velocity just prior to atrial contraction (E-at-A velocity). The left ventricular (LV) isovolumic relaxation time (IVRT) is the time interval from aortic valve closure (Ac) to mitral valve opening. Mitral deceleration time (Mdt) is from peak E-wave velocity to a line extrapolated down the decreasing velocity to the zero baseline. The duration of mitral A wave (Adur) is from the E-at-A (preA) velocity to the time the A wave returns to the zero baseline. (From Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–46, ix.)

TABLE 10-1 MITRAL FLOW VELOCITY IN NORMALS: AGE-RELATED CHANGES AGE (yr)

n

IVRT (msec)

E (mmHg)

A (mmHg)

MDT (msec)

ADUR (msec)

2–20 21–40 41–60 >60

46 51 33 10

50 ± 9 67 ± 8 74 ± 7 87 ± 7

88 ± 14 75 ± 13 71 ± 13 71 ± 11

49 ± 12 51 ± 11 57 ± 13 75 ± 12

142 ± 19 166 ± 14 181 ± 19 200 ± 29

113 ± 17 127 ± 13 133 ± 13 138 ± 19

Normal age-related values for mitral E- and A-wave velocities, and mitral E/A wave ratios are shown ± SD. All individuals were free of cardiac disease and had a normal blood pressure, physical exam, and electrocardiography. Left ventricular hypertrophy was excluded, and all E-at-A velocities were <20 cm/sec, so that the peak A-wave velocity was not increased above that expected for the aging process. IVRT = isovolumic relaxation time; Mdt = mitral deceleration time; Adur = duration of mitral A wave. From Hatle LH; unpublished, with permission.

LV FILLING PATTERNS E A IVRT Normal

Impaired relaxation

Pseudonormal

Restrictive

Diastolic abnormalities:

Abnormal relaxation + Normal LA pressure

Abnormal relaxation ↓ compliance + ↑ LAP ↑ LV RFW

Abnormal relaxation ↓↓ compliance + ↑ LAP ↑ LV RFW

The three basic abnormalities of LV ﬁlling patterns were discussed previously and are shown in Figure 10-5, where the arrows indicate that abnormal mitral ﬁlling patterns are a dynamic continuum and may worsen or become more normal with changes in loading conditions. Common usage describes the three abnormal ﬁlling patterns as “impaired,” “pseudonormal,” and “restrictive” relaxation. The diastolic property of impaired LV relaxation is

Figure 10-5 Normal and abnormal LV filling patterns and their associated LV diastolic abnormalities. The degree of abnormality increases from left to right. The arrows indicate their dynamic nature in response to loading conditions and other variables. IVRT, isovolumic relaxation time; LA, left atrial; LAP, LA pressure; RFW, LV rapid filling wave in early diastole.

present in all patterns, the diﬀerence being that with pseudonormal and restrictive ﬁlling, progressively reduced LV compliance raises mean LA pressure to levels that mask their eﬀects on the transmitral pressure gradient and ﬁlling. The changes in LV ﬁlling with normal aging and with cardiac disease states can be combined into a “natural history of LV ﬁlling,” which is shown together with their corresponding PV

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling THE NATURAL HISTORY OF LV FILLING Impaired LV relaxation Normal Young m/sec 1

Middle age

Decrease in LV compliance Older

Mild

Moderate

Severe

E A IVRT

0 0.5

PVs PVd

0 PVa Figure 10-6 The “natural history” of left ventricular (LV) filling patterns with normal aging and with progressive diastolic dysfunction, as assessed by PW Doppler mitral and pulmonary venous flow velocity recordings. Several abnormal LV filling patterns have E/A wave velocity ratios that are similar to those seen in normal individuals. This can occur because different combinations of LV relaxation and left atrial (LA) pressures may result in the same early diastolic transmitral pressure gradient and hence a similar mitral flow velocity pattern. For this reason, additional data, such as pulmonary venous flow velocity, is often helpful in distinguishing normal from abnormal mitral filling patterns, especially of the pseudonormal type. The dashed lines in pulmonary venous flow represent common variations. A, peak mitral flow velocity at atrial contraction; E, peak mitral flow velocity in early diastole; IVRT, LV isovolumic relaxation time; PVa, reverse pulmonary venous flow at atrial contraction; PVd, pulmonary venous flow velocity in diastole; PVs, pulmonary venous flow velocity in systole. (Modified from Appleton CP: The natural history of left ventricular filling abnormalities: Assessment by two-dimensional and Doppler echocardiography. Echocardiography 1992;9:437–457.)

ﬂow velocities in Figure 10-6. Although theoretical when proposed in 1992,24 the progression of abnormalities in LV ﬁlling patterns with disease states (from impaired relaxation to pseudonormal to restrictive), together with changes in LV relaxation and compliance, has been documented in experimental models of congestive heart failure76 and clinically observed in patients with restrictive cardiomyopathies.20 Many variations of LV ﬁlling patterns that do not exactly match the three “classical” abnormal patterns are common because of the multiple combinations of the rate of LV relaxation and compliance. However, the abnormal LV ﬁlling patterns remain speciﬁc to the alterations in diastolic properties rather than to the type of cardiac disease, with all three patterns, depending on disease stage, being seen in disorders as diverse as restrictive and dilated cardiomyopathies. This “natural history” of LV ﬁlling explains how both young normal individuals and patients with severe disease and a restrictive ﬁlling pattern can have a high proportion of ﬁlling in early diastole and an audible S3 gallop.77 It also shows that PV ﬂow velocity has its own changes that occur with normal aging and in cardiac disease states (discussed below) and that these associated PV ﬁlling patterns are more distinctive than some similar-appearing normal and abnormal mitral ﬂow velocity patterns.26

Left Ventricular Filling and Changing Cardiac Loading Conditions Simple maneuvers in the echo laboratory to reduce (Valsalva) or increase (leg raising) preload demonstrate that mitral ﬂow velocity patterns are a dynamic continuum.28–30 Plotting the changes in E-wave velocity and mitral DT in individuals after altering loading conditions has even been proposed as a load-independent index of normal and abnormal diastolic ﬁlling.78 During the strain phase of a Valsalva maneuver, preload (mean LA pressure) is reduced, and in normals peak mitral E-wave velocity decreases by at least 20% during maximum strain with a smaller decrease in peak A-wave velocity (Fig. 10-7). Similarly, in patients with an impaired relaxation ﬁlling pattern, mean LA

pressure is normal, so that with preload reduction, the whole diastolic transmitral pressure gradient decreases and both E- and A-wave velocities decrease. In patients with reduced systolic function and an impaired relaxation pattern, increasing preload by leg raising may result in no change in the ﬁlling pattern. However, if a pseudonormal mitral ﬂow velocity pattern results, it indicates a higher cardiovascular morbidity than if their E/A ratio remains less than 1.28 With pseudonormal mitral ﬂow patterns, the Valsalva strain lowers the elevated LA pressure and “unmasks” the underlying impaired LV relaxation.29 A notable feature of this change is the increase in mitral A-wave velocity and duration as the left atrium ejects into a ventricle that has a lower pressure. Preload-sensitive patients with restrictive ﬁlling patterns will revert to a pseudonormal ﬁlling pattern. In individuals who perform an adequate Valsalva and yet remain restrictive, LV stiﬀness is markedly increased, even at the more normal ﬁlling pressures. These patients have a poor prognosis.32

Grading the Degree of Left Ventricular Diastolic Dysfunction by Mitral Flow Velocity Alone A simpliﬁed grading system for diastolic function based on the three abnormal mitral ﬂow velocity patterns alone is shown in Figure 10-848 and has been found to be useful in many patients. Grades Ia and Ib represent an impaired relaxation ﬁlling pattern with normal mean LA pressure and LA size. The diﬀerence is whether all LV ﬁlling pressures are normal (Ia) or whether LV pressure increase with atrial contraction is abnormal and increases LVEDP (Ib). This is important because an increase in LVEDP is the ﬁrst hemodynamic abnormality of diastolic dysfunction (see Fig. 10-2). Grade II indicates pseudonormal ﬁlling with increased mean LA pressure, and grade III is a restrictive LV ﬁlling pattern. Grade IV is restrictive ﬁlling that does not revert to pseudonormal with preload reduction, indicating the most advanced LV diastolic dysfunction and the worst prognosis. Although grading LV diastolic dysfunction by mitral ﬂow velocity pattern alone can be helpful, many patients (especially the

121

122

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling LV FILLING PATTERNS: RESPONSE TO PRELOAD REDUCTION (VALSALVA) Normal

Pattern

Pseudonormal

Valsalva

Baseline

Maximum

Interpretation

Normal

Normal

Impaired relaxation

Normal pressures

Impaired relaxation

↑ LV A wave, ↑ EDP

Pseudonormal

Pseudonormal

Restrictive

Preload sensitive partially reversible

Restrictive

Fixed restrictive

Valsalva

B

A

Figure 10-7 Changes in mitral flow velocity patterns to preload reduction using the Valsalva maneuver. A, PW Doppler mitral flow velocity recordings from a normal individual and a patient with pseudonormal left ventricular (LV) filling. After Valsalva, the normal has both E- and A-wave velocity decrease with little change in E/A ratio, while the lowering of left atrial (LA) pressure in the pseudonormal patient “unmasks” an impaired LV relaxation filling pattern. B, In tabular form the different responses seen in mitral LV filling patterns with a Valsalva maneuver after approximately 10 seconds of strain. In all but fixed restrictive, the E-wave velocity should decrease at least 20%. When mean LA pressure is normal, the mitral A-wave velocity also decreases. No A-wave change with an impaired relaxation filling pattern suggests an elevated LV end diastolic pressure (EDP). With mean LA pressure increased, pseudonormal filling reverts to impaired relaxation filling, and most restrictive patterns to pseudonormal. The exception is irreversibly restrictive, where advanced disease results in no change in filling, even with a moderate decrease in mean LA pressure. (A, From Dumesnil JG et al: Use of Valsalva maneuver to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515– 519. B, From Appleton CP: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix.)

SIMPLIFIED LV DIASTOLIC FUNCTION CLASSIFICATION Normal Grade DHF

IR Ia

IR+ Ib

PN II

III

Restrictive IV*

*No change with Valsalva Figure 10-8 A simplified grading system for diastolic dysfunction is shown that assigns each abnormal mitral flow velocity pattern to a progressively more advanced grade of diastolic heart failure. Impaired relaxation Ia has normal filling pressures, while IR + Ib has an increase in left ventricular (LV) end diastolic pressure, the first hemodynamic abnormality that occurs in diastolic dysfunction. Grade III is restrictive, which will revert to a pseudonormal pattern with Valsalva maneuver and left atrial pressure (preload) reduction, while grade IV diastolic heart failure will not, an ominous prognostic sign. (From Oh JK et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506.)

elderly) may be misclassiﬁed. The rate of LV relaxation and LV compliance and ﬁlling pressures are a continuum, and similar LV ﬁlling patterns are possible with diﬀerent combinations of these diastolic properties.48,49 A major area of misinterpretation concerns patients with markedly impaired LV relaxation where LA pressures are elevated with an increase in the E-wave velocity, yet the ﬁlling pattern appears to be impaired (E/A ratio <1) because of partial fusion of early and late diastole (see Fig. 10-3) or because LV relaxation is so abnormally slow that only marked increases in mean LA pressure will result in pseudonormal ﬁlling. Figure 10-9 shows an example of this latter phenomenon. In this case, three patients with hypertrophic cardiomyopathy have diﬀerent combinations of the speed of LV relaxation and LA pressure,

giving similar mitral E/A wave ratios of approximately 2, yet the mean LA pressure varies threefold because of the markedly different rates of LV relaxation.59 In these cases, ancillary data such as two-dimensional anatomic abnormalities, LVEF reduction, LVH, LA enlargement, or altered PV ﬂow or annular TDI velocities are indicators that abnormal diastolic function and pressures are present.47–49,79 Also some mitral ﬁlling patterns are “atypical,” meaning that a biphasic mitral DT, a mid-diastolic ﬁlling “hump,” or some other unusual feature is present. These less common LV ﬁlling patterns do not ﬁt well into a grading scheme for diastolic dysfunction that uses only the mitral ﬂow velocity pattern and are best understood by evaluating the abnormal diastolic properties and physiology that the altered LV ﬁlling reﬂects.

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

LV relaxation

Figure 10-9 An illustration of how different combinations of impaired left ventricular (LV) relaxation and left atrial (LA) pressure can result in mitral flow velocity patterns with similar E/A ratios but markedly different filling pressures. The pulsed wave (PW) mitral recordings shown are from three patients with hypertrophic cardiomyopathy. The patient on the left is the most normal, with the least impaired LV relaxation and a normal mean LA pressure. The patient on the right has a similar LV filling pattern but marked diastolic dysfunction, with severely impaired LV relaxation and a mean LA pressure of 30 mmHg. In these cases, the grading system of diastolic dysfunction in Figure 10-8 would not work well, and other ancillary variables indicate the true degree of diastolic dysfunction present. (From Nishimura RA et al: Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226–1233.)

LV pressure 7 All combinations = 7 (i.e., LV relaxation + LV pressure = the same filling pattern) E 150 mmHg

E

E

0.2 m/sec

150 mmHg

A

LV

100 mmHg

LV

A

LA

LA

0 mmHg

0 mmHg

0 mmHg

A

LV relaxation LA pressure

9

Grading the Degree of Left Ventricular Diastolic Dysfunction in Epidemiologic Studies Recent landmark studies show that many asymptomatic individuals with a normal LVEF have abnormal diastolic function that is a risk factor for future development of adverse cardiovascular events such as new-onset heart failure, a ﬁrst episode of atrial ﬁbrillation or stroke, and death.50,80 In an eﬀort to improve predictive value beyond that of analyzing mitral ﬂow velocity alone, the classiﬁcation of the degree of LV diastolic abnormality in these studies included mitral inﬂow velocity variables (especially the E/A wave ratio), their response to the Valsalva maneuver, PV ﬂow velocity, and TDI of the mitral annulus. Figure 10-10 shows the multiple echo-Doppler criteria for grading diastolic dysfunction in these epidemiologic studies and provides a preview of the ancillary variables that aid in this interpretation (discussed later in this chapter).

PULMONARY VENOUS FLOW VELOCITY PV velocity, usually obtained with PW Doppler from the right upper pulmonary vein during transthoracic apical imaging, reﬂects the ﬁlling dynamics of the left atrium. With experience, high-quality PW Doppler transthoracic recordings can be obtained in approximately 85% to 90% of patients.75 Within a short time after mitral ﬂow velocity patterns were correlated with hemodynamics, it became apparent that PV ﬂow velocity could be of additional help in assessing LV ﬁlling patterns,26 especially impaired relaxation ﬁlling with increased LVEDP and pseudonormal LV ﬁlling.64–66

14

30

mmHg

While there are now several additional echo-Doppler variables to help identify pseudonormal ﬁlling (LA size, color M-mode [CMM] inﬂow propagation velocity, mitral annular TDI), PV ﬂow velocity analysis remains unique and indispensable to identifying an abnormal increase in LV pressure at atrial contraction. The various components of PV ﬂow velocity change with age, mitral ﬂow velocity, and disease states and can be matched to their corresponding mitral Doppler patterns (see Fig. 10-6). The hemodynamic determinants of PV ﬂow velocity have been studied in vivo81–84 and clinically26,85–87 and related to individual variables (Fig. 10-11). These include peak forward ﬂow velocity in early systole (PVs1), late systole (PVs2), and early diastole (PVd) and peak reverse ﬂow velocity at atrial contraction (PVa) and its duration (PVa dur). A dip or “notch” between PVs1 and PVs2 in early LV systole represents the C wave seen in LA pressure recordings at the time of mitral valve closure. PVs1 blends with PVs2 velocity, and this “notch” is not distinctly seen in most (about 70%) transthoracic ﬂow velocity recordings75 but is observed more often with a ﬁrst-degree atrioventricular (AV) block and in virtually all transesophageal-echo (TEE) recordings in patients in sinus rhythm.86 PVs1 occurs in early ventricular systole as a result of LA relaxation and a decrease in downstream LA pressure at a time when PV pressure is relatively constant. PVs2 peaks later in systole and is due to the increase in PV ﬂow and pressure that results from systolic right ventricular (RV) stroke volume. Maximal PVs2 velocity, its time-velocity integral (TVI), and deceleration of ﬂow reﬂect the pressure diﬀerence between PV and downstream LA pressure as blood ﬁlls both vascular systems. The descent of the

123

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

Mitral inflow at peak Valsalva maneuver

Doppler tissue imaging of mitral annular motion

Pulmonary venous flow

Velocity (m/sec) Velocity (m/sec)

Mitral inflow

Velocity (m/sec)

Severe diastolic dysfunction

Velocity (m/sec)

124

Normal diastolic function

Mild diastolic dysfunction Impaired relaxation

Moderate diastolic dysfunction Pseudonormal

Reversible restrictive

Fixed restrictive

0.75 < E/A < 1.5 DT >140 msec

E/A < 0.75

0.75 < E/A < 1.5 DT > 140 msec

E/A >1.5 DT< 140 msec

E/A >1.5 DT < 140 msec

ΔE/A < 0.5

ΔE/A ≥ 0.5

ΔE/A ≥ 0.5

ΔE/A < 0.5

E/E′ < 10

E/E′ ≥ 10

E/E′ ≥ 10

E/E′ ≥ 10

2.0

E A

0 Adur ΔE/A < 0.5 2.0 E

A

0 E/E′ < 10 0 0.15

E′

A′

S≥D ARdur < Adur 1.0

S

S>D ARdur < Adur

S < D or S < D or S < D or ARdur > Adur + 30 msec ARdur > Adur + 30 msec ARdur > Adur + 30 msec

D ARdur

0

Left ventricular relaxation Left ventricular compliance Atrial pressure

AR Time (msec)

Time (msec)

Time (msec)

Time (msec)

Time (msec)

Normal Normal Normal

Impaired Normal to ↓ Normal

Impaired ↓↓ ↑↑

Impaired ↓↓↓ ↑↑↑

Impaired ↓↓↓↓ ↑↑↑↑

Figure 10-10 A more complicated grading system for left ventricular (LV) diastolic dysfunction that incorporates multiple mitral flow velocity variables, their response to Valsalva maneuver, pulmonary venous flow velocity variables and tissue Doppler imaging of the septal mitral annulus. These criteria have been used in epidemiologic studies to assess the asymptomatic prevalence of diastolic dysfunction in the community and also how LV diastolic dysfunction increases the risk for future adverse cardiac events. (From Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202.)

AV rings with ventricular systole increases LA size and compliance while helping decrease the downstream LA pressure. PV diastolic ﬂow velocity (PVd) initially follows early diastolic mitral ﬂow velocity; but in mid-diastole, LV ﬁlling slows while PVd ﬂow continues with ongoing LA enlargement and appendage ﬁlling. PV ﬂow reversal due to atrial contraction (PVa) is determined by LA contractility and LV compliance, with more and longer reverse ﬂow seen as LV compliance decreases. Changes in PV ﬂow velocity and their relation to LV compliance and LA pressures are shown in Figure 10-12. In patients with impaired relaxation ﬁlling, decreased LV compliance, and normal mean LA pressure, early diastolic ﬁlling (mitral E wave) is reduced. In these cases, LA hypertrophy (LAH) provides a suﬃcient atrial “kick” to ﬁll the left ventricle to its optimal end diastolic volume. An important beneﬁt of LAH is that it conﬁnes the abnormal pressure rise in the atrium, ventricle, and pulmonary veins to the short period associated with atrial contraction so that mean LA pressure remains normal (see Fig. 10-2). PVs1 is increased so that the PV systolic-to-diastolic ﬂow velocity ratio remains above 50%. If LV compliance decreases further, the atrium may begin to decompensate, enlarge, and have contractile dysfunction. A reduced systolic fraction of PV antegrade ﬂow

(<40%) indicates LA systolic dysfunction (decline in PVs1) and has a high speciﬁcity for a pseudonormal LV ﬁlling pattern and increased mean LA pressure (see Fig. 10-12).28,87 The PV A wave and its relation to mitral A-wave duration are of special importance and are discussed in detail below.

Relation of Mitral to Pulmonary Venous A-Wave Duration As shown in Figure 10-13, when both A-wave ﬂow velocity durations are accurately recorded, this relation is an important indication of LV A-wave pressure increase and LV end diastolic pressure,64–66,88,89 even in the pediatric age group.90 Laboratories that do not routinely record PV ﬂow velocity will miss the unique aspects of this derived variable. Unlike other Doppler variables, the relation is independent of age, meaning that mitral A-wave duration remains equal to or longer than PV A-wave duration throughout life in normal individuals. Secondly, the relation of the two A-wave durations is our only echo-Doppler variable that directly relates to the rise in LV pressure at atrial contraction, thereby separating patients with impaired relaxation who have normal ﬁlling pressures from those who have an increased LVEDP

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling PVs2 PVd PVs1 ECG PVs2

PVd

PVs1

0

PVa

PVa

PVa dur

A

PVd

80

200 msec 8 PVs2

PVs2

40

PV LA

PVs1

LA

6

PVd

PVs1

0 –20

PV

PVa mmHg

PV velocity (cm/sec)

Figure 10-11 A, Pulmonary venous (PV) variables obtained with the pulsed wave Doppler technique include peak flow velocity and early systole (PVs1), late systole (PVs2), and early diastole (PVd) and peak reverse flow velocity (PVa) and its duration (PVa dur) at atrial contraction. B, Panel 1 shows simultaneously recording of PV flow velocity together with PV and left atrial (LA) pressures. Panel 2 is a schematic drawing of PV and left atrial (LA) pressures showing the different hemodynamic pressure gradients (hatched areas) that determine the four individual PV flow velocity components. These components are described in the text. (A, From Appleton CP et al: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix. B, From Appleton CP: Hemodynamic determinants of Doppler pulmonary venous flow velocity components: New insights from studies in lightly sedated normal dogs. J Am Coll Cardiol 1997;30:1562–74.)

PVa dur PVa PVa dur

4

B PULMONARY VENOUS FLOW VELOCITY

PVs PVd

PVa Normal

↓ LV compliance ↑ LAP

Impaired relaxation

↓ LV compliance ↑↑ LAP

A

PWP (mmHg)

40

1 m/sec

30

0.4

20 10

0

0 0

20

40

60

80

100 0.4

PV systolic fraction (%)

B

C

Figure 10-12 A, Schematic drawing of pulmonary venous (PV) flow velocity patterns obtained with PW Doppler from normal to most abnormal (left to right). With impaired relaxation, the proportion of PV systolic flow (PVs) increases as PV diastolic flow (PVd) decreases, paralleling the decrease in mitral E-wave velocity. Reverse flow back into the pulmonary veins with atrial contraction (PVa) is variable, being increased in velocity (>35 cm/sec) and duration (>30 msec greater than mitral A-wave duration) if left ventricular (LV) end diastolic pressure is elevated. As LV compliance decreases, and left atrial pressure (LAP) increases, the proportion of PVs flow decreases. At the same time, PVd and E-wave velocity increase with pseudonormal and restrictive LV filling being seen. All mitral and their corresponding PV patterns are shown together in Figure 10-6. B, The relation of PV systolic fraction (in % of total forward flow) to pulmonary wedge pressure (PWP). When PVs is <40% in a patient with heart disease, PWP is elevated. C, PW Doppler mitral and PV flow velocity in a patient with pseudonormal to restrictive filling who has an enlarged left atrium and whose contractile function is failing. PVs is decreased with a systolic fraction <40%, PVd is increased, and the velocity and duration of PVa exceed those of the mitral A-wave (vertical lines). This indicates that mean LA pressure, LV A-wave pressure rise, and LV end diastolic pressure are all increased. (B, From Kuecherer HF et al: Pulmonary venous flow patterns by transesophageal pulsed Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693.)

125

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling MITRAL VS. PULMONARY VENOUS A - WAVE DURATION: RELATION TO LVEDP

40

S D Svti

PVa-d

Dvti

30

LVEDP

Velocity

–30

20

PVa-vti Ddt

10

PVa

0 –100

A

Velocity

E

–50

0

50

100

MVA dur – PVa dur

B Edt

Adur

m/sec

EDP

LVa

Pulmonary venous

Mitral

1– Pressure

126

0.5–

0

Pre-a 0 Adur 121 msec

A

0.5–

PVa Adur 200 msec

C

Figure 10-13 A, Schematic diagram of the relation of pulmonary venous (PVa-d) and mitral flow velocity A-wave duration (Adur), which relates to the left ventricular (LV) pressure rise at atrial contraction (LVa). The graph combines Doppler data from three separate studies (from references 64–66) and shows that when the reverse duration of PV compared with mitral A-wave flow exceeds 30 msec, LV end diastolic pressure (LVEDP) is usually >15 mmHg. C, PW Doppler mitral and PV flow velocity from a patient with LV hypertrophy and impaired relaxation filling. The mitral A-wave duration is 121 msec and PV Awave duration 200 msec, so that flow backward into the pulmonary vein continues for 80 msec after flow into the left ventricle stops. This indicates that LV A-wave pressure increases and LV end diastolic pressure is elevated. (A, From Kuecherer HF et al: Pulmonary venous flow patterns by transesophageal pulsed Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693.)

(>12 mmHg), the ﬁrst hemodynamic abnormality seen with diastolic dysfunction. Under normal circumstances when the left atrium contracts, the net volume and duration of ﬂow should be greater forward into the left ventricle than backward into the pulmonary veins. If the PV A wave is increased in either velocity (>35 cm/sec) or duration (>30 msec longer than mitral A wave), LV A-wave pressure is increased and LVEDP is elevated (see Fig. 10-13). Even in cases where the atrium is enlarged, markedly hypokinetic, and failing, the PV A-wave duration of reverse ﬂow continues to be more than 30 msec longer than the abbreviated mitral A-wave inﬂow duration. If the PV A-wave duration is diﬃcult to measure due to a suboptimal recording, referencing the end of both A-wave ﬂows to the QRS complex is helpful, as PV ﬂow duration is abnormal if it exceeds that of the mitral A wave. A detailed guide to obtaining high-quality PW Doppler PV ﬂow velocity recordings has been published.75 The interpretation of mitral versus PV A-wave duration may not be reliable if the mitral velocity at the start of atrial contraction is greater than 20 cm/sec,88 or if atrial contraction occurs before PVd has reached the zero velocity baseline.49 In the ﬁrst case, the peak mitral A-wave velocity, TVI, and A-wave duration are longer than normal to accommodate the increased atrial stroke volume that is present; and in the second case, the PV Adur is

shorter because it starts above the conventional measuring point of the zero velocity baseline.

CLINICAL APPLICATIONS: INTERPRETATION OF INDIVIDUAL MITRAL FLOW VELOCITY VARIABLES Studying the factors that inﬂuence individual mitral ﬂow velocity variables is often useful in interpreting LV ﬁlling patterns in difﬁcult or uncommon cases. It is also a powerful tool for deciding which diastolic property is most abnormal, which helps in the planning of possible clinical interventions in individual patients.

Left Ventricular Isovolumic Relaxation Time LV IVRT is the interval from aortic valve closure to mitral valve opening and the start of mitral inﬂow (see Fig. 10-4). This interval can be a powerful tool for physicians in helping to evaluate diastolic dysfunction and ﬁlling pressures, especially when the mitral E wave is increased or atrial ﬁbrillation is present. We suggest it be measured on all echo-Doppler studies.91 In normal patients, IVRT varies with age, being shorter in the young, who have rapid LV relaxation that results in an earlier mitral valve opening, and then becoming lengthened as relaxation

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling slows with age.17 Figure 10-14 compares the eﬀect of changes in the rate of LV relaxation and LA pressure on the IVRT interval, timing of the mitral valve opening, and LV ﬁlling pattern using a normal subject and a patient with impaired LV relaxation. The IVRT interval is most helpful when it is at its extremes, meaning farthest from expected norms, being either short (<60 msec) or long (>110 msec). It is less useful in-between these values. A normal IVRT for a middle-aged adult is approximately 80 msec. A short IVRT (<60 msec) indicates an early mitral valve opening; a long IVRT (>100 msec), a delayed LV relaxation and a late valve opening. In patients with impaired relaxation ﬁlling and normal pressures, a prolonged IVRT is an early indicator of LV diastolic dysfunction.60,92 If mean LA pressures remain normal, extremely slow LV relaxation can result in IVRT values that approach 200 msec. The higher ﬁlling pressure in pseudonormal ﬁlling patterns causes the mitral valve to open earlier, so the IVRT shortens. More normal values of 60 to 100 msec are usually seen, and the IVRT value is less useful. A short IVRT of 40 to 60 msec can be seen in young, healthy, normal individuals or in patients with very high mean LA pressure and restrictive ﬁlling. This clinical distinction is easily made by normal versus abnormal two-dimensional anatomic ﬁndings, especially of LA size and contractile function. Effect of the speed of LV relaxation on TMPG and LV IVRT

A common instance when IVRT duration can be very helpful is when heavy mitral annular calciﬁcation is present and there is a question of mild calciﬁc mitral stenosis versus LV diastolic dysfunction. The mitral annular narrowing may increase E-wave velocity, the E/A wave velocity ratio, and LA size, making the assessment of LV diastolic dysfunction diﬃcult. If the pressure half-time is normal or borderline but the IVRT is short (20 msec less than expected for age), LA pressure is likely elevated due to a noncompliant left ventricle. Conversely, if E-wave velocity is increased but the IVRT is normal, mild annular narrowing is likely the cause for the increased velocity. A markedly prolonged pressure half-time indicates calciﬁc mitral stenosis, in which case a short IVRT would also indicate increased mean LA pressure, similar to the auscultatory ﬁndings of a short opening snap interval.

Left Ventricular Intracavitary Flow During Isovolumic Relaxation Time LV IVRT ﬂow is usually apically directed, from one part of the ventricle to another, occurring when both aortic and mitral valves are closed during IVRT.93 The importance of recognizing IVRT ﬂow is twofold; it indicates that abnormal, dyssynchronous LV

LV pressure

Mitral flow velocity Abnormal relaxation

LV

Ac LAP Abnormal relaxation

LV IVRT

C

A Effect of LAP on TMPG and LV IVRT

Mitral flow velocity Ao

Ao

1 m/sec LV c m/sec

LV

–50 LV Ac LAP Normal relaxation

LV IVRT

B

Abnormal relaxation

D

Figure 10-14 The left ventricular (LV) isovolumic relaxation time (IVRT). A, The effect of the speed of LV relaxation on early diastolic (E-wave) transmitral pressure gradient (TMPG) and IVRT with constant left atrial (LA) pressure. The slower the LV relaxation, the longer the IVRT interval and the smaller the TMPG (E wave). B, The effect of different LA pressures (LAP) on LV IVRT with a constant rate of LV relaxation. The higher the LAP, the shorter the IVRT and the earlier the mitral valve opening. C, D, Schematic of LV pressure and mitral flow velocity (top) and PW Doppler mitral flow velocity recordings in two subjects (bottom), illustrating the principles in the left panel. The normal subject shows rapid relaxation, a normal LV filling pattern, and normal IVRT of 70 msec (small vertical arrows). The patient on the left has hypertension and slower LV relaxation. With a normal mean LAP, this results in a longer IVRT (110 msec), lower E-wave, increased A-wave velocity, and the familiar impaired LV relaxation filling pattern. (C, D, From Hatle LK et al: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)

127

128

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling relaxation is present between apex and base and that its peak velocity should not be confused with the mitral E-wave velocity that immediately follows it. In the normal situation, no signiﬁcant LV ﬂow is detected during the IVRT period. When present, IVRT ﬂow is most easily detected from an apical transducer position with CW or CMM Doppler because both techniques scan the long axis of the ventricle. PW Doppler can then be used for better velocity deﬁnition. When present, IVRT ﬂow is usually 20 to 60 cm/sec but can occasionally be as high as 1 to 2 m/sec, as seen in Figure 10-15. When IVRT ﬂow is present, the most common cause is systolic LV narrowing at the papillary muscle level, due to either LVH or hyperdynamic systolic function, which increases late systolic ﬂow velocities. The increased mid- or late systolic load placed on the LV apical segments causes the apex to relax prematurely before the basal myocardial segments, with blood ﬂow moving toward the lower pressure in the apex before the mitral valve opens. “Bidirectional” IVRT ﬂow is occasionally seen when apical directed ﬂow “turns around,” ﬂowing back toward the annulus as basilar relaxation reduces pressure below that in the apex. IVRT ﬂow can also be observed in the left ventricle with dyssynchronous LV relaxation due to coronary artery disease (CAD) with a left bundle branch block (LBBB) and in the RV apex when it is hyperdynamic and exhibits systolic cavity obliteration.

stroke volume. Cardiac output is this stroke volume times the heart rate. Since the mitral oriﬁce is larger than the aortic annulus, the mitral TVI should be smaller than the LV outﬂow tract (LVOT) TVI, typically by about 30%. If cardiac output is either elevated or decreased, the mitral-toLVOT TVI ratio should remain normal. With signiﬁcant mitral regurgitation (MR) or mitral stenosis (MS), the mitral TVI will increase and be as large or larger than the LVOT TVI. With isolated aortic regurgitation, the reverse relation may exist, increasing the diﬀerence from aortic to mitral TVI. As early and late diastolic mitral TVIs represent the sum of LV ﬁlling, an inverse relation exists. A large early diastolic mitral TVI will be associated with a smaller TVI at atrial contraction. Conversely, when the E-wave TVI is decreased, the ventricle can reach a normal end diastolic volume only if there is a corresponding increase in A-wave TVI. If mitral E and A waves are partially fused at rest, a low proportion of E-wave versus A-wave TVIs may be present. Patients often have a reduced functional aerobic capacity because of an inability to increase LV diastolic volume adequately with exercise.72

Peak Mitral E-Wave Velocity The early diastolic transmitral pressure gradient52 (see Fig. 10-1) determines peak mitral E-wave velocity, whose values in normals of various ages have been published but have wide conﬁdence limits.16–18 These studies were performed before additional variables such as LA volume or TDI annular velocities were routinely performed, which would verify that normal cardiac physiology was present. Table 10-1 lists E-wave velocities in individuals of various ages without histories of cardiac disease, in whom these newer variables were included, and who also had normal blood

Mitral Time-Velocity Integral Though rarely considered when discussing the assessment of LV diastolic function, the absolute value of the mitral TVI is often helpful in interpreting mitral ﬂow velocity patterns. In the absence of signiﬁcant mitral or aortic regurgitation, mitral TVI multiplied by the mitral valve cross-sectional oriﬁce area represents the LV

CMM DOPPLER IVRT flow PW DOPPLER MID-LV CAVITY 1.5 m/sec

IVRT flow

E

A

Sys

1.0

E 1.0

A

1.5 0.5 CW DOPPLER

E

Sys [m/sec]

IVRT flow

–0.5 1.0 MR

1.5

2.0 100 mm/sec

83 HR

Figure 10-15 Isovolumic relaxation time (IVRT) flow in the mid–left ventricular (LV) cavity in a patient with LV hypertrophy and near systolic cavity obliteration. All recordings are from an apical transducer position. The color M-mode (CMM, top left) is directed through the mitral valve. Midcavity systolic flow (Sys) is followed by bidirectional IVRT flow, first toward the apex (orange) and then a shorter period toward the base (blue, arrows). This is followed by mitral E and A waves. CW Doppler shows the apically directed IVRT flow, followed by mitral E-wave and mild mitral regurgitation. PW Doppler at the mid-LV cavity shows late peaking systolic flow acceleration at the area of LV narrowing (papillary muscle level), and then very prominent IVRT flow first toward the apex (1.6 m/sec, arrow above baseline) and then lower velocity toward the base (0.3 m/sec, arrow below baseline).

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling pressure, ECG, and echo-derived LV mass. Therefore, although sample sizes are much smaller in terms of absolute patient numbers, the conﬁdence limits are smaller and the results more likely to represent true normal values. Since E-wave and LVOT velocities are related to stroke volume and oriﬁce area, a predictable ratio between these variables exists in normals regardless of heart rate and cardiac output. The normal LVOT velocity is approximately 1 m/sec. Table 10-1 shows that the mitral/LVOT velocity ratio is about 80% in younger individuals, decreasing to 70% in middle age and 60% in the elderly as LV relaxation slows slightly and E-wave velocity decreases. Routinely checking this E-wave/LVOT velocity ratio improves the assessment of LV ﬁlling patterns and diastolic function. An Ewave/LVOT velocity ratio lower than expected indicates impaired LV relaxation and normal mean LA pressure. A normal ratio with increased or decreased E- and A-wave velocities is seen with reduced or increased cardiac output. Higher than expected ratios indicate that peak E-wave velocity is elevated, which may occur for several reasons. These include MS, MR, or increased mean LA pressure. Patients with MS or MR have increased E-wave velocities that may not reﬂect diastolic dysfunction. Mean transvalvular gradient and pressure half-times help assess the severity of MS, while IVRT reﬂects mean LA pressure. Signiﬁcant MR increases Ewave velocity due to the regurgitant volume recrossing the mitral valve in early diastole. Normally the ventricle and left atrium become more compliant as they undergo chamber enlargement and eccentric hypertrophy through a rightward shift in the pressure-volume relation. Mitral DT and PA pressures remaining normal despite the volume overload reﬂect this normal adaptation. A shortening of mitral DT or increased pulmonary artery pressures suggest acute MR or an abnormal decrease in LV compliance due to additional pathology. Many elderly patients with hypertension and LVH have an elevated E-wave velocity of 1 m/sec or greater with a mitral E/A wave ratio of less than 1. Using a diastolic function assessment by mitral ﬁlling pattern alone frequently labels these patients as having “impaired LV relaxation,” suggesting that mean LA pressure is normal when in fact the increased E-wave velocity is due to increased mean LA pressure. The higher A-wave velocity reﬂects LAH or partial fusion of E- and A-wave velocities due to a relatively fast heart rate or ﬁrst-degree AV block. Clues that patients with an impaired relaxation pattern actually have moderate diastolic dysfunction and elevated mean LA pressure equivalent to pseudonormal ﬁlling are: marked LVH, LA enlargement, and a preA velocity greater than 20 cm/sec. The diﬀerentiation between a normal and a pseudonormal ﬁlling pattern can be made by two-dimensional ﬁndings (vigorous LV and RV contraction, normal LA size) or other ancillary variables, such as PV systolic fraction, CMM mitral inﬂow propagation velocity, and mitral annular TDI. The change to a less abnormal LV ﬁlling pattern with a Valsalva maneuver (see Fig. 10-7) reveals the preload sensitivity of the abnormal diastolic function. Figure 10-16 shows increased E-wave velocities from expected values in several patients, illustrating the concepts we have discussed.

Mitral Deceleration Time Mitral DT is arguably the most important mitral variable for prognosis when heart disease is present, regardless of LVEF.21,32,94,95 In cardiac patients, mitral DT relates to LV chamber stiﬀness96;

the shorter the mitral DT and the more “restrictive” the LV ﬁlling pattern, the higher the mortality. The acceleration of E-wave mitral ﬂow velocity is related to the maximum early diastolic transmitral pressure gradient. The deceleration of this ﬂow, the mitral DT, is related to how fast (or slow) LV pressure increases in early diastole as volume enters the ventricle (the rapid ﬁlling wave as shown in Figs. 10-1 and 10-2). As with other mitral ﬂow velocity variables, mitral DT changes with age, lengthening as the rate of LV relaxation slows and less volume is transferred to the ventricle in early diastole (see Table 10-1). A short mitral DT (140–160 msec) is normal in healthy, young individuals due to the high proportion of ﬁlling in early diastole that occurs because of LV elastic recoil. As E-wave velocity and the proportion of early diastolic ﬁlling declines with age, mitral DT increases to about 200 msec by age 65 (see Table 10-1). With impaired LV relaxation and normal mean LA pressure, early diastolic ﬁlling is reduced (E/A wave ratio <1) and mitral DT is prolonged roughly in proportion to the slowing in the rate of LV relaxation.97 With pseudonormal mitral ﬁlling, the elevated mean LA pressure increases ﬁlling in early diastole into the noncompliant ventricle, and the rapid ﬁlling wave shortens the DT, with values that appear more normal for age. More advanced disease and further decreases in LV compliance cause such high LA pressure that blood is forced rapidly into a stiﬀ ventricle in early diastole, which causes a very rapid, abnormal rise in LV pressure.19 A short mitral DT (<140 msec) characterizes this restrictive ﬁlling, which is most commonly seen in advanced dilated or restrictive cardiomyopathies. In these cases, and despite the widely variable LVEFs, mitral DT is strongly related to both the elevated ﬁlling pressures51 and survival.21,94 Mitral DT is dynamic and will change with alterations in preload and afterload that change the transmitral pressure gradient. Patients who are volume overloaded may lengthen their DT with diuresis. Similarly, mitral DT may lengthen and become less restrictive in response to a Valsalva maneuver (see Fig. 10-7) that lowers preload.30 Persistence of a restrictive LV ﬁlling pattern in a cardiomyopathy despite a Valsalva maneuver or after maximum medical therapy is the most severe form of diastolic dysfunction (grade IV; Figs. 10-7, 10-8, and 10-10), an ominous prognostic sign that indicates a very high mortality.32 Mitral DT is also useful in patients with MR, where the welladapted ventricle will retain a normal DT. Shortening of the mitral DT from expected normal values for age indicates increased ventricular stiﬀness and is a better indicator of myocardial pathology than is peak E-wave velocity (see Fig. 10-16).

Mitral Flow Velocity at the Start of Atrial Contraction Although rarely measured, or even considered, mitral ﬂow velocity at the start of atrial contraction (see Fig. 10-4) is important because it aﬀects peak mitral A-wave velocity, the mitral E/A wave ratio, and the mitral A-wave duration. Therefore, we encourage its routine measurement along with those of the other mitral ﬂow velocity variables to improve the accuracy of assessing LV diastolic function. In normal individuals, the heart rate at rest is slow enough to keep this velocity at under 20 cm/sec. This maximizes early and mid-diastolic ventricular ﬁlling and minimizes the proportion of ﬁlling associated with the booster pump function of atrial contraction. With exercise, fusion of early and late diastolic ﬁlling will occur, but only at relatively rapid heart rates because of the eﬀects

129

130

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling m/sec 2.0

1.5

1.0

0.5

0 NI

IR

PN

PN-V

RST

MR

MS

Figure 10-16 PW Doppler recordings of mitral flow velocity in seven individuals (left to right panels), illustrating how different E-wave velocities compared with expected values aid in the interpretation of left ventricular (LV) filling patterns, some of which might be misdiagnosed by a scheme of grading diastolic dysfunction by E/A wave ratio alone. All individuals had a left ventricular outflow tract (LVOT) velocity of approximately 1 m/sec. The last two subjects have mitral valve disease. The 35-year-old normal (NI) has a mitral E-wave/LVOT velocity ratio of 85%. This ratio is reduced to 50% in the second patient, who has impaired LV relaxation. The patient with pseudonormal filling has a normal-appearing E/A wave ratio, but the E-wave velocity of 1.2 m/sec is 20% higher than LVOT velocity, indicating the increase in mean LA pressure. The next patient appears to have an impaired relaxation filling pattern with an E/A wave ratio <1 but really has a pseudonormal pattern variant (PN-V) caused by the partial fusion of early and late diastolic filling. Pseudonormal abnormalities present include an E-wave velocity elevated at 1 m/sec and an A-wave that would be much smaller (with a higher E/A ratio) if the heart rate were slower and atrial contraction had occurred after the mitral flow velocity had fallen below 20 cm/sec. The next patient has a dilated cardiomyopathy and restrictive (RST) filling with a short mitral DT (130 msec) and diminished atrial filling contribution. The last two patients have an increased E-wave velocity due to mitral valve disease. The patient with severe mitral regurgitation (MR) has an E-wave velocity of 1.4 m/sec, 40% higher than LVOT velocity. A shorter than expected mitral DT (170 msec) indicates reduced LV compliance, in this case from coronary artery disease and diabetes. The last patient has rheumatic mitral stenosis (MS), a high E-wave velocity, increased mean gradient, and prolonged pressure half-time.

of shortening of the P-R interval and faster LV relaxation (see Fig. 10-3). If mitral ﬂow velocity does not have suﬃcient time to fall below 20 cm/sec before atrial contraction, early and late diastolic ﬁlling (E and A waves) begin to merge, as shown in Figure 10-17. This decreases ﬂuid dynamic and ﬁlling eﬃciency and may increase the workload and size of the left atrium. The fusion of early and late diastolic ﬁlling most often occurs when the heart rate is too fast for a diastolic ﬁlling period that is shortened by impaired LV relaxation from LVH, an LBBB, or CAD. A ﬁrst-degree AV block may also cause mitral E- and A-wave fusion due to atrial contraction occurring only shortly after mitral valve opening instead of later in diastole. Depending on the physiology present, fusion can occur at heart rates as low as 70 to 80 bpm. In both cases, the A velocity is higher than if no fusion were present, and the E/A ratio is reduced compared with early and late diastolic ﬁlling that are separated. The consequences of resting or premature fusion of early and late diastolic ﬁlling are frequently seen in a “limited” ability to increase mitral TVI (the LV stroke volume) and LV end diastolic volume during exercise, with associated decrease in exercise capacity.72,74 The ability to see if the resting heart rate is well matched to the cardiac physiology present in individual patients by observing the LV ﬁlling pattern is one of the great strengths of the echo-Doppler technique that cannot be determined by physical exam. If possible, altering the heart rate to restore a normal separation between early and late diastolic ﬁlling frequently improves patient symptoms and exercise capacity.

Peak Mitral A-Wave Velocity The mitral A-wave velocity is determined by the late diastolic transmitral pressure gradient (see Fig. 10-1) and varies from 50 cm/sec in younger individuals to 75 cm/sec in normals over

60 years (see Table 10-1). In patients with impaired relaxation ﬁlling and reduced E-wave velocity, an increased A-wave velocity and TVI are expected and necessary to maintain a normal LV end diastolic volume and cardiac output. When LV relaxation is slowed, the reduced ﬁlling in early diastole results in less LV pressure increase after LV minimum pressure, so that the atrium contracts into a relatively low pressure, compliant chamber. By two-dimensional echo, the left atrium is usually normal in size and appears “hypercontractile,” with exaggerated annular movement superiorly toward the pulmonary veins. The A-wave peak velocity is increased, A-wave TVI is relatively large, and the ﬂow duration is increased, usually to more than 140 msec. An A-wave velocity below 1 m/sec or atrial DT that is unusually short (<110 msec) may indicate a decrease in late diastolic LV chamber compliance and an increase in LV A-wave and end diastolic pressures.

Mitral A-Wave Duration The importance of mitral A-wave duration is in what it reveals about late diastolic LV compliance. It is best used in conjunction with PV A-wave duration, as discussed previously. Like all mitral variables, A-wave duration varies with age in normals, being about 120 msec in the young and 140 msec in individuals over 60 (see Table 10-1). In general, when viewed in patients with cardiovascular disease, the longer the mitral A-wave duration, the more likely ﬁlling pressures are normal, while a shortened A-wave duration indicates increased LVEDP. Mitral A-wave duration, like peak A-wave velocity, is determined by the transmitral pressure gradient at atrial contraction (see Fig. 10-1). Under normal circumstances, the pressure increase in the atrium is larger than that in the ventricle. In pseudonormal or restricted LV ﬁlling patterns, the mitral A-wave duration is shortened because the reduced LV compliance results in an

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling P wave HR 70 preA 15 cm/sec A E HR 82 preA 70 cm/sec

E

A

HR 74 1° AVB LBBB preA 90 cm/sec A HR 105 1° AVB A wave only

E

E

A

A

HR 78 PR 276 LBBB preA 1 m/sec followed by PVC PVC

Figure 10-17 Variable mitral E-wave velocity at the start of atrial contraction (preA velocity, dotted vertical line) and how it affects the left ventricular (LV) filling pattern and especially E/A wave ratio and A-wave duration. PW Doppler recordings of mitral flow velocity in five separate patients are shown, and referred to from top to bottom. The echocardiography at the bottom relates to the bottom-most patient only. These fused LV filling patterns make assessment of diastolic dysfunction more challenging but are important because these patients are frequently symptomatic. For reference, the vertical dashed line (p wave) is aligned to the start of atrial contraction in all recordings. Only the top patient with an impaired relaxation mitral pattern has a preA velocity <20 cm/sec, the cutoff value at which E/A ratio, peak A velocity, and A-wave duration are unaffected by partial “fusion” of early and late diastolic LV filling. Patients 2 and 3 are in their 70s and have histories of hypertension. They have higher E-wave velocities than expected for age, yet the high preA velocity increases the peak A-wave velocity and makes the E/A ratio <1. Since the mitral time-velocity integral (TVI) represents LV filling volume, the higher pre-A velocity reduces E-wave TVI, which results in a larger A-wave TVI and A-wave duration. Slower heart rates would decrease peak A-wave velocity and increase the E/A wave ratio. Patient 4 has sinus tachycardia so that only an A wave is present. The A-wave velocity is high (1.6 m/sec) because all LV filling must occur during the P-R interval. Finally, patient 5 shows how after a premature ventricular contraction (PVC) and compensatory pause, the longer R-R interval markedly changes the E/A ratio and LV filling pattern. 1º AVB, first-degree atrioventricular block; LBBB, left bundle branch block. (From Hatle LK: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)

excessive rise in LV pressure with atrial contraction, which abruptly terminates transmitral ﬂow (Fig. 10-18).98 The reduced time of a positive transmitral pressure gradient is indicated by a shorter mitral A-wave duration whose DT is shorter than its acceleration time.99 Observing changes in A-wave duration over time (or after changes in loading conditions or medical therapy [see Fig. 10-18]) may conﬁrm that LV diastolic function is improving more easily than examining other Doppler variables. For instance, in patients with hypertensive heart disease and an impaired LV relaxation ﬁlling pattern, a lengthening of A-wave duration after medical therapy is helpful in conﬁrming if an increase in peak E-wave velocity represents improved LV relaxation and not increased LA pressure.100 Conditions that aﬀect mitral A-wave duration and make it more diﬃcult for use in assisting the evaluation of LV diastolic function include partial fusion of early and late diastolic ﬁlling101 (see Fig. 10-17), variation in cardiac cycle length due to sinus arrhythmia, premature atrial or ventricular beats, second- or third-degree AV block, and a short (<120 msec) P-R interval. Longer cycles result in more mid-diastolic LV ﬁlling and pressure

increase, so that when the atrium ﬁnally contracts, A-wave duration and velocity integral are reduced. Conversely, shorter R-R intervals result in longer A-wave durations. A short P-R interval (<120 msec) will have a reduced A-wave duration because the rise in LV pressure soon after atrial contraction will result in mitral valve closure and abrupt termination of A-wave ﬂow. Advanced degrees of heart block continually change the relation between early and late diastolic ﬁlling so that virtually every A wave has a diﬀerent velocity and duration.

Mitral Peak E/A Wave Velocity Ratio Peak E/A ratio has been the single most important variable used to help characterize the overall mitral ﬂow velocity pattern47–49,79,102–105 and deﬁne diastolic function in patient groups in previous research studies (see Figs. 10-8 and 10-10).80,106 In patients with systolic heart failure, the E/A ratio is related to ﬁlling pressures and prognosis. While the diastolic function evaluation by E/A wave ratio “pattern recognition” is quick, using it without consideration of the individual variables for mitral velocities previously described, other two-dimensional ﬁndings, and

131

132

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling LA-LV pressure gradient

LV

mmHg 20

20

20

LA

10

A wave 140 msec (+) TMPG

90 msec

75 msec

A Nitroglycerin

Angina at rest 1 min

5 min

1 m/sec

Mitral DT A duration

120 msec 80 msec

140 msec 100 msec

160 msec 140 msec

B Figure 10-18 The hemodynamic determinants of mitral A-wave peak velocity and duration (top), and an example of their dynamic variation in a patient with rest angina treated with sublingual nitroglycerin (bottom). A, High-fidelity recordings of left ventricular (LV) and left atrial (LA) pressure show the positive late diastolic transmitral pressure gradient (TMPG) associated with LA contraction (dotted lines) in three individuals. In the normal subject (left), LA pressure rise at atrial contraction exceeds that seen in the ventricle, so that the positive (+) A-wave TMPG goes on until LA pressure falls below LV pressure during atrial relaxation. The patient in the middle panel has a decrease in LV compliance. The maximal LA-LV pressure gradient at atrial contraction is approximately the same, but the rise in LV pressure exceeds LA pressure at 90 msec, shortening the (+) A-wave TMPG and A-wave duration but not its peak velocity. The patient on the right has a marked decrease in LV compliance. LV pressure increases rapidly after LA contraction, so the maximum (+) TMPG and duration is further shortened, resulting in a lower peak A-wave velocity with a shorter duration. B, Patient with angina at rest. The pulsed wave mitral flow velocity shows a high E-wave velocity, a short, “restrictive” like mitral DT, and a low A-wave velocity and duration, which are partially “masked” by some fusion of early and late diastolic filling (velocity at the start of atrial contraction >20 cm/sec). One minute after taking sublingual nitroglycerin, LV hemodynamics are improving, as evidenced by a longer diastolic filling period, lower E-wave velocity, longer mitral deceleration (DT), and wider A-wave duration. By 5 minutes, the improvement in mitral filling variables are even more obvious. (A, From Matsuda Y et al: Change of left atrial systolic pressure waveform in relation to left ventricular end-diastolic pressure. Circulation 1990;82:1659–67. B, From Hatle LK et al: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)

ancillary Doppler variables will lead to a certain number of patients being misclassiﬁed. The E/A ratio is most helpful when the mitral DT is linear and preA velocity is below 20 cm/sec. If mitral DT is curved or biphasic or if there is partial fusion of Eand A-wave velocities, then the LV ﬁlling pattern needs a careful assessment in relation to the other echo-Doppler ﬁndings.

ANCILLARY DATA THAT HELP THE INTERPRETATION OF MITRAL FLOW VELOCITY PATTERNS A criticism of the assessment of LV diastolic dysfunction by mitral ﬂow velocity variables and LV ﬁlling pattern is that they are aﬀected by multiple confounding variables and therefore are unsuitable for determining LV diastolic properties,107 and by implication LV diastolic dysfunction. This discounts the large body of evidence now accumulated on the predictive value of these variables in clinical medicine21,28,31,32,80,94,108–113 and the fact

that additional ancillary data are available to further document the cardiac abnormalities present for both diagnosis and treatment.49

M-Mode and Two-Dimensional Echocardiography There is considerable information about LV diastolic function and ﬁlling pressures available from M-mode and two-dimensional cardiac ultrasound recordings to complement Doppler variables.5,49,114 With practice, the visual interpretation of these anatomic ﬁndings usually will suggest what Doppler LV ﬁlling patterns are present. From the parasternal long axis view, observing the movement at the AV groove helps identify the cardiac rhythm, LA size, and contractility. In the parasternal short axis, the normal left atrium appears approximately the same size or slightly larger than the aorta. From apical views, the sizes of both atria in relation to their respective ventricles can be determined, as well as comparisons made of their respective sizes and contractilities. Diﬀerences are usually obvious. A normal-sized left atrium

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling that appears “hypercontractile” indicates reduced LV ﬁlling in early diastole, increased ﬁlling at atrial contraction, and an impaired relaxation pattern. LA enlargement and reduced contractility are often associated with elevated pressures and pseudonormal or restrictive mitral ﬁlling patterns as long as there have been no recent atrial arrhythmias. At the same time, noting asymmetry in the rate of LV and RV contractility and relaxation, and the excursion of AV longitudinal plane movement, often indicates the abnormalities of ventricular diastolic ﬁlling that will be seen on Doppler exam. LVH slows LV relaxation independent of other cardiac abnormalities and results in an impaired relaxation that is often obvious in M-mode LV recordings (Fig. 10-19). In the absence of MR, arrhythmias, or cardiac conduction system disease, LA enlargement usually indicates an elevated mean LA pressure associated with pseudonormal and restrictive mitral ﬂow velocity patterns.86,106,115 Because maximal LA volume is strongly associated with adverse cardiac events such as new-onset atrial ﬁbrillation, congestive heart failure, and stroke,106,115,116 we agree that it should be measured according to the guidelines of the American Society of Echocardiography and the European Society of Cardiology117 in all patients. Conversely, normal LA size suggests that mean LA pressure is normal. Left atrial minimum volume is related to pulmonary wedge pressure with a correlation coeﬃcient equal to that of most other Doppler variables.89

Tricuspid Flow Velocity Tricuspid and mitral ﬂow velocity patterns are normally qualitatively similar, and in RV pathology the alterations are similar to

those seen on the left side of the heart. Since the tricuspid leaﬂet oriﬁce is larger, tricuspid velocities are slightly lower. Tricuspid ﬂow velocity increases signiﬁcantly with respiration, which diﬀers from left heart ﬁlling (this aspect will be discussed in the section on assessing RV diastolic function). Diﬀerences between mitral and tricuspid ﬁlling patterns usually reﬂect cardiac pathology. Since most cardiac diseases aﬀect the left heart, the more abnormal ﬁlling pattern is usually seen in LV ﬁlling, although the right heart is also aﬀected through the involvement of the intraventricular septum. For instance, in an individual with an ischemic cardiomyopathy who has a pseudonormal LV ﬁlling pattern, tricuspid ﬁlling often “lags behind,” showing an impaired relaxation pattern.49

Mitral Annular Velocities in Tissue Doppler Imaging and Relation to Left Ventricular Filling The recently developed TDI ultrasound modality (discussed in detail in Chapter 12 of this volume) has underlying physics and principles similar to those of conventional PW spectral Doppler. From the apical views, the velocities are related to LV contraction and relaxation. In interpreting LV ﬁlling patterns, TDI of myocardial velocities has its greatest use in distinguishing normal and pseudonormal LV ﬁlling.39 The ratio of peak mitral E-wave velocity to myocardial E′ velocity is used to estimate mean LA pressure.64,118–120 The normal diastolic velocity pattern of myocardial velocities obtained from TDI is similar to that of transmitral ﬂow in patients in sinus rhythm, except inverted.39,121–127 There is positive (above the zero velocity baseline) movement toward the apex with

LV DIASTOLIC FUNCTION

1 m/sec

1 m/sec

IVRT - 70 msec Normal

A

IVRT - 110 msec LVH abnormal relaxation

B

IVRT - 95 msec LVH ↑ LVEDP

C

Figure 10-19 Pulsed wave mitral flow velocity together with M-mode recordings of the left ventricular (LV) cavity in three individuals, illustrating how the diastolic wall motion pattern helps in interpreting the LV filling pattern. Compared with the normal subject (A), the patient in B with LV hypertrophy (LVH) has impaired relaxation filling. Their longer isovolumic relaxation time (IVRT) and reduced E-wave velocity matches the slower rate of early diastolic LV filling seen in the LV posterior wall (arrow). The patient in C has a mitral pattern that may appear similar to the normal so as to be difficult to interpret without additional data. However, the M-mode recording shows marked LVH, very delayed early diastolic filling with relaxation, and mid-diastolic LV cavity expansion continuing to occur up to the time of atrial contraction. These findings, along with the increased E-wave velocity (1 m/sec), indicate pseudonormal LV filling and moderate diastolic dysfunction. Small vertical arrows indicate LV IVRT period and mitral A-wave duration for comparison. (From Hatle LK et al: Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370.)

133

134

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling systolic contraction and negative movement back toward the pulmonary veins with LV ﬁlling in early (E′) and late diastole (A′). In patients with normal ventricular diastolic function, the E′/A′ and mitral E/A ﬂow velocity wave ratios are similar. Patients with impaired relaxation ﬁlling have a myocardial velocity E′/A′ ratio of under 1, again mirroring the ﬁndings seen with mitral ﬂow velocity. However, in pseudonormal mitral ﬂow velocity patterns, a myocardial velocity E′/A′ ratio of less than 1, rather than higher than 1, is present, reﬂecting the impaired LV relaxation that separates these patients from true normals. This is similar to the relaxation abnormality seen in the myocardial M-mode in Figure 10-19, despite the “normal”-appearing Doppler LV ﬁlling pattern. With restrictive LV ﬁlling, the E′/A′ ratio frequently is greater than 1 because the majority of ﬁlling occurs in early diastole, with little contribution from atrial contraction. Figure 10-20 shows a schematic diagram of normal and abnormal mitral LV ﬁlling patterns together with LV pressure, TDI myocardial velocity, and PV ﬂow velocity for reference. The interpretation of TDI myocardial velocities is enhanced by an awareness of the factors that inﬂuence these annular movements. The E′/A′ ratio is higher in the lateral as compared with the septal annulus because the septal is tethered to the right ventricle and other structures in the middle of the heart. The E′ diastolic annular movement predominates in normals because LV longitudinal movement at the base in both systole and diastole is greater than displacement in a radial direction. In patients with a normal LVEF and pseudonormal ﬁlling, a reduced E′ is present because LVH causes an increase in systolic radial movement that is reversed (outward LV motion) in early diastole. The E′/A′ ratio will be less abnormal if there is another reason for the reduced LV compliance than LVH or if the LVEF is decreased. Regardless of LVH, a large volume of blood ﬂow across the mitral valve in early diastole due to MR will ﬁll the ventricle and increase upward annular movement and E′ velocity so that the E′/A′ ratio will appear more normal.

As shown in Figure 10-3 and discussed (see the section “Exercise and Left Ventricular Diastolic Function”), impaired relaxation reduces the time available for diastolic ﬁlling and myocardial perfusion and sets in motion a process that leads to limitation in cardiac output (Fig. 10-21).72,74 In patients presenting with exertional dyspnea, examining changes in the ratio of mitral E-wave and TDI E′ velocity at rest and exercise has been proposed as a diastolic stress.128 Using supine bicycle exercise and classifying points by E/E’ of more than 10, exercise duration was signiﬁcantly longer in patients whose E/E′ ratios were equal to or greater than 10 and did not increase with exercise. These preliminary results suggest that the hemodynamic consequences of exercise-induced increase in diastolic ﬁlling pressure may be possible noninvasively with exercise Doppler ECG (see Chapter 17).

Pulmonary Artery Pressures The estimation of PA systolic and diastolic pressures is a valuable adjunct to assessing LV ﬁlling patterns. Using the modiﬁed Bernoulli equation, this can be accomplished in a high percentage of patients with right-sided valvular regurgitation. The velocity of pulmonary regurgitation at end diastole together with an estimate of central venous pressure (physical exam, size of inferior vena cava, and degree of respiratory collapse) is used to estimate PA diastolic pressure. In the absence of pulmonary vascular disease, this is a surrogate estimate of mean LA pressure. Similarly, peak velocity of tricuspid regurgitation (TR) together with central venous pressure helps estimate PA systolic pressure. Patients with impaired relaxation in LV ﬁlling are expected to have normal or at worst borderline increases in PA pressure in the absence of pulmonary parenchymal or vascular disease. Pseudonormal ﬁlling is associated with elevated mean LA pressure, and so PA pressures are passively elevated. With the higher left heart pressures seen in restrictive ﬁlling, PA systolic pressure can be quite elevated, in the 50–70 mmHg range.

LV FILLING PATTERNS Decrease in compliance Normal

Abnormal relaxation

Moderate

Marked

Irreversible

Normal

IR

PN

RST

Irreversible RST

LV pressure Mitral flow velocity Tissue Doppler

Pulmonary vein

Figure 10-20 Schematic diagram showing the correlation of pulsed wave tissue Doppler imaging (TDI) recordings of the mitral annulus with normal and abnormal left ventricular (LV) filling patterns, LV pressures, and pulmonary venous (PV) flow velocity; IR, impaired relaxation; PN, pseudonormal; RST, restrictive. TDI is especially helpful in distinguishing normal from PN LV filling in most circumstances. Note that in normal and IR filling, the mitral and TDI patterns are inverted but similar in terms of early and late diastolic ratios. In contrast, PN filling has a markedly disparate TDI with reduced longitudinal movement in early diastole and increased movement at atrial contraction, a pattern that reflects the impaired LV relaxation. The TDI patterns in RST filling can be variable depending on disease process and LV ejection fraction, with the most typical shown. The dashed lines and arrows in impaired relaxation filling in LV pressure and PV A-wave refer to patients with decreased LV compliance in late diastole who have an increase in LV end diastolic pressure.

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling HOCM 68F s/p myectomy

HR 57 TVI-16 CO 4.4 L/min

Pulmonary wedge pressure (mmHg)

B

A

Reduced FAC Normal subjects

30 Peak exercise 20

Peak exercise

10 Rest

0 60

140

LV end-diastolic volume (ml)

HR 87 TVI-17 CO 6.7 L/min

C

100

D

Figure 10-21 Reduced functional aerobic capacity in a patient due to left ventricular (LV) diastolic rather than systolic dysfunction. The patient has hypertrophic obstructive cardiomyopathy (HOCM) (A) and is status postsurgical septal myectomy with resultant gradient reduction but also a left bundle branch block (LBBB). At rest, an impaired relaxation pattern is present (B). With exercise, (C) an increase in heart rate (HR) to 87 bpm, a premature fusion of early and late diastolic filling is seen with only a small increase in mitral time-velocity integral (TVI), which represents LV filling. Therefore, the cardiac output increase is mostly from the increase in heart rate. As shown in the graph (D), the inadequate diastolic filling blunts the normal increase in end diastolic volume, reducing cardiac output while also causing an increase in pulmonary pressures and venous congestion. (B, From Kitzman DW et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072.)

PERFORMING AN ECHO-DOPPLER EVALUATION OF LEFT VENTRICULAR DIASTOLIC FUNCTION The assessment of LV diastolic function requires high-quality two-dimensional images and Doppler recordings of mitral, PV, and TDI ﬂow velocities. Guides are available for optimizing these recordings and avoiding pitfalls, with many examples.91 Techniques for optimizing CMM mitral inﬂow velocity propagation and TDI of the mitral annulus are covered in Chapter 18 of this volume. Organizing an echo-Doppler assessment of LV diastolic function into a standard routine helps both the sonographer (Chapter 17) and the physician improve their technical and interpretive skills.61,69,129 We recommend starting with M-mode and twodimensional anatomic imaging to obtain measurements of chamber sizes, maximal LA volume, and LV diastolic and systolic volumes. LV mass, relative wall thickness,130 and LVEF are then calculated. Variables of special importance include absolute LV mass and LV relative wall thickness (normal <42%) and maximal LA size (normal <32 ml/m2).

After the two-dimensional exam is ﬁnished, an apical fourchamber color Doppler screen is performed to check for signiﬁcant valvular regurgitation. CMM of mitral inﬂow and LV outﬂow is then used to preview the LV ﬁlling pattern and mitral E-wave ﬂow velocity propagation, as well as whether systolic LV intracavitary gradients or IVRT ﬂow is present. CW Doppler is activated to proﬁle the LV ﬁlling and ejection velocities throughout the ventricle. CW technique is used before PW Doppler because CW proﬁles the mitral inﬂow pattern, provides a reference for the peak E- and A-wave velocities that will be obtained during the subsequent PW Doppler interrogation, and displays IVRT ﬂow and the magnitude of any systolic intracavitary gradients. PW Doppler mitral inﬂow velocity, mitral velocity response to Valsalva maneuver, and PW Doppler of PV ﬂow is then performed. If confusion still exists regarding the normalcy of the LV ﬁlling pattern, TDI spectral Doppler of mitral annular motion (lateral, medial, or both) will usually help make this distinction, and together with peak mitral E-wave velocity may indicate whether normal or increased mean LA pressure is present. Before leaving the left side of the heart, any LV intracavitary gradients or IVRT ﬂow seen on

135

136

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling the CMM screen are located and quantiﬁed by PW Doppler. The transducer is then moved medially toward the sternum, and PW Doppler of tricuspid inﬂow along with estimation of PA systolic pressures using peak TR velocity by CW Doppler is performed. Finally, PW analysis of Doppler hepatic veins and superior vena caval ﬂow throughout respiration is recorded.131 With practice and performing a complete diastolic function exam on every patient, the components we have listed can be completed with only an additional 5 to 10 minutes of scanning time. The information derived not only helps assess LV diastolic function, ﬁlling pressures, and future possible adverse cardiovascular events, but also aids patient management decisions.

MITRAL FLOW VELOCITY PATTERNS: INTERPRETIVE CHALLENGES Mitral E/A Ratio Below 1 The most common mitral ﬁlling pattern is also the one most frequently misinterpreted and therefore deserves special mention. The “true” impaired relaxation ﬁlling pattern is due to slow LV relaxation with normal mean LA pressure (see Fig. 10-14). Criteria include normal LA volume, with “hypercontractile”appearing LA systolic function (especially in the parasternal long axis view) due to ejection into a ventricle with a lower than normal preA pressure. Compared with normal age-related values, the LV IVRT and mitral DT should be prolonged, mitral E-wave velocity should be lower than expected for age and LVOT velocity, and the preA velocity should be below 20 cm/sec. If the analysis stops here, the interpretation is incomplete, for it has not been determined whether LV end diastolic compliance and pressure are normal or abnormal, the latter being the ﬁrst indication of elevated LV ﬁlling pressures (see Fig. 10-2). This can be determined only by comparing the duration of mitral and PV ﬂow velocity A waves, as previously described. If PVa duration is more than 30 msec longer than mitral A-wave duration, LVED pressure is elevated and LV compliance is reduced, indicating that early diastolic dysfunction is present (see Fig. 10-13). There are two common instances where the E/A wave velocity ratio is less than 1, implying an impaired relaxation ﬁlling pattern, and yet the diastolic abnormalities are more severe and closer to pseudonormal with decreased LV compliance and increased mean LA pressure. The ﬁrst occurs when the mitral velocity at atrial contraction is above 20 cm/sec and there is fusion of early and late diastolic LV ﬁlling (see Figs. 10-16, 10-17, and 10-21). In this case, the A-wave velocity is higher than it would be at a slower heart rate or shorter P-R interval, which reduces the E/A wave ratio to below 1. A premature beat or slower heart rate will reveal the pseudonormal ﬁlling pattern. An E/A ratio of less than 1 with increased ﬁlling pressures can also be seen in patients with marked LVH and severely impaired LV relaxation. In these cases, a markedly elevated LA pressure may be needed before the ﬁlling pattern appears pseudonormal (see Fig. 10-9). In both instances, the presence of moderate or severe LVH, increased LA volume, E-wave velocity that approaches or exceeds LVOT velocity, and increased E/E′ ratio are all clues that despite the E/A wave ratio of below 1, mean LA pressure is elevated.

Mitral Regurgitation and Stenosis Hemodynamically signiﬁcant MR will increase the volume returning through the mitral valve in early diastole and increase

the mitral E-wave velocity. LA size and the mitral E-wave/LVOT velocity ratio will both be increased. However, LV diastolic dysfunction and ﬁlling pressures are not necessarily abnormal since the normal adaptation of the left atrium and ventricle to chronic volume overload is a rightward shift in the pressure-volume relation, which makes both chambers more compliant. A normal mitral DT is the best indicator of a healthy adaptation to the chronic volume overload of MR. Conversely, a shortened mitral DT indicates an abnormal rise in early diastolic LV pressure from reduced LV chamber compliance. This ﬁnding is expected in acute MR because of a lack of time for the ventricle to adapt, but in chronic regurgitation it signiﬁes an increase in myocardial stiﬀness from a process unrelated to the valve disease. A shortened mitral IVRT, decrease in PV systolic fraction, and increase in TR velocity are other indicators of increased left heart ﬁlling pressures. MS increases E-wave velocity by reducing oriﬁce size and is associated with a prolonged mitral pressure half-time as well as LA enlargement. Impaired LV relaxation may prolong the mitral DT, while reduced LV myocardial compliance may shorten it independent of valve area. When MS is present, a clinically useful approach is to measure the LV IVRT (whose shortening indicates the degree of mean LA pressure elevation), calculate the mean mitral gradient while noting the heart rate, estimate the mitral valve area by the pressure half-time method, and estimate the PA pressure by TR velocity. If mitral preA velocity is greater than 20 cm/sec, slowing the heart rate may improve the hemodynamic abnormalities and patient symptoms. In patients with mixed MS and MR, the focus is on the valve disease and its consequences rather than LV diastolic dysfunction. The LV IVRT, mitral valve area, and PA pressures become important objective data to relate to patient symptoms.

Sinus Tachycardia: Effect on Left Ventricular Filling Previous animal studies link the normal cardiac pathophysiology that occurs as heart rate increases with changes in mitral ﬂow velocity (see Fig. 10-14). The method by which heart rate is increased (withdrawal of parasympathetic tone, increase in sympathetic tone or exercise) markedly aﬀects when mitral E and A waves begin to fuse and when complete fusion (A-wave ﬂow only) occurs. In normal dogs, withdrawal of parasympathetic tone with atropine administration results in complete fusion of E and A waves at 160 bpm, while with isoproterenol infusion this is not observed until a heart rate of 220 bpm. These diﬀerences relate to the eﬀect of each intervention on LV contractility and the degree of shortening of the P-R interval. Increased contractility shortens the LV isovolumic contraction, ejection, and relaxation times so that diastolic ﬁlling time is maximized, while shortening of the P-R interval provides for more diastolic ﬁlling before atrial contraction. With exercise, increased venous return and LA pressure also result in an earlier mitral valve opening, which also helps keep early and late diastolic ﬁlling separated. LVH, systolic dysfunction, increased wall stress, and cardiac conduction system disease (ﬁrst-degree or LBBB) prolong systolic periods and shorten the diastolic ﬁlling time so that Eand A-wave fusion occur at lower heart rates (see Fig. 10-3). This may limit LV ﬁlling and result in a reduced exertional cardiac output and functional aerobic capacity, as previously discussed (see Fig. 10-21).

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

Uncommon Mitral Valve Velocity Patterns Variations in LV ﬁlling patterns are seen where impaired LV relaxation persists into mid-diastole, or altered compliance is present only in early diastole rather than throughout the diastolic ﬁlling period. This physiology is most commonly present with marked LVH, especially in the elderly with severe and longstanding hypertension132 or in patients with hypertrophic cardiomyopathy. Figure 10-22 shows examples of uncommon mitral LV ﬁlling patterns in ﬁve such patients. Most typically the initial mitral E-wave velocity is increased compared with LVOT velocity, and there is a short initial mitral DT. The predominant abnor-

mality present is markedly impaired LV relaxation, which causes a severe decrease in LV compliance (the short initial mitral DT) but is conﬁned to early diastole, perhaps because of delayed actinmyosin cross-bridge detachment. In mid-diastole there is continued LV relaxation and a fall in pressure so that the mitral DT markedly slows and becomes nonlinear, or a mid-diastolic ﬁlling hump is seen. The width of the A wave is variable depending on the end diastolic compliance of the ventricle. Because of the profound relaxation abnormality, these patients often do well with very slow (40–55 bpm) resting heart rates, while faster heart rates result in inadequate LV ﬁlling, exercise intolerance, and pulmonary congestion.

m/sec 1.0

0.5

0

A

B

C

LV pressure

60 cm/sec

D

E

Figure 10-22 Five patients (A to E) with markedly impaired left ventricular (LV) relaxation that results in unusual PW Doppler mitral flow velocity recordings that do not fit conventional LV filling patterns of diastolic dysfunction. All patients are in normal sinus rhythm. Each peak E-wave velocity is followed by an initial restrictive-like mitral DT and then variable degrees of additional filling in mid-diastole and with atrial contraction, indicating profound myocardial relaxation abnormalities and dynamic changes in LV compliance throughout diastole. Patient A has marked LV hypertrophy (LVH) from long-standing hypertension and a normal LV ejection fraction (LVEF). The initial mitral deceleration time (DT) is 100 msec, which then dramatically changes slope to 280 msec in mid-diastole with A-wave duration of 100 msec. LV posterior wall M-mode motion showed continuous filling throughout mid-diastole, indicating ongoing LV relaxation. Patient B is a 35-year-old on dialysis with LVH and normal LVEF. Without the abnormal mid-diastolic filling “hump,” the mitral pattern might be mistaken for normal. Patient C is elderly with hypertension and slight sinus arrhythmia. With a slower heart rate, the filling pattern would be similar to B, but the slightly faster heart rate results in the mid-diastolic filling blending into the A wave, making its true duration difficult to measure except on the first beat. Patient D has a 50-year history of nonobstructive hypertrophic cardiomyopathy with a giant left atrium. The initial mitral DT is only 80 msec, with over two thirds of LV filling occurring in mid-diastole (middle hump) and then with atrial contraction. The patient reports feeling best with a resting heart rate of 40–45 bpm. Functional aerobic capacity is severely reduced with any increase in heart rate. Patient E has a mitral flow velocity somewhat similar to patient D. Patient E’s LV pressure recording shows an initial rapid filling wave correlating with the restrictive early diastolic mitral DT, but then LV pressure declines in mid-diastole with reestablishment of transmitral flow. The cellular mechanisms that result in these marked derangements of LV relaxation and early diastolic restrictive physiology, which are transient rather than fixed, are under investigation.

137

138

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling

Increased Mitral Respiratory Flow Velocity Variation The diagnosis of a number of important conditions is dependent on a measure of increased variations in mitral respiratory ﬂow velocity. The presence of these conditions would be missed in laboratories that do not record mitral ﬂow velocity initially at the slower sweep speed of 50 cm/sec to observe whether increased respiratory variation is present. Although respiratory variation in tricuspid E-wave ﬂow velocity is expected to be 15% to 25%, the respiratory change in mitral E-wave velocity in normals is less than 5%.133 Increased changes in both mitral and tricuspid inﬂow velocities with respiration can be seen in patients with acute or chronic pulmonary disease134 or pericardial abnormalities, including tamponade,135,136 constriction,133,134,137 and pericardial restraint due to acute cardiac dilation from RV infarction, pulmonary embolus, or acute valvular regurgitation. So that abnormal respiratory mitral changes are not overlooked, we recommend recording mitral ﬂow velocity using CW Doppler from the apical transducer position at a sweep speed of 50 mm/ sec. Any variation greater than 10% with a regular heart rate is considered abnormal. Accompanying changes in the LV IVRT verify that the alterations in velocity are due to alterations in LA pressure and the timing of mitral valve opening. A PW Doppler exam of mitral ﬂow velocity with a respirometer is then performed. The clinical history and characteristic two-dimensional ﬁndings (such as an inspiratory septal shift) are noted, along with the exact timing of the ﬂow velocity changes. This will help determine whether pulmonary or pericardial disease is present. The hepatic venous Doppler is especially important and should always be recorded because in primary pericardial disease the heart has difﬁculty ﬁlling normally (low velocities), while with pulmonary disease the heart overﬁlls due to the excessive swings in intrathoracic pressure and RV minimum pressure.134

Atrial Flutter and Fibrillation Regardless of whether there is 2 : 1 or higher-degree AV block, almost no assessment of LV diastolic function can be made from mitral ﬂow velocity when atrial ﬂutter is present. All LV ﬁlling is due to atrial contractions, so that no E velocity, E/A wave ratio, or mitral DT is available for measurement. If 3 : 1 or 4 : 1 AV block is present, multiple ﬁlling waves are seen with diastolic MR interspersed between each. PA pressure calculated from peak TR velocity may be the best indicator of increased left heart ﬁlling pressures if no lung disease is present. New-onset “coarse” atrial ﬁbrillation may resemble atrial ﬂutter in that multiple pulses of blood ﬂowing from atrial contraction enter the ventricle in diastole. This makes the interpretation of peak E-wave velocity and mitral DT diﬃcult to relate to LV diastolic properties. Chronic atrial ﬁbrillation, when LA mechanical function is negligible and the rate is <100 bpm, is easier to interpret. In patients with heart disease, the mitral E wave to TDI E′ ratio119 or LV IVRT is a good indicator of whether ﬁlling pressures are elevated. Since all LV ﬁlling must occur without an atrial booster pump, mean LA pressure and peak E-wave velocity are usually slightly higher than normal for age, except in young patients with lone atrial ﬁbrillation and vigorous elastic recoil. Mitral DT is generally about 20 msec shorter than in normal sinus rhythm, and PV ﬂow should have a reduced but not absent systolic fraction, since the S1 component due to atrial relaxation is absent. In adult cardiac patients, a short LV IVRT (<60 msec),

mitral E-wave velocity equal to LVOT velocity, short mitral DT (<160 msec), and reduced (<25%) PV systolic fraction and increased E/E′ ratio all suggest reduced LV compliance and increased ﬁlling pressures. A mitral DT under 140 msec has been shown to have the same unfavorable prognosis as for patients in sinus rhythm.95 When recording atrial ﬁbrillation, CW technique is again suggested ﬁrst to display the maximum velocities and measure the LV IVRT. PW Doppler is used for mitral DT, and ﬁve beats are averaged to assess mitral variables. Beats with short R-R intervals should be excluded, especially if systole causes an abrupt cessation of mitral inﬂow. Examples of mitral ﬂow velocity in atrial ﬂutter and atrial ﬁbrillation are shown in Figure 10-23.

Diastolic Mitral and Tricuspid Regurgitation Regurgitation occurs when there is a reverse diastolic transmitral pressure gradient where LV pressure exceeds LA pressure in diastole. Although the magnitude of the reverse transmitral pressure gradient can exceed the normal forward-ﬂow gradient, the amount of regurgitation is hemodynamically insigniﬁcant because it is limited by a small AV valve oriﬁce area.138 There are several situations in which diastolic MR and aortic regurgitation can be seen. By far the most common is with ﬁrst-, second-, or third-degree AV block,139 or with atrial ﬂutter and greater than 2 : 1 AV block (see Fig. 10-23). In these cases, the atrium contracts, and atrial and ventricular pressures both increase. However, in the absence of a normal P-R interval and properly timed ventricular systole, atrial relaxation causes its pressure to fall below ventricular pressure, and diastolic regurgitation occurs. Diastolic MR due to ﬁrst-degree AV block is usually not seen until the P-R interval exceeds 280 msec. The Doppler ﬁndings of ﬁrst-degree AV block are worth noting, especially if it is causing partial fusion of early and late diastolic ﬁlling. Diastolic MR is more pathologic when associated with advanced restrictive LV ﬁlling. After ﬁlling in mid-diastole or after atrial contraction, there is a marked increase in LV pressure that not only decelerates, but transiently reverses transmitral ﬂow in mid-diastole or after atrial contraction. Aortic regurgitation with marked bradycardia or atrial ﬁbrillation and a very slow ventricular rate is an additional uncommon etiology.

RIGHT VENTRICULAR DIASTOLIC FUNCTION The same Doppler analysis and variables used for mitral ﬂow velocity can be applied to tricuspid inﬂow and RV ﬁlling (see Chapter 14 in this volume).91,140 Because inspiration increases RV ﬁlling, changes in tricuspid ﬂow velocity are seen throughout the respiratory cycle, while on the left side of the heart, Doppler mitral variables vary only about 5%.133 This increase in inspiratory RV ﬁlling can be used, in conjunction with hepatic and superior vena cava ﬂow velocities, to assess the diastolic properties of the right ventricle. PW Doppler tricuspid DT is about 25 msec longer than its mitral counterpart. With normal RV diastolic function, this value changes little with the increased ﬂow during inspiration, and hepatic A-wave reversals decrease in velocity and duration. With a decrease in late diastolic RV compliance, hepatic venous A-wave velocity and duration increase with inspiration. An inspiratory shortening of tricuspid DT, diastolic predominance of hepatic venous ﬂow with prominent V- and A-wave reversals are signs of

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling ATRIAL FIBRILLATION Mitral Figure 10-23 PW Doppler mitral flow velocity in a patient with atrial flutter and atrial fibrillation. In atrial flutter, left ventricular (LV) filling is a regular pulsation of A waves (arrows), often with mild diastolic mitral regurgitation (dMR) during atrial relaxation. Left atrial (LA) size is often enlarged from the arrhythmia, the isovolumic relaxation time (IVRT) is affected by the atrial contractions, and there is no E wave or mitral deceleration (DT) to measure, making the assessment of diastolic function problematic. In atrial fibrillation (Af ), peak E-wave velocity and mitral DT can be measured but can also be affected by the fibrillatory contractions of the atrium (Af flow = arrows). It is likely that this patient does have an increase in mean LA pressure because the LV IVRT is short (50 msec) and pulmonary venous systolic (PVs) filling is negligible, a sign of reduced LA compliance.

Pulmonary vein

Atrial flutter E

PVd

A A Af

A

Af

–3

–2

dMR

PVs

2

1

a marked decrease in RV compliance and increased diastolic ﬁlling pressures.140 The early diastolic slope and A-wave decrease in velocity in pulmonary regurgitation Doppler signals can also be used to assess early and late diastolic RV compliance. The assessment of right heart pressures from inferior vena cava size141 and systemic venous ﬂow (hepatic vein and superior vena cava) has also been described.142,143

USING LEFT VENTRICULAR FILLING PATTERNS FOR PATIENT MANAGEMENT If the only information available from examining LV ﬁlling patterns is whether the patient has elevated LA pressure, this can be usually ascertained from the patient’s history, physical examination, chest x-ray, and brain natriuretic peptide level (see Chapter 32). Unique information available from an echo-Doppler study is the identiﬁcation of early diastolic dysfunction (impaired relaxation ﬁlling pattern with elevated LVEDP), with the relation of LV systolic to diastolic function identifying which diastolic property (relaxation or compliance) is most abnormal and which parts of diastole are most aﬀected by these abnormalities. In addition, seeing whether the patient’s heart rate at rest is well matched to the cardiac physiology present is a great strength of the echoDoppler technique that cannot be done reliably by physical exam. Using this information is a powerful tool for intervening to prevent progression of diastolic abnormalities and for treating patients with symptoms of diastolic heart failure to improve their functional status and prognosis. After the echo-Doppler study is completed, the ﬁrst question is, What is the main cardiac abnormality present: systolic dysfunction, diastolic dysfunction, or valvular heart disease? In patients with a reduced LVEF, diastolic dysfunction is expected and is usually “matched” to the reduction in LVEF. For example, patients with a moderate reduction in LVEF (30%–35%) often have a pseudonormal mitral ﬁlling pattern, while patients with severe reduction in LVEF (<20%) commonly demonstrate restrictive ﬁlling. A “mismatch” between these expected relations is

notable. Better diastolic than systolic function suggests a welladapted, compliant ventricle. Such individuals often have a good functional capacity and a favorable prognosis.28 Conversely, a pseudonormal or restrictive mitral ﬁlling pattern with mild systolic function suggests volume overload (easily detected by imaging of the inferior vena cava) or pathology, which increases myocardial stiﬀness. Why patients with LV systolic dysfunction have such variability in LV compliance remains a key enigma that requires further investigation. In patients with normal LV systolic function and diastolic heart failure, questions to be answered include whether abnormalities of LV relaxation or compliance predominate, and during what part(s) of diastole are the abnormalities present. This gives an idea of the best approach for short-term therapy and whether altering the heart rate is likely to improve the patient’s symptoms. Although classifying patients as having one of the three abnormal ﬁlling patterns is often useful for this purpose, enough variations in LV ﬁlling patterns and combinations of LA pressure and rates of LV relaxation exist that the choice of treatments to beneﬁt the patient are still best determined by carefully examining the mitral ﬂow velocity pattern and its individual Doppler variables, as in the patients in Figures 10-15 through 10-19 and Figures 10-21 and 10-22.

FUTURE RESEARCH The greatest limitation to the echo-Doppler assessment of LV diastolic dysfunction is the experience to discern from the information available which of the key diastolic properties (LV relaxation or compliance) is most abnormal, how these are related to LV systolic function, and how both interact to aﬀect the overall LV ﬁlling pattern. When ﬁrst learning to interpret LV diastolic function, there is a tendency to try to make all variables ﬁt into one abnormal LV ﬁlling pattern or another, when in reality there are nearly endless variations and exceptions to deﬁned “criteria.” This is why we believe that examining the mitral ﬁlling pattern

139

140

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling together with all available two-dimensional and Doppler information is most helpful for patient management. This approach acknowledges that the variables used are imperfect indicators of individual diastolic ﬁlling properties or pressures and can sometimes appear contradictory, but in aggregate they usually provide suﬃcient information to be clinically useful in the great majority of patients. Another common limitation is the lack of technical experience in acquiring high-quality Doppler recordings so that all variables are accurately measured. It can be expected that even when performing a routine diastolic-function examination on every patient undergoing ECG, it could take at least 6 months for sonographers and physicians to master these skills. With the advent of Doppler annular TDI recordings and measurement of LA volume, the problem of identifying patients with pseudonormal LV ﬁlling has improved. However, the number of labs that routinely obtain PV ﬂow velocity recordings has likely declined, decreasing the likelihood of identiﬁcation of an elevated LVEDP at its earliest stage. Therefore, additional and simpler ways to identify LV diastolic dysfunction at its earliest and most treatable stages are needed, as are load-independent indices of LV diastolic ﬁlling.78 Atrial ﬁbrillation is becoming increasingly prevalent. More research is needed on ways to assess LV diastolic dysfunction and ﬁlling pressures in this important group. Pediatric patients present their own challenges. Isolated diastolic dysfunction is rare in this group, and there is much less literature available to establish when abnormal diastolic properties are present.

ACKNOWLEDGMENTS I am grateful to Dr. Liv Hatle for her help editing the manuscript and ﬁgures and the expert preparation of the ﬁgures by my friend Marvin Ruona.

ABBREVIATIONS 2D: two-dimensional (echo) bpm: beats per minute CMM: color M-mode (Doppler) CW Doppler: continuous wave Doppler (technique) DHF: diastolic heart failure HF: heart failure IR: impaired relaxation (LV ﬁlling) IVRT: isovolumic relaxation time LA: left atrial LBBB: left bundle branch block LV: left ventricular LVEF: LV ejection fraction LVEDP: LV end diastolic pressure LVOT: LV outﬂow tract LA A-wave: LV pressure rise due to atrial contraction LVH: LV hypertrophy MAM: mitral annular motion Mitral Adur: duration if mitral A-wave velocity Mitral DT: mitral deceleration time MR: mitral regurgitation MS: mitral stenosis PA: pulmonary artery

PN: pseudonormal (LV ﬁlling) PV: pulmonary venous PVs1: PV ﬂow velocity in early systole PVs2: PV ﬂow velocity in middle and late systole PVa: ﬂow pulmonary venous ﬂow PV Adur: reverse PV ﬂow velocity at atrial contraction PW Doppler: pulsed wave Doppler (technique) RST: restrictive (LV ﬁlling) RV: right ventricular SHF: systolic heart failure TDI: tissue Doppler imaging TMPG: transmitral pressure gradient TR: tricuspid regurgitation REFERENCES 1. Ingels NB Jr., Daughters GT 2nd, Nikolic SD, et al: Left atrial pressureclamp servomechanism demonstrates LV suction in canine hearts with normal mitral valves. Am J Physiol 1994;267:H354–362. 2. Child JS, Perloﬀ JK: The restrictive cardiomyopathies. Cardiol Clin 1988;6:289–316. 3. Braunwald E: Hypertrophic cardiomyopathy—continued progress. N Engl J Med 1989;320:800–802. 4. Hammermeister KE, Warbasse JR: The rate of change of left ventricular volume in man. II. Diastolic events in health and disease. Circulation 1974;49:739–747. 5. Gibson DG, Brown DJ: Measurement of peak rates of left ventricular wall movement in man. Comparison of echocardiography with angiography. Br Heart J 1975;37:677–683. 6. Upton MT, Gibson DG, Brown DJ: Echocardiographic assessment of abnormal left ventricular relaxation in man. Br Heart J 1976;38: 1001–1019. 7. Soufer R, Wohlgelernter D, Vita NA, et al: Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985;55: 1032–1036. 8. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. 9. Little WC, Applegate RJ: Invasive evaluation of left ventricular diastolic performance. Herz 1990;15:362–376. 10. Hanrath P, Mathey, DG, Siegert, R, Bleifeld, W: Left ventricular relaxation and ﬁlling pattern in diﬀerent forms of left ventricular hypertrophy: An echocardiographic study. Am J Cardiol 1980;45:15–23. 11. Rokey R, Kuo LC, Zoghbi WA, et al: Determination of parameters of left ventricular diastolic ﬁlling with pulsed Doppler echocardiography: Comparison with cineangiography. Circulation 1985;71:543–550. 12. Spirito P, Maron BJ, Bonow RO: Noninvasive assessment of left ventricular diastolic function: Comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Coll Cardiol 1986;7: 518–526. 13. Kitabatake A, Inoue M, Asao M, et al: Transmitral blood ﬂow reﬂecting diastolic behavior of the left ventricle in health and disease—a study by pulsed Doppler technique. Jpn Circ J 1982;46:92–102. 14. Tanouchi J, Kitabatake A, Asao M, et al: Role of left ventricular relaxation on transmitral ﬂow dynamics during early diastole: Pulsed Doppler ﬂowmetry. J Cardiogr 1983;13:301–307. 15. Kuo LC, Quinones MA, Rokey R, et al: Quantiﬁcation of atrial contribution to left ventricular ﬁlling by pulsed Doppler echocardiography and the eﬀect of age in normal and diseased hearts. Am J Cardiol 1987;59: 1174–1178. 16. Gardin JM, Drayer JI, Weber M, et al: Doppler echocardiographic assessment of left ventricular systolic and diastolic function in mild hypertension. Hypertension 1987;9:I190–I196. 17. Klein AL, Burstow DJ, Tajik AJ, et al: Eﬀects of age on left ventricular dimensions and ﬁlling dynamics in 117 normal persons. Mayo Clin Proc 1994;69:212–224. 18. Miyatake K, Okamoto, M, Kinoshita, N, et al: Augmentation of atrial contribution to left ventricular inﬂow with aging as assessed by intracardiac Doppler ﬂowmetry. Am J Cardiol 1984;70:586–589. 19. Appleton CP, Hatle LK, Popp RL: Relation of transmitral ﬂow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440.

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 20. Klein AL HL, Taliercio CP, Oh JK, et al: Prognostic signiﬁcance of diastolic function in cardiac amyloidosis. A Doppler echocardiographic study. Circulation 1991;83:808–816. 21. Pinamonti B, Di Lenarda A, Sinagra G, Camerini F: Restrictive left ventricular ﬁlling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: Clinical, echocardiographic and hemodynamic correlations and prognostic implications. Heart Muscle Disease Study Group. J Am Coll Cardiol 1993;22:808–815. 22. Rich MW, Stitziel NO, Kovacs SJ: Prognostic value of diastolic ﬁlling parameters derived using a novel image processing technique in patients > or = 70 years of age with congestive heart failure. Am J Cardiol 1999;84:82–86. 23. Xie GY, Berk MR, Smith MD, et al: Prognostic value of Doppler transmitral ﬂow patterns in patients with congestive heart failure. J Am Coll Cardiol 1994;24:132–139. 24. Appleton CP: The natural history of left ventricular ﬁlling abnormalities: Assessment by two-dimensional and Doppler echocardiography. Echocardiography 1992;9:437–457. 25. Keren G, Pardes A, Miller HI, et al: Pulmonary venous ﬂow determined by Doppler echocardiography in mitral stenosis. Am J Cardiol 1990;65: 246–249. 26. Klein AL: Doppler assessment of pulmonary venous ﬂow in healthy subjects and patients with heart disease. J Am Soc Echocardiogr 1991;4:379– 392. 27. Kuecherer HF, Muhiudeen IA, Kusumoto FM, et al: Estimation of mean left atrial pressure from transesophageal pulsed Doppler echocardiography of pulmonary venous ﬂow. Circulation 1990;82:1127–1139. 28. Pozzoli M, Traversi E, Cioﬃ G, et al: Loading manipulations improve the prognostic value of Doppler evaluation of mitral ﬂow in patients with chronic heart failure. Circulation 1997;95:1222–1230. 29. Dumesnil JG, Gaudreault G, Honos GN, Kingma JG Jr: Use of Valsalva maneuver to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515–519. 30. Hurrell DG, Nishimura RA, Ilstrup DM, Appleton CP: Utility of preload alteration in assessment of left ventricular ﬁlling pressure by Doppler echocardiography: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1997;30:459–467. 31. Klein AL, Hatle LK, Taliercio CP, et al: Prognostic signiﬁcance of Doppler measures of diastolic function in cardiac amyloidosis. A Doppler echocardiography study. Circulation 1991;83:808–816. 32. Pinamonti B, Zecchin M, Di Lenarda A, et al: Persistence of restrictive left ventricular ﬁlling pattern in dilated cardiomyopathy: An ominous prognostic sign. J Am Coll Cardiol 1997;29:604–612. 33. Brun P, Tribouilloy C, Duval AM, et al: Left ventricular ﬂow propagation during early ﬁlling is related to wall relaxation: A color M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 34. Garcia MJ, Rodriguez L, Ares M, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–114. 35. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler ﬂow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 2000;35: 201–208. 36. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32: 865–875. 37. Kovacs SJ Jr, Barzilai B, Perez JE: Evaluation of diastolic function with Doppler echocardiography: The PDF formalism. Am J Physiol 1987;252: H178–187. 38. Kovacs SJ, Meisner JS, Yellin EL: Modeling of diastole. Cardiol Clin 2000;18:459–487. 39. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 40. Yellin EL, Meisner JS: Physiology of diastolic function and transmitral pressure-ﬂow relations. Cardiol Clin 2000;18:411–433, vii. 41. Thomas JD, Newell JB, Choong CY, Weyman AE: Physical and physiological determinants of transmitral velocity: Numerical analysis. Am J Physiol 1991;260:H1718–H1731. 42. Choong CY, Abascal VM, Thomas JD, et al: Combined inﬂuence of ventricular loading and relaxation on the transmitral ﬂow velocity proﬁle in dogs measured by Doppler echocardiography. Circulation 1988;78:672– 683.

43. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol 2001;280:H2507– H2515. 44. Greenberg NL, Vandervoort PM, Thomas JD: Automated assessment of color Doppler M-mode ﬂow velocity propagation features. Computers in Cardiology 1996:201–204. 45. Riordan MM, Kovacs SJ: Quantitation of mitral annular oscillations and longitudinal “ringing” of the left ventricle: A new window into longitudinal diastolic function. J Appl Physiol 2006;100:112–119. 46. Riordan MM, Kovacs SJ: Absence of diastolic mitral annular oscillations is a marker for relaxation-related diastolic dysfunction. Am J Physiol Heart Circ Physiol 2007;292:H2952–H2958. 47. Garcia MJ: Comprehensive echocardiographic assessment of diastolic function. Heart Fail Clin 2006;2:163–178. 48. Oh JK, Hatle L, Tajik AJ, Little WC: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 49. Appleton CP, Firstenberg MS, Garcia MJ, Thomas JD: The echo-Doppler evaluation of left ventricular diastolic function. A current perspective. Cardiol Clin 2000;18:513–546, ix. 50. Bursi F, Weston SA, Redﬁeld MM, et al: Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–2216. 51. Giannuzzi P, Temporelli PL, de Vito F, et al: Doppler-derived mitral deceleration time of early ﬁlling as a strong predictor of pulmonary wedge pressure in postinfarction patients with left ventricular dysfunction. J Am Coll Cardiol 1994;23:1630–1637. 52. Ishida Y, Meisner JS, Tsujioka K, et al: Left ventricular ﬁlling dynamics: Inﬂuence of left ventricular relaxation and left atrial pressure [published erratum appears in Circulation 1986 Sep;74(3):462]. Circulation 1986;74:187–196. 53. Nishimura RA, Rihal CS, Tajik AJ, Holmes DR Jr: Accurate measurement of the transmitral gradient in patients with mitral stenosis: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1994;24:152–158. 54. Thomas JD, Choong CY, Flachskampf FA, Weyman AE: Analysis of the early transmitral Doppler velocity curve: Eﬀect of primary physiologic changes and compensatory preload adjustment. J Am Coll Cardiol 1990;16:644–655. 55. Nishimura RA, Housmans PR, Hatle LK, Tajik AJ: Assessment of diastolic function of the heart: Background and current applications of Doppler echocardiography. Part I. Physiologic and pathophysiologic features. Mayo Clin Proc 1989;64:71–81. 56. Cheng CP, Freeman GL, Santamore WP, et al: Eﬀect of loading conditions, contractile state, and heart rate on early diastolic left ventricular ﬁlling in conscious dogs. Circ Res 1990;66:814–823. 57. Ingels NB Jr, Daughters GT, Nikolic SD, et al: Left ventricular diastolic suction with zero left atrial pressure in open-chest dogs. Am J Physiol 1996;270:H1217–1224. 58. Takagi S, Yokota M, Iwase M, et al: The important role of left ventricular relaxation and left atrial pressure in the left ventricular ﬁlling velocity proﬁle. Am Heart J 1989;118:954–962. 59. Nishimura RA, Schwartz RS, Tajik AJ, Holmes DR Jr: Noninvasive measurement of rate of left ventricular relaxation by Doppler echocardiography. Validation with simultaneous cardiac catheterization. Circulation 1993;88: 146–155. 60. Snider AR, Gidding SS, Rocchini AP, et al: Doppler evaluation of left ventricular diastolic ﬁlling in children with systemic hypertension. Am J Cardiol 1985;56:921–926. 61. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246–270. 62. Redﬁeld MM: Understanding “diastolic” heart failure. N Engl J Med 2004;350:1930–1931. 63. Appleton CP, Gonzalez MS, Basnight MA: Relationship of left atrial pressure and pulmonary venous ﬂow velocities: Importance of baseline mitral and pulmonary venous ﬂow velocity patterns studied in lightly sedated dogs. J Am Soc Echocardiogr 1994;7:264–275. 64. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular ﬁlling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 65. Rossvoll O, Hatle LK: Pulmonary venous ﬂow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696.

141

142

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 66. Yamamoto K, Nishimura RA, Burnett JC Jr, Redﬁeld MM: Assessment of left ventricular end-diastolic pressure by Doppler echocardiography: Contribution of duration of pulmonary venous versus mitral ﬂow velocity curves at atrial contraction. J Am Soc Echocardiogr 1997;10:52–59. 67. Nishimura RA, Appleton CP, Redﬁeld MM, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular ﬁlling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226– 1233. 68. Vanoverschelde JL, Raphael DA, Robert AR, Cosyns JR: Left ventricular ﬁlling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 69. Rakowski H, Appleton C, Chan KL, et al: Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: From the Investigators of Consensus on Diastolic Dysfunction by Echocardiography. J Am Soc Echocardiogr 1996;9:736–760. 70. Appleton CP, Hatle LK, Popp RL: Demonstration of restrictive ventricular physiology by Doppler echocardiography. J Am Coll Cardiol 1988;11: 757–768. 71. Cheng CP, Igarashi Y, Little WC: Mechanism of augmented rate of left ventricular ﬁlling during exercise. Circ Res 1992;70:9–19. 72. Kitzman DW, Higginbotham MB, Cobb FR, et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072. 73. Appleton CP: Inﬂuence of incremental changes in heart rate on mitral ﬂow velocity: Assessment in lightly sedated, conscious dogs. J Am Coll Cardiol 1991;17:227–236. 74. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic ﬁlling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. 75. Jensen JL, Williams FE, Beilby BJ, et al: Feasibility of obtaining pulmonary venous ﬂow velocity in cardiac patients using transthoracic pulsed wave Doppler technique. J Am Soc Echocardiogr 1997;10:60–66. 76. Ohno M, Cheng CP, Little WC: Mechanism of altered patterns of left ventricular ﬁlling during the development of congestive heart failure. Circulation 1994;89:2241–2250. 77. Manson AL, Nudelman SP, Hagley MT, et al: Relationship of the third heart sound to transmitral ﬂow velocity deceleration. Circulation 1995;92:388–394. 78. Shmuylovich L, Kovacs SJ: Load-independent index of diastolic ﬁlling: Model-based derivation with in vivo validation in control and diastolic dysfunction subjects. J Appl Physiol 2006;101:92–101. 79. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 1997;30:8–18. 80. Redﬁeld MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 81. Hoit BD, Shao Y, Gabel M, Walsh RA: Inﬂuence of loading conditions and contractile state on pulmonary venous ﬂow. Validation of Doppler velocimetry. Circulation 1992;86:651–659. 82. Basnight MA, Gonzalez MS, Kershenovich SC, Appleton CP: Pulmonary venous ﬂow velocity: Relation to hemodynamics, mitral ﬂow velocity and left atrial volume, and ejection fraction. J Am Soc Echocardiogr 1991;4:547–558. 83. Appleton CP: Hemodynamic determinants of Doppler pulmonary venous ﬂow velocity components: New insights from studies in lightly sedated normal dogs. J Am Coll Cardiol 1997;30:1562–1574. 84. Smiseth OA, Thompson CR, Lohavanichbutr K, et al: The pulmonary venous systolic ﬂow pulse—its origin and relationship to left atrial pressure. J Am Coll Cardiol 1999;34:802–809. 85. Keren G, Sherez J, Megidish R, et al: Pulmonary venous ﬂow pattern—its relationship to cardiac dynamics. A pulsed Doppler echocardiographic study. Circulation 1985;71:1105–1112. 86. Bartzokis T, Lee R, Yeoh TK, et al: Transesophageal echo-Doppler echocardiographic assessment of pulmonary venous ﬂow patterns. J Am Soc Echocardiogr 1991;4:457–464. 87. Kuecherer HF, Kusumoto F, Muhiudeen IA, et al: Pulmonary venous ﬂow patterns by transesophageal pulsed Doppler echocardiography: Relation to parameters of left ventricular systolic and diastolic function. Am Heart J 1991;122:1683–1693. 88. Klein AL, Abdalla I, Murray RD, et al: Age independence of the diﬀerence in duration of pulmonary venous atrial reversal ﬂow and transmitral A-wave ﬂow in normal subjects. J Am Soc Echocardiogr 1998;11:458–465.

89. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular ﬁlling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the diﬀerence in duration of pulmonary venous and mitral ﬂow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. 90. O’Leary PW, Durongpisitkul K, Cordes TM, et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end-diastolic pressure. Mayo Clin Proc 1998;73:616–628. 91. Appleton CP, Jensen JL, Hatle LK, Oh JK: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal ﬂow velocity recordings. J Am Soc Echocardiogr 1997;10:271– 292. 92. Nishimura RA, Abel MD, Hatle LK, Tajik AJ: Assessment of diastolic function of the heart: Background and current applications of Doppler echocardiography. Part II. Clinical studies. Mayo Clin Proc 1989;64: 181–204. 93. Sasson Z, Hatle L, Appleton CP, et al: Intraventricular ﬂow during isovolumic relaxation: Description and characterization by Doppler echocardiography. J Am Coll Cardiol 1987;10:539–546. 94. Klein AL, Hatle LK, Taliercio CP, et al: Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;16:1135–1141. 95. Hurrell DG, Oh JK, Mahoney DW, et al: Short deceleration time of mitral inﬂow E velocity: Prognostic implication with atrial ﬁbrillation versus sinus rhythm. J Am Soc Echocardiogr 1998;11:450–457. 96. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiﬀness from the time for deceleration of early left ventricular ﬁlling. Circulation 1995;92:1933–1939. 97. Hirota Y: A clinical study of left ventricular relaxation. Circulation 1980;62:756–763. 98. Matsuda Y, Toma Y, Matsuzaki M, et al: Change of left atrial systolic pressure waveform in relation to left ventricular end-diastolic pressure. Circulation 1990;82:1659–1667. 99. Tenenbaum A, Motro M, Hod H, et al: Shortened Doppler-derived mitral A wave deceleration time: An important predictor of elevated left ventricular ﬁlling pressure. J Am Coll Cardiol 1996;27:700–705. 100. Nishimura RA, Schwartz RS, Holmes DR Jr, Tajik AJ: Failure of calcium channel blockers to improve ventricular relaxation in humans. J Am Coll Cardiol 1993;21:182–188. 101. Sohn DW, Choi YJ, Oh BH, et al: Estimation of left ventricular enddiastolic pressure with the diﬀerence in pulmonary venous and mitral A durations is limited when mitral E and A waves are overlapped. J Am Soc Echocardiogr 1999;12:106–112. 102. Appleton CP: Doppler assessment of left ventricular diastolic function: The reﬁnements continue. J Am Coll Cardiol 1993;21:1697–1700. 103. Garcia MJ: Diastolic dysfunction and heart failure: Causes and treatment options. Cleve Clin J Med 2000;67:727–729, 733–738. 104. Nishimura RA, Appleton CP: “Diastology”: Beyond E and A. J Am Coll Cardiol 1996;27:372–374. 105. Quinones MA: Assessment of diastolic function. Prog Cardiovasc Dis 2005;47:340–355. 106. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284–1289. 107. Maurer MS, Spevack D, Burkhoﬀ D, Kronzon I: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44: 1543–1549. 108. Badano LP, Albanese MC, De Biaggio P, et al: Prevalence, clinical characteristics, quality of life, and prognosis of patients with congestive heart failure and isolated left ventricular diastolic dysfunction. J Am Soc Echocardiogr 2004;17:253–261. 109. Moller JE, Poulsen SH, Sondergaard E, et al: Impact of early changes in left ventricular ﬁlling pattern on long-term outcome after acute myocardial infarction. Int J Cardiol 2003;89:207–215. 110. Oh JK, Ding ZP, Gersh BJ, et al: Restrictive left ventricular diastolic ﬁlling identiﬁes patients with heart failure after acute myocardial infarction. J Am Soc Echocardiogr 1992;5:497–503. 111. Ommen SR, Tsang TS, Ammash NM, et al: Usefulness of serial echocardiographic parameters for predicting the subsequent occurrence of atrial ﬁbrillation. Am J Cardiol 2001;87:1298–1301. 112. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779.

Chapter 10 • Evaluation of Diastolic Function by Two-Dimensional and Doppler Assessment of Left Ventricular Filling 113. Tsang TS, Gersh BJ, Appleton CP, et al: Left ventricular diastolic dysfunction as a predictor of the ﬁrst diagnosed nonvalvular atrial ﬁbrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636– 1644. 114. Gibson DG, Prewitt TA, Brown DJ: Analysis of left ventricular wall movement during isovolumic relaxation and its relation to coronary artery disease. Br Heart J 1976;38:1010–1019. 115. Abhayaratna WP, Seward JB, Appleton CP, et al: Left atrial size: Physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47: 2357–2363. 116. Tsang TS, Barnes ME, Bailey KR, et al: Left atrial volume: Important risk marker of incident atrial ﬁbrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467–475. 117. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantiﬁcation: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantiﬁcation Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 118. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527– 1533. 119. Nagueh SF, Kopelen HA, Quinones MA: Assessment of left ventricular ﬁlling pressures by Doppler in the presence of atrial ﬁbrillation. Circulation 1996;94:2138–2145. 120. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular ﬁlling pressure in sinus tachycardia. A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. 121. Alam M, Wardell J, Andersson E, et al: Characteristics of mitral and tricuspid annular velocities determined by pulsed wave Doppler tissue imaging in healthy subjects. J Am Soc Echocardiogr 1999;12:618–628. 122. Garcia MJ, Rodriguez L, Ares M, et al: Myocardial wall velocity assessment by pulsed Doppler tissue imaging: Characteristic ﬁndings in normal subjects. Am Heart J 1996;132:648–656. 123. Garcia MJ, Thomas JD: Tissue Doppler to assess diastolic left ventricular function. Echocardiography 1999;16:501–508. 124. Oki T, Tabata T, Mishiro Y, et al: Pulsed tissue Doppler imaging of left ventricular systolic and diastolic wall motion velocities to evaluate diﬀerences between long and short axes in healthy subjects. J Am Soc Echocardiogr 1999;12:308–313. 125. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921–928. 126. Rodriguez L, Garcia M, Ares M, et al: Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inﬂow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131:982–987. 127. Nagueh SF, Rao L, Soto J: Hemodynamic mechanisms that account for the variable eﬀect of preload on tissue Doppler early diastolic velocity. Circulation 2002;107:2306.

128. Ha JW, Oh JK, Pellikka PA, et al: Diastolic stress echocardiography: A novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography. J Am Soc Echocardiogr 2005;1 8:63–68. 129. Cohen GI, Pietrolungo JF, Thomas JD, Klein AL: A practical guide to assessment of ventricular diastolic function using Doppler echocardiography. J Am Coll Cardiol 1996;27:1753–1760. 130. Koren MJ, Casale PN, Savage DD, Laragh JH: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352. 131. Appleton CP, Hatle LK, Popp RL: Superior vena cava and hepatic vein Doppler echocardiography in healthy adults. J Am Coll Cardiol 1987;10:1032–1039. 132. Ha JW, Oh JK, Redﬁeld MM, et al: Triphasic mitral inﬂow velocity with middiastolic ﬁlling: Clinical implications and associated echocardiographic ﬁndings. J Am Soc Echocardiogr 2004;17:428–431. 133. Hatle LK, Appleton CP, Popp RL: Diﬀerentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370. 134. Boonyaratavej S, Oh JK, Tajik AJ, et al: Comparison of mitral inﬂow and superior vena cava Doppler velocities in chronic obstructive pulmonary disease and constrictive pericarditis. J Am Coll Cardiol 1998;32:2043– 2048. 135. Burstow DJ, Oh JK, Bailey KR, et al: Cardiac tamponade: Characteristic Doppler observations. Mayo Clin Proc 1989;64:312–324. 136. Appleton CP, Hatle LK, Popp RL: Cardiac tamponade and pericardial eﬀusion: Respiratory variation in transvalvular ﬂow velocities studied by Doppler echocardiography. J Am Coll Cardiol 1988;11:1020–1030. 137. McCully RB, Higano ST, Oh JK: Diagnosis of constrictive pericarditis. Circulation 1999;99:2476. 138. Appleton CP, Basnight MA, Gonzalez MS: Diastolic mitral regurgitation with atrioventricular conduction abnormalities: Relation of mitral ﬂow velocity to transmitral pressure gradients in conscious dogs. J Am Coll Cardiol 1991;18:843–849. 139. Schnittger I, Appleton CP, Hatle LK, Popp RL: Diastolic mitral and tricuspid regurgitation by Doppler echocardiography in patients with atrioventricular block: New insight into the mechanism of atrioventricular valve closure. J Am Coll Cardiol 1988;11:83–88. 140. Klein AL, Hatle LK, Burstow DJ, et al: Comprehensive Doppler assessment of right ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;15:99–108. 141. Simonson JS, Schiller NB: Sonospirometry: A new method for noninvasive estimation of mean right atrial pressure based on two-dimensional echographic measurements of the inferior vena cava during measured inspiration. J Am Coll Cardiol 1988;11:557–564. 142. Nageh MF, Kopelen HA, Zoghbi WA, et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451, A8. 143. Nagueh SF, Kopelen HA, Zoghbi WA: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.

143

L. LEONARDO RODRIGUEZ, MD

11

Evaluation of Diastolic Function by Color M-Mode Doppler INTRODUCTION BACKGROUND Obtaining and Measuring Flow Propagation Color M-Mode Intraventricular Pressure Gradients Pathophysiology

CLINICAL RELEVANCE Pseudonormal Filling Patterns Estimation of Left Atrial Pressures Use of Color M-Mode in Clinical Settings Limitations of Color M-Mode Indices FUTURE RESEARCH

COLOR M-MODE DOPPLER AND DIASTOLIC FUNCTION

INTRODUCTION Pulsed-wave Doppler velocities of mitral inﬂow are the most commonly used indices of diastolic function. Their application is nevertheless limited by their load dependency. Flow propagation (Vp) using Doppler color M-mode (CMM) has been proposed as a complementary technique to evaluate left ventricular (LV) relaxation. Color Doppler M-mode echocardiography provides a spatiotemporal map of blood distribution (v(s,t)) within the heart, with a typical temporal resolution of 5 ms, a spatial resolution of 300 microns, and a velocity resolution of 3 cm/s. By aligning the cursor parallel to the streamlines of ﬂow, we can observe the propagation of ﬂow from the mitral valve to the apex (Fig. 11-1). Assessment of diastolic ﬂow propagation has oﬀered novel information about LV ﬁlling dynamics and has been applied in a variety of clinical conditions. Since the initial descriptions by Jacobs1 and later Brun,2 computer simulation,3 in vitro modeling,4 and animal5,6 and clinical studies2,5–8 have improved our understanding of the determinant of Vp but also have shown the complexity of this index. Vp appears to be relatively independent of loading conditions and therefore may overcome one of the main limitations of Doppler-based techniques.2,5,7,9 In this chapter we will review the current understanding of how ﬂow propagates from the base to the apex of the left ventricle, its major determinants, how to properly obtain a color M-mode

tracing, and clinical situations in which this technique may be applied. We will also describe its application in the calculation of intraventricular pressure gradients (IVPGs).

BACKGROUND It is now well recognized that in early diastole small but signiﬁcant intraventricular mitral-to-apex pressure gradients are generated.10,11 These IVPGs are related to elastic recoil12–14 and apical untwisting. They represent one of the driving forces of the blood entering the left ventricle (ventricular “suction”). As a result, when the mitral valve opens, a column of blood accelerates from the atrium toward the ventricular apex. In normal ventricles, ﬂow propagates very rapidly, while in dilated, poorly contracted ventricles it occurs comparatively slowly (Fig. 11-2, right).2 Mitral inﬂow propagation displayed by CMM has a complex pattern. The earliest CMM velocities often occur during isovolumic relaxation. After the mitral valve opens, there is a rapid initial component (phase I), often followed by a slower component (phase II). Finally, the last component in late diastole is associated with atrial contraction (see Fig. 11-1). Computer and in vitro modeling have studied the phenomenon of ﬂow propagation. During phase I, blood moves almost simultaneously in the whole left ventricle, behaving as an incompressible ﬂuid column (columnar ﬂow).3,4 Phase II is a ﬂow wave thought to be caused by 145

146

Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler propagation of a ring vortex formed at the ventricular base.3,4,15,16 Vortices are formed during the acceleration phases of the early and atrial ﬁlling waves. During the deceleration phases, the vortices are ampliﬁed and convected into the ventricle (Figs. 11-3 and 11-4).3 The formation of a vortex is aﬀected by the size of the inlet (mitral oriﬁce)4 and the geometry and size of the receiving chamber. In small, tubular ventricles there is predominant columnar ﬂow with no space from the mitral leaﬂets to the ventricular wall for vortex formation. In dilated ventricles with decreased ratio of mitral valve oriﬁce to ventricular diameter, there would be predominant vortex formation and propagation.4 In this circumstance, ﬂow velocities at the mitral tips can be relatively high, but the velocity of the front wave propagation remains slow. This explains why patients with a restrictive ﬁlling pattern can have a peak E-wave velocity greater than 1 m/sec at the level of the mitral level tips and at the same time a ﬂow velocity propagation of 40 cm/sec or less. In in vitro modeling, the ratio of ﬂow velocity to vortex propagation is around 2 : 1.4

Obtaining and Measuring Flow Propagation CMM ﬂow propagation is usually measured from the apical fourchamber view. The M-mode cursor is carefully aligned with direc.45

Late (A Wave) Color M-Mode Flow Propagation

.75 22

tion of ﬂow, maximizing the distance from mitral tips to apex. At least 4 cm of CMM depth should be obtained and displayed at 100 cm/sec sweep speed. In the initial description by Brun,2 CMM ﬂow propagation was measured as the slope of colornoncolor interface. The use of the slope of the color-noncolor interface is limited by its interference with isovolumic ﬂow. Since then, several other methods have been proposed. This constitutes one of the main limitations of this technique, as it is diﬃcult to compare studies among diﬀerent authors. The slope of the ﬁrst aliasing velocity has also been used by several authors, setting the aliasing velocity at a percentage (40%–70%) of the maximal inﬂow velocity (see Fig. 11-2).5,17 An aliasing velocity of 40% of the peak E-wave velocity appears to be more reproducible and to better reﬂect the velocity of propagation.17 There are no consensus guidelines as to whether phase I or phase II should be measured. Garcia et al. proposed the use of phase II when present.18 Stugaard et al. used a computer algorithm to detect the maximal velocities along the center of the ﬂow propagation wave and measured the time delay between the velocity at mitral tips and apex.8 This method is attractive, for it appears to be more objective, but it is not widely available. An automated way to measure the slope of Vp has been described.19 Normal values depend on the methodology used. With the slope of ﬁrst aliasing (40%–50% of peak E velocity), values greater than 45 cm/sec are considered normal. The interobserver variability of Vp measurements has been reported to be around 12%20 but can be as high as 20%.15

Cal = 10mm I

II

IVF AC

Most of the studies have focused in the propagation of early mitral inﬂow. There are limited data about the importance and clinical signiﬁcance of the propagation of ﬂow during atrial contraction. There is a fundamental diﬀerence between early and late ﬂow propagation. During early propagation, blood is pulled into the ventricle, while during late propagation, it is pushed (atrial contraction). A ratio of early to late ﬂow propagation has been reported in patients with pseudonormal ﬁlling patterns,21 although the advantage of this over early Vp alone or E/Vp is unclear.

133

Figure 11-1 Color M-mode of mitral inflow obtained from the apical window. Several components can be appreciated from this tracing. Phase I is faster, followed by the slower phase II (vortex) component. A short flow during isovolumic relaxation (IVF) is also seen, as well as late flow during atrial contraction (AC).

Color M-Mode Intraventricular Pressure Gradients Given the complexity of CMM inﬂow patterns and the variability of the measurements of ﬂow propagation, a more objective analysis of LV ﬁlling is desirable. It is well known that the presence of

Figure 11-2 Example of a young normal individual (left) and a patient with delayed relaxation (right). Note the difference in Vp slope between the two.

Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler

Figure 11-3 Computer simulation of vortex formation, flow patterns, and calculated 2D color Doppler echocardiograms at six different points in time during filling. Note that the vortex is amplified during the deceleration phase of the early filling wave and moves into the left ventricle toward the apex. (From Vierendeels JA et al: Hydrodynamics of color M-mode Doppler flow wave propagation velocity V(p): A computer study. J Am Soc Echocardiogr 2002;15: 219–224.)

Figure 11-4 In vitro model of diastolic flow obtained by injecting liquid dye of the same density as water from two opposing thin needles placed at the top and bottom of the orifice. This model produced a succession of vortex rings. The driving waveforms resulted in trailing vortex rings in addition to a primary ring. (From Cooke J et al: Characterizing vortex ring behavior during ventricular filling with Doppler echocardiography: An in vitro study. Ann Biomed Eng 2004;32:245–256.)

regional pressure diﬀerences in the left ventricle is related to LV relaxation and suction. Ling et al. demonstrated in a canine model the presence of regional diastolic IVPGs between the base and the apex of the left ventricle. These gradients resulted in the active ﬁlling of the ventricle. Courtois et al.11,22 validated these ﬁndings and later demonstrated a reduction in IVPG during myocardial ischemia in an animal model. These IVPGs are related to elastic recoil and to apical untwisting.23 Greenberg and Thomas24 used the Euler equation to calculate local pressure gradients, ∂p ∂v ⎤ ⎡ ∂v = −ρ ⎢ + ν ⎥ , ∂s ∂s ⎦ ⎣ ∂t where p, s, t, and v are pressure, distance, time, and velocity, respectively. Integrating the Euler equation from the LV base to apex IVPG can be estimated by

ΔPIV (t ) =

apex

∂p ds ∂s base

∫

where ΔPIV(t) represents IVPG.25 This methodology has been reproduced by others26 and opens the possibility of evaluating diastole in a more fundamental way by measuring one of the driving forces of early ﬁlling.

Pathophysiology In abnormal ventricles, IVPGs are blunted22 or even reversed— the initial, faster phase is then lost; vortex formation predominates, slowing the progression of the wavefront toward the apex (see Fig. 11-2). Factors that can aﬀect the formation of IVPGs

147

148

Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler include regional wall motion abnormalities, increased end systolic volume, and dyssynchrony of relaxation.15 The magnitude of pressure gradient formation also depends on ventricular size. In small ventricles, intraventricular gradient formation is enhanced. Vortex formation and propagation require that the ventricular diameter exceed the mitral diameter.4 In dilated, spherical ventricles, the diﬀerence in axial velocity between the blood already in the ventricle and blood coming through the mitral valve creates a larger vortex.4

COLOR M-MODE DOPPLER AND DIASTOLIC FUNCTION Human and animal studies have shown that ﬂow propagation velocity of early transmitral ﬂow (Vp) correlates well with the time constant of isovolumic relaxation (Tau, τ).2,5,6,27 This correlation is maintained under a variety of loading and inotropic5 conditions and also in children.28 The strength of the correlation varies according to the technique used to measure Vp, with r values ranging from 0.5 to 0.9.5,6,27,28 Vp is also related to −dP/dt and minimal LV diastolic pressure.27 Vp appears to be a more complex parameter than a simple index of ventricular relaxation.29,30 Vp is inﬂuenced not only by the rate of LV relaxation, but also by ventricular geometry,31 the ratio between mitral oriﬁce size and LV cavity size, and dyssynchrony of relaxation.4,30,32 Because Vp correlates well with tau, which is preload independent, CMM ﬂow propagation has been proposed as a loadinsensitive method of assessing LV relaxation.5,7 Although most clinical studies have found that Vp is relatively load independent, there is still some controversy, particularly regarding patients with normal systolic function and hypertrophy.30,33–36 In this group of patients, LV geometry may play a predominant role. It has also been reported that in patients with congestive heart failure, Vp may decrease after medical treatment and is correlated with changes in pulmonary capillary wedge pressure (PCWP).37

CLINICAL RELEVANCE Pseudonormal Filling Pattern In patients with elevated left atrial (LA) pressure, the mitral inﬂow Doppler pattern can be indistinguishable from normal diastolic function. This important limitation of pulsed Doppler regarding mitral inﬂow has led to a search for other techniques. One of the early applications of CMM was to diﬀerentiate normal from pseudonormal ﬁlling patterns. In patients with a pseudonormal mitral ﬁlling pattern, CMM will show slow ﬂow propagation.27,38 Takatsuji et al. studied patients with decreased ejection fractions and mitral E/A ratios less than 1 and equal to or greater than 1 and compared them with a group with normal ejection fractions. The rate of velocity propagation of CMM was signiﬁcantly lower in patients with low ejection fractions, regardless of the mitral inﬂow pattern.27

Estimation of Left Atrial Pressures The main determinants of Doppler peak E-wave velocity (E) are LA pressure (LAP) and relaxation. By using 1/Vp as a surrogate for relaxation, it is in theory possible to estimate LA pressure, by substituting Vp α 1/τ in E α LAP/τ to yield E α LAP × Vp, which is then rearranged LAP α E/Vp.

This method has been investigated in patients under several conditions, in sinus rhythm and atrial ﬁbrillation.39 Garcia et al. studied 45 patients and found a robust correlation of E/Vp with PCWP (r = 0.80) with a regression equation: PCWP = 5.27 × [E/Vp] + 4.6. The limitations of this method to calculate a numerical value for LA pressure lie in the diﬃculty in measuring a reliable and reproducible slope of the CMM. As an example, the same group published the relation of CWP and Vp in normal subjects. The regression equation in this group was: PCWP = 25.6 × Vp − 26.1 (r = 0.81). Adding isovolumic relaxation time (IVRT) to the calculation appears to improve the correlation with CWP. Gonzales-Vilchez and Ares40 modiﬁed the Weiss equation to derive: PCWP = (0.9 × SBP) × e−IVRT×Vp, where SBP is systolic blood pressure. Using this equation, they found an improved correlation compared with the E/Vp ratio alone (r = 0.80 vs. 0.55).40 Another approach is to use the ratio of E/Vp to identify patients with normal versus elevated PCWP. An E/Vp of less than 1.4 or 1.5 appears to have high sensitivity and reasonable speciﬁcity to identify PCWP under 15 mmHg in patients in sinus rhythm or even in atrial ﬁbrillation.39 Other authors have used a ratio of 2.540 to predict elevated CWP, once again reﬂecting variability in measuring the slope of Vp.

Use of Color M-Mode in Clinical Settings Abnormalities in Vp have been described in ischemic heart disease,6,8,38,41,42 before cardiac resynchronization43 and constrictive pericarditis,44 and in dilated,1,21 hypertrophic,45 and restrictive cardiomyopathies.46,47 In all clinical conditions with abnormal relaxation, the velocity of propagation is diminished. In patients with isolated constrictive physiology, where the intrinsic properties of the myocardium are normal and the left ventricle has small end systolic volume, Vp is normal or even augmented despite elevated ﬁlling pressures.44 The prognostic value of Vp has been investigated in patients after their initial myocardial infarction. Patients with a pseudonormal pattern, deﬁned by normal E/A ratio and slow Vp, had an adverse prognosis.38 The researchers found that an E/Vp greater than 1.5 was a strong predictor of in-hospital heart failure in patients with acute myocardial infarction (Fig. 11-5).48 The Vp has been studied in patients with congestive heart failure. The E/Vp ratio has a modest correlation with brain natriuretic peptide (BNP) levels.49 In patients with hypertensive heart disease and normal function who present with dyspnea to the emergency room, E/Vp has a sensitivity of 73%, a speciﬁcity of 75%, and an accuracy of 74.3% for diagnosis of heart failure for the optimal cutoﬀ of 1.5.50 Others have found that an E/Vp of 1.8 has a sensitivity of 83% and a speciﬁcity of 86% to predict pulmonary congestion in patients with normal or low ejection fraction and correlated with LV end diastolic pressure (r = 0.73).51 As mentioned previously, in patients with heart failure, Vp may show some dependency on loading conditions,37,52 and Vp can be lower after heart failure treatment. This may limit the application of Vp for assessing therapy in patients with congestive heart failure. In this situation, E/Vp appears to be still useful, as E decreases more than Vp, and therefore the ratio diminishes in the

Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler 100 E/Vp < 1.5

FUTURE RESEARCH Automatic or semiautomatic methods are necessary to introduce more objectivity into the measurements of Vp.19 A better understanding of the hydrodynamic and mechanical phenomena occur-

E/Vp > 1.5

50 40 30 20 10

Log rank 28; p < 0.00001

0 0

3

6

9

12

15

18

21

24

27

30

33

Days

IVPG = 3.5 – 0.056*t0 + 0.11*PCW p < 0.001 r = 0.58 4

2

80 60 40

s)

The main limitation of Vp is its high variability in measuring the slope of CMM. There is no agreement in how to measure it, and even if there were, the color display is often complex, bifurcated, and curvilinear. In some patients, prominent isovolumic ﬂow interferes with measurement of the slope. Normal or increased Vp in patients in whom we expect delayed relaxation has been described,34 a condition named by some authors as pseudonormalization of Vp.15 This appears to be limited to small, hypertrophic ventricles with small end systolic volumes.

60

(m

Limitations of Color M-Mode Indices

70

τ0

direction of hemodynamic improvement. Further research in this area is necessary. In patients with systolic heart failure, E/Vp greater than 2.7 independently predicts the composite end point of death, transplantation, or hospitalization.52 The calculation of IVPG using CMM has yielded important information in patients with hypertrophic cardiomyopathy and has been used as a tool to study basic physiologic changes of aging25 and exercise.23,25,53 Rovner et al.53 found that exercise capacity and its maximum oxygen use, VO2 max, have a tight relationship with changes in IVPG with exercise. Notably, basal IVPG was not related to exercise capacity. Normal aging impairs the relationship between IVPGs and preload, probably through age-dependent decline in relaxation, and is independent of changes in ventricular compliance.25 IVPGs appear to be inﬂuenced by τ and preload (Fig. 11-6).25,51 More recently, a close relation between IVPGs and velocity of apical untwisting has been shown at rest and with exercise.23 The increase in IVPGs during exercise appears to be an essential mechanism to augment stroke volume during this condition. The precise relationship between CMM-derived IVPGs and Vp has not yet been well characterized. This relationship is probably complex, involving not only the absolute pressure diﬀerence but also the temporal and spatial location of local pressure gradients. In an animal model of ischemia, time delay of Vp from base to apex correlated closely with IVPGs (r = 0.94).

80

IVPG (mmHg)

Figure 11-5 Kaplan-Meier curves showing the effect of the ratio of peak E-wave velocity and flow propagation velocity (E/Vp) on cardiac survival in patients after first myocardial infarction. (From Moller JE et al: Ratio of left ventricular peak E-wave velocity to flow propagation velocity assessed by color M-mode Doppler echocardiography in first myocardial infarction: Prognostic and clinical implications. J Am Coll Cardiol 2000;35:363–370.)

Cumulative survival (%)

90

8

20

4 0

P PCW

12

16

20

24

Hg)

(mm

Elderly sedentary Young Figure 11-6 Three-dimensional scatterplot that shows correlation between time constant of ventricular relaxation (τ0, x-axis), pulmonary capillary wedge pressure (PCWP) (y-axis), and intraventricular pressure gradient (IVPG) (z-axis). Data are from both elderly (solid circles) and young (open circles) subjects around the regression plane. A highly significant, moderately strong correlation of IVPG with relaxation and preload was observed. Note that separation of young and elderly subjects according to their IVPG values disappears when both τ0 and PCWP are taken into account. (From Popovic ZB et al: Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and fitness. Am J Physiol Heart Circ Physiol 2006;290:H1454–H1459.)

ring during isovolumic relaxation and early ﬁlling will allow development of more precise methods to quantitate ﬂow propagation and may explain the discrepancies among studies—in particular, the load dependency of this technique. Further research into the correlation of Vp with ventricular torsion in clinical situations will greatly help us understand the determinants of Vp.23 The estimation of IVPG using CMM has been used only in limited clinical conditions but is a promising technique if calculations can be automatized and widely available in diﬀerent echocardiographic machines.

149

150

Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler The issue of preload independence of CMM is not settled, and further studies are necessary. Larger numbers of patients in different clinical conditions and with a variety of LV volumes and ejection fractions need to be studied. The Vp and IVPG under diﬀerent loading conditions may be useful to our understanding of the discrepancies among studies. REFERENCES 1. Jacobs LE, Kotler MN, Parry WR: Flow patterns in dilated cardiomyopathy: A pulsed-wave and color ﬂow Doppler study. J Am Soc Echocardiogr 1990;3:294–302. 2. Brun P, Tribouilloy C, Duval AM, et al: Left ventricular ﬂow propagation during early ﬁlling is related to wall relaxation: A color M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 3. Vierendeels JA, Dick E, Verdonck PR: Hydrodynamics of color M-mode Doppler ﬂow wave propagation velocity V(p): A computer study. J Am Soc Echocardiogr 2002;15:219–224. 4. Steen T, Steen S: Filling of a model left ventricle studied by colour M mode Doppler. Cardiovasc Res 1994;28:1821–1827. 5. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler ﬂow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 2000;35: 201–208. 6. Stugaard M, Smiseth OA, Risoe C, Ihlen H: Intraventricular early diastolic velocity proﬁle during acute myocardial ischemia: A color M-mode Doppler echocardiographic study. J Am Soc Echocardiogr 1995;8:270–279. 7. Garcia MJ, Palac RT, Malenka DJ, et al: Color M-mode Doppler ﬂow propagation velocity is a relatively preload-independent index of left ventricular ﬁlling. J Am Soc Echocardiogr 1999;12:129–137. 8. Stugaard M, Brodahl U, Torp H, Ihlen H: Abnormalities of left ventricular ﬁlling in patients with coronary artery disease: Assessment by colour M-mode Doppler technique. Eur Heart J 1994;15:318–327. 9. Abali G, Tokgozoglu L, Ozcebe OI, et al: Which Doppler parameters are load independent? A study in normal volunteers after blood donation. J Am Soc Echocardiogr 2005;18:1260–1265. 10. Ling D, Rankin JS, Edwards CH 2nd, et al: Regional diastolic mechanics of the left ventricle in the conscious dog. Am J Physiol 1979;236: H323–H330. 11. Courtois M, Kovacs SJ Jr, Ludbrook PA: Transmitral pressure-ﬂow velocity relation. Importance of regional pressure gradients in the left ventricle during diastole. Circulation 1988;78:661–671. 12. Nikolic SD, Feneley MP, Pajaro OE, et al: Origin of regional pressure gradients in the left ventricle during early diastole. Am J Physiol 1995;268: H550–H557. 13. Suga H, Goto Y, Igarashi Y, et al: Ventricular suction under zero source pressure for ﬁlling. Am J Physiol 1986;251:H47–H55. 14. Ingels NB Jr, Daughters GT, Nikolic SD, et al: Left ventricular diastolic suction with zero left atrial pressure in open-chest dogs. Am J Physiol 1996;270:H1217–H1224. 15. De Boeck BW, Oh JK, Vandervoort PM, et al: Colour M-mode velocity propagation: A glance at intra-ventricular pressure gradients and early diastolic ventricular performance. Eur J Heart Fail 2005;7:19–28. 16. Nakamura M, Wada S, Mikami T, et al: Computational study on the evolution of an intraventricular vortical ﬂow during early diastole for the interpretation of color M-mode Doppler echocardiograms. Biomech Model Mechanobiol 2003;2:59–72. 17. Seo Y, Ishimitsu T, Ishizu T, et al: Assessment of propagation velocity by contrast echocardiography for standardization of color Doppler propagation velocity measurements. J Am Soc Echocardiogr 2004;17:1266– 1274. 18. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular ﬁlling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 19. Greenberg NL, Firstenberg MS, Cardon LA, et al: Automated assessment of noninvasive ﬁlling pressure using color Doppler M-mode echocardiography. Comput Cardiol. 2001;28:601–604. 20. Khan S, Bess RL, Rosman HS, et al: Which echocardiographic Doppler left ventricular diastolic function measurements are most feasible in the clinical echocardiographic laboratory? Am J Cardiol 2004;94:1099–1101. 21. Patrianakos AP, Parthenakis FI, Mavrakis HE, et al: Late left ventricular color M-mode Doppler in the assessment of diastolic dysfunction in patients with dilated cardiomyopathy. J Am Soc Echocardiogr 2005;18:979.

22. Courtois M, Kovacs SJ, Ludbrook PA: Physiological early diastolic intraventricular pressure gradient is lost during acute myocardial ischemia. Circulation 1990;81:1688–1696. 23. Notomi YM, Oryszak SJ, Shiota T, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533. 24. Greenberg NL, Vandervoort PM, Firstenberg MS, et al: Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol 2001;280:H2507–H2515. 25. Popovic ZB, Prasad A, Garcia MJ, et al. Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and ﬁtness. Am J Physiol Heart Circ Physiol 2006;290:H1454–H1459. 26. Bermejo J, Antoranz JC, Yotti R, et al: Spatio-temporal mapping of intracardiac pressure gradients. A solution to Euler’s equation from digital postprocessing of color Doppler M-mode echocardiograms. Ultrasound Med Biol 2001;27:621–630. 27. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular ﬁlling ﬂow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27:365–371. 28. Border WL, Michelfelder EC, Glascock BJ, et al: Color M-mode and Doppler tissue evaluation of diastolic function in children: Simultaneous correlation with invasive indices. J Am Soc Echocardiogr 2003;16: 988–994. 29. Stoylen A, Skjelvan G, Skjaerpe T: Flow propagation velocity is not a simple index of diastolic function in early ﬁlling: A comparative study of early diastolic strain rate and strain rate propagation, ﬂow and ﬂow propagation in normal and reduced diastolic function. Cardiovasc Ultrasound 2003;1:3. 30. Barbier P, Grimaldi A, Alimento M, et al: Echocardiographic determinants of mitral early ﬂow propagation velocity. Am J Cardiol 2002;90:613– 619. 31. Baccani B, Domenichini F, Pedrizzetti G, Tonti G: Fluid dynamics of the left ventricular ﬁlling in dilated cardiomyopathy. J Biomech 2002;35: 665–671. 32. Smiseth OA, Thompson CR: Atrioventricular ﬁlling dynamics, diastolic function and dysfunction. Heart Fail Rev 2000;5:291–299. 33. Ie EH, Vletter WB, ten Cate FJ, et al: Preload dependence of new Doppler techniques limits their utility for left ventricular diastolic function assessment in hemodialysis patients. J Am Soc Nephrol 2003;14:1858– 1862. 34. Alegret JM, Borras X, Carreras F, et al: Restrictive left ventricular ﬁlling and preserved ventricular function: A limitation in the noninvasive estimation of pulmonary wedge pressure by Doppler echocardiography. J Am Soc Echocardiogr 2002;15:334–338. 35. Hsiao SH, Huang WC, Lee TY, et al: Preload and ﬂow propagation velocity: Insight into patients with uremia and diﬀerent left ventricular systolic function. J Am Soc Echocardiogr 2005;18:1254–1259. 36. Hsiao SH, Huang WC, Sy CL, et al: Doppler tissue imaging and color Mmode ﬂow propagation velocity: Are they really preload independent? J Am Soc Echocardiogr 2005;18:1277–1284. 37. Seo Y, Ishimitsu T, Ishizu T, et al: Preload-dependent variation of the propagation velocity in patients with congestive heart failure. J Am Soc Echocardiogr 2004;17:432–438. 38. Moller JE, Sondergaard E, Poulsen SH, Egstrup K: Pseudonormal and restrictive ﬁlling patterns predict left ventricular dilation and cardiac death after a ﬁrst myocardial infarction: A serial color M-mode Doppler echocardiographic study. J Am Coll Cardiol 2000;36:1841–1846. 39. Nagueh SF, Kopelen HA, Quinones MA: Assessment of left ventricular ﬁlling pressures by Doppler in the presence of atrial ﬁbrillation. Circulation 1996;94:2138–2145. 40. Gonzalez-Vilchez F, Ares M, Ayuela J, Alonso L: Combined use of pulsed and color M-mode Doppler echocardiography for the estimation of pulmonary capillary wedge pressure: An empirical approach based on an analytical relation. J Am Coll Cardiol 1999;34:515–523. 41. De Sutter J, De Mey S, De Backer J, et al: Diastolic dysfunction, infarct size, and exercise capacity in remote myocardial infarction: A combined approach of mitral E-wave deceleration time and color M-mode ﬂow propagation velocity. Am J Cardiol 2002;89:593–595. 42. Stugaard M, Smiseth OA, Risoe C, Ihlen H: Intraventricular early diastolic ﬁlling during acute myocardial ischemia, assessment by multigated color M-mode Doppler echocardiography. Circulation 1993;88:2705–2713. 43. Waggoner AD, Faddis MN, Gleva MJ, et al: Cardiac resynchronization therapy acutely improves diastolic function. J Am Soc Echocardiogr 2005;18:216–220.

Chapter 11 • Evaluation of Diastolic Function by Color M-Mode Doppler 44. Rajagopalan N, Garcia MJ, Rodriguez L, et al: Comparison of new Doppler echocardiographic methods to diﬀerentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiol 2001;87:86–94. 45. Nishihara K, Mikami T, Takatsuji H, et al: Usefulness of early diastolic ﬂow propagation velocity measured by color M-mode Doppler technique for the assessment of left ventricular diastolic function in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2000;13:801–808. 46. Palecek T, Linhart A, Lubanda JC, et al: Early diastolic mitral annular velocity and color M-mode ﬂow propagation velocity in the evaluation of left ventricular diastolic function in patients with Fabry disease. Heart Vessels 2006;21:13–19. 47. Salemi VM, Picard MH, Mady C: Assessment of diastolic function in endomyocardial ﬁbrosis: Value of ﬂow propagation velocity. Artif Organs 2004;28:343–346. 48. Moller JE, Sondergaard E, Seward JB, et al: Ratio of left ventricular peak E-wave velocity to ﬂow propagation velocity assessed by color M-mode Doppler echocardiography in ﬁrst myocardial infarction: Prognostic and clinical implications. J Am Coll Cardiol 2000;35:363–370. 49. Troughton RW, Prior DL, Pereira JJ, et al: Plasma B-type natriuretic peptide levels in systolic heart failure: Importance of left ventricular diastolic func-

50.

51.

52.

53.

tion and right ventricular systolic function. J Am Coll Cardiol 2004;43: 416–422. Arques S, Roux E, Sbragia P, et al: Comparative accuracy of color M-mode and tissue Doppler echocardiography in the emergency diagnosis of congestive heart failure in chronic hypertensive patients with normal left ventricular ejection fraction. Am J Cardiol 2005;96:1456– 1459. Schwammenthal E, Popescu BA, Popescu AC, et al: Association of left ventricular ﬁlling parameters assessed by pulsed wave Doppler and color M-mode Doppler echocardiography with left ventricular pathology, pulmonary congestion, and left ventricular end-diastolic pressure. Am J Cardiol 2004;94:488–491. Troughton RW, Prior DL, Frampton CM, et al: Usefulness of tissue Doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT study). Am J Cardiol 2005;96:257–262. Rovner A, Greenberg NL, Thomas JD, Garcia MJ: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005;289: H2081–H2088.

151

MARIO J. GARCIA, MD

12

Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis INTRODUCTION PATHOPHYSIOLOGY Tissue Doppler Velocities Myocardial Strain and Strain Rate Left Ventricular Torsion CLINICAL APPLICATIONS Assessment of Left Ventricular Relaxation Evaluation of Left Ventricular Filling Pressures

Ischemic Heart Disease Dilated Cardiomyopathies Restrictive Cardiomyopathies Constrictive Pericarditis Hypertrophy Cardiomyopathies Transplant Rejection Diabetes and Myocardial Disease Tissue Doppler Parameters and Prognosis FUTURE RESEARCH

INTRODUCTION Early Doppler echocardiographic indices of left ventricular (LV) diastolic function have studied the mechanics of left atrial (LA) and ventricular ﬁlling. These ﬁlling indices have been proven to be useful, providing prognostic information in heart failure patients.1–3 However, ﬁlling indices have limited accuracy predicting intrinsic parameters of diastolic function due to the confounding eﬀects of extrinsic loading conditions and valvular hemodynamic performance. Doppler ultrasound and more recently two-dimensional speckle tracking may be applied to study LV myocardial mechanics. Since myocardial mechanical events precede LA and LV ﬁlling, they may be potentially less dependent on extrinsic variables and therefore more accurate in characterizing intrinsic myocardial properties. In this chapter, we will review the role of tissue Doppler and two-dimensional particle tracking–derived myocardial velocities and their derivatives for the assessment of LV diastolic function.

PATHOPHYSIOLOGY Tissue Doppler Velocities In technical terms, tissue Doppler echocardiography (TDE) diﬀers from standard Doppler by eliminating the highpass ﬁlter and using low gain ampliﬁcation to display the velocities of the myocardium. TDE velocities may be displayed in spectral pulsed mode or in color-encoded two-dimensional maps superimposed on structural images (Figs. 12-1 and 12-2).4 The technical principles and limitations of these modalities are similar to those encountered with standard Doppler ﬂow systems. Myocardial velocities may be obtained from multiple locations of the myocardium. In a typical spectral display, the myocardial velocity is a positive waveform representing ventricular systole (SM) and two waves corresponding to early ﬁlling (EM) and atrial contraction (AM). From the apical acoustic windows, the diastolic myocardial velocities obtained from any of the LV myocardial segments appear as a mirror image of the mitral inﬂow early (E) and atrial (A) ﬁlling velocities. In normal humans, the peak of EM precedes 153

154

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

2

SM 1

3 Figure 12-1 Longitudinal axis tissue Doppler velocities obtained using spectral Doppler from the basal lateral left ventricular segment. AM, atrial contraction velocity; EM, early diastolic velocity; SM, systolic velocity.

AM EM

A

B

the peak of LV ﬁlling E velocity, suggesting that active relaxation of the myocardium generates negative pressures in the LV cavity that initiate LV ﬁlling. TDE velocities are aﬀected not only by regional LV mechanical events, but also by global translation and rotation of the heart. Accordingly, spectral TDE velocities are usually obtained from the apical acoustic window, since LV longitudinal velocities are less aﬀected by translational motion (Figs. 12-3 and 12-4).5 Alternatively, translational motion may be corrected by oﬄine analysis from color-encoded TDE velocities. One method plots the velocity of each adjacent scan line from the distance of the epicardium to the endocardium. From a parasternal color M-mode image, the rates of circumferential ﬁber shortening and lengthening are proportional to the slope of the velocity/distance regression line. The value of this slope has been referred to as the myocardial velocity gradient (MVG).

Figure 12-2 Color-encoded tissue Doppler velocities obtained from the four-chamber view during systole (A) and diastole (B).

SM

AM EM

MYOCARDIAL STRAIN AND STRAIN RATE The change in length of the myocardial ﬁber (end diastolic length, end systolic length/end diastolic length) is also known as myocardial strain. The spiral architecture of the myocardial ﬁber bundles determines strain deformation in multiple directions. Thus,

Figure 12-3 Regional values derived from the color-encoded velocities obtained from different regions of the myocardium. Notice that velocities that are obtained closer to the base have a higher magnitude, due to the added translation produced by the contraction and relaxation of middle and apical segments. AM, atrial contraction velocity; EM, early diastolic velocity; SM, systolic velocity.

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis changes in LV geometry during LV systole relate primarily to radial (short axis), longitudinal (long axis), and meridional (LV torsion) strain (Fig. 12-5). Myocardial strain may be quantiﬁed noninvasively using magnetic resonance imaging (MRI), TDE, or high-frame-rate two-dimensional echocardiography with speckle tracking. (Strain analysis using MRI is described in detail in a separate chapter.) TDE-derived strain quantiﬁes tissue deformation based on Doppler velocity shifts. Unlike tissue Doppler velocities, tissue strain is less aﬀected by segmental tethering and translational motion; therefore, it reﬂects primarily the intrinsic deformation of the myocardial segment within the sample region. The strain rate (SR) of a segment of a given length (L0) is given

by: SR = (V1 − V2)/L0, where V1 and V2 are the tissue Doppler velocities at each end of the segment (L0). Strain (ε) represents the percent deformation for the given segment over its initial value, and is obtained by integrating SR over the systolic (shortening) or diastolic interval (lengthening) of the cardiac cycle (Figs. 12-6 and 12-7). Recent studies have demonstrated a closed correlation between SR and indices of LV contractility and between ε and LV stroke volume.6,7 Unfortunately, Doppler-derived strain is limited to interrogating segments aligned in parallel with the Doppler angle of incidence. More recently, strain analysis derived from two-dimensional speckle tracking has become available. This method promises to be more robust than Doppler-derived strain,

SM εl εl : Longitudinal strain εr εr : Radial strain εc

εc : Circumferential strain

EM AM

Figure 12-4 Regional values derived from the color-encoded velocities obtained from different regions of the myocardium from a patient with abnormal relaxation. AM, atrial contraction velocity; EM, early diastolic velocity; SM, systolic velocity.

Figure 12-5 Diagram indicating the direction of different myocardial strain vectors.

Velocity

Strain rate

d

V2 V1

Strain rate = (V2−V1)/d Strain

Strain rate

Systolic strain

Systolic strain rate

Diastolic strain rate

Figure 12-6 Diagram indicating the mathematical steps used to derive strain rate and strain from tissue velocities. d, distance; V, velocity.

∫ (Strain rate) δ time = strain

Diastolic strain

155

156

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis Time

AL

+

BL

AS ML

ML AL

MS BL BS

AS MS BS SRI M-mode/curved M-mode

–

Figure 12-7 Curved M-mode display of the strain rate derived from different myocardial segments. The vertical axis indicates the spatial location. The horizontal axis represents time, according to the electrocardiographic tracing above. The colors represent the magnitude of tissue deformation: Red corresponds to systolic contraction, blue corresponds to diastolic expansion, and green indicates absence of deformation. BS, basal septum; MS, midseptum; AS, apical septum; AL, apical lateral; ML, midlateral; BL, basal lateral.

Figure 12-8 Diagram indicating the vectors of apical counterclockwise and basal clockwise twist. Torsion is the sum of both components. (From Notomi Y et al. Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol 2005;45:2034–2041.)

and may provide strain analysis in multiple directions, from virtually any echocardiographic image.

LEFT VENTRICULAR TORSION In addition to radial and longitudinal deformation, there is torsional deformation of the left ventricle during the cardiac cycle due to the helical orientation of the myocardial ﬁbers.8–15 During systole, the basal segments of the LV myocardium rotate or twist in counterclockwise direction, whereas the apical segments twist in clockwise direction. During diastole, untwisting occurs in the opposite direction. Systolic torsion represents the net eﬀect of basal and apical twist. Apical twisting is the main component of global LV systolic torsion, and in the next diastole, the apical untwisting also plays the dominant role, whereas basal rotation is of less importance. Torsional deformation may be quantiﬁed by MRI or by either TDE velocities or high-frame-rate twodimensional echocardiography with speckle tracking (Fig. 12-8). Systolic LV torsion tends to equalize sarcomere shortening between endocardial and epicardial layers of the left ventricle and is a possible mechanism by which potential energy can be stored during ejection and then released during early diastole to generate suction and rapid ﬁlling by “elastic recoil.” LV untwisting has been shown to be dissociated from ﬁlling and accentuated by catecholamines, with the untwisting rate related to LV pressure decay. The magnitude of the restoring force appears to be inversely related to end systolic volume.16,17 Epicardial contraction dominates the direction of torsion because these ﬁbers are at larger radii and therefore produce greater torque than

do those in the inner layers. The process can be viewed as a global LV spring between the epicardium and endocardium that is stretched during systole, storing potential energy for release in early diastole. Accordingly, LV myocardial contraction and relaxation are tightly interconnected: The potential energy stored during systole is converted to kinetic energy during diastole, thus eﬀectively bridging the two periods. Peak LV untwisting velocity occurs approximately 60 msec earlier than long-axis lengthening and short-axis expansion18 and may be accentuated by catecholamine infusion. Left ventrical untwisting is 40% to 50% completed by the time of mitral valve opening and continues during early LV ﬁlling.14

CLINICAL APPLICATIONS Doppler myocardial velocities and, to a lesser extent, strain analysis have been used to evaluate myocardial relaxation in a variety of cardiac diseases associated with LV diastolic dysfunction. In addition, TDE combined with LV ﬁlling Doppler indices has been used to evaluate LV ﬁlling pressures.

Assessment of Left Ventricular Relaxation Several studies have shown an inverse relationship between EM and LV relaxation (τ)19,20 in patients with both normal and elevated preload. Tissue Doppler EM has been shown to be less inﬂuenced by preload alterations than standard Doppler LV ﬁlling indices, particularly in the presence of slow ventricular relaxation.21 Clinical studies suggest that EM is a better discrimi-

Evaluation of Left Ventricular Filling Pressures Several investigators have studied the utility of Doppler ECG for the assessment of LV ﬁlling pressures.24–27 Previous studies have demonstrated a relationship between mean LA pressure and pulmonary venous systolic (S)/diastolic (D) ratio, mitral E/A ratio, isovolumic relaxation time (IVRT), and deceleration time (DT). All pulsed Doppler–based methods are accurate when applied to groups of patients with homogeneously impaired LV relaxation since they assume that reduction in IVRT, atrial ﬁlling fraction, pulmonary venous S/D ratio, and DT will occur solely as a consequence of elevated LA pressure. However, when these methods are applied to younger patients and those with minimal structural heart disease with a normal ejection fraction (EF), they overestimate actual LV ﬁlling pressure since they cannot separate the eﬀect of LV relaxation and preload as confounding variables. TDE velocities used as an index of LV relaxation may be combined with standard Doppler ﬂow indices in order to separate these confounding eﬀects. Since pulsed Doppler E velocity is determined equally by both LA pressure and LV relaxation, whereas TDE EM is related primarily to LV relaxation, the ratio of E/EM may be used to predict LA pressure. This concept has been developed and validated in relatively heterogeneous groups of patients undergoing right heart catheterization.28 In subjects with normal LV relaxation and normal LA pressure, both E and EM are elevated. In subjects with impaired relaxation and normal LA pressure, both E and EM are decreased. In patients with impaired relaxation and elevated LA pressure, E is elevated but EM is reduced. An E/EM ratio greater than 15 is almost invariably associated with a mean LA pressure greater than 15 mmHg. The combined E/EM ratio also appears to be an important independent predictor of exercise capacity. In 121 subjects who were studied with Doppler echocardiography before maximal exercise testing, exercise capacity was similar in the population with a normal mitral inﬂow pattern (E/A >1) and those with a slow relaxation pattern (E/A <1) only when E/Ea was less than 10 (Fig. 12-9).29 However, those subjects with slow relaxation and E/Ea less than 10 had reduced exercise tolerance. Compared with other echocardiographic and clinical parameters, E/Ea had the best correlation with exercise capacity (r = 0.684, p < 0.001) and was the strongest independent predictor of exercise capacity less than 7 metabolic equivalents (METs) by multivariate analysis.

20

p < 0.001

n = 85

15 n = 36

10 5 0

≥ 10

< 10 E/EM

A Exercise performance (METs)

nator between diastolic dysfunction and normal patients, compared with any other single or combined index of transmitral ﬁlling and pulmonary venous Doppler ﬂows.22 LV torsion and untwisting also correlate well with the relaxation time constant15 and with the early LV diastolic intraventricular pressure gradient (IVPG) (that is, LV suction). Delayed LV untwisting has been reported in patients with severe aortic stenosis and impaired LV relaxation.13 Enhanced LV torsion during exercise is associated with increased IVPG.18 We have recently demonstrated that the ability to increase IVPG during exercise is directly related to aerobic capacity in normals and in heart failure patients.23

Exercise performance (METs)

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

20

n = 44

p < 0.001 n = 40*

15 n = 19†

10

n = 18

5 0 Normal

Slow relaxation *E/EM < 10

†E/E ≥ M

Pseudonormal/ restrictive 10

B Figure 12-9 A, Exercise capacity in patients with normal or increased E/EM (<10 vs. ≥10). Exercise capacity was greater by a mean of 5.0 METs in patients with E/EM ≥10. B, Exercise capacity in patients categorized by their mitral inflow pattern. Patients in slow relaxation group were subdivided into those with normal and increased E/Ea. Box plot shows median (center line), first and third quartiles (top and bottom of box), and lowest and highest values (vertical lines) of exercise performance. (Modified from Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004;109:972–977.)

to a pattern of impaired LV relaxation. Doppler LV ﬁlling patterns will vary according to the extent, duration, and severity of ischemia. These patterns have been shown to carry important prognostic information after an acute myocardial infarction30 and in chronic ischemic heart disease.24 TDE myocardial velocities and strain indices may identify myocardial ischemia and viability during pharmacologic stress testing (Fig. 12-10).31 Strain rate imaging may be used to identify not only the magnitude but also the time of peak systolic myocardial contraction. Postsystolic shortening is a sensitive marker of ischemia. In pigs subjected to acute myocardial ischemia during angioplasty balloon inﬂation, there is a strong direct correlation between the spatial distributions of postsystolic shortening measured by strain rate imaging and myocardium at risk.32 In patients with ischemic cardiomyopathy, an increase of peak systolic strain rate from rest to dobutamine stimulation by more than −0.23 s−1 allowed accurate discrimination of viable from nonviable myocardial segments, as determined by 18-ﬂuorodeoxyglucose positron emission tomography with a sensitivity of 83% and a speciﬁcity of 84%. In this study, strain imaging was superior to TDE and two-dimensional wall thickening subjective assessment.

Dilated Cardiomyopathies Ischemic Heart Disease Ischemia aﬀects relaxation by limiting the availability of energy substrates in the form of adenosine triphosphate (ATP). The reabsorption of Ca++ ions by the sarcoplasmic reticulum is an energy-dependent process, which is required for the deactivation of the troponin-tropomyosin complex. In the presence of normal systolic function at baseline, ischemia is manifested by a change

In many patients with dilated cardiomyopathies, conduction abnormalities result in the late activation and contraction of the LV lateral wall. This ventricular dyssynchrony and associated mechanical abnormalities result in an ineﬃcient global contraction that in turn results in reduced stroke volume.33 Cardiac resynchronization therapy (CRT), via biventricular pacing, can restore electrical and mechanical synchrony. Clinical studies have

157

158

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

Figure 12-10 Regional strain derived from speckle tracking in a patient with a lateral wall infarct. Notice the dyskinetic (+) systolic strain in the basal lateral wall.

shown that CRT may reduce symptoms, increase exercise capacity, reduce hospitalizations for heart failure, induce ventricular reverse remodeling, and improve survival in symptomatic heart failure patients.34–37 However, a signiﬁcant proportion of eligible patients do not respond, some may experience increased event rates after CRT,38 and it appears that a signiﬁcant number of patients who have a wide QRS do not have signiﬁcant mechanical dyssynchrony. The mechanical delay or dyssynchrony is not always evident by visual assessment of regional wall motion. TDE may be used to determine mechanical dyssynchrony in heart failure patients who are being evaluated for CRT. An intraventricular delay of greater than 65 msec measured by TDE before CRT identiﬁes patients who experience superior outcomes, including improved 6-minute walk time and greater reduction in LV end systolic volume. Changes in LV end systolic volume after CRT are strong predictors of long-term survival and heart failure events in these patients.39

Restrictive Cardiomyopathies The restrictive cardiomyopathies are a group of primary and secondary myocardial diseases characterized by small LV cavity size, abnormal LV relaxation, and increased LV stiﬀness. Commonly, in restrictive cardiomyopathies, LV wall thickness is normal or increased due to inﬁltration or ﬁbrosis. Systolic function is abnormal only in advanced stages of disease. Pulsed Doppler LV ﬁlling patterns vary according to the severity of the disease. Initially, a pattern of delayed relaxation is seen, progressing to pseudonormal and ﬁnally to restrictive ﬁlling patterns in advanced disease. Therefore, early diagnosis by conventional echocardiography is often diﬃcult. Tissue Doppler early diastolic myocardial velocity (EM) is abnormally reduced in patients with restrictive cardiomyopathies.5 A recent study also demonstrated reduced myocardial systolic strain in patients with amyloidosis, even before the development of congestive heart failure symptoms.40

Constrictive Pericarditis Diastolic dysfunction in constrictive pericarditis results from increased pericardial constraint on the LV that is related to the

thickness and rigidity of the pericardium. Patients present with signs and symptoms of right-sided heart failure, which are similar to those found in restrictive cardiomyopathy.41 Two-dimensional echocardiogrpahy does not always demonstrate increased pericardial thickness and the typical interventricular septal bounce. Right ventricular (RV) and LV Doppler ﬁlling patterns may demonstrate respiratory variability. However, these ﬁndings are not always present and are not speciﬁc. Acute respiratory illnesses can increase intrathoracic pressure swings, increasing also respiratory ﬂow variability. Excessive preload may attenuate the eﬀect of intrathoracic pressure swings and decrease respiratory variability, whereas low preload can decrease the constraining eﬀect of the pericardium, also masking the characteristic Doppler signs of constriction. Tissue Doppler myocardial velocities are useful in diﬀerentiating restrictive cardiomyopathy from constrictive pericarditis. In restrictive cardiomyopathy patients, both relaxation and stiﬀness are abnormal. On the other hand, relaxation is preserved in pure constrictive pericarditis, in the absence of other myocardial disease. Patients with constrictive pericarditis and normal systolic function have normal or elevated EM velocities (>8 cm/sec), probably reﬂecting their preserved ventricular relaxation.5 In a study that included 30 consecutive patients with suspected pericardial constriction versus restrictive myocardial disease, an EM greater than 8.0 cm/sec diﬀerentiated patients with constriction from restriction with 89% sensitivity and 100% speciﬁcity (Fig. 12-11).42

Hypertrophy Cardiomyopathies The most common form of hypertrophic cardiomyopathy is characterized by prominent increase in global or segmental LV wall thickness and histologically by myocardial ﬁber disarray.43 Diastolic function is characterized by increased LV chamber stiﬀness and decreased relaxation of variable severity due to the asynchronous deactivation of the muscle ﬁbers.44,45 Patients with hypertrophic cardiomyopathies can have symptoms even in the absence of systolic obstruction of the LV outﬂow tract (LVOT), although recent studies suggest that relief of the LVOT gradient after alcohol embolization may be accompanied by an improvement in LV relaxation.46,47 Pulsed Doppler LV ﬁlling usually shows

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

30

Peak EM (cm/sec)

25 20 15 10

Y = 8.0 cm/sec

These abnormalities can often be found in asymptomatic carriers of genetic mutations, even in the absence of phenotypic expression (Fig. 12-13).50 In hypertrophic cardiomyopathy patients with β-myosin heavy chain (β-MHC) mutation, genotype (+) individuals with LVH and genotype (+) individuals without LVH have lower EM than gender- and age-matched controls. Similar ﬁndings have been reported in Fabry’s disease, a cardiomyopathy secondary to α-galactosidase A deﬁciency. Mutation-positive Fabry’s patients have signiﬁcant reduction of EM and higher E/EM compared with normal control subjects, even before the development of LVH.51 TDE has been used to study myocardial performance in patients with Friedreich’s ataxia, a 25

Averaged EM velocity (cm/sec)

impaired relaxation or pseudonormal patterns and rarely restrictive patterns because of the markedly increased wall thickness and impaired relaxation. Two-dimensional echocardiography can establish the diagnosis in patients with either asymmetric hypertrophy or LVOT obstruction. However, many patients with hypertrophic cardiomyopathies have concentric hypertrophy without obstruction, which is indistinguishable from the physiologic hypertrophy seen in endurance athletes or in patients with hypertensive heart disease. TDE velocities may help to diﬀerentiate myocardial hypertrophy seen in athletes from hypertrophic cardiomyopathy, where these velocities are abnormally decreased.48 Tissue Doppler can also identify abnormal regional strain, predominantly in areas of localized hypertrophy (Fig. 12-12).49 In fact, it appears that the greater the extent of segmental wall thickness, the greater the reduction in myocardial strain.

20 *†

15

*

10

5 0 CP RCM Figure 12-11 Peak early longitudinal axial velocities (EM) in patients with constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). A value of greater than 8.0 cm/sec differentiated patients with constrictive pericarditis with 89% sensitivity and 100% specificity. (Modified from Rajogopalan N et al: Comparison of new Doppler echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiology 2001;87:86–94.)

Figure 12-12 Regional strain obtained at the septum from a patient with hypertrophic cardiomyopathy. The thicker midseptal segment (blue line) is dyskinetic (+ strain in systole). (Modified from Yang H et al: Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2003;16:233–239.)

5 G+/LVH– Controls G+/LVH+ Figure 12-13 Averaged EM velocity in two hypertrophic cardiomyopathy subgroups and normal control subjects. Mean values (䊉) and SD (vertical line) are indicated. *p < 0.0001 compared with control subjects; †p < 0.0001 compared with β-myosin gene (+) and left ventricular hypertrophy group (G+/LVH+). (Modified from Ho CY et al: Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–2997.)

159

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis neurodegenerative disorder associated with cardiomyopathy and impaired glucose tolerance (Fig. 12-14). The genetic basis for this inherited disease is a glucosidase acid alpha (GAA) trinucleotide repeat expansion in the ﬁrst intron of gene X25, which encodes a 210–amino acid protein, frataxin. It appears that the GAA expansion leads to reduced levels of frataxin, resulting in abnormalities of mitochondrial iron transport and antioxidant systems. Asymptomatic patients who are homozygous for the GAA expansion in the Friedreich’s ataxia gene have reduced MVGs during systole and in early diastole.52 There appears to be a strong relationship between age-corrected early diastolic MVG and the GAA expansion in the smaller allele of the Friedreich’s ataxia gene, suggesting that TDE-derived MVGs may be used to determine the extent of genotypic expression.

Transplant Rejection Heart transplant patients often receive serial echocardiography in an eﬀort to detect abnormalities related to organ rejection. It has been proposed that serial echocardiographic studies may help in reducing the frequency of surveillance biopsies. Transplant rejection is associated with lymphocytic inﬁltration and edema, resulting in increased myocardial stiﬀness and abnormal relaxation. Diastolic myocardial velocities measured by TDE may be reduced in heart transplant patients with rejection and may return to normal after successful treatment.53,54 One caution that has to be taken, however, when interpreting these results is that factors other than rejection may aﬀect LV relaxation and EM in these patients, such as the age of the donor heart and the time after transplantation. Thus lower velocities may not imply rejection if the organ belonged to an older donor or if these velocities are obtained several years following transplantation. One way to circumvent this problem would be to compare the results of serial studies obtained in the same patient. In most circumstances, however, the diagnosis of rejection requires the integration of clinical data in addition to the detection of several echocardiographic markers, such as pericardial eﬀusions, increased wall thickness, and diastolic abnormalities.55

Diabetes and Myocardial Disease Glycemic control in diabetic patients has been associated with microvascular complications. Microvascular disease may lead to ischemia and subsequent impaired LV relaxation and increased myocardial stiﬀness. Advanced glycation end-products (AGEs) have been associated with microvascular complications of type 1 diabetes mellitus and may be a pathophysiologic mechanism for diastolic dysfunction in these patients. Advanced glycation end-products may lead to early reversible glycation products, followed by irreversible Amadori products and subsequent diabetic cardiomyopathy. We performed echocardiographic studies on 25 patients with type 1 diabetes without clinical evidence of heart disease.56 Compared with 26 nondiabetic controls, type 1 diabetic subjects had worse diastolic function with lower tissue Doppler EM. Furthermore, glycosylated hemoglobin (HgbA1C) was correlated with E/EM (r = 0.68, p = 0.0002). These results demonstrate that asymptomatic diastolic dysfunction is common in patients with type 1 diabetes mellitus and that its severity is correlated with glycemic control. Furthermore, our data suggest that asymptomatic diabetic patients have increased LV ﬁlling pressure as measured by E/EM, and a larger LA size.

Tissue Doppler Parameters and Prognosis A reduced EM has been associated with reduced survival in patients with cardiac disease. In a study that followed for 2 years 165 normals and 353 patients with hypertension, ischemic heart disease, valvular heart disease, heart failure, diabetes, and obstructive sleep apnea, a reduced EM was independently predictive of cardiac death (Fig. 12-15).57 In another recent study, which followed 225 patients with symptomatic systolic heart failure, E/EM was associated with an increased risk of death or transplant (p < 0.05) (Fig. 12-16).58 Those patients with an E/EM ratio 1.0

.9 Cum survival

15 MVG in early diastole (s–1), age corrected

160

r = –0.68 p < 0.001 10

.8 5 Em > 5 cm/sec 3 < Em ≤ 5 cm/sec Em ≤ 3 cm/sec

0 0

250

500

750

1000

1250

GAA repeats on smaller frataxin allele Figure 12-14 Relationship between size of GAA expansion in smaller allele of Friedreich’s ataxia gene and myocardial velocity gradients in early diastole, corrected for age. (Modified from Dutka JP et al: Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation 2000;102:1276–1282.)

.7 0

10

20

30

40

Follow time (months) Figure 12-15 Cumulative cardiac death by tertiles of EM in patients with cardiac disease. (Modified from Wang M et al: Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820–826.)

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis

E/Vp < 2.7 0.9 0.8 E/Vp > 2.7

0.7 P < 0.01 0.6 0

greater than 17 had a mortality of approximately 40% at 36 months compared with 5% in those with an E/EM ratio of less than 17 (p < 0.001). In a study that included 250 nonselected patients who had had an echocardiogram 1.6 days after a myocardial infarction followed up for a median of 13 months, the most powerful predictor of survival was an E/EM ratio of greater than 15.59 In this study, E/EM was a stronger predictor than other Doppler echocardiographic indices, including the LV ﬁlling pulsed Doppler DT.

FUTURE RESEARCH The introduction of tissue Doppler techniques has led to signiﬁcant advance in our understanding of cardiac physiology. However, more studies are needed to help understand the relationship between TDE indices and myocardial morphology and cellular function. In addition, it will be important to better deﬁne how these indices are related to exercise performance. We foresee that TDE will become a valuable tool for the evaluation of novel therapeutic interventions. REFERENCES 1. Klein AL, Hatle LK, Burstow DJ, et al: Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1989;13:1017–1026. 2. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 3. Redﬁeld MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 4. Miyatake K, Yamagishi M, Tanaka N, et al: New method for evaluating left ventricular wall motion by color-coded tissue Doppler imaging: In vitro and in vivo studies. J Am Coll Cardiol 1995;25:717–724. 5. Garcia MJ, Rodriguez L, Ares MA, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in the longitudinal axis by tissue Doppler imaging. J Am Coll Cardiol 1996;27:108–114. 6. Greenberg NL, Firstenberg MS, Castro PL, et al: Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility. Circulation 2002;105:99–105. 7. Weidemann F, Jamal F, Sutherland GR, et al: Myocardial function deﬁned by strain rate and strain during alterations in inotropic states and heart rate. Am J Physiol 2002;283:H792–H799. 8. Streeter DD Jr, Spotnitz HM, Patel DP, et al: Fiber orientation in the canine left ventricle during diastole and systole. Circ Res 1969;24:339–347. 9. Arts T, Reneman RS: Dynamics of left ventricular wall and mitral valve mechanics—a model study. J Biomech 1989;22:261–271. 10. Beyar R, Yin FC, Hausknecht M, et al: Dependence of left ventricular twistradial shortening relations on cardiac cycle phase. Am J Physiol 1989;257: H1119–H1126.

12

24 Months

36

Death or heart transplant

Figure 12-16 Cumulative survival by the ratio of LV filling pulsed Doppler E to color M-mode propagation velocity (VP) and E to EM. (Modified from Troughton RW et al: Usefulness of tissue Doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT study). Am J Cardiol 2005;96:257–262.)

Death or heart transplant

1

161

1 E/EM < 17 0.9 0.8 E/EM > 17 0.7 P < 0.001 0.6 0

12

24

36

Months

11. Ingels NB Jr, Hansen DE, Daughters GT 2nd, et al: Relation between longitudinal, circumferential, and oblique shortening and torsional deformation in the left ventricle of the transplanted human heart. Circ Res 1989;64:915–927. 12. Rademakers FE, Buchalter MB, Rogers WJ, et al: Dissociation between left ventricular untwisting and ﬁlling. Accentuation by catecholamines. Circulation 1992;85:1572–1581. 13. Stuber M, Scheidegger MB, Fischer SE, et al: Alterations in the local myocardial motion pattern in patients suﬀering from pressure overload due to aortic stenosis. Circulation 1999;100:361–368. 14. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 2000;87:235–240. 15. Dong SJ, Hees PS, Siu CO, et al: MRI assessment of LV relaxation by untwisting rate: A new isovolumic phase measure of tau. Am J Physiol Heart Circ Physiol 2001;281:H2002–H2009. 16. Nikolic S, Yellin EL, Tamura K, et al: Passive properties of canine left ventricle: Diastolic stiﬀness and restoring forces. Circ Res 1988;62:1210–1222. 17. Yellin EL, Hori M, Yoran C, et al: Left ventricular relaxation in the ﬁlling and nonﬁlling intact canine heart. Am J Physiol 1986;250:H620–629. 18. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524– 2533. 19. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by tissue Doppler imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 20. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed tissue Doppler imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921–928. 21. Firstenberg MS, Greenberg NL, Main ML, et al. Determinants of diastolic myocardial tissue Doppler velocities: Inﬂuences of relaxation and preload. J Appl Physiol 2001;90:299–307. 22. Farias CA, Rodriguez L, Garcia MJ, et al: Assessment of diastolic function by tissue Doppler echocardiography: Comparison with standard transmitral and pulmonary venous ﬂow. J Am Soc Echocardiogr 1999;12:609–617. 23. Rovner A, Greenberg NL, Thomas JD, et al: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005;289:H2081– H2088. 24. Vanoverschelde JL, Raphael DA, Robert AR, et al: Left ventricular ﬁlling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 25. Stork TV, Muller RM, Piske GJ, et al: Noninvasive measurement of left ventricular ﬁlling pressures by means of transmitral pulsed Doppler ultrasound. Am J Cardiol 1989;64:655–660. 26. Mulvagh S, Quinones, MA, Kleiman NS, et al: Estimation of left ventricular end-diastolic pressure from Doppler transmitral ﬂow velocity in cardiac patients independent of systolic performance. J Am Coll Cardiol 1992;20:112–119. 27. Vanoverschelde JL, Robert AR, Gerbaux A, et al: Noninvasive estimation of pulmonary arterial wedge pressure with Doppler transmitral ﬂow velocity pattern in patients with known heart disease. Am J Cardiol 1995;75:383–389. 28. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527–1533. 29. Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004;109:972–977.

162

Chapter 12 • Evaluation of Diastolic Function by Tissue Doppler, Strain, and Torsion Analysis 30. Oh JK, Ding ZP, Gersh BJ, et al: Restrictive left ventricular diastolic ﬁlling identiﬁes patients with heart failure after acute myocardial infarction. J Am Soc Echocardiogr 1992;5:497–503. 31. Hoﬀmann R, Altiok E, Nowak B, et al: Strain rate measurement by Doppler echocardiography allows improved assessment of myocardial viability in patients with depressed left ventricular function. J Am Coll Cardiol 2002;39:3:443–449. 32. Pislaru C, Belohlavek M, Bae RY, et al: Regional asynchrony during acute myocardial ischemia quantiﬁed by ultrasound strain rate imaging. J Am Coll Cardiol 2001;37:1141–1148. 33. Prinzen FW, Augustijn CH, Arts T, et al: Redistribution of myocardial ﬁber strain and blood ﬂow by asynchronous activation. Am J Physiol 1990;259: H300–H308. 34. Cazeau S, Ritter P, Lazarus A, et al: Multisite pacing for end-stage heart failure: Early experience. Pacing Clin Electrophysiol 1996;19:1748–1757. 35. Cazeau S, Leclercq C, Lavergne T, et al: Eﬀects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873–880. 36. Abraham WT, Fisher WG, Smith AL, et al: Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 37. Cleland JG, Daubert JC, Erdmann E, et al: The eﬀect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549. 38. Bax JJ, Bleeker GB, Marwick TH, et al: Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:1834–1840. 39. Yu CM, Bleeker GB, Fung JW, et al: Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580–1586. 40. Koyama J, Ray-Sequin PA, Falk RH: Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 2003;107:2446–2452. 41. Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 1994;23:154– 162. 42. Rajogopalan N, Garcia MJ, Rodriguez L, et al: Comparison of new Doppler echocardiographic methods to diﬀerentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiology 2001;87: 86–94. 43. Wigle ED: Diastolic dysfunction in hypertrophic cardiomyopathy. In Gaasch WH, Lewinter MM (eds): Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, Lea and Febiger, 1994:373–389. 44. Brutsaert DL, Rademakers FE, Sys SU: Triple control of relaxation: Implications in cardiac disease. Circulation 1984;69:190–196. 45. Brutsaert DL, Sys SU, Gillebert TC: Diastolic failure: Pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318–325.

46. Nagueh SF, Lakkis NM, Middleton KJ, et al: Changes in left ventricular diastolic function 6 months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 1999;99:344– 347. 47. Rovner A, Smith R, Greenberg NL, et al: Improvement in diastolic intraventricular pressure gradients in patients with HOCM after ethanol septal reduction. Am J Physiol 2003;285: H2492–H2499. 48. Palka P, Lange A, Fleming AD et al: Diﬀerences in myocardial velocity gradient measured throughout the cardiac cycle in patient with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760–768. 49. Yang H, Sun JP, Lever HM, et al: Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiog 2003;16:233–239. 50. Ho CY, Sweitzer NK, McDonough B, et al: Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–2997. 51. Pieroni M, Chimenti C, Ricci R, et al: Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation 2003;107:1978– 1984. 52. Dutka JP, Donnelly JE, Palka P, et al: Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation 2000;102: 1276–1282. 53. Mankad S, Murali S, Mandarino WA, et al: Assessment of acute cardiac allograft rejection by quantitative tissue Doppler echocardiography. Circulation 1997;96:I–342. 54. Puleo JA, Aranda JM, Weston MW, et al: Noninvasive detection of allograft rejection in heart transplant recipients by use of Doppler tissue imaging. J Heart Lung Transplant 1998;17:176–184. 55. Sun JP, Abdalla IA, Asher CR, et al: Non-invasive evaluation of orthotopic heart transplant rejection of echocardiography. J Heart Lung Transplant 2005;24:160–165. 56. Shishehbor MH, Hogwerf BJ, Schoenhagen P, et al: Relation of hemoglobin A1C to left ventricular relaxation in patients with type 1 diabetes mellitus and without overt heart disease. Am J Cardiol 2003;91:1514– 1517. 57. Wang M, Yip GWK, Wang AYM, et al: Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820–826. 58. Troughton RW, Prior DL, Frampton CM, et al: Usefulness of tissue Doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT study). Am J Cardiol 2005;96:257–262. 59. Hillis GS, Moller JE, Pellikka PA, et al: Noninvasive estimation of left ventricular ﬁlling pressure by E/e’ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360–367.

13

SATOSHI NAKATANI, MD, PhD

Assessment of Left Atrial Size and Function INTRODUCTION PATHOPHYSIOLOGY Quantification of Left Atrial Size Assessment of Left Atrial Function

diseases. For example, increased LA size is associated with atrial ﬁbrillation, stroke, and adverse cardiovascular outcomes.5,8,9–15 LA size has also been known to correlate with overall mortality after myocardial infarction16,17 and risk of death and hospitalization in patients with dilated cardiomyopathy.18–21

CLINICAL RELEVANCE Diastolic Dysfunction and Left Atrial Size FUTURE RESEARCH

PATHOPHYSIOLOGY Quantification of Left Atrial Size Measurement of Left Atrial Diameter

INTRODUCTION The left atrium is an oval chamber with thin, muscular walls, located between the aorta and the esophagus. Because of this location, it is easily recognized not only by transthoracic but also by transesophageal echocardiography. The left atrium collects blood from the pulmonary veins and ejects it into the left ventricle. The left atrial (LA) chamber changes its size during a cardiac cycle, being largest at ventricular systole and smallest at atrial systole. This phasic change involves mainly the anteroposterior and supero-inferior diameters, while the mediolateral diameter does not change signiﬁcantly. The left atrium has three functions in a cardiac phase (see Chapter 4). During ventricular systole, the left atrium functions as a reservoir that collects pulmonary venous ﬂow; and during early diastole, following passive atrial emptying, it functions as a conduit allowing the passage of stored blood from the left atrium to the left ventricle. During atrial contraction, the left atrium acts as a contractile pump that delivers as much as one-third of the left ventricular (LV) ﬁlling.1 This atrial contraction makes a signiﬁcant contribution to maintaining cardiac output, especially in patients with LV dysfunction.2–4 Because the left atrium is connected to the left ventricle, enlargement of LA size suggests the presence of elevated ﬁlling pressure and diastolic dysfunction.5–7 Thus, LA size has been noted to be a good prognosticator in various cardiovascular

LA size is usually measured at end systole, when the left atrium is most dilated. Traditionally, it is measured at the parasternal long-axis view using M-mode or B-mode echocardiography (Fig. 13-1). When the M-mode technique is used, the cursor should pass through the aortic valve. The largest anteroposterior diameter is measured from the trailing edge of the posterior aortic wall to the leading edge of the posterior LA wall. Although the convention for M-mode is to measure from the leading edge to the leading edge, the trailing edge of the posterior aortic root is recommended by the American Society of Echocardiography, to avoid the variable extent of space between the left atrium and the aortic root.22 When the M-mode cursor is not perpendicular to the posterior aortic wall or the posterior LA wall, measurement based on B-mode echocardiography should be done.

Measurement of Left Atrial Area by Echocardiography The left atrium can be observed at multiple views besides the parasternal long axis. It can also be observed at apical two- and four-chamber views and a parasternal short-axis view, and a diameter can be measured at each. Anteroposterior and supero-inferior diameters can be measured at the parasternal long-axis view. Anteroposterior and mediolateral diameters can be measured at the parasternal short-axis view, and supero-inferior and mediolateral diameters can be measured at the four-chamber view (Fig. 13-2). The normal values for each diameter are shown in Table 13-1.23 163

164

Chapter 13 • Assessment of Left Atrial Size and Function

Measurement of Left Atrial Volume by Echocardiography Linear measurements have been reported to correlate with the angiographically determined LA size.24,25 However, the left atrium has an oval shape that changes asymmetrically according to disease state and loading conditions. Therefore, it is not always the case that the anteroposterior diameter represents LA size.26,27 For example, patients with mitral stenosis have an enlarged anteroposterior diameter, but patients with mitral regurgitation due to mitral valve prolapse often have an enlarged supero-inferior diameter. Thus, the measurement of LA anteroposterior diameter may be misleading, and LA volume, instead of diameter, should be determined in both clinical practice and research. LA volume can be calculated using either an ellipsoid method or Simpson’s method.5,8,15,16,24–26,28–30 In the ellipsoid method, the left atrium is assumed to be represented as a prolate ellipse, and the volume can be calculated by Volume = 4π/3 (L/2) (D1/2) (D2/2), where L is the LA long-axis diameter at the four-chamber view, and D1 and D2 are anteroposterior and mediolateral diameters

obtained at the parasternal long- and short-axis views, respectively.30–32 The method based on diameter measurements is dependent on selection of the location and direction of the minoraxis diameters and has been shown to signiﬁcantly underestimate LA volume.30 Alternatively, volume can be calculated using the biplane ellipsoid area-length method: Volume = 8 (A1) (A2)/3π (L), where A1 and A2 represent the maximal LA area acquired from the apical four- and two-chamber views, respectively. L is the shortest LA long-axis diameter, determined as the distance of the perpendicular line connecting the mitral annular plane and the superior aspect of the left atrium at either the four-chamber or the two-chamber view. The ellipsoid method assumes that the atrium can be represented by an ellipsoid. However, this assumption often fails when the atrium is deformed by external compression or ventricular distortion. On such occasions, Simpson’s method is more appropriate. Simpson’s method states that the volume of a large ﬁgure can be calculated from the sum of the volumes of a series of smaller ﬁgures of similar shape. Thus, the LA volume can be obtained as the sum of the volumes of a series of smaller elliptic cylinders of known height (h): Volume = π/4 (h) Σ (D1) (D2),

TABLE 13-1 NORMAL VALUES FOR LEFT ATRIAL DIAMETER MEAN ± SD (cm)

RANGE (cm)

Parasternal long-axis view Anteroposterior diameter Supero-inferior diameter

3.0 ± 0.3 4.8 ± 0.8

2.3–3.8 3.1–6.8

Parasternal short-axis view Anteroposterior diameter Mediolateral diameter

2.9 ± 0.4 4.2 ± 0.6

2.2–4.1 3.1–6.0

Apical 4-chamber view Supero-inferior diameter Mediolateral diameter

4.1 ± 0.6 3.8 ± 0.4

2.9–5.3 2.9–4.9

0

Left atrial diameter

40 Figure 13-1 Measurement echocardiography.

of

left

atrial

diameter

by

M-mode

D1

From Weyman AE: Normal cross-sectional echocardiographic measurements. In Weyman AE (ed): Principles and Practice of Echocardiography, 2nd ed. Philadelphia, Lea & Febiger, 1994:1289–1298.

D1 D3

D3

D2

D2

A

B

C

Figure 13-2 Left atrial diameter measures. A, In the parasternal long-axis view; B, in the parasternal short-axis view; and C, in the apical four-chamber view. D1, anteroposterior diameter; D2, mediolateral diameter; D3, supero-inferior diameter.

Chapter 13 • Assessment of Left Atrial Size and Function where D1 and D2 are orthogonal minor and major axes of each cylinder (Fig. 13-3). For these calculations, the planimetered LA areas at the orthogonal views, such as apical four-chamber and two-chamber, are required. The pulmonary veins and the LA appendage should be excluded, and the inferior border should be represented by the mitral annular plane when the LA border is traced. Normal LA volume determined by echocardiography in a number of studies is 22 ± 6 ml/m2.5,32–34 Table 13-2 shows reference limits and partition values for LA measurements obtained from a Framingham Heart Study cohort.22 Because the entire left atrium cannot always ﬁt into the image sector when using the transesophageal approach, measurements of LA volume cannot be reliably performed. However, LA diameter can be estimated combining measurements from diﬀerent imaging planes.

Measurement of Left Atrial Volume by Other Methods LA volume has been determined by computed tomography, biplane contrast ventriculography, and magnetic resonance imaging.24,28,29,35,36 LA volume determined by echocardiography has been shown to correlate well with or to underestimate measurements by these methods.24,28,29,36 In a dog model, LA volume can be estimated accurately with two pairs of sonomicrometers sewn into the anteroposterior and mediolateral walls of the left atrium.37

Assessment of Left Atrial Function The left atrium has several physiologic functions. During LV systole, the left atrium collects and stores blood (a reservoir func-

TABLE 13-2 REFERENCE LIMITS AND PARTITION VALUES FOR LEFT ATRIAL DIMENSION AND VOLUME WOMEN

LA diameter, cm LA diameter/BSA, cm/m2 LA area LA volume, mL LA volume/BSA, ml/m2

MEN

REFERENCE RANGE

MILDLY ABNORMAL

MODERATELY ABNORMAL

SEVERELY ABNORMAL

REFERENCE RANGE

MILDLY ABNORMAL

MODERATELY ABNORMAL

SEVERELY ABNORMAL

2.7–3.8 1.5–2.3

3.9–4.2 2.4–2.6

4.3–4.6 2.7–2.9

≥4.7 ≥3.0

3.0–4.0 1.5–2.3

4.1–4.6 2.4–2.6

4.7–5.2 2.7–2.9

≥5.2 ≥3.0

≤20 22–52 22 ± 6

20–30 53–62 29–33

30–40 63–72 34–39

>40 ≥73 ≥40

≤20 18–58 22 ± 6

20–30 59–68 29–33

30–40 69–78 34–39

>40 ≥79 ≥40

LA, left atrial; BSA, body surface area. Bold italic values: Recommended and best validated. From Lang RM et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463.

A

B

Figure 13-3 Measurement of left atrial volume using modified Simpson’s method. Apical four-chamber view (left) and two-chamber view (right) are obtained at end systole to obtain maximum left atrial size.

165

Chapter 13 • Assessment of Left Atrial Size and Function tion). During LV early diastole, a part of the blood in the left atrium ﬂows into the left ventricle, helping rapid ventricular ﬁlling (passive emptying); and from rapid ﬁlling to mid-diastolic slow ﬁlling, the left atrium helps the passage of blood from the pulmonary veins to the left ventricle (a conduit function). During atrial systole, the left atrium expels blood to the left ventricle against LV diastolic pressure (a contractile function). To facilitate understanding of LA function, the instantaneous changes in LA pressure and volume during a cardiac cycle are shown in Figure 13-4. LA volume increases during LV systole due to LA active relaxation just after atrial active contraction, LV shrinkage by LV contraction, and caudal movement of the inferior aspect of the left atrium. LA pressure decreases after mitral valve closure (“c”) and makes the “x” trough. Then, receiving blood from the right heart, the left atrium is passively expanded, and both volume and pressure increase, making the “v” wave in the pressure tracing. With mitral valve opening, blood ﬂows into the left ventricle rapidly, and LA volume decreases (passive atrial emptying). During this phase, LA pressure also decreases and makes the “y” trough. During mid-diastole, blood from the pulmonary veins ﬂows into the left ventricle (a conduit function). LA volume and pressure increases only a little at this phase in the normal compliant heart. However, in the noncompliant heart, LA pressure increases rapidly. At late diastole, LA volume decreases and LA pressure increases rapidly, making the “a” wave with atrial active contraction. A part of the blood ﬂows back into the pulmonary veins. The atrial pressure-volume relationship has a “ﬁgure 8” shape (Fig. 13-5). It has an “a-loop” during atrial contraction and a “vloop” during the other phase. The ascending limb of the v-loop corresponds to the period between the “x” trough and the peak of the “v” wave and represents LA passive expansion. There have been some studies to calculate LA compliance by ﬁtting the limb to an exponential curve: P = beaV, where P is LA pressure, b is a constant, a is a chamber stiﬀness parameter, and V is LA volume.38–40 LA compliance can be determined as a reciprocal of a chamber stiﬀness parameter. It has been

reported to be 1.60 ± 0.41 ml/mmHg/m2, one-half to one-third of LV compliance.39,40 LA compliance is an important determinant of diastolic ﬁlling and atrial function. Hoit et al. showed that LA compliance was aﬀected by the presence of the LA appendage (see Chapter 4). They found that in a canine model, the diastolic pressure-volume relation of the left atrium was shifted upward and leftward after appendectomy, suggesting that the LA appendage was more distensible than the LA body. Larger compliance of the appendage may be beneﬁcial when LV ﬁlling pressure is increased and atrial distensibility is decreased.41 It has been reported that blood volume ejected by atrial contraction has a linear relationship with LA volume just before atrial contraction.42 This supports the presence of the Frank-Starling mechanism in the atrium. We have recently demonstrated a linear relationship between LA peak change in pressure by time (dP/dt) and LA pressure just before atrial contraction.43 The blood volume ejected by atrial contraction is related to LV function. It is about 20% in normal subjects but is about 35% in patients with myocardial infarction.2 Thus, LA contractile function seems to compensate the reduced LV stroke volume in LV dysfunction. However, when LV end diastolic pressure is very high, with signiﬁcant LV dysfunction, much of the blood ejected by LA contraction goes back to the pulmonary veins, leading to an ineﬃcient LA contraction.

CLINICAL RELEVANCE Diastolic Dysfunction and Left Atrial Size It has been reported that about half of patients with chronic heart failure have preserved LV ejection fraction (diastolic heart failure).44–47 Hypertension, LV hypertrophy, ischemic heart disease, aging, and other cardiovascular disease can potentially cause diastolic dysfunction. Diastolic dysfunction elevates ﬁlling pressures leading to atrial enlargement. Doppler parameters such as transmitral ﬂow and mitral annulus velocity, considered to be useful to assess diastolic function, reﬂect ﬁlling pressures at one time and would be altered if loading conditions changed. In contrast, an enlarged atrium may better reﬂect the cumulative eﬀect of elevated ﬁlling pressures over time. Thus, atrial size has been suggested as a marker of the severity and duration of diastolic 17

ECG

15 a-loop LA pressure (mmHg)

166

LAV

v

13

v-loop

11 9 7

a LVP LAP

c

y

d

x Figure 13-4 Echocardiography (ECG) shows instantaneous changes in left atrial pressure (LAP) and left atrial volume (LAV), along with left ventricular pressure (LVP) during a cardiac cycle.

5

20

30

40

50

60

LA volume (ml) Figure 13-5 Left atrial (LA) pressure-volume relationship.

70

80

Chapter 13 • Assessment of Left Atrial Size and Function

Left Atrial Size and Prognosis Since diastolic heart failure has a poor prognosis, similar to systolic heart failure, enlarged LA size may potentially indicate a worse outcome.55 Tsang et al. noted that LA volume was associated with poor outcome in a community-based elderly population.8 They found that an LA volume index of more than 32 ml/m2 was an independent predictor of cardiovascular events, including congestive heart failure, myocardial infarction, and stroke. However, it has been suggested in another study that LA volume might not be a better predictor than diastolic dysfunction grade.49 Pritchett et al. found that the LA volume index was highly sensitive and speciﬁc for the detection of severe diastolic dysfunction but was not a robust marker of mild or moderate diastolic dysfunction. In addition, they found that although diastolic function grade had prognostic importance, the LA volume index added no

incremental prognostic value beyond that provided by diastolic dysfunction grade.49 The signiﬁcance of LA enlargement in cardiovascular diseases has been demonstrated in many studies. LA enlargement has been reported to be an early sign of hypertensive heart disease.50 LA size is associated with the outcomes in patients with myocardial infarction. Møller et al. found that an LA volume index of greater than 32 ml/m2 measured a median of one day after admission was a powerful and independent predictor of mortality in patients with acute myocardial infarction.16 Moreover, LA volume of greater than 32 ml/m2 has been reported in another study to be an independent predictor of 5-year mortality in patients with acute myocardial infarction (Fig. 13-6).17 These results are well explained by the fact that LA size reﬂects chronically elevated ﬁlling pressure. A recent paper using stress echocardiography suggested that normal resting LA volume (≤28 ml/m2) predicts a normal stress echocardiogram and identiﬁes patients with low ischemic risk.58 This is an interesting observation and should be further assessed for its complementary role in stress testing.

100

90

Survival (%)

dysfunction. There is a famous analogy: Serum glucose is used to assess transient diabetic control, and hemoglobin A1C is used as a long-term biomarker of average metabolic state. Similarly, LV ﬁlling pressure is used to assess transient loading conditions, and LA size is used as a long-term biomarker of average LV diastolic pressure.48 In fact, Pritchett et al. have shown that LA volume increased with worsening of diastolic dysfunction in a general population, as shown in Table 13-3.49 They found that the grade of diastolic dysfunction was positively associated with the LA volume index. Thus, diastolic dysfunction has been considered to contribute to LA remodeling. LA size can be evaluated by diameter and volume. Which is suitable for the assessment of diastolic dysfunction? Previous investigations used mainly LA diameter as an index of the size of the left atrium.10,13,50–52 For example, Vaziri et al. demonstrated that there was a signiﬁcant association between elevated systolic pressure and increased LA diameter in the Framingham Heart Study.53 In contrast, recent studies have demonstrated that LA volume may be more suitable to reﬂect morbid conditions.26,54 Tsang et al. followed 423 patients who had a general medical consultation for subsequent development of new atrial ﬁbrillation, congestive heart failure, stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death. They found that LA volume was a more robust marker of cardiovascular events than was LA diameter or area.55 LA volume has been related to the occurrence of atrial ﬁbrillation54,56 and other cardiovascular events, such as myocardial infarction, congestive heart failure, and stroke.8 It has been shown that both body size and aging inﬂuence LA size.1,54,57 The inﬂuence of body size on LA size is typically corrected by indexing to body surface area.

167

80

70

60

LA volume index < 32 ml/m2 LA volume index ≥ 32 ml/m2

50 0

1

2

3

4

5

Time (years) Figure 13-6 Kaplan-Meier survival curves of patients with acute myocardial infarction with left atrial (LA) volume index ≥32 ml/m2 and with <32 ml/m2. They were adjusted for age, gender, Killip class ≥2, primary reperfusion, diabetes, systemic hypertension, paroxysmal atrial fibrillation, previous myocardial infarction, left ventricular ejection fraction, moderate and severe mitral regurgitation, and left ventricular filling pattern. p = 0.02. (From Beinart R et al: Long-term prognostic significance of left atrial volume in acute myocardial infarction. J Am Coll Cardiol 2004;44:327–334.)

TABLE 13-3 LEFT ATRIAL VOLUME INDEX ACCORDING TO DIASTOLIC FUNCTION GRADE DIASTOLIC GRADE

n

% OF COHORT

LEFT ATRIAL VOLUME INDEX, ml/m2

% MEETING CRITERIA FOR LEFT ATRIAL ENLARGEMENT

Normal Grade I Grade II Grade III to IV

1212 315 118 12

73 19 7 1

23 ± 6 25 ± 8 31 ± 8 48 ± 12

9 17 48 100

Left atrial enlargement, ≥30 ml/m2 in women or ≥33 ml/m2 in men. From Pritchett AM et al: Diastolic dysfunction and left atrial volume: A population-based study. J Am Coll Cardiol 2005;45:87–92.

168

Chapter 13 • Assessment of Left Atrial Size and Function S-v

S-sr

S-s

E-s

E-v E-sr A-sr

A-v

A

B

C

Figure 13-7 A, Left atrial (LA) tissue velocity; B, LA strain; C, LA strain rate. These traces were obtained with a region of interest placed in the midseptum at the four-chamber view. S-v, peak velocity in systole; E-v, peak velocity in early diastole; A-v, peak velocity in late diastole; S-s, peak strain in systole; E-s, peak strain in early diastole; S-sr, peak strain rate in systole; E-sr, peak strain rate in early diastole; A-sr, peak strain rate in late diastole.

LA volume is also helpful to determine prognosis in patients with dilated cardiomyopathy having systolic dysfunction as well as diastolic dysfunction. In the Studies Of Left Ventricular Dysfunction (SOLVD) population, a left atrium larger than 4.17 cm in diameter was closely associated with increased risk of death and cardiovascular hospitalization.18 Rossi et al. showed that determinants of LA volume in patients with dilated cardiomyopathy include LV volume, ejection fraction, the degree of mitral regurgitation, and diastolic dysfunction.19 These parameters all related to the outcome. However, compared with all of these determinants, LA volume has an independent and incremental prognostic value.

FUTURE RESEARCH Since LA size is closely linked to cardiac risk and prognosis, its evaluation, that is, LA volume indexed to body surface area, should be measured routinely in the echocardiographic laboratory. However, the measurement is still cumbersome and may be aﬀected by LA morphology. Sometimes the left atrium is compressed by a marked dilation of the aortic root or extracardiac masses, causing asymmetric atrial morphology. On these occasions, the accuracy of measurements of LA size may be questionable. Recently, real-time three-dimensional echocardiography has emerged as a tool for accurate volume measurements in clinical assessment. Further development of three-dimensional echocardiography would allow accurate and easy measurment of LA volume independent of LA shape. There are a number of articles that show that LA size reﬂects the burden and chronicity of elevated LV ﬁlling pressure and is a strong predictor of outcome. However, there are scant data that show the clinical signiﬁcance of changes in LA size. For example, how much and how sensitively does LA volume decrease after treatment of diastolic dysfunction? How soon does the left atrium shrink following the reduction of ﬁlling pressure? Does the degree of shrinkage relate to the etiology and severity of cardiovascular conditions? Further work should be done to answer these questions.59 The development of new echocardiographic techniques, such as tissue Doppler imaging and strain and strain rate imaging, enables us to quantitate LA function noninvasively (Fig. 13-7). Although tissue Doppler imaging provides accurate measure-

ments of local velocities, it is aﬀected by motion of the adjacent tissues and Doppler incident angle. Since strain and strain rate parameters are determined based on spatial diﬀerences in velocities or moving distance between two diﬀerent regions, they are independent of cardiac translational motion and the tethering eﬀect. Recently, these indexes could be obtained not only by tissue Doppler imaging but also by speckle tracking imaging, which is independent of Doppler incident angle. LA strain and strain rate can be obtained by placing a region of interest on the midsegment of the LA walls at the apical views. It has been reported that LA systolic and early diastolic strain rates are correlated with age.60 Moreover, LA peak systolic strain rate is signiﬁcantly lower in patients with atrial ﬁbrillation than in age-matched control subjects. LA late diastolic strain rate, which corresponds to atrial contraction, is also lower in patients with atrial ﬁbrillation, and this increases gradually after cardioversion.61 LA strain and strain rate have been reduced in various conditions, such as amyloidosis62 and postsurgical correction of atrial septal defect.63 They did not reduce when closure of the atrial septal defect was done with a catheter-based device, suggesting that this was a less invasive procedure to the left atrium. Strain and strain rate imaging is promising because the parameters obtained may reﬂect subtle changes in LA function that are not readily assessed with conventional echocardiography. REFERENCES 1. Spencer KT, Mor-Avi V, Gorcsan J, et al: Eﬀects of aging on left atrial reservoir, conduit, and booster pump function (a multi-institution acoustic quantiﬁcation study). Heart 2001;85:272–277. 2. Rahimtoola SH, Ehsani A, Sinno MZ, et al: Left atrial transport function in myocardial infarction: Importance of its booster pump function. Am J Med 1975;59:686–94. 3. Matsuda Y, Toma Y, Ogawa H, et al: Importance of left atrial function in patients with myocardial infarction. Circulation 1983;67:566–571. 4. Ruskin J, McHale PA, Harley A, et al: Pressure-ﬂow studies in man: Eﬀect of atrial systole on left ventricular function. J Clin Invest 1970;49:472– 478. 5. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284– 1289. 6. Simek CL, Feldman MD, Haber HL, et al: Relationship between left ventricular wall thickness and left atrial size (comparison with other measures of diastolic function). J Am Soc Echocardiogr 1995;8:37–47.

Chapter 13 • Assessment of Left Atrial Size and Function 7. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular ﬁlling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease: Additional value of analyzing left atrial size, left atrial ejection fraction and the diﬀerence in duration of pulmonary venous and mitral ﬂow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. 8. Tsang TS, Barnes ME, Gersh BJ, et al: Prediction of risk for ﬁrst age-related cardiovascular events in an elderly population: The incremental value of echocardiography. J Am Coll Cardiol 2003;42:1199–2005. 9. Kizer JR, Bella JN, Palmieri V, et al: Left atrial diameter as an independent predictor of ﬁrst clinical cardiovascular events in middle-aged and elderly adults (the strong heart study). Am Heart J 2006;151:412–418. 10. Benjamin EJ, D’Agostino RB, Belanger AJ, et al: Left atrial size and the risk of stroke and death: The Framingham Heart study. Circulation 1995;92:835–841. 11. Di Tullio MR, Sacco RL, Sciacca RR, et al: Left atrial size and the risk of ischemic stroke in an ethnically mixed population. Stroke. 1999;30: 2019–2024. 12. Flaker GC, Fletcher KA, Rothbart RM, et al: Clinical and echocardiographic features of intermittent atrial ﬁbrillation that predict recurrent atrial ﬁbrillation (Stroke Prevention in Atrial Fibrillation [SPAF] investigators). Am J Cardiol 1995;76:355–358. 13. Vaziri SM, Larson MG, Benjamin EJ, et al: Echocardiographic predictors of nonrheumatic atrial ﬁbrillation: The Framingham Heart study. Circulation 1994;89:724–730. 14. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial ﬁbrillation and congestive heart failure in patients >/=65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54–58. 15. Tsang TS, Gersh BJ, Appleton CP, et al: Left ventricular diastolic dysfunction as a predictor of the ﬁrst diagnosed nonvalvular atrial ﬁbrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636–1644. 16. Møller JE, Hillis GS, Oh JK, et al: Left atrial volume. A powerful predictor of survival after acute myocardial infarction. Circulation 2003;107: 2207–2212. 17. Beinart R, Boyko V, Schwammenthal E, et al: Long-term prognostic signiﬁcance of left atrial volume in acute myocardial infarction. J Am Coll Cardiol 2004;44:327–334. 18. Quinones MA, Greenberg BH, Kopelen HA, et al: Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: Signiﬁcance of left ventricular hypertrophy: Studies of left ventricular dysfunction. J Am Coll Cardiol 2000;35:1237–1244. 19. Rossi A, Cicoira M, Zanolla L, et al: Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy. J Am Coll Cardiol 2002;40:1425. 20. Dini FL, Cortigiani L, Baldini U, et al: Prognostic value of left atrial enlargement in patients with idiopathic dilated cardiomyopathy and ischemic cardiomyopathy. Am J Cardiol 2002;89:518–523. 21. Sabharwal N, Cemin R, Rajan K, et al: Usefulness of left atrial volume as a predictor of mortality in patients with ischemic cardiomyopathy. Am J Cardiol 2004;94:760–763. 22. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantiﬁcation: A report from the American Society of Echocardiography’s guidelines and standards committee and the chamber quantiﬁcation writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 23. Weyman AE. Normal cross-sectional echocardiographic measurements. In Weyman AE (ed): Principles and Practice of Echocardiography, 2nd ed. Philadelphia, Lea & Febiger, 1994:1289–1298. 24. Schabelman S, Schiller NB, Silverman NH, et al: Left atrial volume estimation by two-dimensional echocardiography. Catheter Cardiovasc Diagn 1981;7:165–178. 25. Wade MR, Chandraratna PA, Reid CL, et al: Accuracy of nondirected and directed M-mode echocardiography as an estimate of left atrial size. Am J Cardiol 1987;60:1208–1211. 26. Lester SJ, Ryan EW, Schiller NB, et al: Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol 1999;84:829–832. 27. Loperﬁdo F, Pennestri F, Digaetano A, et al: Assessment of left atrial dimensions by cross sectional echocardiography in patients with mitral valve disease. Br Heart J 1983;50:570–578. 28. Rodevan O, Bjornerheim R, Ljosland M, et al: Left atrial volumes assessed by three- and two-dimensional echocardiography compared to MRI estimates. Int J Card Imaging 1999;15:397–410.

29. Vandenberg BF, Weiss RM, Kinzey J, et al: Comparison of left atrial volume by two-dimensional echocardiography and cine-computed tomography. Am J Cardiol 1995;75:754–757. 30. Khankirawatana B, Khankirawatana S, Porter T: How should left atrial size be reported? Comparative assessment with use of multiple echocardiographic methods. Am Heart J 2004;147:369–374. 31. Hiraishi S, DiSessa TG, Jarmakani JM, et al: Two-dimensional echocardiographic assessment of left atrial size in children. Am J Cardiol 1983;52: 1249–1257. 32. Jessurun ER, van Hemel NM, Kelder JC, et al: The eﬀect of maze operations on atrial volume. Ann Thorac Surg 2003;75:51–56. 33. Wang Y, Gutman JM, Heilbron D, et al: Atrial volume in a normal adult population by two-dimensional echocardiography. Chest 1984;86:595– 601. 34. Gutman J, Wang YS, Wahr D, et al: Normal left atrial function determined by 2-dimensional echocardiography. Am J Cardiol 1983;51:336–340. 35. Thomas L, Levett K, Boyd A, et al: Compensatory changes in atrial volumes with normal aging: Is atrial enlargement inevitable? J Am Coll Cardiol. 2002;40:1630–1635. 36. Kircher B, Abbott JA, Pau S, et al: Left atrial volume determination by biplane two-dimensional echocardiography: Validation by cine computed tomography. Am Heart J 1991;121:864–871. 37. Hoit BD, Shap Y, McMannis K, et al: Determination of left atrial volume using sonomicrometry: A cast validation study. Am J Physiol 1993;264(3 Pt 2):H1011–H1016. 38. Nakajima K, Iizuka M, Natsume T, et al: Assessment of left atrial stiﬀness in man. Circulation 1982;66(suppl):327. 39. Nagano T, Arakawa M, Tanaka T, et al: Diastolic compliance of the left atrium in man: A determinant of preload of the left ventricle. Heart Vessels 1989;5:25–32. 40. Arakawa M, Tanaka T, Hirakawa S. Pressure-volume relation of the left atrium in man. In Hori M, Suga H, Baan J, et al. (eds): Cardiac Mechanics and Function in the Normal and Diseased Heart. New York, SpringerVerlag, 1989:147–154. 41. Hoit BD, Shao Y, Tsai LM, et al: Altered left atrial compliance after atrial appendectomy. Inﬂuence of left atrial and ventricular ﬁlling. Circulation Res 1993;72:167–175. 42. Yamaguchi M, Arakawa M, Tanaka T, et al: Study on left atrial contractile performance: Participation of Frank-Starling mechanism. Jpn Circ J 1987; 51:1001–1009. 43. Nakatani S, Garcia MJ, Firstenberg MS, et al: Noninvasive assessment of left atrial maximum dP/dt by a combination of transmitral and pulmonary venous ﬂow. J Am Coll Cardiol 1999;34:795–801. 44. Senni M, Tribouilloy CM, Rodeheﬀer RJ, et al: Congestive heart failure in the community. A study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–2289. 45. Oh JK, Hatle L, Tajiki AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 46. Aurigemma GP, Gaasch WH: Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 47. Cleland JGF, Swedberg K, Follath F, et al: The EuroHeart Failure survey programme—A survey on the quality of care among patients with heart failure in Europe. Part 1: Patient characteristics and diagnosis. Eur Heart J 2003;24:442–463. 48. Douglas PS: The left atrium: A biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol 2003;42:1206– 1207. 49. Pritchett AM, Mohoney DW, Jacobson SJ, et al: Diastolic dysfunction and left atrial volume: A population-based study. J Am Coll Cardiol 2005;45:87–92. 50. Miller JT, O’Rourke RA, Crawford MH: Left atrial enlargement: An early sign of hypertensive heart disease. Am Heart J 1988;116:1048–1051. 51. Gottdiener JS, Reda DJ, Williams DW, et al: Left atrial size in hypertensive men: Inﬂuence of obesity, race and age. Department of Veterans Aﬀairs cooperative study group on antihypertensive agents. J Am Coll Cardiol 1997;29:651–658. 52. Psaty BM, Manolio TA, Kuller LH, et al: Incidence of and risk factors for atrial ﬁbrillation in older adults. Circulation 1997;96:2455–2461. 53. Vaziri SM, Larson MG, Lauer MS, et al: Inﬂuence of blood pressure on left atrial size. The Framingham Heart Study. Hypertension 1995;25: 1155–1160. 54. Pritchett AM, Jacobson SJ, Mahoney DW, et al: Left atrial volume as an index of left atrial size: A population-based study. J Am Coll Cardiol 2003;41:1036–1043.

169

170

Chapter 13 • Assessment of Left Atrial Size and Function 55. Tsang TSM, Abhayaratna WP, Barnes ME, et al: Prediction of cardiovascular outcomes with left atrial size. Is volume superior to area or diameter? J Am Coll Cardiol 2006;47:1018–1023. 56. Tsang TS, Barnes ME, Bailey KR, et al: Left atrial volume: Important risk marker of incident atrial ﬁbrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467–475. 57. 10Vasan RS, Levy D, Larson MG, et al: Interpretation of echocardiographic measurements: A call for standardization. Am Heart J 2000;139:412– 422. 58. Alsaileek AA, Osranek M, Fatema K, et al: Predictive value of normal left atrial volume in stress echocardiography. J Am Coll Cardiol 2006;47: 1024–1028. 59. Abhayaratna WP, Seward JB, Appleton CP, et al: Left atrial size: Physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47: 2357–2363.

60. Inaba Y, Yuda S, Kobayashi N, et al: Strain rate imaging for noninvasive functional quantiﬁcation of the left atrium: Comparative studies in controls and patients with atrial ﬁbrillation. J Am Soc Echocardiogr 2005;18: 729–736. 61. Thomas L, McKay T, Byth K, Marwick TH: Abnormalities of left atrial function after cardioversion: An atrial strain rate study. Heart Online, July 3, 2006. 62. Modesto KM, Dispenzieri A, Cauduro SA, et al: Left atrial myopathy in cardiac amyloidosis: Implications of novel echocardiographic techniques. Eur Heart J 2005;26:173–179. 63. Di Salvo G, Drago M, Pacileo G, et al: Atrial function after surgical and percutaneous closure of atrial septal defect: A strain rate imaging study. J Am Soc Echocardiogr 2005;18:930–933.

SHERIF F. NAGUEH, MD WILLIAM A. ZOGHBI, MD

14 Evaluation of Right Ventricular Diastolic Function INTRODUCTION PATHOPHYSIOLOGY Right Atrial and Ventricular Dimensions Inferior Vena Cava Diameter and Respiratory Collapse Tricuspid and Pulmonary Regurgitation Signals by Continuous Wave Doppler Tricuspid Inflow Hepatic Venous Flow Tissue Doppler Imaging FUTURE RESEARCH

INTRODUCTION Assessment of right ventricular (RV) function is an important component of the comprehensive evaluation of cardiac function in patients with known or suspected heart disease. RV function may be normal when left ventricular (LV) function is depressed, and conversely, RV dysfunction may occur in the presence of normal LV function. Therefore, a careful evaluation of RV function is essential irrespective of LV functional status. In this chapter, we will discuss the assessment of RV diastolic function with echocardiographic and Doppler techniques.

PATHOPHYSIOLOGY RV diastolic function is determined by a number of factors at the cellular, myocardial, and cardiac chamber levels. Therefore, RV

ﬁlling patterns and RV ﬁlling pressures reﬂect the net balance of many variables. Active relaxation is among the important determinants of RV diastolic function and is dependent on calcium uptake by the sarcoplasmic reticulum, intrinsic contractility, uniformity of relaxation, and the load-dependent properties of relaxation. Ventricular suction and active myocardial relaxation in health lead to a small positive pressure gradient between the right atrium and the right ventricle, hence the predominant RV ﬁlling in early diastole. In addition, recent animal studies with threedimensional real-time echocardiography have drawn attention to the presence of vortical motion during early diastolic RV ﬁlling, which is reduced with chamber dilatation.1 This vortical motion can facilitate RV ﬁlling by shunting kinetic energy that could otherwise lead to increased convective deceleration and therefore a reduced right atrial (RA) to RV pressure gradient. With impaired RV relaxation, an increase in RA pressure is needed to maintain adequate RV ﬁlling and stroke volume. Myocardial stiﬀness, RV chamber geometry (dimensions and wall thickness), and RA systolic function determine RV ﬁlling later in diastole. In particular, RA systolic function appears to play an important compensatory role in preventing heart failure in the presence of pulmonary hypertension.2 In addition, factors extrinsic to the right ventricle determine RV ﬁlling, including pericardial properties, LV ﬁlling, and extrinsic compression by mediastinal masses or large pleural eﬀusions. In turn, RV ﬁlling can aﬀect LV diastolic volume and pressure.3 It is possible to assess RV relaxation invasively by using highﬁdelity pressure catheters to measure peak negative pressure/time change (dP/dt) and the time constant of pressure decay during isovolumic relaxation (τ). Both measurements, however, are load dependent,4,5 with an inverse linear relation to systolic load. There is a paucity of data with respect to human measurements that 171

172

Chapter 14 • Evaluation of Right Ventricular Diastolic Function include small numbers of patients with coronary artery disease,6 pulmonary hypertension,5 and hypertrophic cardiomyopathy.7 RV chamber stiﬀness can also be quantiﬁed using the combination of RV diastolic pressures and volumes.4,8 In comparison with invasive measurements, echocardiography has the advantages of safety, versatility, and portability, and therefore is the modality that is most frequently utilized to gain insight into RV diastolic function and ﬁlling pressures (Table 14-1).

Right Atrial and Ventricular Dimensions The assessment of RV diastolic function should begin with the evaluation of RV dimensions and systolic function, as patients with reduced RV systolic performance have diastolic dysfunction. RV systolic function is usually assessed in a qualitative manner by paying attention to RV dimensions and fractional area change. This is done utilizing two-dimensional echocardiography, with images acquired from the parasternal, apical, and subcostal views. Likewise, the presence of RV hypertrophy is associated with diastolic dysfunction. RA volume is another useful parameter obtained with twodimensional echocardiography. It is usually increased in patients with RV diastolic dysfunction. RA volumes should be considered when drawing conclusions about RA pressure in patients with

TABLE 14-1 ECHO DOPPLER INDICES FOR ASSESSMENT OF RIGHT VENTRICULAR DIASTOLIC FUNCTION 1. Right atrial volumes (maximum, minimum, and emptying fraction) 2. Inferior vena cava diameter and collapse index 3. Downslope of tricuspid regurgitation jet by continuous wave (CW) Doppler 4. Deceleration rate of pulmonary regurgitation jet by CW Doppler 5. Tricuspid inflow velocities (E, A, E/A ratio, and deceleration time of E velocity) 6. Hepatic venous flow (systolic, diastolic, and atrial reversal velocities) 7. Tricuspid annulus early (Ea) and late (Aa) diastolic velocities by tissue Doppler (TD) 8. Isovolumic relaxation time by TD: time between end of systolic velocity and onset of Ea 9. Early (SRe) and late (Sra) diastolic strain rate

NORMAL RA VOLUME

RA

equivocal ﬁndings in Doppler parameters. Although RA volumes can be measured at any time during the cardiac cycle, maximal RA volumes (Fig. 14-1) are most frequently measured before tricuspid valve opening at end systole; RA minimum volume is measured after tricuspid valve closure at end diastole. RA emptying fraction can be computed as the diﬀerence between RA maximum and minimum volumes/RA maximum volume. In patients with increased mean RA pressure, RA maximum and minimum volumes are increased, whereas RA emptying fraction is decreased.9 The correlation of RA volumes with RA pressure, however, is weak and is heavily modiﬁed by RA stiﬀness and contractility. In addition, RA volumes may be increased for reasons other than diastolic dysfunction, such as atrial ﬁbrillation and tricuspid valve disorders.

Inferior Vena Cava Diameter and Respiratory Collapse Inferior vena cava (IVC) diameter and its change during inspiration are useful indicators of RA pressure. Previous studies have noted that the segment within 2 cm of the RA-IVC junction is the region most responsive to changes in respiratory eﬀort.10,11 In particular, IVC expiratory and inspiratory diameters as well as percent collapse were reported to have signiﬁcant relations with RA pressure in patients with spontaneous respiration.9–11 Clinically, IVC imaging is acquired in the subcostal view at rest and with inspiratory eﬀort, or a “sniﬀ test.” The presence of at least 50% collapse is usually seen with an RA pressure less than 10 mmHg, whereas patients with RA pressure greater than 10 mmHg typically exhibit less than 50% IVC collapse.11 Figure 14-2 is from a patient with an increased RA mean pressure (>20 mmHg) who exhibits a dilated IVC and minimal change in IVC diameter with inspiration. The limitations of this method occur in patients with dyspnea and those on mechanical ventilation. In patients on mechanical ventilation, IVC percent collapse relates poorly (Fig. 14-3) to mean RA pressure,9,12 whereas IVC diameter at expiration has a somewhat better correlation (r = .58). An IVC diameter no greater than 12 mm appears highly accurate in identifying patients with an RA pressure less than 10 mmHg, whereas a diameter greater than 12 mm has no predictive value in this population.12 In addition, it is possible to image the left hepatic vein from the same window. In one study, the transverse diameter of this vein at expiration and inspiration, as well as end expiratory apnea, was shown to relate signiﬁcantly to mean RA pressure in a group

MARKEDLY ENLARGED RA

RA

Figure 14-1 Right atrial (RA) end systolic volume from two patients: one with normal RA volume at 26 ml (left) and the other with pulmonary hypertension, a dilated and hypertrophied right ventricle, and a markedly enlarged right atrium, with a maximum volume of 156 ml.

Chapter 14 • Evaluation of Right Ventricular Diastolic Function Expiration

Inspiration

Normal RAP

Figure 14-2 Examples of inferior vena cava (IVC) diameter changes with inspiration (between arrows) from a patient with normal right atrial pressure (RAP) (upper panel) and another with increased RAP (lower panel). In the upper panel, there is complete collapse of the IVC with inspiration, whereas in the lower panel, the IVC is dilated with minimal change in its diameter with inspiration. The latter observation is consistent with an RAP >20 mmHg.

Mean right atrial pressure by catheter (mmHg)

30

Overall

Increased RAP

r = –0.63, y = 16.6 – 0.16x n = 35, SEE = 4.4 mmHg

25 – vent r = –0.76, SEE = 4.1 mmHg + vent r = 0.24, p = ns

20

15

10

5

0 0

20

40

60

80

100

IVC collapse index (%) Figure 14-3 Relation between mean right atrial pressure and inferior vena cava (IVC) percent collapse. Patients on mechanical ventilation are shown as blue circles, whereas those with spontaneous breathing are shown as red circles. A significant inverse correlation was present only in the group with spontaneous breathing. (From Nagueh SF et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)

of 32 patients presenting with acute myocardial infarction.13 Assessment of the left hepatic vein diameter could be helpful in patients where the IVC is not well visualized. However, there is a paucity of data on the clinical application of this approach in patients on mechanical ventilation.

Tricuspid and Pulmonary Regurgitation Signals by Continuous Wave Doppler The rate of rise and fall in tricuspid regurgitation (TR) jet velocity by continuous wave (CW) Doppler parallels the corresponding events in RV pressure, assuming minimal ﬂuctuations of RA pressure throughout the cardiac cycle. Therefore, it is possible to calculate RV peak positive and peak negative dP/dt by using the TR jet and applying the modiﬁed Bernoulli equation to convert the TR velocity to RV pressure. In one study,14 a strong correlation was observed between the invasive measurement and the noninvasive estimate of peak negative dP/dt. The limitations of this approach include the need for a complete TR signal and the underestimation of peak negative dP/dt in patients with an RA “v” wave pressure of at least 10 mmHg. For clinical application, one depends more on the shape of the signal (slow decay of the peak velocity to baseline) than the actual measurement, as shown in Figure 14-4. A pulmonary regurgitation (PR) signal by CW Doppler can be recorded in many patients, particularly in the presence of pulmonary hypertension. In addition, it is possible to enhance the signal by using intravenous contrast.15 Once an adequate signal is recorded, its peak velocity can be used to estimate mean pulmonary artery pressure, whereas its end diastolic velocity in conjunction with mean RA pressure can be used to estimate pulmonary artery diastolic pressure.16 Discrepancies may occur if RV end diastolic pressure is signiﬁcantly diﬀerent than mean RA pressure. In addition, in the absence of signiﬁcant PR, the deceleration slope and the pressure half-time of the PR jet by CW Doppler can provide unique insight into RV diastolic function. Patients with increased RV stiﬀness and rapidly rising RV diastolic pressure have a rapid equalization of the pressure gradient between the pulmonary artery and the right ventricle and therefore a short pressure half-time (Fig. 14-5). In one study, which used right heart catheterization, a pressure half-time of no greater than

173

174

Chapter 14 • Evaluation of Right Ventricular Diastolic Function NORMAL RV FUNCTION

DEPRESSED RV FUNCTION

Figure 14-4 Example of tricuspid regurgitation jets by CW Doppler from two patients: one with normal right ventricular (RV) function (left) and the other with depressed RV function (right). Notice the slow decay of the peak velocity to the baseline from the patient with depressed RV systolic function compared with the normal, as indicated by the slope of the yellow arrows.

Figure 14-5 Example of pulmonary regurgitation jets by CW Doppler from two patients: one with normal right ventricular (RV) diastolic pressure (left) and the other with highly increased RV diastolic pressures (right). Notice the very steep deceleration of pulmonary regurgitation from the patient in the right panel as indicated by slope of the yellow arrows.

150 ms was the best predictor of RV involvement in patients presenting with acute inferior wall myocardial infarction.17 The same investigators reported that this parameter was the only predictor of overall in-hospital clinical events in the same patient population.18

Tricuspid Inflow Pulsed-wave (PW) Doppler recording of tricuspid inﬂow is essential for the assessment of RV ﬁlling. Care should be exercised to obtain the best alignment with the direction of blood ﬂow, which typically requires a medial movement of the transducer from the conventional apical position.19 The recording is obtained by placing a 1–2 mm sample volume at the valve annulus and tips with ﬁlter and gain adjustments to obtain a clear signal. Respiratory variability is an additional factor that needs to be considered with measurements taken at end expiratory apnea or as the average of ﬁve to seven consecutive cardiac cycles. The latter approach has been shown to yield identical results to those obtained at end expiratory apnea.20

Similar to mitral inﬂow, tricuspid inﬂow (Fig. 14-6) is analyzed for peak early (E) and late (A) diastolic velocity, deceleration time (DT) of E velocity, duration of A velocity, and the fraction of RA contribution to RV ﬁlling (the atrial ﬁlling fraction [AFF]). All measurements except for the A duration are obtained from the Doppler recordings at the level of the valve tips. The A duration is measured from the recording at the level of the tricuspid annulus. Because the tricuspid and pulmonary valves are in different planes, isovolumic relaxation time (IVRT) is measured by Doppler using two time intervals, as the diﬀerence between the duration from the QRS complex to onset of tricuspid inﬂow and the interval from the QRS complex to end of pulmonic ﬂow. Alternatively, IVRT can be calculated by subtracting the time between the QRS complex and the end of pulmonic ejection from the duration of the TR jet. Early diastolic RV ﬁlling is reduced with normal aging,20,21 which should be considered when drawing conclusions about RV diastolic function using tricuspid inﬂow velocities. In general, patients with impaired RV relaxation have a reduced E/A ratio, a prolonged IVRT and DT, and an increased AFF. As RA pres-

Chapter 14 • Evaluation of Right Ventricular Diastolic Function

Hepatic Venous Flow The ﬂow in the hepatic veins is largely determined by RA pressure during the cardiac cycle. In normal subjects, antegrade ﬂow from the hepatic veins to the RA occurs in systole (S) and diastole (D). With RA contraction, as well as in late ventricular systole (Vr), brief retrograde ﬂow (Ar) occurs into the hepatic veins.23 It is feasible to record high-quality signals by transthoracic imaging from the subcostal window. It is also possible to record them by transesophageal echocardiography (TEE) in the course of a transesophageal examination.24 The sample volume (3–4 mm) is placed 1–2 cm in the hepatic veins, close to their entrance into the IVC. Similar to tricuspid inﬂow velocities, ﬂow should be recorded for ﬁve to seven consecutive cardiac cycles or at end expiratory apnea. E VAR

VVR A

AR dur

VS AT

DT

A wave duration

30 r = 0.66 n = 35 y = –1 + 9.6x SEE = 3.8 mmHg

25

20

15

10

5

VD

Figure 14-6 Schematic diagram of tricuspid inflow (left) and hepatic venous flow (right). E, peak early diastolic velocity; A, peak late diastolic velocity; AT, acceleration time of E velocity; DT, deceleration time of E velocity; VS, peak systolic velocity; VD, peak diastolic velocity; VVR, midsystolic reversal velocity; VAR, peak atrial reversal velocity; AR dur, duration of atrial reversal velocity. (From Nagueh M et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)

Figure 14-7 Examples of normal tricuspid inflow (left), impaired relaxation (middle), and restrictive filling (right). E, early velocity; A, velocity with atrial contraction.

Quantitative measurements include the peak velocity, the duration, and the time-velocity integral (TVI) of velocity at each of the phases (see Fig. 14-6), as well as the proportion of forward ﬂow during systole and diastole, using either peak velocity or TVI measurements. Such parameters can be used to assess mean RA pressure in patients who are in sinus rhythm.9 This is based on the following premise: Systolic forward ﬂow from the hepatic veins to the RA depends on RA relaxation, RV systolic function, and RA pressure. In the presence of a normal RA pressure, predominant ﬂow occurs in systole (Fig. 14-9). As the RA pressure increases, the pressure gradient between the hepatic veins and the right atrium decreases, and correspondingly forward systolic ﬂow decreases.9,25 This abnormal pattern of ﬂow is most exaggerated in patients with restrictive physiology with large atrial and venous reversals.22 Systolic forward ﬂow parameters, particularly systolic ﬁlling fraction (systolic ﬂow/total antegrade ﬂow), derived from either TVIs or maximal velocities, have been successfully applied to estimate RA pressure noninvasively in patients with a variety of diseases, including those on mechanical ventilation (Fig. 14-10). Ar duration is also of value, as it has been shown to

Mean right atrial pressure by catheter (mmHg)

sure increases, E/A ratio increases and DT shortens (Fig. 14-7). However, the individual response is highly variable and dependent on the interplay between many hemodynamic parameters, such that the E/A ratio has a signiﬁcant positive relation with mean RA pressure but with a wide scatter (Fig. 14-8). Nevertheless, in patients with RV systolic dysfunction, a short DT is usually associated with increased ﬁlling pressures.9 In addition, diastolic TR, when present and in the absence of atrioventricular (AV) block, indicates the presence of increased RV stiﬀness and highly increased RV ﬁlling pressures.22

175

0 0

1

2

3

Tricuspid E/A ratio Figure 14-8 Relation between tricuspid E/A ratio and mean right atrial pressure. (From Nagueh SF et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)

Chapter 14 • Evaluation of Right Ventricular Diastolic Function

Figure 14-9 Examples of hepatic venous flow. In the example shown on the left, forward flow occurs predominantly in systole, which corresponds to a mean right atrial (RA) pressure ≤5 mmHg. In the example on the right, the peak systolic and diastolic velocities are similar, corresponding to mean RA pressure of 5–10 mmHg.

SYSTOLIC FILLING FRACTION 30 r = –0.86 n = 35 y = 21.6 – 24x SEE = 2.5 mmHg

25

20

15

10

5

0

Mean right atrial pressure by catheter (mmHg)

30 Mean right atrial pressure by catheter (mmHg)

176

r = –0.85 n = 35 y = 23 – 29x SEE = 3 mmHg

25

20

15

10

5

0 0.0

0.2

0.4

0.6

0.8

1.0

TVIS/(TVIS + TVID)

0.0

0.2

0.4

0.6

0.8

1.0

VS/(VS + VD)

Figure 14-10 Correlation between mean right atrial pressure and right atrial systolic filling fraction calculated using the time-velocity integral (left) and peak systolic velocity (right). (From Nagueh SF et al: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169.)

relate to RA pressure9,26 and late diastolic RV pressures (Fig. 14-11). These principles are not applicable to patients in nonsinus rhythms or with cardiac transplants, tricuspid valve disease (signiﬁcant stenosis or regurgitation and prosthetic valves), or pericardial compression syndromes (tamponade or constriction). However, hepatic venous ﬂow may still be helpful in these conditions. For example, patients with severe TR usually exhibit systolic ﬂow reversal (Fig. 14-12) into the hepatic veins.27 Likewise, hepatic venous ﬂow can help diﬀerentiate pericardial constriction from restrictive cardiomyopathy. In patients with constrictive physiology, a predominant systolic or biphasic ﬂow pattern is frequently recorded. In addition, respiratory ﬂow variation presents unique insight into RV and LV ﬁlling, where RA and RV ﬁlling increase with inspiration and the Vr and Ar velocities become more prominent with expiration.28 The latter observation is

dependent upon increased LV ﬁlling with expiration in the presence of a taut pericardium, which leads to reduced RV ﬁlling with RA contraction. Accordingly, RA contraction results in increased ﬂow into the hepatic veins during expiration. Table 14-2 shows a practical summary for estimating mean RA pressure using an IVC collapse index and hepatic venous ﬂow.

Tissue Doppler Imaging Tissue Doppler imaging (TDI) allows the recording of myocardial velocity during the cardiac cycle, including velocities at the tricuspid annulus. In addition, using TDI or recently developed speckle tracking technology, one can measure local rates of systolic compression and early and late diastolic expansion of the myocardium (systolic and diastolic strain rates, respectively). For assessment of RV global diastolic function, tricuspid annulus velocities

Chapter 14 • Evaluation of Right Ventricular Diastolic Function

Figure 14-11 Hepatic venous flow from a patient with pulmonary hypertension and increased late diastolic right ventricular pressures and stiffness. Notice the prominent AR (atrial reversal) velocity.

Figure 14-13 Example of tissue Doppler recording of myocardial velocities from the right ventricular free wall in a normal subject. The inset shows the location of the sample volume at the right side of the tricuspid annulus. Notice the presence of an Sa peak velocity of 15 cm/s, a peak Ea velocity of 18 cm/s, and an Ea/Aa ratio >1. IVRT, isovolumic relaxation time between end of Sa and onset of Ea; Sa, systolic ejection velocity; Ea, early diastolic velocity; Aa, late diastolic velocity.

examination of function of multiple segments simultaneously, in the same beat; however, an estimate of mean myocardial velocities is provided. The velocity measured by color TDI is therefore lower than the maximal velocity measured by PW Doppler, which should always be considered when normal values and results are compared among diﬀerent studies. The following indices of diastolic function are measured by TDI at the tricuspid annulus: ❒ ❒ ❒ ❒ ❒ ❒ Figure 14-12 Hepatic venous flow from a patient with severe tricuspid regurgitation. Notice the presence of flow reversal during systole.

TABLE 14-2 SUMMARY OF RIGHT ATRIAL PRESSURE (RAP) ESTIMATION USING INFERIOR VENA CAVA (IVC) COLLAPSE INDEX AND HEPATIC VENOUS FLOW MEAN RAP (mmHg)

IVC % COLLAPSE

HEPATIC VEINS

0–5 5–10 10–15 ≥20

≥50 ≥50 <50 <50

VS > VD VS = VD VS < VD Flow only with VD

VS = systolic velocity; VD = diastolic velocity.

are recorded by placing the PW Doppler sample volume (4– 5 mm) at the right border of the annulus. It is also possible to use color Doppler two-dimensional images to obtain a display of myocardial and annular velocities. The advantages of the PW approach include online beat-to-beat evaluation and the spectral display of velocities. On the other hand, color TDI allows the

Early diastolic velocity (Ea) Late diastolic velocity (Aa) Ea/Aa ratio RV regional IVRT (Fig. 14-13) Early diastolic strain rate Late diastolic strain rate

A number of studies have evaluated the utility of Ea, Aa, and the Ea/Aa ratio to assess RV diastolic function. Patients with RV diastolic dysfunction usually have reduced Ea velocity and a reduced Ea/Aa ratio. Aa velocity may be increased in the early course of diastolic dysfunction, whereas with increased RV late diastolic pressures, it may decrease. Using these simple and reproducible velocity measurements, a number of investigators have reported on RV diastolic function in several cardiac disorders. These included patients with coronary artery disease,29 inferior wall myocardial infarction and RV involvement,30 dilated cardiomyopathy,31 hypertrophic cardiomyopathy,32 obesity,33,34 congenital heart disease,35 and systemic36 and pulmonary hypertension.37 While the observations in this chapter support an important clinical role for TDI-derived velocities, there have been no direct validation studies in animals or humans against invasive measurements of negative dP/dt or τ. Similar to early diastolic velocity at the mitral annulus, tricuspid Ea is load dependent in normal ventricles.38 On the other hand, the tricuspid Ea/Aa ratio appears unchanged with preload reduction.38 Notwithstanding, existing studies support the conclusion that tricuspid annulus Ea velocity is not positively aﬀected by preload in patients with RV dysfunction, given the presence of an inverse correlation between Ea and mean RA pressure in cardiac patients.39 Accordingly, the ratio of

177

178

Chapter 14 • Evaluation of Right Ventricular Diastolic Function tricuspid E velocity to annular Ea velocity has been applied to predict RV ﬁlling pressures (Figs. 14-14 and 14-15), in an analogous manner to the use of mitral velocities, in both animal40 and human studies.39,41 In the human studies, diﬀerent groups of patients were evaluated, and overall an E/Ea ratio greater than 6 had a sensitivity of 79% and a speciﬁcity of 73% for mean RA pressure of at least 10 mmHg.39 The good correlation of tricuspid E/Ea ratio to mean RA pressure was noted in patients with and without RV systolic dysfunction, as well as in those on mechanical ventilation.39

TRICUSPID INFLOW

100 80

E

cm/sec

60

A

40 20 0 –20 TISSUE DOPPLER 20

cm/sec

Sa

In cardiac transplant recipients, the ratio of E to Ea is also useful (Fig. 14-16), where a ratio greater than 8 had a sensitivity of 78% and a speciﬁcity of 85% for RA pressure of at least 10 mmHg.41 Furthermore, Ea of the tricuspid annulus had no signiﬁcant relation to RA pressure and was not altered by pressure changes. Accordingly, the E/Ea ratio readily detected changes in mean RA pressure of at least 5 mmHg (Fig. 14-17) with a sensitivity of 70% and a speciﬁcity of 75%.41 These observations are in contrast to the limited role of hepatic venous ﬂow in the transplant population as a result of mechanical dissociation between the donor and recipient atria, which alters the systolic and diastolic components of hepatic venous ﬂow and renders their interpretation more challenging. A recent study reported on the clinical application of another TDI-derived measurement, namely the time interval between the end of tricuspid annular systolic velocity and the onset of annular Ea. The latter time interval had a signiﬁcant inverse correlation with mean RA pressure. In a study of 21 patients, a time interval of less than 59 ms had a sensitivity of 80% and a speciﬁcity of 88% in identifying patients with RA pressure greater than 8 mmHg.42 There are advantages to determining mean RA pressure by using TDI. In the case of RV regional IVRT, this is a single measurement that is not aﬀected by angulation. In addition, the tricuspid E/Ea ratio and the above time interval are particularly helpful in patients without subcostal windows where there is concomitant inability to image the IVC and acquire hepatic venous ﬂow. However, these methods may not be accurate in the presence of nonsinus rhythms and tricuspid valve disease.

0

FUTURE RESEARCH

Ea

Aa

–20 Figure 14-14 Upper panel shows early (E) and late (A) diastolic tricuspid inflow velocities. Lower panel shows the annular velocities during systolic ejection (Sa) and early (Ea) and late (Aa) diastole. The E/Ea ratio is 6.75, predicting a mean right atrial pressure of 12 mmHg (catheter pressure 11 mmHg). (From Nageh MF et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451.)

35

y = 0.8 + 1.7x r = 0.75 n = 62

20 (Doppler RAP – Catheter RAP)

30 25 RAP (mmHg)

Evaluation of RV diastolic function is important clinically. Echocardiography and Doppler provide several complementary methods for evaluation of RV diastolic function and prediction of mean RA pressure. These include the evaluation of cardiac structure and function; RV, RA, and IVC size; myocardial velocities; strain rate with tissue Doppler and speckle tracking technology; and hepatic venous ﬂow patterns. These parameters allow a

20 15 10 5 0

15 10 5 0 –5 –10 –15 –20

0

2

4

6

8 E/Ea

10

12

14

16

0

5

10

15

20

25

30

35

(Doppler RAP + Catheter RAP)/2

Figure 14-15 Upper panel: regression plot between mean right atrial pressure (RAP) and tricuspid E/Ea ratio in 62 patients with simultaneous invasive and echocardiographic measurements. Lower panel: Bland-Altman plot of Doppler-derived RAP versus catheter RAP. Mean difference between Doppler and catheter pressures was 0.3 ± 3.7 mmHg. Upper and lower lines represent mean + and mean −2 SDs, respectively. (From Nageh MF et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451.)

Chapter 14 • Evaluation of Right Ventricular Diastolic Function 25

20 (Doppler – Catheter RAP) (mmHg)

r = 0.79 n = 38 y = 1.76× – 3.7

RAP (mmHg)

20

15

10

5

0

15 10 5 0 –5 –10 –15 –20

0

5

10

15

0

E/Ea

5

10

15

20

25

(Doppler + Catheter RAP)/2

Figure 14-16 Left, relation between mean right atrial pressure (RAP) and tricuspid E/Ea ratio in patients who have undergone cardiac transplantation. Right, Bland-Altman plot of Doppler-derived RAP versus catheter RAP. (From Sundereswaran L et al: Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357.)

Δ Doppler RAP (mmHg)

10

15

r = 0.83 n = 18 y = x – 0.2

(Δ Doppler – Δ Catheter RAP) (mmHg)

15

5 0 –5 –10

10 5 0 –5 –10 –15

–15 –15

–10

–5

0

5

10

15

Δ Catheter RAP (mmHg)

–15

–10

–5

0

5

10

15

(Δ Doppler + Δ Catheter RAP)/2

Figure 14-17 Left: relation between changes in mean right atrial pressure (RAP) and those predicted by Doppler in patients who have undergone cardiac transplantation. Right: Bland-Altman plot of changes in RAP by Doppler and changes in mean RAP by right heart catheterization. (From Sundereswaran L et al: Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357.)

comprehensive approach to the evaluation of RV diastolic function and its eﬀect on ﬁlling pressures. The availability of threedimensional technology will undoubtedly improve quantiﬁcation of RV volumes and systolic function. Whether three-dimensional technology will further improve the evaluation of RV diastolic function remains to be determined. In addition, the presence of sensitive indices of RV diastolic function such as early diastolic strain rate may help in the earlier diagnosis of RV dysfunction in cardiomyopathic disorders, as in patients with arrhythmogenic RV dysplasia, where conventional echocardiography may not be diagnostic of RV disease. Furthermore, there is a need to study the presence of systolic and diastolic RV intraventricular dyssynchrony, its impact on global RV diastolic function, and the eﬀect of diﬀerent RV pacing sites on RV performance. Finally, these diﬀerent methods to assess RV function can be used to track functional changes in response to medical/surgical therapy for

several cardiovascular disorders that aﬀect the right ventricle, including congenital heart disease and pulmonary hypertension. REFERENCES 1. Pasipoularides A, Shu M, Shah A, et al: Diastolic right ventricular ﬁlling vortex in normal and volume overload states. Am J Physiol Heart Circ Physiol 2003;284:H1064–H1072. 2. Gaynor SL, Maniar HS, Bloch JB, et al: Right atrial and ventricular adaptation to chronic right ventricular pressure overload. Circulation 2005;112: I212–I218. 3. Moore TD, Frenneaux MP, Sas R, et al: Ventricular interaction and external constraint account for decreased stroke work during volume loading in CHF. Am J Physiol Heart Circ Physiol 2001;281:H2385–H2391. 4. Leeuwenburgh BP, Steendijk P, Helbing WA, Baan J: Indexes of diastolic RV function: Load dependence and changes after chronic RV pressure overload in lambs. Am J Physiol Heart Circ Physiol 2002;282: H1350–H1358.

179

180

Chapter 14 • Evaluation of Right Ventricular Diastolic Function 5. Stein, PD, Sabbah HN, Mazilli M, Anbe DT: Eﬀect of chronic pressure overload on the maximal rate of pressure fall of the right ventricle. Chest 1980;78:10–15. 6. Darsinos, JT, Evagelou AM, Rassidakis AN: Rate of pressure fall in right ventricle during isovolumic relaxation. Angiology 1974;25:520–526. 7. Maeda, M, Yamakado T, Nakano T: Right ventricular diastolic function in patients with hypertrophic cardiomyopathy—an invasive study. Jpn Circ J 1999;63:681–687. 8. Pasipoularides A, Shu M, Shah A, et al: Right ventricular diastolic function in canine models of pressure overload, volume overload, and ischemia. Am J Physiol Heart Circ Physiol 2002;283:H2140–H2150. 9. Nagueh SF, Kopelen HA, Zoghbi WA: Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function. Circulation 1996;93:1160–1169. 10. Simonson JS, Schiller NB: Sonospirometry: A non-invasive method for estimation of mean right atrial pressure based on two dimensional echocardiographic measurements of the inferior vena cava during measured inspiration. J Am Coll Cardiol 1988;11:557–564. 11. Kircher BJ, Himelman RB, Schiller NB: Non-invasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 1990;66:493–496. 12. Jue J, Chung W, Schiller NB: Does inferior vena caval size predict right atrial pressure in mechanically ventilated patients? J Am Soc Echocardiogr 1992;5:613–619. 13. Luca L, Mario P, Giansiro B, et al: Noninvasive estimation of mean right atrial pressure utilizing the 2-D echo transverse diameter of the left hepatic vein. Int J Card Imaging 1992;8:191–195. 14. Imanishi T, Nakatani S, Yamada S, et al: Validation of continuous wave Doppler–determined right ventricular peak positive and negative dP/dt: Eﬀect of right atrial pressure on measurement. J Am Coll Cardiol 1994;23:1638–1643. 15. Tanabe K, Asanuma T, Yoshitomi H, et al: Doppler estimation of pulmonary artery end-diastolic pressure using contrast enhancement of pulmonary regurgitant signals. Am J Cardiol 1996;78:1145–1148. 16. Masuyama T, Kodama K, Kitabatake A, et al: Continuous-wave Doppler echocardiographic detection of pulmonary regurgitation and its application to noninvasive estimation of pulmonary artery pressure. Circulation 1986;74:484–492. 17. Cohen A, Guyon P, Chauvel C, et al: Relations between Doppler tracings of pulmonary regurgitation and invasive hemodynamics in acute right ventricular infarction complicating inferior wall left ventricular infarction. Am J Cardiol 1995;75:425–430. 18. Cohen A, Logeart D, Costagliola D, et al: Usefulness of pulmonary regurgitation Doppler tracings in predicting in-hospital and long-term outcome in patients with inferior wall acute myocardial infarction. Am J Cardiol 1998;81:276–281. 19. Appleton CP, Jensen JL, Hatle LK, Oh JK: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal ﬂow velocity recordings. J Am Soc Echocardiogr 1997;10:271–292. 20. Zoghbi WA, Habib JB, Quiñones MA: Doppler assessment of right ventricular ﬁlling in a normal population: Comparison with left ventricular ﬁlling dynamics. Circulation 1990;82:1316–1324. 21. Berman G, Reicheck N, Brownson D, Douglas PS: Eﬀects of sample volume location, imaging view, heart rate and age on tricuspid velocimetry in normal subjects. Am J Cardiol 1990;65:1026–1030. 22. Appleton CP, Hatle LK, Popp RL: Demonstration of restrictive ventricular physiology by Doppler echocardiography. J Am Coll Cardiol 1988;11: 757–768. 23. Appleton CP, Hatle LK, Popp RL: Superior vena cava and hepatic vein Doppler echocardiography in healthy adults. J Am Coll Cardiol 1987;10: 1032–1039.

24. Pinto FJ, Wranne B, St Goar FG, et al: Hepatic venous ﬂow assessed by transesophageal echocardiography. J Am Coll Cardiol 1991;17:1493– 1498. 25. Sivaciyan V, Ranganathan N: Transcutaneous Doppler jugular venous ﬂow velocity recording. Circulation 1978;57:930–939. 26. Ommen SR, Nishimura RA, Hurrell DG, Klarich KW: Assessment of right atrial pressure with 2-dimensional and Doppler echocardiography: A simultaneous catheterization and echocardiographic study. Mayo Clin Proc 2000;75:24–29. 27. Gonzalez-Vilchez F, Zarauza J, Vazquez de Prada JA, et al: Assessment of tricuspid regurgitation by Doppler color ﬂow imaging: Angiographic correlation. Int J Cardiol 1994;44:275–283. 28. Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 1994;23:154–162. 29. Alam M, Hedman A, Nordlander R, Samad B: Right ventricular function before and after an uncomplicated coronary artery bypass graft as assessed by pulsed wave Doppler tissue imaging of the tricuspid annulus. Am Heart J 2003;146:520–526. 30. Dokainish H, Abbey H, Gin K, et al: Usefulness of tissue Doppler imaging in the diagnosis and prognosis of acute right ventricular infarction with inferior wall acute left ventricular infarction. Am J Cardiol 2005;95: 1039–1042. 31. McMahon CJ, Nagueh SF, Eapen RS et al: Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: A prospective clinical study. Heart 2004;90:908–915. 32. Severino S, Caso P, Cicala S, et al: Involvement of right ventricle in left ventricular hypertrophic cardiomyopathy: Analysis by pulsed Doppler tissue imaging. Eur J Echocardiogr 2000;1:281–288. 33. Willens HJ, Chakko SC, Lowery MH, et al: Tissue Doppler imaging of the right and left ventricle in severe obesity (body mass index >35 kg/m2). Am J Cardiol 2004;94:1087–1090. 34. Wong CY, O’Moore-Sullivan T, Leano R, et al: Association of subclinical right ventricular dysfunction with obesity. J Am Coll Cardiol 2006;47:611– 616. 35. Watanabe M, Ono S, Tomomasa T, et al: Measurement of tricuspid annular diastolic velocities by Doppler tissue imaging to assess right ventricular function in patients with congenital heart disease. Pediatr Cardiol 2003;24:463–467. 36. Cicala S, Galderisi M, Caso P, et al: Right ventricular diastolic dysfunction in arterial systemic hypertension: Analysis by pulsed tissue Doppler. Eur J Echocardiogr 2002;3:135–142. 37. Moustapha A, Lim M, Saikia S, et al: Interrogation of the tricuspid annulus by Doppler tissue imaging in patients with chronic pulmonary hypertension: Implications for the assessment of right-ventricular systolic and diastolic function. Cardiology 2001;95:101–104. 38. Pela G, Regolisti G, Coghi P, et al: Eﬀects of the reduction of preload on left and right ventricular myocardial velocities analyzed by Doppler tissue echocardiography in healthy subjects. Eur J Echocardiogr 2004;5: 262–271. 39. Nageh MF, Kopelen HA, Zoghbi WA, et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448– 1451. 40. Boissiere J, Gautier M, Machet MC, et al: Doppler tissue imaging in assessment of pulmonary hypertension-induced right ventricle dysfunction. Am J Physiol Heart Circ Physiol 2005;289:H2450–H2455. 41. Sundereswaran L, Nagueh SF, Vardan S, et al: Estimation of left and right ventricular ﬁlling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357. 42. Abbas A, Lester S, Moreno FC, et al: Noninvasive assessment of right atrial pressure using Doppler tissue imaging. J Am Soc Echocardiogr 2004;17: 1155–1160.

MIGUEL A. QUINONES, MD

15

Evaluation of Intracardiac Filling Pressures INTRODUCTION PATHOPHYSIOLOGY Definition of Left Ventricular Filling Pressure Two-Dimensional Echocardiography Doppler Echocardiography—Transmitral and Pulmonary Vein Velocities CLINICAL ASSESSMENT Estimation of Filling Pressures Limitations of Transmitral and Pulmonary Vein Velocities

Combination of Transmitral Velocity with Newer Indices of Left Ventricular Relaxation Estimation of Filling Pressures Newer (Less Validated) Methods A Recommended Algorithm for Estimation of Filling Pressures FUTURE RESEARCH

INTRODUCTION

PATHOPHYSIOLOGY

Normal diastolic function allows a ventricle to ﬁll to an adequate volume while maintaining normal diastolic pressures at rest, during exercise, and through a wide range of heart rates. This occurs through the interaction of multiple intracardiac and extracardiac factors (which have been discussed in detail in previous chapters). Failure of these factors to properly operate results in the elevation of left ventricular (LV) diastolic (or ﬁlling) pressures at rest or with exertion and consequently the occurrence of cardiac dyspnea, a common denominator in all forms of heart failure regardless of the resting systolic function. However, there are as many pulmonary causes of dyspnea as there are cardiac, and even in patients with known heart disease, the dyspnea may be of a pulmonary origin. Likewise, elevations of right ventricular (RV) ﬁlling pressures and right atrial pressures (RAPs) result in rightsided failure and edema as its common manifestation; as with dyspnea, edema has also a common list of noncardiac etiologies. Thus, over the past 20 years, there has been great interest in the development of noninvasive methods to estimate left- and rightsided ﬁlling pressures. In this chapter, we will discuss the estimation of left-sided ﬁlling pressures and propose an integrated approach. Assessment of right-sided pressures is discussed in detail in Chapter 14.

Definition of Left Ventricular Filling Pressure Several pressure measurements are collectively referred to as ﬁlling pressures. They include mean left atrial pressure (LAP), mean pulmonary capillary wedge pressure (PCWP) as a corollary of LAP, and LV end diastolic pressure (LVEDP). In addition, diastolic LV pressure (LVP) prior to atrial contraction has been shown to relate closely with mean LAP.1 It is important, however, to understand the clinical diﬀerence between mean LAP (or PCWP) and LVEDP. Although a high LVEDP is indicative of increased LV stiﬀness at end diastole, many of these patients have normal diastolic LVP prior to atrial contraction, and consequently a normal mean LAP. Therefore, when evaluating patients with dyspnea, it is preferable to utilize indices that provide an estimate of mean LAP rather than LVEDP.

Two-Dimensional Echocardiography Echocardiography plays a pivotal role in the evaluation of patients presenting with dyspnea of suspected cardiac origin. It provides an accurate assessment of LV size, regional wall motion, and ejection fraction (EF); allows recognition of patterns of LV hypertrophy and remodeling; and provides an accurate assessment of left 181

182

Chapter 15 • Evaluation of Intracardiac Filling Pressures atrial (LA) enlargement, an extremely frequent ﬁnding in heart failure. The anteroposterior LA dimension has been used for decades to determine LA size, primarily because it was the only measurement available in the era of M-mode echocardiography. However, enlargement of the left atrium does not occur symmetrically, and the anteroposterior dimension consistently underestimates the true LA volume (Fig. 15-1).2 A more accurate assessment is obtained with two-dimensional echocardiography by deriving the volume of the left atrium from planimetry of the chamber in the apical views, using either single or biplane methods.3,4 These volume estimates compare well with measurements obtained with three-dimensional–cine computed tomography and magnetic resonance imaging.5,6 All subsequent reference in this chapter to the value of determining LA size for the estimation of ﬁlling pressures implies that volumes, rather than dimensions, are used. Using echocardiography, the upper limit of normal LA volume, indexed to body surface area, is 28 ml/m2.4 Echocardiography is currently the most widely used imaging technique to distinguish patients with systolic heart failure from those with diastolic heart failure; the former is characterized by LV dilatation, eccentric hypertrophy (dilated cavity with normal ratio of radius to wall thickness), and depressed EF, and the latter by absence of LV dilatation, preservation of EF (≥50%), and often concentric hypertrophy or remodeling7 (see Chapters 2 and 6). Concentric LV hypertrophy is deﬁned as increased mass with an increased radius/thickness ratio (R/Th), and concentric remodeling is deﬁned as normal mass with increased R/Th. Another frequent ﬁnding in patients with diastolic heart failure is a reduction (<8 mm) in the extent of mitral annular descent, an index of the longitudinal vector of contraction and relaxation.8,9 If the echocardiogram in the evaluation of dyspnea demonstrates normal LV size without hypertrophy, normal EF and regional wall motion, normal annular descent, and normal LA size, the cause of dyspnea is unlikely to be cardiac. The contrary may not always be the case, since patients may present with abnormalities of cardiac structure and function, including depressed EF, and have dyspnea of a noncardiac etiology. Perhaps the most reliable ﬁnding is the LA size, since, in the absence of atrial ﬁbrillation or mitral regurgitation/stenosis, it represents a “poor man’s” index of the diastolic load imposed by the left ventricle on the atrium10,11 (see Chapters 10 and 18). In our experience at the

ASSESSMENT OF LEFT ATRIAL SIZE

Methodist DeBakey Heart Center over the past year, 95% of 2500 patients with echo-Doppler evidence of elevated ﬁlling pressures had an enlarged LA volume (unpublished observation).

Doppler Echocardiography—Transmitral and Pulmonary Vein Velocities Determinants of Transmitral Velocity With the advent of pulsed-wave (PW) Doppler echocardiography, recordings of transmitral velocity from the apical window at the tips of the mitral leaﬂets provided an easy-to-use noninvasive tool for the evaluation of diastolic ﬁlling. The peak early velocity (E) and its deceleration time (DT), the atrial (A) velocity, and the E/A ratio became popular indices of diastolic function (Fig. 15-2). E/A ratio is a normalized index that reﬂects early diastolic ﬁlling relative to atrial contraction. Isovolumic relaxation time (IVRT) is the interval between the end of ejection and the onset of mitral inﬂow. IVRT is obtained by recording velocities from an intermediate position between mitral inﬂow and LV outﬂow with either PW or continuous wave (CW) Doppler (Fig. 15-3) (see Chapter 10). The determinants of transmitral velocity and its components have been described in detail elsewhere in this volume. Brieﬂy, transmitral velocity is driven by two major factors: ﬂow and the instantaneous transvalvular pressure gradient (see Fig. 15-2).12,13 During early diastole, active relaxation and LA pressure are the principal determinants of ﬂow and transvalvular gradients. With normal relaxation, LVP decay during isovolumic relaxation occurs rapidly (thus a shorter time constant of relaxation, or Tau), and early ventricular suction is enhanced. This results in a higher E velocity and a shorter DT and IVRT; the opposite occurs with impaired relaxation (longer Tau): less suction, lower E velocity, and longer DT and IVRT. Likewise, with increasing LAP (and a higher LV-LA crossover pressure), IVRT shortens, the early LALV transmitral gradient and E velocity increase, and DT shortens; the opposite occurs with a fall in LA pressure.14,15 The inﬂuence of relaxation and LA pressure on transmitral velocity explains the diﬀerent transmitral patterns described in the literature (Fig. 15-4): the normal healthy pattern seen in young hearts; the “impaired relaxation” pattern, also referred to as ↓ Relaxation

Normal

↓ Relaxation elevated LVFP

IVRT

E

E LAd

A

A

A

E

LA DT

Figure 15-1 Example of a patient in whom the anteroposterior left atrial dimension (LAd) is mildly increased (4.0 cm), whereas in the apical view the left atrium is severely dilated with a volume derived from planimetry of 160 ml (80 ml/m2).

Figure 15-2 Relation of transmitral velocity to the pressure gradient between the left atrium and the left ventricle in three common hemodynamic conditions: normal relaxation, impaired (↓) relaxation, and impaired relaxation with elevated left atrial pressure. No pseudonormal noted. IVRT, isovolumic relaxation time; E, peak early velocity; A, atrial velocity; DT, deceleration time; LVFP, left ventricular filling pressure.

Chapter 15 • Evaluation of Intracardiac Filling Pressures PW-DOPPLER

CW-DOPPLER

IVRT

IVRT

A

B

Figure 15-3 Recording of left ventricular outflow and transmitral velocity. A, PW Doppler; B, CW Doppler. Both recordings provide a measurement of isovolumic relaxation time (IVRT) as the interval from the end of ejection to the onset of mitral inflow.

Figure 15-4 Examples of normal transmitral velocity with the three stages of diastolic dysfunction patterns. Range of values is listed under each pattern. IVRT, isovolumic relaxation time; E, peak early velocity; A, atrial velocity; DT, deceleration time; LVFP, left ventricular filling pressure.

E/A >1 DT 150–240 IVRT <90 msec

stage I diastolic dysfunction13; and both the pseudonormal (stage II) and restrictive (stage III) patterns associated with high ﬁlling pressures. As discussed later, the relation of these patterns to LAP occurs best in patients with depressed EF.

Determinants of Pulmonary Vein Velocity Recordings of pulmonary vein velocity (PVV) by PW Doppler are readily obtained in close to 80% of patients during routine examinations. The determinants of the diﬀerent components of PVV are described in detail in Chapter 10. In brief, atrial relaxation combined with the normal descent of the annulus during ventricular systole contributes to a rapid decline in LAP (the x-descent) that drives ﬂow into the atrium. This is depicted in the PVV recording as an antegrade ﬂow velocity (S-wave) (Fig. 15-5). Following mitral valve opening, there is a second antegrade velocity (D-wave) coincident with the transmitral E velocity. During atrial contraction, there is a small retrograde velocity (AR) into the pulmonary vein. When the x-descent is replaced by an elevated v-wave (as seen frequently during decompensated systolic heart failure), the S-wave becomes diminished and D becomes accentuated in concert with the increase in E velocity previously described. An S/D ratio of less than 1 (S/D derived

↓ RELAXATION STAGE I

PSEUDO-NORMAL STAGE II

E/A <1 DT >240 IVRT >90 msec

Pulmonary Mitral inflow vein (cm/sec) (cm/sec)

NORMAL

RESTRICTIVE STAGE III

E/A 1–2 DT 150–240 IVRT <90 msec

E/A >2 DT <150 IVRT <70 msec

E E

100

100

A

S

E

S

D

A A

D

D S

AR Normal relaxation

AR Normal Lap

High Lap

AR

Impaired LV relaxation

Figure 15-5 Diagrammatic illustration of transmitral and pulmonary vein velocities in normal relaxation, impaired left ventricular (LV) relaxation with normal left atrial pressure (LAP), and impaired relaxation with high LAP. Values of deceleration time for pseudonormal should be 150–240; for restrictive, <150. E, peak early velocity; A, atrial velocity; S, systolic; D, diastolic; Ar, retrograde A velocity.

183

184

Chapter 15 • Evaluation of Intracardiac Filling Pressures using the integral of the velocities) is an index of elevated mean PCWP that, like the E/A ratio and DT, performs more accurately in patients with depressed LVEF.16,17

CLINICAL ASSESSMENT Estimation of Filling Pressures Given that impaired relaxation is present in the vast majority of patients with conditions leading to or associated with heart failure (Box 15-1),18–22 the inﬂuence of LAP on transmitral velocity depends on how much LAP (and LV stiﬀness) overcomes the opposite eﬀect of impaired relaxation (Fig. 15-6). This opposite interaction can be seen even in patients with normal hearts, in whom a very low LAP or preload results in a lowering of the E velocity and E/A ratio despite normal relaxation. A subtle diﬀerence between stage I diastolic dysfunction and normal relaxation with low preload is that the reduction in early ﬁlling induced by impaired relaxation results in a greater residual volume in the left atrium at the time of atrial contraction and a compensatory increase in A velocity that often brings the E/A ratio to less than 0.8. In addition, stage I diastolic dysfunction frequently has a DT of greater than 240 msec. Box 15-1

Conditions Associated with Impaired Relaxation Increased afterload Aging Systemic hypertension Pathologic secondary left ventricular hypertrophy Hypertrophic cardiomyopathy Ischemia Myocardial diseases Infiltrative cardiomyopathies

↓ Relaxation

↑ LA pressure

↓ E-velocity

↑ E-velocity

Measured E-velocity

Figure 15-6 Influence of impaired (↓) left ventricular relaxation and elevated (↑) left atrial (LA) pressure on the transmitral E velocity.

In patients with depressed LVEF (<40%), the presence of a stage I pattern is usually associated with normal (<15 mmHg) resting mean LAPs and a PVV S/D ratio greater than 1.13,23 In contrast, the pseudonormal (stage II) and restrictive (stage III) patterns are associated with increasing elevation of ﬁlling pressures. The stage III pattern is often associated with a diminished A-wave due to the high afterload imposed on the atrium by the elevated LVEDP. In these patients, an S/D ratio of less than 1 in the PVV also implies elevated mean LAP.13,16 Although patients with stage I diastolic dysfunction are often asymptomatic at rest, they are more prone to develop exerciseinduced dyspnea and are at risk for developing heart failure over time, particularly the group with a dilated left atrium.24,25 These patients often have auscultatory evidence of a fourth heart sound and may have a prominent A-wave in LVP tracing. In patients with systolic dysfunction (EF <40%), the presence of stage II and III diastolic dysfunction represents a progression of disease and implies a worsening of LV stiﬀness and higher LAP. Therefore, a gross estimate of mean LAP or PCWP can be inferred from these patterns: Stage I is associated with pressures less than 15 mmHg; stage II is usually associated with pressures between 15 and 25 mmHg; and stage III is associated with pressures greater than 25 mmHg. Several equations have been proposed in the literature to derive mean PCWP.11,23,26–27 They all incorporate multiple measurements from transmitral velocity, and some of them add measurements from the pulmonary veins, LA volume, or both. They all have better accuracy in patients with depressed EF and perform poorly in those with normal systolic function. We have found that the equation Mean PCWP = 17 + (5 × E/A) − (0.11 × IVRT) is simple to use and performs well in the estimation of mean PCWP in patients with depressed EF (Fig. 15-7).23 When estimating mean PCWP, we have not found additional value from recordings of the PVV in patients with systolic heart failure. In contrast, PVV is useful in estimating the LVEDP. During atrial contraction with an elevated LVEDP, LVP may rise over LA pressure, producing a reverse gradient that shortens the duration of the transmitral A velocity (AMV) relative to the pulmonary vein retrograde A velocity (AR) (Fig. 15-8). The interval AR–AMV has been found to relate directly with LVEDP; whenever AR–AMV exceeds 20 msec, LVEDP is likely to be higher than 20 mmHg.28 This ﬁnding is fairly reliable as long as the P-R interval is within a normal range, that is, is neither too short nor too long. The progression from stage I diastolic dysfunction to stage II and III is a “two-way street,” meaning that patients may decompensate into the advanced stages and with proper treatment regress back to stage I (i.e., lower ﬁlling pressures). The preceding equation has been shown to track well changes in mean PCWP in response to therapy. Application of the Valsalva maneuver can be used to assess reversibility, since the increased intrathoracic pressure during the maneuver causes a decrease in preload and a shift in transmitral velocity from stage III to stage II or from II to I.29 Stage IV diastolic dysfunction represents a restrictive pattern that fails to reverse with either Valsalva or heart failure therapy.13 In patients with systolic heart failure, this pattern appears to be a marker of very high LV stiﬀness and ﬁbrosis and is associated with poor prognosis.30,31 In animal models of systolic heart failure, DT has been shown to relate well with LV chamber stiﬀness.15 Likewise, in patients with ischemic cardiomyopathy,

Chapter 15 • Evaluation of Intracardiac Filling Pressures 40

20 15

30

Doppler (mmHg)

Doppler (mmHg)

r = 0.88 y = 4 + 0.7x

20

10

n = 30 r = 0.87 y = 0.2 + 1.2x

5 0 –5 –10

10

–15 = 5 points –20

0 0

10

20

30

40

–20 –15 –10 –5

Catheter pressure (mmHg)

5

10

15

20

Catheter pressure (mmHg)

Mean PCWP = 17 + (5 × E/A) – (0.11 × IVRT)

A

0

Mean PCWP = 17 + (5 × E/A) – (0.11 × IVRT)

B

Figure 15-7 A, Correlation of mean pulmonary capillary wedge pressure (PCWP) estimated by Doppler. B, Correlation of changes in mean PCWP with therapy estimated by Doppler versus catheter measurement. E/A, ratio of peak early velocity to atrial velocity; IVRT, isovolumic relaxation time. (Modified from Nagueh SF et al: Feasibility and accuracy of Doppler echocardiographic estimation of pulmonary artery occlusive pressure in the intensive care unit. Am J Cardiol 1995;75:1256–1262.)

ARPV – AMV = 50 msec Figure 15-8 Transmitral and pulmonary vein velocity recorded in a patient with elevated left ventricular end diastolic pressure. Notice the prolonged duration of the pulmonary vein retrograde A-wave (ARPV ) relative to the mitral A-wave (AMV ).

we have demonstrated an inverse relation between DT and the amount of LV scarring detected by thallium20 scintigraphy.32 Patients with a shorter DT (<150 msec) also had less evidence of viability by dobutamine stress, less recovery of function, more heart failure, and a shorter 12-month survival after coronary revascularization.

Limitations of Transmitral and Pulmonary Vein Velocities As mentioned, the eﬀect of impaired relaxation is to reduce the E velocity, while that of an elevated LAP is to increase the E velocity; thus, the absolute E velocity recorded is the net summation of these two opposing forces (see Fig. 15-6). In patients with

a depressed LVEF and dilated ventricles, the high atrial pressure and prominent v-wave predominate, resulting in changes in transmitral velocity and PVV, as previously discussed. By contrast, patients with diastolic dysfunction but normal LV size and EF often have elevated minimal LV diastolic pressure, greater preservation of the x-descent in the LAP, and increased ﬁlling pressures without prominence of the v-wave. This can result in a stage I pattern despite the presence of elevated ﬁlling pressures. In these instances, the transmitral and the pulmonary vein velocities lose sensitivity for detection of high ﬁlling pressures,20,33,34 with the exception of the AR–AMV interval, which is less accurate but can provide an estimate of LVEDP.33 Although infrequent, a pseudonormal or restrictive transmitral velocity pattern may be seen in patients with diastolic heart failure and mistakenly interpreted as normal diastolic function. Application of the Valsalva maneuver can help by showing regression to stage I diastolic dysfunction.29 These patients usually have other clues of diastolic heart failure, such as concentric LV remodeling, LA enlargement, or both, and may also demonstrate a prolonged AR–AMV. Because of the complex interaction of LV relaxation and LAP, transmitral velocity cannot detect elevated ﬁlling pressures in normal hearts subjected to a high volume load, such as in acute mitral regurgitation, and is also very limited in the absence of sinus rhythm.

Combination of Transmitral Velocity with Newer Indices of Left Ventricular Relaxation As discussed at length elsewhere in this volume, there are currently two noninvasive indices of LV relaxation that have gained considerable clinical interest because they are less aﬀected by changes in LAP or preload. They are the ﬂow propagation velocity, derived with color M-mode Doppler, and the early diastolic mitral annular velocity, derived with tissue Doppler (see Chapters 11 and 12). We will discuss them in brief.

185

186

Chapter 15 • Evaluation of Intracardiac Filling Pressures

Flow Propagation Velocity Following mitral valve opening and under the inﬂuence of relaxation and ventricular suction, a sequence of intracavitary pressure gradients develop from base to apex that promote the propagation of mitral inﬂow toward the LV cavity. The velocity of this ﬂow propagation can be assessed with color Doppler by placing the M-mode cursor within the center of the mitral inﬂow and obtaining a color M-mode recording, preferably at a sweep speed of 100 mm/s (Fig. 15-9) (see Chapter 11). The recording should contain an edge of uniform color during early ﬁlling, the slope of which represents the ﬂow propagation velocity (Vp). Shifting the color Doppler zero baseline to an aliasing velocity near 70% of the E velocity has been proposed as a method to obtain a distinct color border that improves reproducibility of this measurement.35 Vp has been shown to be fairly insensitive to changes in LAP36 and to relate inversely with Tau.37 A reduced Vp (<40 cm/s) implies impaired relaxation and can be used to distinguish a pseudonormal mitral inﬂow pattern from a normal one.38

aging, concordant with other indices of relaxation,42 and is inversely aﬀected by increasing afterload.40,43 In the normally contracting and relaxing heart, Ea is directly altered by changes in preload.40 However, this relation virtually disappears in abnormal hearts with impaired relaxation.44 A reduced Ea (<8 cm/s) implies impaired relaxation (whether caused by LV disease or advanced age) and can be used to distinguish a pseudonormal mitral inﬂow pattern from a normal one.

Estimation of Filling Pressures Transmitral E velocity relates directly with LAP and inversely with Tau. This can be expressed mathematically as: E α LAP/Tau or LAP α E × Tau. Since Vp and Ea relate inversely with Tau, the above equation can be expressed as: LAP α E (1/Vp)

Early Annular Diastolic Velocity The left ventricle has two major vectors of contraction, circumferential and longitudinal. The longitudinal vectors result in shortening of the LV long axis and descent of the mitral annulus toward the apex. The velocity of this motion can be readily obtained with tissue Doppler by placing the sample volume at a corner of the annulus; the recorded velocities reﬂect the longitudinal vector of contraction and relaxation of that particular wall at its base (Fig. 15-10). Although one can obtain recordings from the septal, lateral, anterior, and inferior corners of the annulus, in routine clinical practice the septal and lateral corners provide most of the needed information.39 The early diastolic velocity (referred to in the literature as Ea, Em, or E′) has been shown in experimental animal work and in humans to relate well with invasive indices of relaxation such as Tau, (−)dP/dt, and the lowest diastolic LVP.40–41 In addition, Ea declines gradually with

or LAP α E (1/Ea). From these derivations, one should expect E/Vp and E/Ea to relate directly with LAP. In 1997, Garcia et al. reported a good relation between E/Vp and mean PCWP in patients in sinus rhythm.38 As noted in Figure 15-11, an E/Vp greater than 1.8 is predictive of a mean PCWP of at least 15 mmHg; however, the speciﬁcity is greater when the ratio is greater than 2.5. E/Vp has the added advantage that it can be applied to patients in atrial ﬁbrillation.45 Likewise, in 1996, our laboratory reported a good correlation between E/Ea and mean PCWP (Fig. 15-12A).44 An estimate of mean PCWP can be obtained with the equation Mean PCWP = 1.25E/Ea + 1.9.

FLOW PROPAGATION VELOCITY

A

B

C

Figure 15-9 A, Color Doppler image obtained in an apical four-chamber view with the M-mode cursor positioned through the center of the mitral inflow. B, Transmitral velocity with a measurement of the E velocity. C, The color M-mode tracing was obtained with the aliasing velocity set at 70% of E. Vp (flow propagation velocity) is measured as the slope of the aliasing velocity.

Chapter 15 • Evaluation of Intracardiac Filling Pressures ANNULAR VELOCITY WITH TISSUE DOPPLER 5

4.3 MHz

.21

5

4.3 MHz 10

10 15

15 15 –.21 10

Sa

5 [cm] –5 –10 Ea

Aa

–15 –20

–1.5

A

–1.0

–0.5

100mm/s

Septal

0

–1.5

B

–1.0

–0.5

100mm/s

0.0

Lateral

Figure 15-10 Recordings of annular velocity from the A, septal and B, lateral corners using tissue Doppler. Sa, peak systolic velocity; Ea, early diastolic velocity (also referred to as Em and E′); Aa, atrial velocity.

Figure 15-11 At left is the transmitral velocity and flow propagation velocity (Vp) from a patient with clinical heart failure and an ejection fraction of 35%; E/Vp is 6.0. At right (top) is the correlation between mean pulmonary capillary wedge pressure (PW) and Vp reported by Garcia, with (bottom) 95% confidence limits. (Modified from Garcia MJ et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997; 29:448–454.)

Our ﬁndings have been conﬁrmed by other investigators.46 An E/Ea ratio of no greater than 8 is over 90% predictive of a mean PCWP less than 15 mmHg, while a ratio of at least 15 is over 90% predictive of a mean PCWP of at least 15 mmHg. In the range between 9 and 14, the presence of LA enlargement, a pseudonormal transmitral velocity, or prolonged AR–AMV can be very helpful in supporting a diagnosis of elevated ﬁlling pressures. Importantly, E/Ea can predict ﬁlling pressures fairly well in patients with normal ejection fraction, including those with hypertrophic cardiomyopathy (see Fig. 12B).34,39 It can also be applied to patients with sinus tachycardia and atrial ﬁbrillation.47,48 When tested against several other indices, E/Ea was

found by Ommen et al. to be the most accurate in estimating ﬁlling pressures.46

Limitations of E/Vp E/Vp performs particularly well in dilated ventricles. However, it is limited in patients with concentric hypertrophy and small hyperdynamic ventricles with little space for ﬂow propagation to occur (see Chapter 11). Consequently, these patients can have normal Vp and E/Vp despite having impaired relaxation and elevated LAPs (Fig. 15-13). Recent studies have shown that in

187

188

Chapter 15 • Evaluation of Intracardiac Filling Pressures 35

45 r = 0.87 n = 60

r = 0.76 n = 35

30 LV pre-A pressure (mmHg)

Mean PCWP (mmHg)

40 35 30 25 20 15 10 5

25 20 15 10 5 0

0 0

5

10

15

20

25

30

5

E/Ea

A

10

15 E/Ea

B

E/Vp = 1.3

patients with normal LV size and EFs, E/Ea estimates ﬁlling pressures with more accuracy than does E/Vp (Fig. 15-14).39,46 Vp is also limited by a lower reproducibility resulting from variation in positioning of the M-mode cursor and in the actual measurement of the slope. Quantitative computerized techniques have been applied with excellent results, but they are not available commercially.49 Vp cannot be applied in the presence of mechanical inﬂow obstruction.

Limitations of E/Ea Although measurements of Ea are easy to obtain with good reproducibility using PW tissue Doppler, it is essential that the settings used provide a clear tracing with distinct edges. Some of the older ultrasound systems produced a blurred recording that signiﬁcantly limited the accuracy of the measurements. Some newer systems allow derivation of a recording of annular or myocardial velocities from a color tissue Doppler by placing a small region of interest in the particular segment. However, Ea with this

E/Ea = 16

20

Figure 15-12 A, Correlation of mean pulmonary capillary wedge pressure (PCWP) with E/Ea in a heterogeneous population of patients with a wide range of ejection fractions. B, Correlation of left ventricular pressure before atrial contraction (pre-A) with the ratio of the mitral peak Doppler E-wave to peak mitral annular velocity (E/Ea) in a group of patients with hypertrophic cardiomyopathy. (Modified from Nagueh SF et al: Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99:254–261; Nagueh SF et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1535.)

Figure 15-13 Example of a patient with systemic hypertension, diastolic heart failure, and a small end systolic left ventricular (LV) volume with an ejection fraction greater than 65%. Note the normal flow propagation velocity (Vp) of 60 cm/s. The mitral E velocity (left upper panel) is 80 cm/s, resulting in an E/Vp of 1.3, consistent with normal mean pulmonary capillary wedge pressure (PCWP). In contrast, peak mitral annular velocity (Ea) from the lateral wall (left lower panel) is much reduced (5 cm/s), and the E/Ea ratio is 16, indicative of an elevated mean PCWP.

new technology is consistently lower than when derived with PW Doppler; this results in a diﬀerent set of normal values. Given that all of the literature relating E/Ea to ﬁlling pressures has been obtained using PW tissue Doppler, this technology should be the one used for this purpose. Although Ea relates to global indices of LV relaxation, one must realize that it is a regional index. Errors can, therefore, occur when one extrapolates a single measurement to the entire ventricle, particularly in patients with regional wall motion abnormalities and in those with excessive cardiac translation (since the velocities are measured relative to transducer position). For instance, a patient with acute myocardial infarction can have a depressed Ea in the aﬀected wall and an augmented one in a distant site that is compensating with hyperdynamic motion.39 Because of the preload dependency of Ea in normal hearts, the ratio E/Ea does not reﬂect ﬁlling pressures accurately in normal young subjects or in patients with primary mitral regurgitation or pericardial constriction.50,51 However, the presence of functional mitral regurgitation in a depressed ventricle does not aﬀect the

Chapter 15 • Evaluation of Intracardiac Filling Pressures accuracy of this index.50 Preliminary observations in our laboratory using animal experiments suggest that even in depressed ventricles, Ea still has some preload dependency, particularly at the extremes of high LAPs.52 The clinical correlate of this is seen occasionally in young patients with dilated cardiomyopathy and severe heart failure, who, despite having a restrictive mitral inﬂow pattern, continue to have a normal Ea at the lateral base. Ea in the septum, however, is usually reduced. These limitations lead to the question of where Ea should be measured: septum, lateral wall, or both? In a recent study from our laboratory, an average of the two sites provided a good estimate of mean PCWP in dilated ventricles with a depressed EF;

IMPACT OF LVEF ON ESTIMATION OF FILLING PRESSURES USING TISSUE DOPPLER AND FLOW PROPAGATION VELOCITY r = 0.5 p < 0.001 PCWP (mmHg)

PCWP (mmHg)

30

30

20

r = 0.7 p < 0.001

10

0 0

1

2

3

4

E/Vp

Newer (Less Validated) Methods With a decline in myocardial relaxation, not only does Ea fall, but its onset gets delayed relative to that of transmitral velocity (Fig. 15-15).53,54 The time interval between onset of mitral inﬂow and onset of Ea (TEa-E) relates directly with Tau (r = 0.93) in experimental animal studies and is not altered by changes in LAP.54 TEa-E is derived by subtracting Q-Ea (the interval from the Q-wave on electrocardiogram to the onset of Ea) from Q-E (the interval from the Q-wave to the onset of mitral inﬂow) (see Fig. 15-15). Previous studies have shown that mean LAP can be derived from the equation LAP = LVes × e−IVRT/Tau,

20

10 0

the same was true for patients with regional wall motion abnormalities.39 However, in patients with normal wall motion and EF, the lateral wall was found to provide a better estimate of mean PCWP. Like E/Vp, E/Ea cannot be used in the presence of mitral inﬂow obstruction. The new European guidelines on diastolic heart failure suggest averaging the septal and lateral annuli.52a

5

10

15

20

25

E/Ea-lateral LVEF > 50%

Figure 15-14 Correlation of mean pulmonary capillary wedge pressure (PCWP) with ratio of mitral peak Doppler E-wave and flow propagation velocity (E/Vp) and with ratio of E to peak mitral annular velocity (E/Ea) in a population of patients with ejection fractions greater than 50%. Note the larger scatter and lower correlation coefficient for E/Vp. (Modified from Rivas-Gotz C et al: Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity. Am J Cardiol 2003;91:780–784.)

where LVes = end systolic LVP.55 Our group has tested a noninvasive version of this equation that substitutes TEa-E for Tau and 0.9 × systolic blood pressure for LVes. The results were accurate across a wide range of LVEFs (Fig. 15-16).54 A simpliﬁed approach consisting of the ratio of IVRT to TEa-E related inversely with mean PCWP and allowed separation of patients with normal versus elevated (≥15 mmHg) pressures with a sensitivity and speciﬁcity of 91% and 89%, respectively (Fig. 15-17). Since this new method does not require a measurement of the transmitral E velocity, it is applicable in the presence of inﬂow obstruction and in patients with mitral regurgitation.56 However, as with all new methods, it requires validation by other investigators. Its main limitation is that TEa-E is a small time interval derived from two diﬀerent intervals measured at separate times, and this may limit its reproducibility. Future developments may allow simultaneous recording of annular motion and mitral inﬂow, facilitating the measurement of this interval.

TRANSMITRAL VELOCITY

Figure 15-15 Transmitral velocity, lateral annular velocity, and isovolumic relaxation time (IVRT) in a 75-year-old hypertensive woman with concentric left ventricular hypertrophy, a normal ejection fraction, and diastolic heart failure. The transmitral velocity is elevated (180 cm/sec) in part because of annular calcification resulting in some inflow stenosis. Note the delay in onset of Ea relative to the onset of the transmitral velocity; TEa-E was 40 msec and IVRT/TEa-E was 1.05.

LATERAL ANNULAR VELOCITY

TEa-E = 40 msec IVRT/TEa-E = 1.05

189

190

Chapter 15 • Evaluation of Intracardiac Filling Pressures RELATION OF TEa–E TO FILLING PRESSURES 40

Doppler PCWP – Catheter PCWP

35 Doppler PCWP (mmHg)

20

r = 0.84 n = 33 p < 0.01

30 25 20 15 10 5

15 10 5 0 –5 –10 –15 –20

0

5

10 15

20 25

30 35 15

5

Catheter PCWP (mmHg)

10

15

PCWP = LVes × e–IVRT/Tau = LVes × e–IVRT/TEa–E where LVes = 0.9 × SBP

25

30

35

40

tively simple to use. The use of E/Vp or E/Ea may not be required but can provide valuable conﬁrmation of the ﬁndings derived from the transmitral velocity. However, there are instances where E/Ea and E/Vp should be used. These include: (1) an E/A less than 1.0 with E greater than 80 cm/sec (E/Ea may be elevated if Ea is <8 cm/sec); (2) E and A in close proximity due to a reduced diastolic ﬁlling time; and (3) junctional or pacemaker rhythm in the presence of atrial ﬁbrillation (in these instances, a very short DT [<150 msec] and/or IVRT [<60 msec] are speciﬁc for elevated LAP).

40 Sens = 91% Spec = 89% 30 Mean PCWP (mmHg)

20

(Doppler PCWP + Catheter PCWP)/2

Figure 15-16 Relation of cathetermeasured mean pulmonary capillary wedge pressure (PCWP) to PCWP derived by Doppler using the equation LVes × e−IVRT/Ea–E and substituting TEa-E for Tau. The 95% confidence limits obtained with the BlandAltman analysis are shown on the right. SBP, systolic blood pressure. (Modified from Rivas-Gotz C et al: Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation. Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470.)

20

Patients with a Preserved Ejection Fraction

The following comprehensive approach can provide an excellent clinical tool for the estimation of ﬁlling pressures in patients presenting with symptoms suggestive of heart failure.

In the presence of near-normal (>40%) EF, E/Vp or E/Ea is recommended for the estimation of mean PCWP, with the latter preferred in hypertrophic hearts with small LV cavities. An enlarged left atrium is a sensitive marker of diastolic dysfunction in these patients, particularly when conﬁrmed by observing a reduced Ea or Vp. Likewise, LAP is almost always less than 15 mmHg when LA size and systolic descent of the annulus are normal (E/Ea is usually also normal). Although transmitral velocity is insensitive to an elevated LAP, we have found that when E/A is less than 0.70 and E is no greater than 60 cm/sec, mean PCWP is seldom, if ever, higher than 15 mmHg.57 The transmitral and the pulmonary vein velocities remain speciﬁc for elevated LAP when the E/A ratio is at least 2.0 or S/D is less than 1, as long as the left atrium is enlarged and Vp or Ea conﬁrm the presence of impaired relaxation. AR–AMV may be used to estimate LVEDP, although with less sensitivity than in the presence of a low EF. In a prospective study of patients presenting with possible heart failure, we found that a comprehensive approach that combined echocardiographic and Doppler ﬁndings was superior to measurements of B-type natriuretic peptide (BNP) in detecting heart failure in patients with a normal EF.58 Using the Framingham criteria as the clinical standard, a BNP greater than 150 pg/ml was 79% sensitive and 85% speciﬁc, whereas a comprehensive echo-Doppler evaluation was 85% sensitive and 96% speciﬁc.

Patients with a Depressed Ejection Fraction

Evaluating Discrepant Results

In the presence of a depressed EF (<40%), the mitral E/A ratio, IVRT, and DT are excellent indicators of mean PCWP and are rela-

All of the currently available methods of estimating ﬁlling pressures are imperfect, and consequently there are times when these

10

0 0

5

10

15

20

IVRT/TEa − E Figure 15–17 Correlation between catheter-measured mean pulmonary capillary wedge pressure (PCWP) and isovolumic relaxation time (IVRT)/ TEa-E. The vertical line demarcates a cutoff of 2 for IVRT/ TEa-E, and the horizontal line demarcates a cutoff of 15 for PCWP. TEa-E, time interval between onset of mitral inflow and onset of early diastolic velocity; Sens, sensitivity; Spec, specificity. (Modified from Rivas-Gotz C et al: Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation. Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470.)

A Recommended Algorithm for Estimation of Filling Pressures

Chapter 15 • Evaluation of Intracardiac Filling Pressures methods yield discrepant results, their ﬁndings are in a “gray area” (such as an E/Ea in the 10–15 range), or their estimates of ﬁlling pressure do not match the clinical ﬁndings. In all of these instances, it helps to look for other supporting data. For instance, in a patient with dyspnea, if several echocardiographic or clinical ﬁndings (see Box 15-1) indicate a very high probability for abnormal LV relaxation and one sees a stage II diastolic dysfunction pattern with short (<90 ms) IVRT, mean LAP is likely to be elevated even if E/Ea is between 10 and 15. In day-to-day practice, we ﬁnd the estimation of pulmonary artery systolic pressure (PASP) from the peak velocity of tricuspid regurgitation (TR) to be crucial in resolving diﬃcult cases and helping conﬁrm our estimates of ﬁlling pressures. This requires obtaining a good CW Doppler recording of TR, which may need at times signal enhancement with injections of agitated saline. Since PASP = 4(peak TR velocity)2 + mean RAP, it is important to learn well how to estimate mean RAP (see Chapters 10 and 14). As a general rule, it can be stated that an elevated LAP results in an increased PASP and vice versa (with the exception of instances where cardiac output is extremely reduced). For instance, a dyspneic patient with LA enlargement and an estimated PASP of greater than 40 mmHg is likely to have an elevated mean LAP until proven otherwise. An accurate estimate of PASP can therefore serve as the decisive factor in establishing the presence or absence of an elevated LAP in diﬃcult cases. With the proper use of the concepts described in this chapter, one can establish a cardiac source of dyspnea in the vast majority of patients evaluated.

FUTURE RESEARCH Recent technological improvements have allowed measurements of myocardial strain and strain rate along diﬀerent vectors of contraction and relaxation. Strain is tissue deformation in response to an applied force (see Chapter 12). It represents a fractional change in length (i.e., ΔL/Li). Strain rate is the fractional rate of deformation (i.e., [ΔL/Li]/t). Measurements of systolic and diastolic strain rates provide a new approach to the quantitation of regional function. Because strain is derived from the movement of two adjacent points in the myocardium, the values obtained are less sensitive to cardiac translation. Preliminary studies suggest that strain rate may be superior to myocardial velocities in detecting relaxation abnormalities.59–62 Similarly, other new developments allow an assessment of the clockwise rotation of the base and the counterclockwise rotation of the apex during contraction. This twisting motion of the heart (also referred to as torsion) is an integral part of ventricular ejection, while the untwisting that occurs during LV relaxation is an integral part of rapid ventricular ﬁlling.63,64 Quantiﬁcation of this motion may provide a more accurate global assessment of contraction and relaxation.65,66 Conceivably, one might be able to combine standard indices such as E velocity or IVRT with these newer markers of relaxation to derive a more accurate estimation of LV ﬁlling pressures. REFERENCES 1. Rahimtoola SH, Loeb HS, Ehsani A, et al: Relationship of pulmonary artery to left ventricular diastolic pressures in acute myocardial infarction. Circulation 1972;46:283–290. 2. Schabelman S, Schiller NB, Silverman NH, et al: Left atrial volume estimation by two-dimensional echocardiography. Cathet Cardiovasc Diagn 1981;7:165–178.

3. Lester SJ, Ryan EW, Schiller NB, et al: Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol 1999; 84:829–832. 4. Lang RM, Bierig M, Devereux RB, et al: Recommendation for chamber quantiﬁcation: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantiﬁcation Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 5. Kircher B, Abbott JA, Pau S, et al: Left atrial volume determination by biplane two-dimensional echocardiography: Validation by cine-computed tomography. Am Heart J 1991;121:864–871. 6. Rodevan O, Bjornerheim R, Ljosland M, et al: Left atrial volumes assessed by three- and two-dimensional echocardiography compared to MRI estimates. Int J Card Imaging 1999;15:397–410. 7. Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Deﬁnitions and terminology. Prog Cardiovasc Dis 2005;47:307–313. 8. Simonson JS, Schiller NB: Descent of the base of the left ventricle: An echocardiographic index of left ventricular function. J Am Soc Echocardiogr 1989;2:25–35. 9. Barbier P, Solomon SB, Schiller NB, et al: Left atrial relaxation and left ventricular systolic function determine left atrial reservoir function. Circulation 1999;100:427–436. 10. Basnight MA, Gonzalez MS, Kershenovich SC, et al: Pulmonary venous ﬂow velocity: Relation to hemodynamics, mitral ﬂow velocity and left atrial volume, and ejection fraction. J Am Soc Echocardiogr 1991;4:547–558. 11. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular ﬁlling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the diﬀerence in duration of pulmonary venous and mitral ﬂow velocity at atrial contraction. J Am Coll Cardiol 1993; 22:1972–1982. 12. Ishida Y, Meisner JS, Tsujioka K, et al: Left ventricular ﬁlling dynamics: Inﬂuence of left ventricular relaxation and left atrial pressure. Circulation 1986; 74:187–196. 13. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 14. Choong CY, Abascal VM, Thomas JD, et al: Combined inﬂuence of ventricular loading and relaxation on the transmitral ﬂow velocity proﬁle in dogs measured by Doppler echocardiography. Circulation 1988;78:672–683. 15. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiﬀness from the time for deceleration of early left ventricular ﬁlling. Circulation 1995;92:1933–1939. 16. Kuecherer HF, Muhiudeen IA, Kusumoto FM, et al: Estimation of mean left atrial pressure from transesophageal pulsed Doppler echocardiography of pulmonary venous ﬂow. Circulation 1990;82:1127–1139. 17. Yamamoto K, Nishimura RA, Chaliki HP, et al: Determination of left ventricular ﬁlling pressure by Doppler echocardiography in patients with coronary artery disease: Critical role of left ventricular systolic function. J Am Coll Cardiol 1997;30:1819–1826. 18. Habib GB, Zoghbi WA: Doppler assessment of right ventricular ﬁlling dynamics in systemic hypertension: Comparison with left ventricular ﬁlling. Am Heart J 1992;124:1313–1320. 19. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular ﬁlling after one year of antihypertensive treatment: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071–1076. 20. Nishimura R, Appleton C, Redﬁeld M, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular ﬁlling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226–1233. 21. Quiñones MA: Doppler assessment of left ventricular diastolic function. In Navin C (ed): Doppler echocardiography, 2nd ed. Philadelphia, Lea & Febiger, 1992:197–215. 22. Sartori MP, Quiñones MA, Kuo LC: Relation of Doppler-derived left ventricular ﬁlling parameters to age and radius/thickness ratio in normal and pathologic states. Am J Cardiol 1987;59:1179–1182. 23. Nagueh SF, Kopelen HA, Zoghbi WA: Feasibility and accuracy of Doppler echocardiographic estimation of pulmonary artery occlusive pressure in the intensive care unit. Am J Cardiol 1995;75:1256–1262. 24. Aurigemma GP, Gottdiener JS, Shemanski L, et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2001;37: 1042–1048.

191

192

Chapter 15 • Evaluation of Intracardiac Filling Pressures 25. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial ﬁbrillation and congestive heart failure in patients ≥65years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54–58. 26. Vanoverschelde JL, Robert AR, Gerbaux A, et al: Noninvasive estimation of pulmonary arterial wedge pressure with Doppler transmitral ﬂow velocity pattern in patients with known heart disease. Am J Cardiol 1995; 75:383–389. 27. Pozzoli M, Capomolla S, Pinna G, et al: Doppler echocardiography reliably predicts pulmonary artery wedge pressure in patients with chronic heart failure with and without mitral regurgitation. J Am Coll Cardiol 1996;27: 883–893. 28. Rossvoll O, Hatle LK: Pulmonary venous ﬂow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696. 29. Hurrell DG, Nishimura RA, Ilstrup DM, et al: Utility of preload alteration in assessment of left ventricular ﬁlling pressure by Doppler echocardiography: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1997;30:459–467. 30. Temporelli PL, Corra U, Imparato A, et al: Reversible restrictive left ventricular diastolic ﬁlling with optimized oral therapy predicts a more favorable prognosis in patients with chronic heart failure. J Am Coll Cardiol 1998;31:1591–1597. 31. Hansen A, Haass M, Zugck C, et al: Prognostic value of Doppler echocardiographic mitral inﬂow patterns: Implications for risk stratiﬁcation in patients with chronic congestive heart failure. J Am Coll Cardiol 2001; 37:1049–1055. 32. Yong Y, Nagueh SF, Shimoni S, et al: Deceleration time in ischemic cardiomyopathy: Relation to echocardiographic and scintigraphic indices of myocardial viability and functional recovery after revascularization. Circulation 2001;103:1232–1237. 33. Yamamoto K, Nishimura RA, Chaliki HP, et al: Determination of left ventricular ﬁlling pressure by Doppler echocardiography in patients with coronary artery disease: Critical role of left ventricular systolic function. J Am Coll Cardiol 1997;30:1819–1826. 34. Nagueh SF, Lakkis NM, Middleton KJ, et al: Doppler estimation of left ventricular ﬁlling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99:254–261. 35. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32: 865–875. 36. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular ﬁlling ﬂow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27:365–371. 37. Brun P, Tribouilly C, Duval AM, et al: Left ventricular ﬂow propagation during early ﬁlling is related to wall relaxation: A colour M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 38. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular ﬁlling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 39. Rivas-Gotz C, Manolios M, Thohan V, et al: Impact of left ventricular ejection fraction on estimation of left ventricular ﬁlling pressures using tissue Doppler and ﬂow propagation velocity. Am J Cardiol 2003;91: 780–784. 40. Nagueh SF, Sun H, Kopelen HA, et al: Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 2001;37:278–285. 41. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 199;79:921–928. 42. Rodriguez L, Garcia M, Ares M, et al: Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inﬂow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131:982–987. 43. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 44. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527–1535. 45. Nagueh SF, Kopelen HA, Quiñones MA: Doppler estimation of left ventricular ﬁlling pressure in atrial ﬁbrillation. Circulation 1996;94:2138– 2145. 46. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of

47. 48. 49.

50. 51.

52. 52a.

53. 54.

55.

56. 57.

58.

59. 60.

61. 62.

63. 64. 65. 66.

left ventricular ﬁlling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. Nagueh SF, Mikati I, Middleton KJ, et al: Doppler estimation of left ventricular ﬁlling pressure in sinus tachycardia: A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. Sohn DW, Song JM, Zo JH, et al: Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial ﬁbrillation. J Am Soc Echocardiogr 1999;12:927–931. Stügaard M, Smiseth OA, Risoe C, et al: Intraventricular early diastolic ﬁlling during acute myocardial ischemia, assessment by multigated color M-mode Doppler echocardiography. Circulation 1993;88:2705– 2713. Bruch C, Stypmann J, Gradaus R, et al: Usefulness of tissue Doppler imaging for estimation of ﬁlling pressures in patients with primary or secondary pure mitral regurgitation. Am J Cardiol 2004;93:324–328. Ha JW, Oh JK, Ling LH, et al: Annulus paradoxus: Transmitral ﬂow velocity to mitral annular velocity ratio is inversely proportional to pulmonary capillary wedge pressure in patients with constrictive pericarditis. Circulation 2001 28;104:976–978. Nagueh SF, Rao L, Soto J, et al: Hemodynamic mechanisms that account for the variable eﬀect of preload on tissue Doppler early diastolic velocity [abstract]. Circulation 2002;107(Suppl 3):2306. Paulus WJ, Tschope C, Sanderson JE, et al: How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539–2550. Hasegawa H, Little WC, Ohno M, et al: Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol 2003;41: 1590–1597. Rivas-Gotz C, Khoury DS, Manolios M, et al: Time interval between onset of mitral inﬂow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation. Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470. Thomas JD, Flachskampf FA, Chen C, et al: Isovolumic relaxation time varies predictably with its time constant and aortic and left atrial pressure: Implications for the noninvasive evaluation of ventricular relaxation. Am Heart J 1992;124:1305–1313. Diwan A, McCulloch M, Lawrie GM, et al: Doppler estimation of left ventricular ﬁlling pressures in patients with mitral valve disease. Circulation 2005;111:3281–3289. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal noninvasive assessment of left ventricular ﬁlling pressures: A comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004;20:2432–2439. Dokainish H, Zoghbi WA, Lakkis NM, et al: Comparative accuracy of B-type natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure. Am J Cardiol 2004;93:1130– 1135. Stoylen A, Slordahl S, Skjelvan GK, et al: Strain rate imaging in normal and reduced diastolic function: Comparison with pulsed Doppler tissue imaging of the mitral annulus. J Am Soc Echocardiogr 2001;14:264–274. Kukulski T, Jamal F, D’Hooge J, et al: Acute changes in systolic and diastolic events during clinical coronary angioplasty: A comparison of regional velocity, strain rate, and strain measurement. J Am Soc Echocardiogr 2002;15:1–12. Takemoto Y, Pellikka PA, Wang J, et al: Analysis of the interaction between segmental relaxation patterns and global diastolic function by strain echocardiography. J Am Soc Echocardiogr 2005;18:901–906. Kato TS, Noda A, Izawa H, et al: Discrimination of nonobstructive hypertrophic cardiomyopathy from hypertensive left ventricular hypertrophy on the basis of strain rate imaging by tissue Doppler ultrasonography. Circulation 2004;110:3808–3814. Helle-Valle T, Crosby J, Edvardsen T, et al: New noninvasive method for assessment of left ventricular rotation: Speckle tracking echocardiography. Circulation 2005;112:3149–3156. Notomi Y, Lysyansky P, Setser RM, et al: Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol 2005;45:2034–2041. Notomi Y, Setser RM, Shiota T, et al: Assessment of left ventricular torsional deformation by Doppler tissue imaging: Validation study with tagged magnetic resonance imaging. Circulation 2005;111:1141–1147. Notomi Y, Martin-Miklovic MG, Oryszak SJ, et al: Enhanced ventricular untwisting during exercise: A mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation 2006;113:2524–2533.

CHUWA TEI, MD YUTAKA OTSUJI, MD, PhD

16

Evaluation of Tei Index in Heart Failure INTRODUCTION Concept of the Tei Index PATHOPHYSIOLOGY Measurement of the Tei Index CLINICAL RELEVANCE Load Dependency of the Tei Index The Tei Index and Prognosis

Detection of Cardiac Dysfunction in Various Diseases Hemodynamic Assessment Evaluation of Right Ventricular Function Effects of Interventions Evaluation of Patients with Tachycardia Limitations FUTURE RESEARCH

INTRODUCTION In clinical practice, we use many indices of cardiac function, such as left ventricular ejection fraction (LVEF), maximal positive or negative pressure/time change (dP/dt), Tau (τ), stiﬀness, maximum elastance, and others. The number of indices of cardiac function indicates that the left ventricle performs multiple roles during a single cardiac cycle, and each index of cardiac function expresses only a partial aspect of a heterogeneous process. This can explain frequent discrepancies between patients’ status and the value of functional indices. One such example is relatively preserved LVEF in patients with end-stage chronic heart failure due to cardiac amyloidosis (Fig. 16-1).1,2 Why is LVEF often discrepant with patient status in cardiac amyloidosis? There can be two reasons: (1) LVEF does not express left ventricular (LV) diastolic function, which is severely impaired in this pathology,3 and (2) LVEF does not express true ventricular systolic function, especially in the presence of increased LV wall thickness. Increased LV wall thickness, typically seen in patients with cardiac amyloidosis, hypertrophic cardiomyopathy, or hypertensive heart disease, decreases wall tension, which allows for good wall motion and ejection even in the presence of signiﬁcant myocardial systolic dysfunction.4 Therefore, relatively preserved LVEF or wall motion in patients with cardiac amyloidosis does not mean that their systolic function is only mildly impaired. Severely prolonged isovolumic contraction time (ICT) (see Fig. 16-1), despite normal LVEF in patients with cardiac amyloidosis, highly suggests that systolic function is severely impaired. Further, normal LVEF in the presence of LV hypertrophy (LVH), typically seen in patients with “diastolic heart failure,” may not mean

normal systolic function. Figure 16-2 shows a patient with typical diastolic heart failure, with heart failure symptoms, a normal EF, and LVH. Cardiac time interval analysis demonstrates abnormally prolonged ICT and isovolumic relaxation time (IRT), indicating signiﬁcant impairment of both systolic and diastolic functions.5 Therefore, normal LVEF does not mean normal systolic function in patients with so-called diastolic heart failure, which is one of the most common causes of chronic heart failure (HF).6 The 2005 guidelines of the American Heart Association/ American College of Cardiology prefers “HF and Normal LVEF” for this entity and does not use the phrase “diastolic heart failure.”7 Even in patients with dilated cardiomyopathy, frequently considered as pure systolic dysfunction,8 it is known that LVEF only fairly correlates with exercise capacity, which is closely related to patient status and prognosis.9 Being the most representative index of cardiac function, LVEF expresses only systolic ejection among multiple aspects of systolic and diastolic functions. Therefore, we often encounter discrepancies between values of cardiac functional indices and patient status. Physicians need to evaluate patient status subjectively by combining multiple sources of information, including various indices of cardiac function. In this context, it is reasonable to create an index of cardiac function, which can be a global expression combining systole and diastole or multiple aspects of heterogeneous LV function.

Concept of the Tei Index Due to the big clinical need for an index expressing global cardiac function, the concept of the Tei index has been postulated.10 193

194

Chapter 16 • Evaluation of Tei Index in Heart Failure LV-Tei index

Aortic pressure LV pressure LA pressure

ICT

ET

IRT

Tei index = (a – b)/b = (ICT + IRT)/ET

a Mitral inflow Figure 16-1 End-stage chronic heart failure despite relatively preserved left ventricular ejection fraction (73%) in a patient with cardiac amyloidosis. IVCT (isovolumic contraction time) and IVRT (isovolumic relaxation time) are severely prolonged. ET (ejection time) is severely shortened.

b Aorta outflow

Figure 16-3 Concept of the Tei index. Isovolumic contraction time (ICT) and isovolumic relaxation time (IRT) express systolic and diastolic functions. Ejection time (ET) expresses stroke volume. ICT/ET and IVRT/ET can be sensitive and heart-rate-independent indices of systolic and diastolic function, respectively. Therefore, the sum of ICT/ET and IRT/ET, which is the Tei index, expresses combined systolic and diastolic, therefore global, cardiac function. (From Tei C: New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol 1995;26:135–136.)

PATHOPHYSIOLOGY Measurement of the Tei Index The Tei index can be measured practically with conventional Doppler echocardiography.10,11 Interval a between cessation and re-onset of mitral ﬁlling ﬂow includes ICT, ET, and IRT (Fig. 16-4). Interval b between onset and cessation of aortic ejection ﬂow equals ET. Therefore, the Tei index can be obtained by the following formula: Tei index = (a − b)/b = (ICT + IRT)/ET. Figure 16-2 Abnormally prolonged ICT (isovolumic contraction time) and IRT (isovolumic relaxation time) despite normal left ventricular ejection fraction (78%) in a patient with “diastolic heart failure” due to left ventricular hypertrophy.

ICT is inversely proportional to LV peak positive dP/dt and expresses systolic contraction (Fig. 16-3).12 LV ejection time (ET) is proportional to stroke volume, which can be reduced either by systolic or diastolic dysfunction.13 IRT is inversely proportional to LV peak negative dP/dt and expresses diastolic relaxation.12 However, these cardiac time intervals are heart rate dependent. Systolic dysfunction can result in prolonged ICT and shortened ET. Therefore, ICT/ET (which is ICT corrected by ET) can be a sensitive index to express systolic dysfunction. ICT/ET is also expected to be heart rate independent, due to the cancellation of heart rate dependencies of ICT and ET. For the same reason, IRT/ET (which is IVT corrected by ET) can be a sensitive and heart-rate-independent index to express diastolic function. The sum of ICT/ET and IRT/ET is the Tei index.10,11 Therefore, the Tei index has the potential to express combined systolic and diastolic or global cardiac function.

This measurement is simple, practical, and reproducible. Multiple investigators in multiple institutions have measured the Tei index with almost identical normal values with a narrow range both for the LV and the right ventricular (RV) Tei index.14,15 The normal LV and RV Tei indices in our institution are 0.38 ± 0.04 and 0.28 ± 0.04, respectively. Although standard pulsed Doppler echocardiographic measurement of the Tei index is practical and reproducible, multiple investigators have applied alternative approaches. One such approach is to utilize pulsed tissue Doppler annular velocity to measure the Tei index.16,17 This method has the merit of measuring intervals a and b simultaneously in a single cardiac cycle, while standard pulsed ﬂow Doppler echocardiography requires measurement of intervals a and b in diﬀerent cardiac cycles. Multiple investigators have reported that the Tei index by pulsed tissue Doppler echocardiography correlates well with that by pulsed ﬂow Doppler echocardiography.16,18 However, discrepancy between the tissue Doppler Tei index and the ﬂow Doppler Tei index has also been reported.19–21 It may be questionable whether the Tei index from tissue Doppler annular velocity expresses global cardiac function. Other approaches, including M-mode color tissue Doppler echocardiogram of mitral leaﬂets and conventional M-mode echocardiogram of mitral and aortic leaﬂets, have been utilized to measure the Tei index, with good agreement

Chapter 16 • Evaluation of Tei Index in Heart Failure

Figure 16-4 How to measure the Tei index. Interval a between cessation and onset of mitral filling flow includes isovolumic contraction time (ICT), ejection time (ET), and isovolumic relaxation time (IRT). Interval b from onset to cessation of aortic ejection flow is ET. Therefore, the Tei index (0.35) can be simply calculated as (a − b)/b.

Figure 16-5 Measurement of the left ventricular Tei index in a patient with dilated cardiomyopathy. Tei index was clearly abnormal with a value of 0.99.

with the standard pulsed Doppler ﬂow method.22,23 The LV area/ time curve by automated border detection was also utilized to measure the Tei index, with good agreement with the standard pulsed ﬂow Doppler method.24

CLINICAL RELEVANCE The Tei index was initially measured in normal subjects as well as in patients with clear RV or LV dysfunction.10,11 The value of the Tei index has a narrow range in normal subjects. The RV Tei index is clearly increased (0.67 ± 0.20) in patients with RV dysfunction, such as those with RV infarction, dysplasia, or cor pulmonale. The LV Tei index is also clearly increased (0.92 ± 0.22) in patients with idiopathic or ischemic cardiomyopathies (Fig. 16-5). There is no overlap of values between normal subjects and patients with clear RV or LV dysfunction. Therefore, the Tei index is clearly abnormal in patients with a signiﬁcant level of such dysfunction.

Load Dependency of the Tei Index Because load dependency needs to be evaluated for all indices of cardiac function, the Tei index has also been evaluated regarding its load dependency. Studies have shown no signiﬁcant correlation between heart rate and the Tei index in normal subjects.10 Dependency for heart rate has further been investigated by changing heart rate in patients with a pacemaker implantation.25 The Tei index signiﬁcantly increased with elevation of heart rate in this study. However, the increase was subtle, from a mean value of 0.40 at 50 bpm to 0.51 at 100 bpm. Therefore, the Tei index is generally heart rate independent in clinical practice. The Tei index has also been evaluated during preload modiﬁcations such as the Valsalva maneuver, leg lifting, or sublingual nitroglycerin administration in normal subjects as well as in patients with prior myocardial

infarction.26 These preload alterations caused an increase in the Tei index, but only to a small degree (0.034 ± 0.05) in normal subjects, and did not cause signiﬁcant changes in the Tei index in patients with prior myocardial infarction. Therefore, the Tei index is relatively preload independent in patients with cardiac disease. In addition, the Tei index has no signiﬁcant correlation with blood pressure in patients with LV dysfunction.11,27 Although these investigations indicate that the Tei index is generally load independent, aortic stenosis causes it to signiﬁcantly reduce. After surgery for valvular heart disease, patients with aortic stenosis showed a signiﬁcant 29% increase in the Tei index, while those with aortic regurgitation, mitral stenosis, or regurgitation showed only minor changes.28 Correction of the prolongation of ET by aortic stenosis was the main cause of increase in the Tei index after surgical valve replacement.

The Tei Index and Prognosis Because the Tei index is a global expression, it is related to multiple pathophysiologic parameters of cardiac function. The prognostic utility of the Tei index was initially evaluated in patients with cardiac amyloidosis.29 In this study, patients with a greater Tei index had signiﬁcantly worse survival (Fig. 16-6). Of note is that the Tei index enabled better separation of patients with poorer and better survival compared with LVEF. After this initial study, many studies have demonstrated the utility of the Tei index to evaluate prognosis in dilated cardiomyopathy, prior or acute myocardial infarction, chronic HF, and others.30–37 A strong relation between the Tei index and prognosis in patients with coronary artery disease suggests that the index may enable prediction of complications after acute myocardial infarction. An increased Tei index at admission to a coronary care unit predicted subsequent development of complications (Fig. 16-7).38–40 An increased Tei index greater than 0.70 before mitral valvuloplasty is also a risk factor, doubling postoperative mortality.41 Recently, the utility

195

196

Chapter 16 • Evaluation of Tei Index in Heart Failure of the Tei index to predict development of chronic HF or cardiac death has been demonstrated in a population-based cohort of elderly men.42,43 Therefore, an increased Tei index is a risk factor for the development of chronic HF as well as cardiac death. 1.0 0.8

(11)

0.6

(10)

(10)

(4)

0.4 0.2 0.0 0.0

0.5

1.0

1.5

2.0

2.5

3.0

Years Tei index ≤ 0.77 Tei index > 0.77 Figure 16-6 Relation between Tei index and survival in patients with cardiac amyloidosis. Increased Tei index was a significant risk factor of later mortality. (From Tei C, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664.)

0.6 0.5 0.4

ia

c

de

ry eu Ca

An

at h VT Br ad , Vf yc ar di Ru a No p co tu re m pl ica tio ns

sm

F

F

,A Af

CH

Sh

oc

k

Upper Normal Range

rd

Tei index

1.0

Figure 16-7 Relation between initial Tei index at admission to coronary care unit and subsequent complications in patients with acute anteroseptal myocardial infarction. (From Yuasa T, et al: Noninvasive prediction of complications with anteroseptal acute myocardial infarction by left ventricular Tei index. J Am Soc Echocardiogr 2005;18:20–25.)

Detection of Cardiac Dysfunction in Various Diseases Multiple studies have reported that rejection after cardiac transplantation can cause myocardial damage and result in an increase in the Tei index.44–47 The Tei index is also signiﬁcantly correlated with exercise capacity in several studies.48–52 Dobutamine stress echocardiography often requires subjective evaluation in patients with unclear response of LV wall motion. The Tei index showed signiﬁcant increase at peak stress only in patients with positive response for ischemia, suggesting an incremental role of the Tei index in evaluation by dobutamine stress echocardiography.53 Reperfusion in patients with acute myocardial infarction results in an improvement in cardiac function. An increased Tei index of greater than 0.50 suggests absence of adequate reperfusion with thrombolysis in myocardial infarction (TIMI) grade 3 in patients with acute anteroseptal myocardial infarction (Fig. 16-8).37,54 Because abnormalities in ICT, ET, and IRT by cardiac dysfunction can be augmented in ICT/ET and IRT/ET, the Tei index has the potential to express subtle changes in cardiac function. Many investigators have applied the Tei index to detect small changes in cardiac function by various conditions, including hypothyroidism,56 diabetes mellitus,57 acromegaly,58 preconditioning with preceding angina,59 sleep apnea syndrome,60 and others.

Hemodynamic Assessment As expected from its deﬁnition, the Tei index has close correlation with both systolic and diastolic functions, such as maximal + and − LV dP/dt, maximum mitral E-wave velocity, and τ.10,61 Although the Tei index does not include mid- to late-diastolic components, it has fair but signiﬁcant correlation with LV stiﬀness.62,63 The Tei index is also signiﬁcantly correlated with LV diastolic ﬁlling pressure. However, the correlation with pressure is modest, potentially due to the fact that LV ﬁlling pressure is determined by both ventricular function and loading.27,64,65 Nevertheless, the Tei index enables practical evaluation of impaired hemodynamics in patients with acute myocardial infarction with potentially minimal modiﬁcation of loading in the acute phase before aggressive interventions to alter loading.32,67 A Tei index greater than 0.6 suggests impaired hemodynamics with Forrester classiﬁcations II–IV in patients with acute anteroseptal myocardial infarction (Fig. 16-9). Further, the Tei index enables practical diﬀerentiation of normal from pseudonormal mitral ﬂow, deﬁned by mitral E/A greater than 1.0 with elevated

LV-Tei index

0.7

0.5

0.3

0.1

#6 #6 (–) (+) Reperfusion

#7 #7 (+) (–) Reperfusion

#8 #8 (+) (–) Reperfusion

#9 (–)

Figure 16-8 Relation between Tei index at admission to the coronary care unit and coronary reperfusion with thrombolysis in myocardial infarction, grade 3, immediately evaluated by angiography in patients with acute anteroseptal myocardial infarction. (From Kuwahara E, et al: Increased Tei index suggests absence of adequate coronary reperfusion in patients with first anteroseptal acute myocardial infarction. Circ J 2006;70:248–253.)

Chapter 16 • Evaluation of Tei Index in Heart Failure ❒

1.0

❒

Tei index

0.8

0.6

0.4

Upper normal

0.2

0 I

II

III

IV

Forrester class

High

Category III (uncommon)

Category IV (common)

Low

Left ventricular filling pressure

Figure 16-9 Relation between Tei index and Forrester’s hemodynamic classification evaluated by catheterization in patients with acute anteroseptal myocardial infarction. (From Takasaki K, et al: Noninvasive estimation of impaired hemodynamics in patients with acute myocardial infarction by Tei index. J Am Soc Echocardiogr 2004;17:615–621.)

Category I (common)

Category II (not uncommon)

Good

Poor Left ventricular function

Figure 16-10 Relation between cardiac function or Tei index and left ventricular filling pressure. Categories II and III cause discrepancy between cardiac function and the filling pressure. Patients in category III are uncommon, and those in category II cause discrepancy between left ventricular function and filling pressure. (From Zhang H, et al: Noninvasive estimation of left ventricular diastolic filling pressure from Doppler Tei index: Different feasibilities in patients with higher and lower early to late diastolic mitral flow velocity ratio. J Echocardiogr 2003;1:15–22.)

LV ﬁlling pressure.64,65 It may seem strange that the Tei index practically separates patients with mitral E/A greater than 1.0 with or without elevated LV ﬁlling pressure, while the index is only fairly correlated with ﬁlling pressure. The Tei index shows signiﬁcant and better correlation with LV ﬁlling pressure in patients with mitral E/A greater than 1.0 compared with those with mitral E/A no greater than 1.0 because LV function and its ﬁlling pressure can be placed into four categories (Fig. 16-10)68–69: ❒ ❒

Category I: normal LV function and normal ﬁlling pressure Category II: poor LV function and normal ﬁlling pressure

Category III: normal LV function and high ﬁlling pressure Category IV: poor LV function and high ﬁlling pressure

Patients in category III are not common, and those in category II seem to be the main reason for signiﬁcant but only fair correlation between the Tei index and LV ﬁlling pressure. Normal LV ﬁlling pressure despite LV dysfunction in category II suggests no signiﬁcant increase in preload, and most patients with a discrepant Tei index and ﬁlling pressure have mitral E/A of less than 1.0,68 being related to reduced preload.70 Therefore, the Tei index has signiﬁcant and good correlation with the LV ﬁlling pressure in patients with mitral E/A greater than 1.0 and enables feasible diﬀerentiation of normal from pseudonormal mitral ﬂow.64,65,71 A signiﬁcant correlation between the Tei index and brain natriuretic peptide concentration also indicates signiﬁcant relation between the Tei index and degree of chronic HF.72,73

Evaluation of Right Ventricular Function Due to the complex geometry of the right ventricle, it is still difﬁcult to evaluate RV function. Measurement of RVEF seems not to be common practice in many institutions. However, the RV Tei index can be measured independently from chamber geometry by cardiac time interval analysis with tricuspid ﬁlling and pulmonary ejection ﬂow. An increased RV Tei index predicts poor outcome in patients with primary pulmonary hypertension.74 Of note is that prediction of outcome is better with the Tei index compared with prediction on the basis of systolic pulmonary artery pressure. This indicates that RV dysfunction with increased pulmonary artery resistance rather than increased pulmonary artery pressure per se is more important to evaluate the severity of the disease. Clinical evaluation of the degree of RV dysfunction was proportional to the increase in the RV Tei index in patients with Ebstein’s anomaly.75 RV involvement of cardiac amyloidosis has also been evaluated by the Tei index.76 The RV Tei index is also signiﬁcantly correlated with EF, measured by radionuclide angiography or cine magnetic resonance imaging.77,78 Further, an increased RV Tei index in patients with left-sided chronic HF is related to poor prognosis.79

Effects of Interventions Because the Tei index expresses global cardiac function with a sensitive nature, it is reasonable to apply the index to evaluate interventions, especially with potentially minor inﬂuences. The most common application of the Tei index to evaluate therapeutic intervention is probably cardiac resynchronization. Multiple investigators uniformly reported an improved Tei index with improvement in patient status.80–85 The Tei index has also been applied to guide pacemaker treatment to achieve maximal beneﬁt.86–90 The Tei index is inversely proportional to quality of life or cardiac output in these patients. Signiﬁcant but relatively small eﬀects of various pharmacologic agents have been evaluated by the Tei index.91–93 A decrease in the Tei index after administration of carvedilol is an early sign of improvement of chronic HF.94 Improvement in exercise capacity by exercise training in patients with recent myocardial infarction is not associated with changes in EF but may be detected by the Tei index.95 An improved Tei index with low-dose dobutamine is associated with myocardial viability.96 Improvement in RV function can also be evaluated by an RV Tei index in patients with pulmonary hypertension.97,98

197

Chapter 16 • Evaluation of Tei Index in Heart Failure Worsening cardiac function following procedures can also be sensitively evaluated by the Tei index. An increase in the Tei index with low-dose dobutamine in patients with acute myocardial infarction suggests poorer outcome with progressive remodeling and doubled events or mortality.99,100 Early detection of cardiac toxicity by anthracycline can also be detected with the Tei index before the development of abnormality in EF.101–103 Adverse eﬀects of RV pacing with augmented dyssynchrony can also be evaluated by the Tei index.104,105 Therefore, many investigators or clinical physicians utilize the Tei index to evaluate eﬀects of various interventions in multiple disease entities.

40

PCWP (mmHg)

198

r = 0.59 p < 0.0001 SEE = 6.0

30

20

10

0 0.2

Evaluation of Patients with Tachycardia Measurement of LV volumes by two-dimensional echocardiography can be a problem in the presence of high heart rate and relatively low echocardiographic frame rate. However, pulsed Doppler echocardiography has excellent temporal resolution, suggesting that the Tei index is suitable to evaluate cardiac function even in the presence of advanced heart rate, such as in fetuses or small animal models. The Tei index has been reported to be heart rate independent in the fetus.106 Both the LV and RV Tei indices are abnormally increased in fetuses with intrauterine growth retardation.106,107 An increased LV Tei index suggests poor prognosis in fetuses with severe tricuspid valve disease,108 and an increased RV Tei index is a marker of poor prognosis in fetuses with tetralogy of Fallot and absent pulmonary valve.109 The Tei index is correlated with both systolic and diastolic functions in small animal models of chronic HF or myocardial infarction.110–112 Both the LV and RV Tei indices are sensitive measures to detect cardiac dysfunction in mice and rats.113,114

0.4

0.6

0.8

1

Tei index Figure 16-11 Relation between pulmonary capillary wedge pressure (PCWP) and Tei index in consecutive patients with acute anteroseptal myocardial infarction. A marked increase in Tei index is usually associated with significant increase in the filling pressure, and normal or only small increase in the index is associated with normal or only finite increase in the filling pressure. There is a wide scatter of left ventricular filling pressure in patients with mild to moderate increase in the Tei index. A significant increase in the filling pressure despite only mild increase in the index suggests that the Tei index may be pseudonormalized in these patients.

Not severe RV infarction

Normal

Severe RV infarction

Limitations Because the Tei index utilizes cardiac time intervals, it may not accurately express global cardiac function when ICT, ET, or IRT does not express cardiac function. One such example is the case with a paradoxically shortened IRT caused by a marked increase in left atrial pressure.115 A scattergram between LV ﬁlling pressure and the Tei index in consecutive patients with acute anteroseptal myocardial infarction demonstrated (1) an advanced increase in the Tei index with a signiﬁcant increase in the ﬁlling pressure, (2) a normal or only small increase in the index with a normal or only ﬁnite increase in the ﬁlling pressure, and (3) a mild to moderate increase in the Tei index with a wide scatter of the ﬁlling pressure (Fig. 16-11). A marked increase in the ﬁlling pressure despite only a mild increase in the Tei index suggests that the Tei index may be pseudonormalized in these patients.116,117 Most of these patients had shortened mitral E deceleration time, which combined with the Tei index may enable better evaluation of hemodynamics in patients with HF. Of note is that no patient showed a totally normal Tei index despite advanced HF, although some showed a modest increase. The Tei index is expected to be more resistant to pseudonormalization compared with IRT per se because the component of the Tei index or ratio of IRT to ET is more diﬃcult to be pseudonormalized, as ET usually shortens with elevation of the ﬁlling pressure. In addition, the Tei index is a sum of ICT/ET and IRT/ET, which seems to be further resistant to pseudonormalization.69 In the right ventricle, elevation of RV end diastolic pressure causes approximate equalization of diastolic pulmonary artery

ICT ET

IRT

Figure 16-12 Mechanism of pseudonormalized right ventricular Tei index in patients with severe right ventricular infarction. Severely elevated right ventricular end diastolic pressure results in advanced shortening of isovolumic contraction time (ICT) despite clear right ventricular systolic dysfunction. ET, ejection time; IRT, isovolumic relaxation time. (From Yoshifuku S, et al: Pseudonormal Doppler Tei index in patients with right ventricular acute myocardial infarction. Am J Cardiol 2003;91:527.)

and RV pressure, with extreme shortening of ICT despite severely impaired RV systolic contraction (Fig. 16-12).118

FUTURE RESEARCH We often see discrepancies between values of cardiac functional indices and patient status. The reason is often due to the fact that conventional indices express only one aspect of heterogeneous systolic or diastolic function. The Tei index enables evaluation of combined systolic and diastolic function, and therefore global cardiac function. The Tei index is related to patient prognosis. Because it sensitively expresses global cardiac function, evaluation of interventions in cardiac function is feasible with this index and should be an area of future research. The Tei index also enables practical evaluation of RV function with geometric complexity and clinical diﬃculty with other approaches. Other potential clinical applications of the Tei index will require further investigation.

Chapter 16 • Evaluation of Tei Index in Heart Failure REFERENCES 1. Cueto-Garcia L, Reeder GS, Kyle RA, et al: Echocardiographic ﬁndings in systemic amyloidosis: Spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 1985;6:737–743. 2. Swanton RH, Brooksby IAB, Davies MJ, et al: Systolic and diastolic ventricular function in cardiac amyloidosis. Am J Cardiol 1977;39:658–664. 3. Klein AL, Hatle LK, Burstow DJ, et al: Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1989;13:1017–1026. 4. Shimizu G, Hirota Y, Kita Y, et al: Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressureoverload hypertrophy. Circulation 1991;83:1676–1684. 5. Bruch C, Gradaus R, Gunia S, et al: Doppler tissue analysis of mitral annular velocities: Evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr 2003;16:1031–1036. 6. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999;33: 1948–1955. 7. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;20:112: e154–e235. 8. Andersson B, Caidahl K, Waagstein F: An echocardiographic evaluation of patients with idiopathic heart failure. Chest 1995;107:680–689. 9. Sakate Y, Yoshiyama M, Hirata K, et al: Relationship between Dopplerderived left ventricular diastolic function and exercise capacity in patients with myocardial infarction. Am J Cardiol 2001;65:627–631. 10. Tei C: New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol 1995;26:135–136. 11. Tei C, Ling LH, Hodge DO, et al: New index of combined systolic and diastolic myocardial performance: A simple and reproducible measure of cardiac function—a study in normals and dilated cardiomyopathy. J Cardiol 1995;26:357–366. 12. Tei C, Nishimura RA, Seward JB, Tajik AJ: Noninvasive Doppler-derived myocardial performance index: Correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 1997;10:169–178. 13. Le Feuvre C, Baubion N, Berdah J, et al: Doppler parameters of systolic function and heart rate. Arch Mal Coeur Vaiss 1992;85:199–202. 14. Eto G, Ishii M, Tei C, et al: Assessment of global left ventricular function in normal children and in children with dilated cardiomyopathy. J Am Soc Echocardiogr 1999;12:1058–1064. 15. Eidem BW, Edwards JM, Cetta F: Quantitative assessment of fetal ventricular function: Establishing normal values of the myocardial performance index in the fetus. Echocardiography 2001;18:9–13. 16. Harada K, Masamichi T, Toyono M, et al: Assessment of global left ventricular function by tissue Doppler imaging. Am J Cardiol 2001;88: 927–932. 17. Bahler RC, Mohyuddin T, Finkelhor RS, Jacobs IB: Contribution of Doppler tissue imaging and myocardial performance index to assessment of left ventricular function in patients with Duchenne’s muscular dystrophy. J Am Soc Echocardiogr 2005;18:666–673. 18. Abd el Rahman MY, Hui W, Dsebissowa F, et al: Comparison of the tissue Doppler–derived left ventricular Tei index to that obtained by pulse Doppler in patients with congenital and acquired heart disease. Pediatr Cardiol 2005;26:391–395. 19. Gaibazzi N, Petrucci N, Ziacchi V: Left ventricle myocardial performance index derived either by conventional method or mitral annulus tissueDoppler: A comparison study in healthy subjects and subjects with heart failure. J Am Soc Echocardiogr 2005;18:1270–1276. 20. Rojo EC, Rodrigo JL, Perez de Isla L, et al: Disagreement between tissue Doppler imaging and conventional pulsed wave Doppler in the measurement of myocardial performance index. Eur J Echocardiogr 2006;7:356–364. 21. Voon WC, Su HM, Yen HW, et al: Left ventricular Tei index: Comparison between ﬂow and tissue Doppler analyses. Echocardiography 2005;22: 730–735. 22. Kjaergaard J, Hassager C, Oh JK, et al: Measurement of cardiac time intervals by Doppler tissue M-mode imaging of the anterior mitral leaﬂet. J Am Soc Echocardiogr 2005;18:1058–1065.

23. Tham EB, Silverman NH: Measurement of the Tei index: A comparison of M-mode and pulse Doppler methods. J Am Soc Echocardiogr 2004;17: 1259–1265. 24. Spencer KT, Weinert L, Avi VM, et al: Automated calculation of the Tei index from signal averaged left ventricular acoustic quantiﬁcation wave forms. J Am Soc Echocardiogr 2002;15:1485–1489. 25. Poulsen SH, Nielsen JC, Andersen HR: The inﬂuence of heart rate on the Doppler-derived myocardial performance index. J Am Soc Echocardiogr 2000;13:379–384. 26. Moller JE, Poulsen SH, Egstrup K: Eﬀect of preload alterations on a new Doppler echocardiographic index of combined systolic and diastolic performance. J Am Soc Echocardiogr 1999;12:1065–1072. 27. Bruch C, Schmermund A, Marin D, et al: Tei-index in patients with mild-to-moderate congestive heart failure. Eur Heart J 2000;21:1888– 1895. 28. Haque A, Otsuji Y, Yoshifuku S, et al: Eﬀects of valve dysfunction on Doppler Tei index. J Am Soc Echocardiogr 2002;15:877–883. 29. Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664. 30. Dujardin KS, Tei C, Yeo TC, et al: Prognostic value of a Doppler index combining systolic and diastolic performance in idiopathic-dilated cardiomyopathy. Am J Cardiol 1998;82:1071–1076. 31. Harjai KJ, Scott L, Vivekananthan K, et al: The Tei index: A new prognostic index for patients with symptomatic heart failure. J Am Soc Echocardiogr 2002;15:864–868. 32. Poulsen SH, Jensen SE, Tei C, et al: Value of the Doppler index of myocardial performance in the early phase of acute myocardial infarction. J Am Soc Echocardiogr 2000;13:723–730. 33. Poulsen SH, Jensen SE, Nielsen JC, et al: Serial changes and prognostic implications of a Doppler-derived index of combined left ventricular systolic and diastolic myocardial performance in acute myocardial infarction. Am J Cardiol 2000;85:19–25. 34. Moller JE, Egstrup K, Kober L, et al: Prognostic importance of systolic and diastolic function after acute myocardial infarction. Am Heart J 2003;145: 147–153. 35. Anavekar NS, Mirza A, Skali H, et al: Risk assessment in patients with depressed left ventricular function after myocardial infarction using the myocardial performance index—Survival and Ventricular Enlargement (SAVE) experience. J Am Soc Echocardiogr 2006;19:28–33. 36. Acil T, Wichter T, Stypmann J, et al: Prognostic value of tissue Doppler imaging in patients with chronic congestive heart failure. Int J Cardiol 2005;103:175–181. 37. Kato M, Dote K, Sasaki S, et al: Myocardial performance index for assessment of left ventricular outcome in successfully recanalised anterior myocardial infarction. Heart 2005;91:583–588. 38. Ascione L, De Michele M, Accadia M, et al: Myocardial global performance index as a predictor of in-hospital cardiac events in patients with ﬁrst myocardial infarction. J Am Soc Echocardiogr 2003;16:1019–1023. 39. Yuasa T, Otsuji Y, Kuwahara E, et al: Noninvasive prediction of complications with anteroseptal acute myocardial infarction by left ventricular Tei index. J Am Soc Echocardiogr 2005;18:20–25. 40. Yilmaz R, Celik S, Baykan M, et al: Pulsed wave tissue Doppler–derived myocardial performance index for the assessment of left ventricular thrombus formation risk after acute myocardial infarction. Am Heart J 2004;148:1102–1108. 41. Al-Mukhaini M, Argentin S, Morin JF, et al: Myocardial performance index as predictor of adverse outcomes following mitral valve surgery. Eur J Echo 2003;4:128. 42. Arnlov J, Lind L, Andren B, et al: A Doppler-derived index of combined left ventricular systolic and diastolic function is an independent predictor of cardiovascular mortality in elderly men. Am Heart J 2005;149: 902–907. 43. Arnlov J, Ingelsson E, Riserus U, et al: Myocardial performance index, a Doppler-derived index of global left ventricular function, predicts congestive heart failure in elderly men. Eur Heart J 2004;25:2220–2225. 44. Mooradian SJ, Goldberg CS, Crowley DC, Ludomirsky A: Evaluation of a noninvasive index of global ventricular function to predict rejection after pediatric cardiac transplantation. Am J Cardiol 2000;86:358–360. 45. Vivekananthan K, Kalapura T, Mehra M, et al: Usefulness of the combined index of systolic and diastolic myocardial performance to identify cardiac allograft rejection. Am J Cardiol 2002;90:517–520. 46. Leonard GT Jr, Fricker FJ, Pruett D, et al: Increased myocardial performance index correlates with biopsy-proven rejection in pediatric heart transplant recipients. J Heart Lung Transplant 2006;25:61–66.

199

200

Chapter 16 • Evaluation of Tei Index in Heart Failure 47. Tona F, Caforio AL, Piaserico S, et al: Abnormal total ejection isovolume index as early noninvasive marker of chronic rejection in heart transplantation. Transpl Int 2005;18:303–308. 48. Sato T, Harada K, Tamura M, et al: Cardiorespiratory exercise capacity and its relation to a new Doppler index in children previously treated with anthracycline. J Am Soc Echocardiogr 2001;14:256–263. 49. Parthenakis FI, Kanakaraki MK, Kanoupakis EM, et al: Value of Doppler index combining systolic and diastolic myocardial performance in predicting cardiopulmonary exercise capacity in patients with congestive heart failure: Eﬀects of dobutamine. Chest 2002;121:1935–1941. 50. Skaluba SJ, Bray BE, Litwin SE: Close coupling of systolic and diastolic function: Combined assessment provides superior prediction of exercise capacity. J Card Fail 2005;11:516–522. 51. Norozi K, Buchhorn R, Bartmus D, et al: Elevated brain natriuretic peptide and reduced exercise capacity in adult patients operated on for tetralogy of Fallot is due to biventricular dysfunction as determined by the myocardial performance index. Am J Cardiol 2006;97:1377–1382. 52. Kasikcioglu E, Oﬂaz H, Akhan H, Kayserilioglu A: Right ventricular myocardial performance index and exercise capacity in athletes. Heart Vessels 2005;20:147–152. 53. Ling LH, Tei C, McCully RB, et al: Analysis of systolic and diastolic time intervals during dobutamine-atropine stress echocardiography: Diagnostic potential of the Doppler myocardial performance index. J Am Soc Echocardiogr 2001;14:978–986. 54. Kuwahara E, Otsuji Y, Takasaki K, et al: Increased Tei index suggests absence of adequate coronary reperfusion in patients with ﬁrst anteroseptal acute myocardial infarction. Circ J 2006;70:248–253. 55. Reference deleted in proofs. 56. Doin FL, Borges Mda R, Campos O, et al: Eﬀect of central hypothyroidism on Doppler-derived myocardial performance index. J Am Soc Echocardiogr 2004;17:622–629. 57. Andersen NH, Poulsen SH, Helleberg K, et al: Impact of essential hypertension and diabetes mellitus on left ventricular systolic and diastolic performance. Eur J Echocardiogr 2003;4:306–312. 58. Bruch C, Herrmann B, Schmermund A, et al: Impact of disease activity on left ventricular performance in patients with acromegaly. Am Heart J 2002;144:538–543. 59. Baykan M, Yilmaz R, Celik S, et al: Assessment of left ventricular systolic and diastolic function by Doppler tissue imaging in patients with preinfarction angina. J Am Soc Echocardiogr 2003;16:1024–1030. 60. Dursunoglu D, Dursunoglu N, Evrengul H, et al: Impact of obstructive sleep apnoea on left ventricular mass and global function. Eur Respir J 2005;26:283–288. 61. Morgan EE, Faulx MD, McElfresh TA, et al: Validation of echocardiographic methods for assessing left ventricular dysfunction in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 2004;287: H2049–H2053. 62. Cannesson M, Jacques D, Pinsky MR, Gorcsan J 3rd: Eﬀects of modulation of left ventricular contractile state and loading conditions on tissue Doppler myocardial performance index. Am J Physiol Heart Circ Physiol 2006;290: H1952–H1959. 63. LaCorte JC, Cabreriza SE, Rabkin DG, et al: Correlation of the Tei index with invasive measurements of ventricular function in a porcine model. J Am Soc Echocardiogr 2003;16:442–447. 64. Zhang H, Otsuji Y, Matsukida K, et al: Noninvasive diﬀerentiation of normal from pseudonormal/restrictive mitral ﬂow using TEI index combining systolic and diastolic function. Circ J 2002;66:831–836. 65. Abd el-Rahim AR, Otsuji Y, Yuasa T, et al: Noninvasive diﬀerentiation of pseudonormal/restrictive from normal mitral ﬂow by Tei index: A simultaneous echocardiography-catheterization study in patients with acute anteroseptal myocardial infarction. J Am Soc Echocardiogr 2003;16:1231–1236. 66. Reference deleted in proofs. 67. Takasaki K, Otsuji Y, Yoshifuku S, et al: Noninvasive estimation of impaired hemodynamics in patients with acute myocardial infarction by Tei index. J Am Soc Echocardiogr 2004;17:615–621. 68. Zhang H, Otsuji Y, Matsukida K, et al: Noninvasive estimation of left ventricular diastolic ﬁlling pressure from Doppler Tei index: Diﬀerent feasibilities in patients with higher and lower early to late diastolic mitral ﬂow velocity ratio. J Echocardiogr 2003;1:15–22. 69. Otsuji Y, Tei C: Evaluation of left ventricular ﬁlling pressure by the Tei index. J Am Soc Echocardiogr 2004;17:710. 70. Courtois M, Vered Z, Barzilai B, et al: The transmitral pressure-ﬂow velocity relation. Eﬀect of abrupt preload reduction. Circulation 1988;78: 1459–1468.

71. Su HM, Lin TH, Voon WC, et al: Diﬀerentiation of left ventricular diastolic dysfunction, identiﬁcation of pseudonormal/restrictive mitral inﬂow pattern and determination of left ventricular ﬁlling pressure by Tei index obtained from tissue Doppler echocardiography. Echocardiography 2006;23: 287–294. 72. Ono M, Tanabe K, Asanuma T, et al: Doppler echocardiography–derived index of myocardial performance (TEI index): Comparison with brain natriuretic peptide levels in various heart disease. Jpn Circ J 2001;65: 637–642. 73. Okawa M, Kitaoka H, Matsumura Y, et al: Functional assessment by myocardial performance index (Tei index) correlates with plasma brain natriuretic peptide concentration in patients with hypertrophic cardiomyopathy. Circ J 2005;69:951–957. 74. Yeo TC, Dujardin KS, Tei C, et al: Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol 1998;81:1157– 1161. 75. Eidem BW, Tei C, O’Leary PW, et al: Nongeometric quantitative assessment of right and left ventricular function: Myocardial performance index in normal children and patients with Ebstein anomaly. J Am Soc Echocardiogr 1998;11:849–856. 76. Kim WH, Otsuji Y, Yuasa T, et al: Evaluation of right ventricular dysfunction in patients with cardiac amyloidosis using Tei index. J Am Soc Echocardiogr 2004;17:45–49. 77. Miller D, Farah MG, Liner A, et al: The relation between quantitative right ventricular ejection fraction and indices of tricuspid annular motion and myocardial performance. J Am Soc Echocardiogr 2004;17:443–447. 78. Salehian O, Schwerzmann M, Merchant N, et al: Assessment of systemic right ventricular function in patients with transposition of the great arteries using the myocardial performance index: Comparison with cardiac magnetic resonance imaging. Circulation. 2004;110:3229–3233. 79. Meluzin J, Spinarova L, Hude P, et al: Prognostic importance of various echocardiographic right ventricular functional parameters in patients with symptomatic heart failure. J Am Soc Echocardiogr 2005;18:435– 444. 80. Saxon LA, De Marco T, Schafer J, et al, for VIGOR Congestive Heart Failure Investigators: Eﬀects of long-term biventricular stimulation for resynchronization on echocardiographic measures of remodeling. Circulation 2002;105:1304–1310. 81. Yu CM, Chau E, Sanderson JE, et al: Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438–445. 82. Breithardt OA, Stellbrink C, Franke A, et al: Acute eﬀects of cardiac resynchronization therapy on left ventricular Doppler indices in patients with congestive heart failure. Am Heart J 2002;143:34–44. 83. Sutton MG, Plappert T, Abraham WT, et al: Eﬀect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;22:1985–1990. 84. Yu CM, Lin H, Fung WH, et al: Comparison of acute changes in left ventricular volume, systolic and diastolic functions, and intraventricular synchronicity after biventricular and right ventricular pacing for heart failure. Am Heart J 2003;145:E18. 85. Sutton MG, Plappert T, Hilpisch KE, et al: Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: Quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation 2006;113:266–272. 86. Toda N, Ishikawa T, Nozawa N, et al: Doppler index and plasma level of atrial natriuretic hormone are improved by optimizing atrioventricular delay in atrioventricular block patients with implanted DDD pacemakers. Pacing Clin Electrophysiol 2001;24:1660–1663. 87. Kato M, Dote K, Sasaki S, et al: Determination of the optimal atrioventricular interval in sick sinus syndrome during DDD pacing. Pacing Clin Electrophysiol 2005;28:892–897. 88. Moro E, Caprioglio F, Berton G, et al: DDD versus VVIR versus VVI mode in patients with indication to dual-chamber stimulation: A prospective, randomized, controlled, single-blind study. Ital Heart J 2005;6:728–733. 89. Bernheim A, Ammann P, Sticherling C, et al: Right atrial pacing impairs cardiac function during resynchronization therapy: Acute eﬀects of DDD pacing compared to VDD pacing. J Am Coll Cardiol 2005;45: 1482–1487. 90. Porciani MC, Dondina C, Macioce R, et al: Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol 2005;95:1108–1110.

Chapter 16 • Evaluation of Tei Index in Heart Failure 91. Karvounis HI, Zaglavara TA, Parharidis GE, et al: An angiotensinconverting enzyme inhibitor improves left ventricular systolic and diastolic function in transfusion-dependent patients with beta-thalassemia major. Am Heart J 2001;141:281. 92. Harada K, Tamura M, Toyono M, Yasuoka K: Eﬀect of dobutamine on a Doppler echocardiographic index of combined systolic and diastolic performance. Pediatr Cardiol 2002;23:613–617. 93. Nearchou NS, Tsakiris AK, Lolaka MD, et al: Inﬂuence of perindopril on left ventricular global performance during the early phase of inferior acute myocardial infarction: Assessment by Tei index. Echocardiography 2003; 20:319–327. 94. Palloshi A, Fragasso G, Silipigni C, et al: Early detection by the Tei index of carvedilol-induced improved left ventricular function in patients with heart failure. Am J Cardiol 2004;94:1456–1459. 95. Ueshima K, Suzuki T, Nasu M, et al: Eﬀects of exercise training on left ventricular function evaluated by the Tei index in patients with myocardial infarction. Circ J 2005;69:564–566. 96. Palmieri V, Innocenti F, Agresti C, et al: Traditional and color M-mode parameters of left ventricular diastolic function during low-dose dobutamine stress echocardiography: Relations to contractility reserve. J Am Soc Echocardiogr 2006;19:483–490. 97. Sebbag I, Rudski LG, Therrien J, et al: Eﬀect of chronic infusion of epoprostenol on echocardiographic right ventricular myocardial performance index and its relation to clinical outcome in patients with primary pulmonary hypertension. Am J Cardiol 2001;88:1060–1063. 98. Seyfarth HJ, Pankau H, Hammerschmidt S, et al: Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest 2005;128:709–713. 99. Norager B, Husic M, Moller JE, et al: The Doppler myocardial performance index during low-dose dobutamine echocardiography predicts mortality and left ventricular dilation after a ﬁrst acute myocardial infarction. Am Heart J 2005;150:522–529. 100. Norager B, Husic M, Moller JE, et al: Changes in the Doppler myocardial performance index during dobutamine echocardiography: Association with neurohormonal activation and prognosis after acute myocardial infarction. Heart 2006;92:1071–1076. 101. Ishii M, Tsutsumi T, Himeno W, et al: Sequential evaluation of left ventricular myocardial performance in children after anthracycline therapy. Am J Cardiol 2000;86:1279–1281. 102. Eidem BW, Sapp BG, Suarez CR, Cetta F: Usefulness of the myocardial performance index for early detection of anthracycline-induced cardiotoxicity in children. Am J Cardiol 2001;87:1120–1122. 103. Belham M, Kruger A, Pritchard C: The Tei index identiﬁes a diﬀerential eﬀect on left and right ventricular function with low-dose anthracycline chemotherapy. J Am Soc Echocardiogr 2006;19:206–210. 104. Tantengco MV, Thomas RL, Karpawich PP: Left ventricular dysfunction after long-term right ventricular apical pacing in the young. J Am Coll Cardiol 2001;15:2093–2100.

105. Lin MS, Lin JL, Liu YB, et al: Immediate impairment of left ventricular mechanical performance and force-frequency relation by rate-responsive dual-chamber, but not atrial pacing: Implications from intraventricular isovolumic relaxation ﬂow. Int J Cardiol 2005;26. 106. Niewiadomska-Jarosik K, Lipecka-Kidawska E, Kowalska-Koprek U, et al: Assessment of cardiac function in fetuses with intrauterine growth retardation using the Tei Index. Med Wieku Rozwoj 2005;9:153– 160. 107. Ichizuka K, Matsuoka R, Hasegawa J, et al: The Tei index for evaluation of fetal myocardial performance in sick fetuses. Early Hum Dev 2005;81: 273–279. 108. Inamura N, Taketazu M, Smallhorn JF, Hornberger LK: Left ventricular myocardial performance in the fetus with severe tricuspid valve disease and tricuspid insuﬃciency. Am J Perinatol 2005;22:91–97. 109. Inamura N, Kado Y, Nakajima T, Kayatani F: Left and right ventricular function in fetal tetralogy of Fallot with absent pulmonary valve. Am J Perinatol 2005;22:199–204. 110. Broberg CS, Pantely GA, Barber BJ, et al: Validation of the myocardial performance index by echocardiography in mice: A noninvasive measure of left ventricular function. J Am Soc Echocardiogr 2003;16:814–823. 111. Jegger D, Jeanrenaud X, Nasratullah M, et al: Noninvasive Doppler-derived myocardial performance index in rats with myocardial infarction: Validation and correlation by conductance catheter. Am J Physiol Heart Circ Physiol 2006;290:H1540–H1548. 112. Schaefer A, Meyer GP, Hilﬁker-Kleiner D, et al: Evaluation of tissue Doppler Tei index for global left ventricular function in mice after myocardial infarction: Comparison with pulsed Doppler Tei index. Eur J Echocardiogr 2005;6:367–375. 113. Santos RA, Castro CH, Gava E, et al: Impairment of in vitro and in vivo heart function in angiotensin-(1–7) receptor MAS knockout mice. Hypertension 2006;47:996–1002. 114. Boissiere J, Gautier M, Machet MC, et al: Doppler tissue imaging in assessment of pulmonary hypertension-induced right ventricle dysfunction. Am J Physiol Heart Circ Physiol 2005;289:H2450–H2455. 115. Appleton CP, Hatle LK, Popp RL: Relation of transmitral ﬂow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. 116. Nearchou NS, Tsakiris AK, Tsitsirikos MD, et al: Tei index as a method of evaluating left ventricular diastolic dysfunction in acute myocardial infarction. Hellenic J Cardiol 2005;46:35–42. 117. Abd el Rahman MY, Abdul-Khaliq H, Vogel M, et al: Value of the new Doppler-derived myocardial performance index for the evaluation of right and left ventricular function following repair of tetralogy of Fallot. Pediatr Cardiol 2002;23:502–507. 118. Yoshifuku S, Otsuji Y, Takasaki K, et al: Psedonormalized Doppler Tei index in patients with right ventricular acute myocardial infarction. Am J Cardiol 2003;91:527–531.

201

DALANE W. KITZMAN, MD JERRY M. JOHN, MD

17

Exercise Intolerance in Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY OF EXERCISE INTOLERANCE Determinants of Oxygen Consumption Exercise Intolerance in Systolic Versus Diastolic Heart Failure Hemodynamic Alterations During Exercise in Heart Failure Patients

Angiotensin Receptor Blockers Calcium Channel Blockers Aldosterone Inhibitors Glucose Cross-Link Breakers Pacemaker Therapy Exercise Training FUTURE RESEARCH ACKNOWLEDGMENT

CLINICAL RELEVANCE: INTERVENTIONS TO IMPROVE EXERCISE TOLERANCE

INTRODUCTION Exercise intolerance is the primary symptom of chronic diastolic heart failure (DHF). This chapter discusses the fundamental aspects of exercise physiology and the assessment, pathophysiology, and potential treatment of exercise intolerance associated with DHF. Exercise intolerance is central to the very deﬁnition of heart failure, as well as its pathophysiology, diagnosis, prognosis, and therapy. Heart failure is deﬁned as a syndrome in which cardiac output is insuﬃcient to meet metabolic demands. Inherent in this deﬁnition is that consequences of insuﬃcient cardiac output will be expressed symptomatically. Indeed, while the natural history of heart failure is punctuated by occasional episodes of acute decompensation with overt systemic volume overload and pulmonary edema,1,2 the primary chronic symptoms in patients with chronic heart failure, whether associated with reduced or normal ejection fraction, are exertional fatigue and dyspnea.3 In addition, these symptoms are the primary determinants of patients’ healthrelated quality of life. Furthermore, measures of exercise tolerance are powerful independent predictors of mortality.4,5 The severity of exercise intolerance can be quantiﬁed by a variety of methods. These include semiquantitative assessments, such as interviews (New York Heart Association [NYHA] classiﬁcation) and surveys (the Minnesota Living with Heart Failure and Kansas City Cardiomyopathy questionnaires), and quantita-

tive methods, including timed walking tests (6-minute walk distance) and graded exercise treadmill or bicycle exercise tests. Cardiopulmonary exercise testing on a motorized treadmill or a bicycle ergometer provides the most accurate and reliable assessment of exercise tolerance and yields multiple important outcomes, including exercise time, exercise workload, rate-pressure product, and metabolic equivalents (METs). Peak oxygen consumption (VO2) and carbon dioxide generation (VCO2) can be measured simultaneously by expired gas analysis using instruments that are reliable and highly automated. The quality of the exercise data, and in particular whether the patient gave a maximal or near-maximal eﬀort, can be assessed not only by perceived exertion scales, such as the Borg scale, and percent age-predicted maximal heart rate, but also by the respiratory exchange ratio, which is unbiased by other variables. In addition to assessing peak exercise capacity with peak VO2, submaximal exercise capacity can be assessed by determining the ventilatory anaerobic threshold. Submaximal exercise capacity is more applicable to everyday life and is relatively eﬀort independent. We have shown that measurements of both peak and ventilatory anaerobic threshold with automatic instruments are valid and highly reproducible in elderly patients with diastolic as well as systolic heart failure (Fig. 17-1). In addition to these key variables, cardiopulmonary exercise testing with expired gas analysis can assess the slope of expired ventilation (VE)/VCO2, which is a powerful predictor of survival, independent of VO2.6 203

204

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure

PATHOPHYSIOLOGY OF EXERCISE INTOLERANCE

Determinants of Oxygen Consumption Assessment of peak VO2 gives insight into the pathophysiology of exercise intolerance, since, by the Fick equation, it is the product of cardiac output and arteriovenous oxygen (A-V O2) diﬀerence. Thus, exercise intolerance will be closely related to one or both of these factors and to the factors that comprise them. Measurement of peak exercise VO2 and at least one of these other two factors (cardiac output or A-V O2) allows one to calculate the remaining unknown factor and therefore to isolate speciﬁc factors that contribute to exercise intolerance within individual patients and groups (Fig. 17-3). We performed a series of cardiopulmonary exercise studies in order to examine the determinants of exercise performance in normal humans and in patients with heart failure.7–13 The methods included symptom-limited upright bicycle exercise with indwelling pulmonary artery and brachial artery catheters, and simultaneous expired gas analysis and radionuclide ventriculography.7–15 Cardiac output was determined by the Fick principle for oxygen and was indexed to body surface area. The left ventricular (LV) end diastolic volume index (EDVI) and end systolic volume index (ESVI) were calculated from the Fick stroke volume index (SVI) and the radionuclide LV ejection fraction (LVEF), according to the formulas: EDVI = SVI/LVEF, and ESVI = EDVI − SVI. During upright bicycle exercise in healthy young and middleaged male volunteers, VO2 increased 7.7-fold from rest to peak exercise.7 This was achieved by a 3.2-fold increase in cardiac output and a 2.5-fold increase in A-V O2 diﬀerence. The increase in cardiac output resulted from a 2.5-fold increase in heart rate and a 1.4-fold increase in stroke volume. Stroke volume increased during the initial low levels of exercise via the Frank-Starling mechanism, whereas end diastolic volume increased with small

In a comparative study from our laboratory, maximal exercise testing with expired gas was performed in 119 older subjects divided among three groups: heart failure with severe LV systolic dysfunction (mean ejection fraction [EF], 30%); isolated DHF (EF >50%; no signiﬁcant coronary, valvular, pericardial, or pulmonary disease; and no anemia); and age-matched controls.3 In comparison with the normal controls, peak VO2, an objective measure of exercise capacity, was severely reduced in the patients with DHF, and to a similar degree as in those with systolic heart failure (SHF) (Fig. 17-2).3 In addition, submaximal exercise capacity, as measured by the ventilatory anaerobic threshold, was similarly reduced in patients with DHF versus those with SHF, and this was accompanied by reduced health-related quality of life.3

Test 2 (VO2max, ml/min)

2000 1800 1600 1400 1200 1000 800

r = 0.92 p ≤ 0.0004

600 400 400

600

800

1000 1200 1400 1600 1800 2000

Test 1 (VO2max, ml/min)

VO2 (ml/min)

1500 Start of exercise

1000

Heart rate: Chronotropic incompetence

500

Test 1 Test 2

Stroke volume: ↓ Contractility (systolic dysfunction: ESV) ↓ LV filling (diastolic dysfunction: EDV)

0 0

0.08 3

0.16 7

0.25

0.33 3

0.41 7

0.5

0.58 3

Arteriovenous O2 difference: ↓ Peripheral vascular function ↓ Skeletal muscle bulk and function ↓ Hemoglobin (anemia)

Time (min) Figure 17-1 Excellent reproducibility of peak exercise VO2 in older patients with heart failure, including those with normal LV ejection fraction. Group data shown in top panel; representative patient with 15-second averaged data shown in bottom. (From Marburger et al: Reproducibility of cardiopulmonary exercise testing in elderly heart failure patients. Am J Cardiol 1998;82:905–909.)

SUBMAXIMAL

25 20 15

‡

‡

SD

DD

10 5 0 NO

VO2 (ml/min/kg) at AT

Peak VO2 (ml/kg/min)

PEAK

Figure 17-3 Potential mechanisms of exercise intolerance from the factors of the Fick equation. ESV, end systolic volume; LV, left ventricular; EDV, end diastolic volume.

16 14 12 10 8 6 4 2 0 NO

‡

‡

SD

DD

Figure 17-2 Exercise oxygen consumption (VO2) during peak exhaustive exercise (left panel) and during submaximal exercise at the ventilatory anaerobic threshold (right panel) in age-matched normal subjects (NO), elderly patients with heart failure due to systolic dysfunction (SD), and elderly patients with heart failure with normal systolic function and presumed diastolic dysfunction (DD). Exercise capacity is severely reduced in patients with diastolic heart failure compared with normals (p < 0.001) and to a similar degree as in those with systolic heart failure. Overall, peak exercise VO2 was 33% lower in the women compared with the men (not shown). (Modified from Kitzman et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150.)

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure increases in pulmonary wedge pressure. During higher levels of exercise, stroke volume increased predominantly because of increased contractility with decreases in end systolic volume; end diastolic volume may even decline slightly because of tachycardia and limited ﬁlling time. A similar hemodynamic exercise response occurs in healthy women.14 Aging is known to be accompanied by reduced peak exercise VO2. This is due to age-related declines in peak exercise cardiac output, heart rate, stroke volume, LVEF, and end diastolic volume, while pulmonary wedge pressure is relatively unaﬀected.8,9 Thus, stroke volume and end diastolic volume response are important contributors to the increase in VO2 and cardiac output during upright exercise in normal subjects and are altered by normal aging but not by gender.

Exercise Intolerance in Systolic Versus Diastolic Heart Failure In order to examine the cardiovascular response to exercise in classic SHF, 30 patients with heart failure associated with severe LV systolic dysfunction (mean LVEF = 24 ± 8%) were compared with 12 healthy volunteers of similar gender and age group.11 Exercise tolerance was severely reduced in the patients, whose mean peak workload was 50% of that achieved by the healthy subjects. Maximal VO2 was reduced by 53%, and this was associated with a 53% reduction in cardiac output; maximal A-V O2 diﬀerence was lower but not signiﬁcantly diﬀerent from normals. Maximal stroke volume was severely reduced in the patients. In addition, maximal heart rate was mildly reduced, a ﬁnding that has been reported by others as well. When the patients were grouped according to whether their exercise was limited by fatigue or by dyspnea, the peak pulmonary capillary wedge pressure (PCWP) was similar in both groups. Furthermore, in a signiﬁcant fraction of patients, pulmonary wedge pressure was normal during rest and exercise, even though all had marked exercise intolerance and early lactate formation at submaximal workloads. These data suggest that in patients with chronic heart failure and severe systolic LV dysfunction, exercise intolerance is closely related to reduced exercise cardiac output, which is caused by severely reduced stroke volume and mildly reduced heart rate responses during exercise. A subsequent report in 40 patients with severe LV systolic dysfunction conﬁrmed that stroke volume was reduced during rest and exercise compared with normal subjects.8 However, the relative increase in stroke volume from rest to peak exercise was similar and was 48% in patients and 42% in normal subjects.8 While some of the increase in stroke volume during exercise was attributable to increased contractility, stroke volume increased in patients in whom there was no change in LVEF. Furthermore, there was a signiﬁcantly greater increase in EDVI during exercise in the patients compared with the normal subjects, and the increase in LV end diastolic volume per increase in PCWP was nearly threefold greater in patients compared with normal subjects. Shen et al.16 reported similar ﬁndings, although some patients do not increase end diastolic volume during exercise, due either to diastolic LV dysfunction or to pericardial constraint.8 Thus, in most patients with heart failure caused by systolic LV dysfunction, the Frank-Starling mechanism not only contributes signiﬁcantly to the increase in stroke volume during exercise but also partially compensates for reduced inotropic and chronotropic reserves. With these background data in SHF, we sought to examine the cardiovascular response to exercise in patients with DHF by per-

forming similar cardiopulmonary exercise testing in seven patients with severe but stable chronic heart failure (NYHA functional class III or IV). Six of the patients had had at least one episode of clinically and radiographically documented pulmonary edema.10 No patient was included who had signiﬁcant coronary artery disease by coronary angiography, abnormal LVEF (<50%), wall motion abnormalities by radionuclide ventriculography, or clinical or echocardiographic evidence of valvular or pericardial disease. Most of the patients had a history of chronic systemic hypertension; there was also increased LV wall thickness and mass by echocardiography compared with normal controls (107 ± 27 vs. 79 ± 14 g/m2; p < 0.01). Ten age-matched and gender-matched healthy volunteers underwent similar testing to serve as normal controls. The patients with DHF exhibited marked exercise intolerance, indicated by a reduction in peak workload compared with the normal subjects. This corresponded to a 48% reduction in peak VO2 (11.6 ± 4.0 vs. 22.7 ± 6.1 ml/kg/min; p < 0.001). In all patients and normal subjects, exercise was limited primarily by leg fatigue, although dyspnea was also frequently reported at peak exercise.10 The peak respiratory exchange ratio was similar in patients and normal subjects (1.24 ± 0.15 vs. 1.33 ± 0.16; p = 0.24), suggesting a near-maximal exercise eﬀort in both groups. Arterial lactate concentration increased from 0.5 ± 0.3 mmol/ liter at rest to 3.7 ± 2.8 mmol/liter at peak exercise in the patients and from 0.5 ± 0.4 mmol/liter to 7.2 ± 2.0 mmol/liter in the normal subjects. During submaximal exercise at 50 watts, where VO2 was similar in patients and normals, lactate concentration tended to be higher in the patients compared with the normal subjects (2.2 ± 1.1 vs. 1.4 ± 0.7 mmol/liter; p < 0.07). At rest, there were no diﬀerences in cardiac output, central A-V O2 diﬀerence, SVI, or heart rate between the two groups. However, during exercise in the patients compared with normal subjects, cardiac output was signiﬁcantly reduced at comparable submaximal workloads and was markedly reduced by 41% at peak exercise (p < 0.001), in proportion to the reduction in peak VO2 (Fig. 17-4A). Central A-V O2 diﬀerence was increased by approximately 10% in the patients during the submaximal exercise workloads, partially compensating for the reduced cardiac output (Fig. 17-4B). However, at peak exercise, this mechanism was outstripped, and A-V O2 diﬀerence was reduced by 13% compared with the normal subjects (p = 0.08). In the patients, the change in cardiac output from rest to peak exercise correlated closely with the increase in VO2 during exercise (r = 0.81, p < 0.03), but the change in A-V O2 diﬀerence did not (r = 0.34, p = 0.43).

Hemodynamic Alterations During Exercise in Heart Failure Patients Stroke Volume The indexed stroke volume is reduced by 26% in heart failure patients compared with the normal subjects during submaximal exercise (p < 0.01) (Fig. 17-4C). In contrast to the increase in SVI during low levels of exercise followed by a plateau observed in the normal subjects, a ﬂat stroke volume response was observed in these patients.10 Heart rate increased slightly in patients compared with controls during submaximal exercise, but was reduced by 18% compared with controls at peak exercise (p < 0.01) (Fig. 17-4D). The change in SVI from rest to peak exercise correlated closely with the increase in cardiac output during exercise (r = 0.86, p < 0.01) in heart failure patients, but the change in heart rate did not (r = 0.60, p = 0.14). Thus, in patients with DHF at

205

Arteriovenous O2 difference (ml/dl)

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure

Cardiac index (l/min/m2)

206

10.0 8.0 6.0 4.0 2.0

*

* †

0

12 10 8 6 4 2

Rest 150 300 450 600 750

Rest 150 300 450 600 750

B

60

200 Heart rate (min –1)

Stroke volume index (ml/m2)

A

50 40 30 20

*

† †

†

160 * 120 80 40

10

0 Rest 150 300 450 600 750 PT max

Rest 150 300 450 600 750

NL max

PT max

Workload (kpm/min)

C

NL max

Workload (kpm/min)

D

peak exercise, reduced SVI was the primary factor responsible for reduced cardiac output, and reduced peak cardiac output was the primary factor responsible for the 48% reduction in peak VO2 observed in our study.10 Factors that could contribute to the abnormal stroke volume response in patients with DHF are displayed in Figure 17-5. The LVEF and ESVI during rest and exercise and the change from rest to peak exercise were not diﬀerent from those in the normal subjects (see Fig. 17-5A and B). In contrast, EDVI was reduced markedly during submaximal and at peak exercise in patients compared with normal subjects. This results in an abnormal, ﬂattened curve that is similar to the abnormal stroke volume response (see Fig. 17-5C). In patients with DHF, the change in EDVI from rest to peak exercise correlated strongly with the change in SVI (r = 0.97, p < 0.0001) and in cardiac output (r = 0.80, p < 0.03) during exercise.10

Left Ventricular Filling Pressures Pulmonary wedge pressure was mildly increased in patients with DHF compared with normal subjects at rest and became markedly elevated during exercise (see Fig. 17-5D). However, the change in pulmonary wedge pressure from rest to peak exercise did not correlate signiﬁcantly with the change in SVI or the increase in VO2 during exercise.

Left Ventricular Compliance Although the LV end diastolic pressure-volume ratio tended to be elevated in patients with DHF compared with normal subjects

Figure 17-4 Cardiovascular function assessed by invasive cardiopulmonary exercise testing in patients with heart failure and normal systolic function (blue boxes) and age-matched normals (red boxes). A, B, The primary components of the Fick equation for oxygen consumption: cardiac output and arteriovenous oxygen difference. C, D, The components of cardiac output: stroke volume and heart rate. The x-axis is exercise workload in kpm/min; 150 kpm/min is equivalent to 25 watts. (From Kitzman et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–1067.)

(0.12 ± 0.11 vs. 0.03 ± 0.03 mmHg/ml; p = 0.07) at rest, during exercise this ratio became markedly elevated in the patients compared with the normal subjects (peak, 0.28 ± 0.15 vs. 0.06 ± 0.05 mmHg/ml; p < 0.0001). The abnormal LV end diastolic pressure-volume relationship demonstrated by patients with DHF is further illustrated in Figure 17-6. At rest, the patients demonstrated a shift upward and to the left. In contrast to the normal subjects, who demonstrated approximately linear increases in end diastolic volume and pulmonary wedge pressure during exercise, the patients’ exaggerated and progressive increases in pulmonary wedge pressure were not accompanied by increases in end diastolic volume.10 Thus, these patients with normal rest and exercise LVEF demonstrated an abnormal pressure-volume relationship during exercise and an inability to augment stroke volume by means of the FrankStarling mechanism, suggesting that their exercise intolerance was due primarily to diastolic LV dysfunction. This is in contrast to patients with heart failure and reduced systolic function, who have an operating pressure-volume relationship that is shifted upward and to the right during exercise.17

Noninvasive Measures of Left Ventricular Filling Pressures The pattern of invasively assessed LV ﬁlling pressures oﬀers key insights into exercise intolerance; however, their invasive nature limits their overall utility. Noninvasive Doppler mitral ﬁlling indices have given substantial insight into LV diastolic function but are confounded by many variables. The more recently developed tissue Doppler indices are relatively free of confounding

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure End systolic volume index (ml/m2)

80 60 40 20 0

Figure 17-5 A–D, The components of the LV stroke volume response during exercise, LV ejection fraction, end systolic volume, end diastolic volume, and LV filling pressure. Not shown are systolic and mean arterial pressure, which were not different between groups. The x-axis is exercise workload in kpm/min; 150 kpm/min is equivalent to 25 watts. (From Kitzman et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–1067.)

End diastolic volume index (ml/m2)

A

90 75 60 45 *

30

C

Pulmonary capillary wedge pressure (mmHg)

30 Peak exercise

20 15 Peak exercise

10 Rest 5 0 60

80

100

120

30 20 10 0

40 †

†

32 †

24 16

*

8 0

D

35

25

40

B Pulmonary wedge pressure (mmHg)

L.V. ejection fraction (%)

100

140

160

Left ventricular end diastolic volume (ml) Figure 17-6 LV diastolic function assessed by invasive cardiopulmonary exercise testing. The pressure-volume relation was shifted upward and leftward at rest. In the patients with exercise, LV diastolic volume did not increase despite marked increase in diastolic (pulmonary wedge) pressure. Due to diastolic dysfunction, failure of the Frank-Starling mechanism resulted in severe exercise intolerance. The x-axis is exercise workload in kpm/min; 150 kpm/min is equivalent to 25 watts. (From Kitzman et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–1067.)

inﬂuence. Further, the time constant of isovolumic pressure decline (τ) can be estimated noninvasively by measuring the early diastolic velocity of the mitral annulus (E′).18 In addition, the ratio of early LV diastolic ﬁlling velocity (E) to E′ correlates well with invasively measured LV end diastolic pressures.19 Notably, an increased E/E′ ratio at rest has been correlated with maximal and submaximal exercise intolerance.20,21

Moreover, an increase in E/E′ during exercise correlates with exercise intolerance.22 M-mode color Doppler has been used to noninvasively estimate the intraventricular pressure gradient (IVPG) from the left atrium to the left ventricle, a correlate of τ and an analogue of ventricular “suction.” Changes in the IVPG from rest to peak exercise are powerful independent predictors of maximal exercise tolerance in patients with heart failure and systolic dysfunction.23 These eloquent noninvasively obtained data conﬁrm ﬁndings from invasive studies and show that individuals with heart failure as a group have increased LV ﬁlling pressures at rest and during exercise associated with impaired diastolic function and that impaired myocardial relaxation is associated with reduced diastolic suction during exercise. It is instructive to compare and contrast the exercise cardiovascular responses in the two diﬀerent groups of heart failure patients described: those with normal EFs10 and those with reduced EFs.8,10,11 Both heart failure patient groups have severe exertional symptoms and objective evidence of exercise intolerance, as well as markedly reduced peak cardiac output and stroke volume, mildly reduced peak heart rate, and slightly reduced peak A-V O2 diﬀerence (Fig. 17-7). In addition, both groups had mildly elevated resting and markedly elevated exercise mean PCWPs. However, the mechanisms by which LV stroke volume was reduced diﬀered markedly between the two groups. In one group,8,11 patients had profound systolic contractile dysfunction and were able to utilize markedly increased LV ﬁlling pressure to produce greater than normal use of the Frank-Starling mechanism to partially compensate and maintain some increase in exercise stroke volume. In the other group, despite normal systolic contractile function,10 patients were unable to use the FrankStarling mechanism to increase stroke volume during exercise and had markedly increased LV ﬁlling pressure. These data highlight the pivotal inﬂuence of the end diastolic pressure-volume response during exercise in healthy subjects and in patients with heart failure (see Fig. 17-7).24

207

208

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure CENTRAL HEMODYNAMIC RESPONSE TO UPRIGHT BICYCLE EXERCISE IN SHF vs. DHF COMPARED WITH NORMALS SHF (EF 30%) Sullivan 1989, Higginbotham 1987 • RER 1.18 • Peak VO2 ↓ 50% • CO ↓ 40% • A-V O2 diff ↓ 12% • SV ↓ 30% • Heart rate ↓ 13% • Upright resting PCWP ↑ at 9 mmHg (normal = 3) • Peak PCWP ↑ 27 mmHg (nl = 12) • Unable to decrease ESV (↑ contractility) during exercise

DHF (EF 56%) Kitzman 1991 • RER 1.24 • Peak VO2 ↓ 48% • CO ↓ 41% • A-V O2 diff ↓ 13% • SV ↓ 26% • HR ↓ 18% • Upright resting PCWP ↑ at 9 mmHg (normal = 3) • Peak PCWP ↑ at 25 mmHg (nl = 12) • Unable to increase EDV (↑ diastolic filling) during exercise

Group

Young Normal

Old Normal

Elderly Diastolic HF

VO2 Max (ml/kg/min)

28.6

22.6

12.7

Aortic distensibility (10–3 mmHg)–1

9.1

4.7

0.2

Ascending aortic wall thickness (mm)

2.1

2.2

Arterial Compliance Abnormal afterload and abnormal ventricular-vascular coupling are prime candidates to be responsible for the abnormal FrankStarling response seen in patients with DHF. Nearly all (88%) of such patients have a history of chronic systemic hypertension.25–27 In animal models, diastolic dysfunction develops early in systemic hypertension, and LV diastolic relaxation is very sensitive to increased afterload.28–33 Increased afterload may impair relaxation, leading to increased LV ﬁlling pressures, decreased stroke volume, and subsequently in patients, symptoms of dyspnea and congestion.1,2,31 From studies in animal models and humans it is known that chronic systolic hypertension accelerates and magniﬁes the agerelated increase in ﬁbrotic thickening of the aortic wall and the resultant increase in aortic stiﬀness, which in turn is a major determinant of LV afterload and ventricular-vascular coupling.34,35 In order to test the hypothesis that abnormally decreased aortic distensibility contributes to the severe exercise intolerance in heart failure with normal EF, we performed magnetic resonance imaging and maximal exercise testing with expired gas analysis in a group of elderly patients with so-called isolated DHF, as previ-

3.3

Figure 17-7 Comparison of characteristic central and peripheral cardiovascular response to exercise in patients with heart failure associated with severe LV systolic dysfunction versus normal LV ejection fraction. RER, respiratory exchange ratio.

Figure 17-8 MRI data and images from representative subjects from healthy young, healthy elderly, and elderly patients with diastolic heart failure (HF). Maximal exercise oxygen consumption (VO2 max), aortic distensibility at rest, and left ventricular mass/volume ratio. Patients with diastolic heart failure have severely reduced exercise tolerance (VO2 max) and aortic distensibility and increased aortic wall thickness. (Modified from Hundley et al: Cardiac cycle dependent changes in aortic area and aortic distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802.)

ously deﬁned (in the section “Pathophysiology of Exercise Intolerance”). Young healthy subjects and age-matched healthy subjects were studied as healthy normal controls. The patients with DHF had severe exercise intolerance that was associated with increased pulse pressure and concentric hypertrophic LV remodeling. Thoracic aortic wall thickness was increased 50%, and there was markedly decreased aortic distensibility (Fig. 17-8). In univariate analysis, decreased aortic distensibility correlated closely with patients’ severely decreased peak exercise VO2 (Fig. 17-9).36 In multivariate analysis, decreased aortic distensibility was the strongest independent predictor of reduced exercise capacity. These data support a potentially important role of increased aortic stiﬀness, due to underlying aging and ampliﬁed by chronic hypertension, in the pathophysiology of chronic heart failure symptoms.37

Chronotropic Response In addition to reduced stroke volume, decreased heart rate response can also contribute to reduced peak exercise cardiac output and thence reduced peak exercise VO2. Indeed, chrono-

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure

209

Figure 17-9 There is a close relationship between peak exercise VO2 (horizontal axis) and proximal aortic distensibility (vertical axis) in a group of 30 subjects (10 healthy young, 10 healthy old, and 10 elderly DHF patients). Each symbol represents the data from one participant. (From Hundley et al: Cardiac cycle dependent changes in aortic area and aortic distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802.)

10 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0

tropic incompetence has been a frequent ﬁnding during cardiopulmonary exercise studies in SHF. However, few if any data had been available in older patients and particularly those with normal EFs. Accordingly, we examined heart rate and expired gas analysis responses in elderly patients with DHF in comparison with a group of age- and gender-matched patients with SHF and healthy normal controls. Using the most standard deﬁnition of chronotropic incompetence, we found that it was present in 20% to 25% of older heart failure patients, that the prevalence was similar in DHF compared with SHF, that the presence of chronotropic incompetence was a signiﬁcant contributor to the degree of exercise intolerance, measured as maximal VO2, and that this was independent of medications, including beta-adrenergic antagonists.38 The important contribution of chronotropic incompetence to exercise intolerance in patients with DHF was conﬁrmed by Borlaug et al., who studied a cohort of primarily elderly, African American women with hypertension and heart failure with a preserved EF. The researchers reported signiﬁcant reductions in heart rate increase during exercise, which was a primary contributor to reduced peak cardiac output and maximal exercise VO2 (Fig. 17-10).39 Despite the many physiological exercise studies that have been performed with heart failure patients, there has remained uncertainty regarding the ﬁnal stimulus that causes heart failure patients to stop exercising at lower workloads than healthy subjects.40,41 It has been thought that increased exercise pulmonary wedge pressure and stimulation of pulmonary J-receptors cause reﬂex hyperventilation and hypoxia, leading to the sensation of severe dyspnea, causing the patient to stop exercise prematurely. However, about 50% of patients with heart failure, whether systolic or diastolic, discontinue exercise, due primarily to general fatigue or leg fatigue rather than dyspnea. In addition, investigators15,42 have demonstrated that arterial hypoxia does not occur

y = 0.0002x − 0.0021, r = 0.665

0

10

30

20

40

Peak VO2 (ml/kg/min)

HEART RATE ACCELERATION 110 p = 0.02 100 Beats per minute

Aortic distensibility (10 –3 mmHG–1)

RELATIONSHIP OF AORTIC DISTENSIBILITY WITH EXERCISE CAPACITY

Con

90 HFpEF 80

70

60 0

30

60

90

Seconds Figure 17-10 Chronotropic incompetence during exercise. Blunted increase in heart rate during exercise in 7 patients with heart failure and preserved ejection fraction >50% (HFpEF) compared with 14 matched control subjects. (From Borlaug BA et al: Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006;114:2138–2147.)

during exercise in patients with heart failure and that excess ventilation is related to pulmonary hypoperfusion and reduced cardiac output rather than elevated LV ﬁlling pressures. The decreased exercise cardiac output likely causes skeletal muscle hypoperfusion, a potent stimulus for early anaerobic metabolism, and subsequent generation of muscle lactate and other metabolites, which could produce the sensation of peripheral and central fatigue.43,44

210

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure In a randomized, crossover, blinded trial, Little et al. compared the calcium channel antagonist verapamil with the angiotensin receptor antagonist candesartan with the outcomes of peak exercise blood pressure, exercise time, and quality of life.62 While both agents blunted the peak systolic blood pressure response to exercise, only candesartan, and not verapamil, improved exercise time and quality of life (Fig. 17-12).62 In a subsequent trial with similar randomized, crossover, blinded design, the diuretic hydrochlorothiazide was compared with the angiotensin receptor antagonist losartan on the outcomes of peak exercise blood pressure, exercise time, and quality of life.63 While both agents blunted the peak systolic blood pressure response to exercise, only losartan, not hydrochlorothiazide, improved exercise time and quality of life.63

CLINICAL RELEVANCE: INTERVENTIONS TO IMPROVE EXERCISE TOLERANCE Angiotensin Receptor Blockers Pulse pressure can provide a crude estimate of the stiﬀness of the central large arteries, and its major determinant is systolic blood pressure.45 During exercise in normal subjects, systolic and pulse pressures increase substantially, and this response is magniﬁed by increased arterial stiﬀness. Data from animal models suggest that the exercise-related increase in systolic blood pressure is mediated in part by exercise-induced increases in circulating angiotensin II. Indeed, in a randomized, double-blind, placebocontrolled crossover trial, angiotensin receptor blockade reduced the exaggerated exercise increase in systolic and pulse pressures, resulting in signiﬁcantly improved exercise treadmill time and quality of life (Fig. 17-11).46 Aronow et al. showed in a group of patients with NYHA class III heart failure and presumed diastolic dysfunction (EF >50%) that the angiotensin converting enzyme (ACE) inhibitor enalapril signiﬁcantly improved functional class, exercise duration, EF, diastolic ﬁlling, and LV mass.47

Aldosterone Inhibitors The addition of low-dose spironolactone (12.5–50.0 mg daily) to standard therapy has been shown to improve exercise tolerance in patients with severe SHF. Aldosterone antagonism has numerous potential beneﬁts in patients with DHF, including LV remodeling, reversal of myocardial ﬁbrosis, and improved LV diastolic and vascular function.64–66 However, few data are presently available regarding aldosterone antagonism in DHF. In one small study, low-dose spironolactone was well tolerated and appeared to improve exercise capacity and quality of life in older women with isolated DHF.67 In another, spironolactone improved measures of myocardial function in hypertensive patients with DHF.68

Calcium Channel Blockers In hypertrophic cardiomyopathy, a disorder in which diastolic dysfunction is common, verapamil appears to improve symptoms and objectively measured exercise capacity.48–51 This agent also improves ventricular-vascular coupling and exercise performance in aged individuals with hypertension.52 In laboratory animal models, calcium antagonists, particularly dihydropyridines, prevent ischemia-induced increases in LV diastolic stiﬀness53 and improve diastolic performance in pacing-induced heart failure.54–56 However, negative inotropic calcium antagonists signiﬁcantly impair early relaxation56–60 and have in general shown a tendency toward adverse outcome in patients with SHF.56 Setaro et al. examined 22 men (mean age 65) with clinical heart failure despite an EF greater than 45% in a randomized, doubleblind, placebo-controlled crossover trial of verapamil.61 There was a 33% improvement in exercise time and signiﬁcant improvements in clinico-radiographic heart failure scoring and peak ﬁlling rate.

PEAK SYSTOLIC BP DURING EXERCISE

Glucose Cross-Link Breakers Glucose cross-links increase with aging and presence of diabetes, and they cause increased vascular and myocardial stiﬀness. Alagebrium, a novel cross-link breaker, improved vascular and LV stiﬀness in dogs. In a small, open-label, 4-month trial of this agent in elderly patients, LV mass, quality of life, and tissue Doppler diastolic function indices improved, but there were no signiﬁcant improvements in exercise capacity or aortic distensibility, the primary outcomes of the trial.69 A variety of other agents and strategies are currently being evaluated or are under consideration for this syndrome, including a selective endothelin antagonist.

EXERCISE TIME

300 18 16 250

Exercise time (min)

Peak systolic BP (mmHg)

275

225 200 175 150 125

p = ns p<0.05 p<0.05 Baseline

Placebo

Losartan

14 12 10 8 6

p = ns

p<0.05 p<0.05

4 Baseline

Placebo

Losartan

Figure 17-11 Plots of peak systolic blood pressure and exercise duration during baseline, during placebo, and during losartan therapy in a randomized, controlled, crossover trial. Treatment with the angiotensin II antagonist losartan increased exercise time. (From Warner et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572.)

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 40

300 200 100 0 –100

p<0.05

Control

Candesartan

30 20 10 0 –10 –20 –30 –40 p<0.05

p = ns

–200

A

Change in quality of life score (# of symptoms)

Change in exercise time (sec)

400

–50 Verapamil

B

p = ns

Control

Candesartan

Verapamil

Figure 17-12 Effect of candesartan angiotensin receptor antagonist compared with verapamil calcium channel blocker on A, exercise time and B, quality of life in patients with diastolic dysfunction. From survival of patients admitted with congestive heart failure by ejection fraction. (From Little WC et al: Effect of candesartan and veramapil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288–293.)

Pacemaker Therapy The substantial chronotropic incompetence seen in DHF and its correlation with reduced exercise capacity we have described provide a rationale for electronic pacing interventions to improve exercise capacity. Indeed, one modest-sized single-center study used such a strategy in selected patients with hypertensive LV hypertrophy with supranormal systolic ejection and distal cavity obliteration who had debilitating exertional fatigue and dyspnea and demonstrated substantially improved exercise performance.70 These data merit conﬁrmation in larger, multicenter, randomized, controlled trials. Thus, a variety of pharmacological and other interventions in small studies have shown improvements in exercise tolerance with verapamil,61 enalapril,47 angiotensin receptor antagonism,46,62 and aldosterone antagonism.67 It should be remembered that in patients with SHF, some types of pharmacological interventions that improve exercise tolerance have had paradoxical eﬀects on long-term survival.71,72 Because of this, the VE/VCO2 slope during exercise, which is a powerful predictor of survival independent of VO2, should be included in future intervention trials of exercise tolerance.6

Exercise Training Aerobic exercise training has the potential to improve a variety of key abnormalities in patients with heart failure and normal EF, including LV diastolic compliance, aortic distensibility, blood pressure, and skeletal muscle function.73–75 Indeed, in SHF, aerobic exercise training has been shown to improve exercise tolerance, likely via favorable eﬀects on multiple factors.12,76,77 A recent report indicates that LV diastolic compliance is preserved in older master athletes compared with their age-matched and young counterparts, suggesting that exercise training may be beneﬁcial in DHF as well.78 A preliminary report indicates that exercise training improves exercise tolerance and quality of life in older patients with heart failure and normal EF.79 Although the role of exercise training in the clinical management of this syndrome remains to be deﬁned, as is the accepted practice in SHF, it would seem prudent to recommend regular, moderate physical activity as tolerated. The eﬀect of exercise training on survival in patients with SHF is being examined in a

large, multicenter, randomized, controlled trial (HF-ACTION) sponsored by the U.S. National Institutes of Health. Presently, there is no trial examining this issue in patients with heart failure and normal EF.

FUTURE RESEARCH Patients with heart failure and normal EF have severe, chronic exercise intolerance. The pathophysiology of exercise intolerance in this syndrome is incompletely understood, but as in SHF, it is likely multifactorial. Current data suggest that important contributors include decreased LV diastolic compliance, decreased aortic distensibility, exaggerated exercise systolic blood pressure, relative chronotropic incompetence, and possibly anemia and skeletal muscle remodeling. Exercise intolerance is an attractive therapeutic target because it is a primary determinant of quality of life, can be quantiﬁed objectively, is reproducible, and is modiﬁable. Based on lengthy experience seeking to understand exercise intolerance in patients with SHF, it is likely that several factors in addition to those discussed in this chapter may contribute to exercise intolerance in patients with DHF, including chronotropic incompetence, abnormal peripheral arterial vasodilation, anemia, and skeletal muscle bulk, ﬁber type, and function.11,80–88 This will likely be a fruitful area for future research. A number of pharmacological and other interventions appear to improve exercise intolerance in DHF. Although it is unknown whether these will be accompanied by improved survival, the concomitant ﬁndings of improved quality of life conﬁrm the clinical relevance of exercise performance outcomes.

ACKNOWLEDGMENTS This work was supported in part by NIH R37 AG18915. REFERENCES 1. Gandhi SK, Powers JE, Fowle KM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2000;344:17–22. 2. Powers JE, Gandhi SK, Kramer RK, et al: Predictors of poor outcome in patients with hypertensive pulmonary edema. J Am Coll Cardiol 2004;43: 227A.

211

212

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 3. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 4. Bol E, de Vries WR, Mosterd WL, et al: Cardiopulmonary exercise parameters in relation to all-cause mortality in patients with chronic heart failure. Int J Cardiol 2000;72:255–263. 5. Jones RC, Francis GS, Lauer MS: Predictors of mortality in patients with heart failure and preserved systolic function in the Digitalis Investigation Group trial. J Am Coll Cardiol 2004;44:1025–1029. 6. Francis DP, Shamin W, Davies LC, et al: Cardiopulmonary exercise testing for prognosis in chronic heart failure: Continuous and independent prognostic value from VE/VCO2 slope and peak VO2. Eur Heart J 2000;21: 154–161. 7. Higginbotham MB, Morris KG, Williams RS, et al: Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986;58:281–291. 8. Kitzman DW, Sullivan M, Cobb FR, Higginbotham MB: Exercise cardiac output declines with advancing age in normal subjects. J Am Coll Cardiol 1989;13:241A. 9. Higginbotham MB, Morris KG, Williams RS, et al: Physiologic basis for the age-related decline in aerobic work capacity. Am J Cardiol 1986;57: 1374–1379. 10. Kitzman DW, Higginbotham MB, Cobb FR, et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072. 11. Sullivan M, Knight JD, Higginbotham MB, Cobb FR: Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure: Muscle blood ﬂow is reduced with maintenance of arterial perfusion pressure. Circulation 1989;80:769–781. 12. Sullivan M, Higginbotham MB, Cobb FR: Exercise training in patients with chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance. Circulation 1989;79:324–329. 13. Higginbotham MB, Sullivan M, Coleman RE, Cobb FR: Regulation of stroke volume during exercise in patients with severe left ventricular dysfunction: Importance of Starling mechanism. J Am Coll Cardiol 1987;9:58A. 14. Sullivan M, Cobb FR, Knight JD, Higginbotham MB: Stroke volume increases by similar mechanisms in men and women. Am J Cardiol 1991;67:1405–1412. 15. Sullivan M, Higginbotham MB, Cobb FR: Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 1988;77:552– 559. 16. Shen WF, Roubin GS, Hirasawa K, et al: Left ventricular volume and ejection fraction response to exercise in chronic congestive heart failure: Diﬀerence between dilated cardiomyopathy and previous myocardial infarction. Am J Cardiol 1985;55:1027–1031. 17. Sullivan M, Cobb FR: Central hemodynamic response to exercise in patients with chronic heart failure. Chest 1992;101:340S–346S. 18. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527–1533. 19. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular ﬁlling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 20. Hadano Y, Murata K, Yamamoto T, et al: Usefulness of mitral annular velocity in predicting exercise tolerance in patients with impaired left ventricular systolic function. Am J Cardiol 2006;97:1025–1028. 21. Skaluba SJ, Litwin SE: Mechanisms of exercise intolerance: Insights from tissue Doppler imaging. Circulation 2004;109:972–977. 22. Ha JW, Oh JK, Pellikka PA, et al: Diastolic stress echocardiography: A novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography. J Am Soc Echocardiogr 2005;18: 63–68. 23. Rovner A, Greenberg NL, Thomas JD, Garcia MJ: Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol 2005;289(5): H2081–H2088. 24. Kitzman DW, Sullivan M: Exercise intolerance in patients with heart failure: Role of diastolic dysfunction. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart. Boston, Kluwer Academic, 1994: 295–302. 25. Kitzman DW, Gardin JM, Gottdiener JS, et al: Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS

26. 27. 28. 29. 30.

31. 32. 33. 34. 35. 36.

37.

38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.

Research Group. Cardiovascular Health Study. Am J Cardiol 2001;87: 413–419. Iriarte M, Murga N, Morillas M, et al: Congestive heart failure from left ventricular diastolic dysfunction in systemic hypertension. Am J Cardiol 1993;71:308–312. Iriarte MM, Perez OJ, Sagastagoitia D, et al: Congestive heart failure due to hypertensive ventricular diastolic dysfunction. Am J Cardiol 1995;76: 43D–47D. Little WC: Enhanced load dependence of relaxation in heart failure: Clinical implications. Circulation 1992;85:2326–2328. Gelpi RJ: Changes in diastolic cardiac function in developing and stable perinephritic hypertension in conscious dogs. Circ Res 1991;68:555–567. Shannon RP, Komamura K, Gelpi RJ, Vatner SF: Altered load: An important component of impaired diastolic function in hypertension and heart failure. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart. Boston, Kluwer Academic, 1994:177–185. Little WC, Braunwald E: Assessment of cardiac performance. In Braunwald E (ed): Heart Disease. Philadelphia, WB Saunders, 1999. Hoit BD, Walsh RA: Diastolic dysfunction in hypertensive heart disease. In Gaasch WH, LeWinter MM (eds): Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, Lea & Febiger, 1994:354–372. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiﬀness from the time for deceleration of early left ventricular ﬁlling. Circulation 1995;92:1933–1939. Lakatta E: Cardiovascular aging research: The next horizons. J Am Geriatr Soc 1999;47:613–625. Lakatta EG, Levy D: Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises. Part I: Aging arteries: A “set up” for vascular disease. Circulation 2003;107:139–146. Hundley WG, Kitzman DW, Morgan TM, et al: Cardiac cycle dependent changes in aortic area and aortic distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802. Rerkpattanapipat P, Hundley WG, Link KM, et al: Relation of aortic distensibility determined by magnetic resonance imaging in patients = 60 years of age to systolic heart failure and exercise capacity. Am J Cardiol 2002;90: 1221–1225. Brubaker PH, Joo KC, Stewart KP, et al: Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil 2006;26:86–89. Borlaug BA, Melenovsky V, Russell SD, et al: Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006;114:2138–2147. Myers J, Froelicher V: Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med 1991;115:377–386. Franciosa JA: Role of ventricular function in determining exercise capacity in patients with chronic left ventricular failure. Adv Cardiol 1986;34: 170–8:170–178. Fink LI, Wilson JR, Ferraro N: Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am J Cardiol 1966;57:249–253. Sullivan M, Cobb FR: The anaerobic threshold in chronic heart failure. Circulation 1990;81:II-47–II-58. Green HJ: Manifestations and sites of neuromuscular fatigue. Biochem Exercise 1990;VII:13–35. Deedwania PC, Gottlieb S, Ghali JK, et al: Eﬃcacy, safety and tolerability of beta-adrenergic blockade with metoprolol CR/XL in elderly patients with heart failure. Eur Heart J 2004;25:1300–1309. Hornig B, Maier V, Drexler H: Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996;93:210–214. Sanders P, Kistler PM, Morton JB, et al: Remodeling of sinus node function in patients with congestive heart failure: Reduction in sinus node reserve. Circulation 2004;110:897–903. Nagaya N, Moriya J, Yasumura Y, et al: Eﬀects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004;110:3674–3679. Sullivan JJ, Green HJ, Cobb FR: Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990;81: 518–527. Adamopoulos S, Coats A, Brunotte F, et al: Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol 1993;21:1101–1106. Stratton J, Dunn JF, Adamopoulos S, et al: Training partially reverses skeletal muscle metabolic abnormalities during exercise in heart failure. J Appl Physiol 1994;76:1575–1582.

Chapter 17 • Exercise Intolerance in Diastolic Heart Failure 52. Kouba EJ, Hundley WG, Brubaker PH, et al: Skeletal muscle remodeling and exercise intolerance in elderly patients with diastolic heart failure. Am J Geriatr Cardiol 2003;12:135. 53. Felker GM, Adams KF Jr, Gattis WA, O’Connor CM: Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol 2004; 44:959–966. 54. Chae CU, Pfeﬀer MA, Glynn RJ, et al: Increased pulse pressure and risk of heart failure in the elderly. JAMA 1999;281:634–639. 55. Warner JG, Metzger C, Kitzman DW, et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572. 56. Aronow WS, Kronzon I: Eﬀect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993;71: 602–604. 57. Vandenberg VF, Rath LS, Stuhlmuller P, et al: Estimation of left ventricular cavity area with on-line, semiautomated echocardiographic edge detection system. Circulation 1992;86:159–166. 58. Bonow RO, Leon MB, Rosing DR, et al: Eﬀects of verapamil and propranolol on left ventricular systolic function and diastolic ﬁlling in patients with coronary artery disease: Radionuclide angiographic studies at rest and during exercise. Circulation 1981;65:1337–1350. 59. Bonow RO, Dilsizian V, Rosing DR, et al: Verapamil-induced improvement in left ventricular diastolic ﬁlling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term eﬀects. Circulation 1985;72:853–864. 60. Udelson J, Bonow RO: Left ventricular diastolic function and calcium channel blockers in hypertrophic cardiomyopathy. In Gaasch WH (ed): Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, Lea & Febiger, 1996:465–489. 61. Chen CH, Nakayama M, Talbot M, et al: Verapamil acutely reduces ventricular-vascular stiﬀening and improves aerobic exercise performance in elderly individuals. J Am Coll Cardiol 1999;33:1602–1609. 62. Serizawa T, Shin-Ichi M, Nagai Y, et al: Diastolic abnormalities in low-ﬂow and pacing tachycardia-induced ischemia in isolated rat hearts—modiﬁcation by calcium antagonists. In Lorell BH, Grossman W (eds): Diastolic Relaxation of the Heart. Boston, Kluwer Academic, 1996:266–274. 63. Cheng CP, Pettersson K, Little WC: Eﬀects of felodipine on left ventricular systolic and diastolic performance in congestive heart failure. J Pharma and Exper Thera 1994;271:1409–1417. 64. Cheng CP, Noda T, Ohno M, Little WC: Diﬀerential eﬀects of enalaprilat and felodipine on diastolic function during exercise in dogs with congestive heart failure. Circulation 1993;88:I-294. 65. Little WC, Cheng CP, Elvelin L, Nordlander M: Vascular selective calcium entry blockers in the treatment of cardiovascular disorders: Focus on felodipine. Cardiovasc Drugs Ther 1995;9:657–663. 66. Ten Cate FJ, Serruys PW, Mey S, Roelandt JR: Eﬀects of short-term administration of verapamil on left ventricular ﬁlling dynamics measured by a combined hemodynamic-ultrasonic technique in patients with hypertrophic cardiomyopathy. Circulation 1983;68:1274–1279. 67. Hess OM, Murakami T, Krayenbuehl HP: Does verapamil improve left ventricular relaxation in patients with myocardial hypertrophy? Circulation 1996;74:530–543. 68. Brutsaert DL, Rademakers F, Sys SU, et al: Analysis of relaxation in the evaluation of ventricular function of the heart. Prog Cardiovasc Dis 1985;28:143–163. 69. Brutsaert DL, Sys SU, Gillebert TC: Diastolic failure: Pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318–325.

70. Setaro JF, Zaret BL, Schulman DS, Black HR: Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic ﬁlling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981–986. 71. Little WC, Wesley-Farrington DJ, Hoyle J, et al: Eﬀect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004;43:288–293. 72. Little WC, Zile MR, Klein AL, et al: Eﬀect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and diastolic dysfunction. Am J Cardiol 2006;98:383–385. 73. Pitt B, Reichek N, Willenbrock R, et al: Eﬀects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: The 4E–left ventricular hypertrophy study. Circulation 2003;108:1831–1838. 74. Rajagopalan S, Pitt B: Aldosterone as a target in congestive heart failure. Med Clin North Am 2003;87:441–457. 75. Zannad F, Alla F, Dousset B, et al: Limitation of excessive extracellular matrix turnover may contribute to survival beneﬁt of spironolactone therapy in patients with congestive heart failure: Insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000;102:2700–2706. 76. Daniel KR, Wells GL, Fray B, et al: The eﬀect of spironolactone on exercise tolerance and quality of life in elderly women with diastolic heart failure. Am J Geriatr Cardiol 2003;12:131. 77. Mottram PM, Haluska B, Leano R, et al: Eﬀect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558–565. 78. Little WC, Zile MR, Kitzman DW, et al: The eﬀect of alagebrium chloride (ALT–711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191–195. 79. Kass DA, Chen CH, Talbot MW, et al: Ventricular pacing with premature excitation for treatment of hypertensive-cardiac hypertrophy with cavityobliteration. Circulation 1999;100:807–812. 80. Packer M, Carver JR, Chesebro J, et al: Eﬀect of oral milrinone on mortality in severe chronic heart failure: The Prospective Randomized Milrinone Survival Evaluation (PROMISE). N Engl J Med 1991;325:1468–1475. 81. Creager MA, Massie BM, Faxon DP, et al: Acute and long-term eﬀects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure. J Am Coll Cardiol 1985;6:163–173. 82. Peters DG, Mitchell HL, McCune SA, et al: Skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase gene expression in congestive heart failure. Circ Res 1997;81:703–710. 83. Sullivan M: Role of exercise conditioning in patients with severe systolic left ventricular dysfunction. In Fletcher GF (ed): Cardiovascular Response to Exercise. New York, Futura, 1994:359–372. 84. Vaitkevicius PV, Fleg J, Engel JH, et al: Eﬀects of age and aerobic capacity on arterial stiﬀness in healthy adults. Circulation 1993;88:1456–1462. 85. Pina IL, Apstein CS, Balady GJ, et al: Exercise and heart failure: A statement from the American Heart Association committee on exercise, rehabilitation, and prevention. Circulation 2003;107:1210–1225. 86. Coats A, Adamopoulos S, Radaelli A, et al: Controlled trial of physical training in chronic heart failure. Circulation 1992;85:2119–2131. 87. Arbab-Zadeh A, Dijk E, Prasad A, et al: Eﬀect of aging and physical activity on left ventricular compliance. Circulation 2004;110:1799–1805. 88. Kitzman DW, Brubaker PH, Abdelahmed A, Stewart KP: Eﬀect of exercise training on exercise capacity, quality of life, and ﬂow-mediated arterial dilation in elderly patients with diastolic heart failure. J Am Coll Cardiol 2004;110:III-558.

213

ANNITTA J. MOREHEAD, BA, RDCS

18

Sonographer’s Perspective of Evaluating Diastolic Function INTRODUCTION TECHNIQUE OF PERFORMING A DIASTOLIC ECHOCARDIOGRAPHIC DOPPLER EXAMINATION Atrial Chamber Size Left Ventricular Inflow Isovolumic Relaxation Time Pulmonary Venous Flow Color M-Mode Evaluation of Left Ventricular Inflow Tissue Doppler Imaging Right Ventricular Inflow Hepatic Veins Inferior Vena Cava

Superior Vena Cava Sonographic Approach to Imaging Strain, Strain Rate, and Torsion TOOLS USED TO ASSIST THE SONOGRAPHER IN GAINING ADDITIONAL INFORMATION Respirometer Doppler Enhanced Contrast Echocardiography Maneuvers SUMMARY AND FUTURE DIRECTIONS ABBREVIATIONS

INTRODUCTION Heart failure, a common ailment in older adults, is a major public health epidemic in the United States1–3 that aﬀected 5.2 million people in 2006.4 Diagnosis of systolic heart failure with a reduced ejection fraction is well documented, while diastolic heart failure in the presence of a normal ejection fraction is less understood.5–8 The cardiac sonographer plays a crucial role in the evaluation process of patients with both systolic and diastolic heart disease. There is truly an art to collecting accurate and reproducible imaging data in the evaluation of these patients. One must possess high technical competence, suﬃcient knowledge of left ventricular (LV) ﬁlling mechanics, and a thorough understanding of Doppler principles in order to obtain high-quality ﬂow velocity data that are required for obtaining an accurate and reproducible diastolic function examination. Echocardiographic diastolic function information, when collected correctly, can yield meaningful results that will help guide patient management.9–15 Sonographers should

routinely perform a diastolic examination on all patients to perfect their imaging skills and establish a consistent examination protocol. A comprehensive and systematic approach to performing a diastolic examination is outlined in this chapter and involves the use of echocardiographic tools, such as M-mode, twodimensional echo, conventional Doppler, and tissue Doppler. A skilled sonographer must be proﬁcient in these techniques and be able to recognize common pitfalls. When armed with this knowledge, the sonographer plays an important role in the noninvasive assessment of diastolic function. A diastolic echocardiographic evaluation begins with a careful review of the patient’s medical chart. Diastolic dysfunction is associated with a wide array of common clinical presentations and related diseases. Common clinical presentations and related disorders should alert the sonographer that a diastolic echocardiographic examination is indicated. The sonographer should pay close attention to obvious and subtle two-dimensional clues indicating potential diastolic heart disease, such as increased LV wall thickness, left atrial (LA) enlargement, a “ground glass” or 215

216

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function speckled myocardium, a thickened pericardium, and reduced atrioventricular (AV) motion (Table 18-1).

TECHNIQUE OF PERFORMING A DIASTOLIC ECHOCARDIOGRAPHIC DOPPLER EXAMINATION In combination with a standard echocardiographic examination, a diastolic evaluation includes two-dimensional, M-mode, pulsedwave (PW) Doppler, and color Doppler modalities (see Chapter 10).16,17 An attribute of color Doppler is that it can help reduce the length of time needed to perform the examination by aiding the sonographer in locating the center of ventricular inﬂow, the pulmonary veins, the hepatic vein, and the superior vena cava (SVC). Additionally, color Doppler M-mode (CMM) is a useful tool in displaying a preview of the LV ﬁlling pattern. The examination should also include evaluation of chamber size, especially the left atrium and right atrium, LV wall thickness, myocardial tissue characterization (i.e., ground glass appearance), movement of the AV groove from the apical four-chamber view, increased pericardial thickness, and abnormal septal bounce.

lateral mitral annulus. Commence tracing the chamber until reaching the opposite mitral annulus, subsequently closing the area automatically from one annulus to the other. Avoid inclusion of the LA appendage, pulmonary veins, and the mitral tenting area to prevent overestimation of the LA volume measurement (Fig. 18-1).16,18

Left Ventricular Inflow The LV inﬂow Doppler is probably the most commonly used measurement in the diastolic echo examination because the

Atrial Chamber Size Increased atrial size in a patient without valvular disease or atrial ﬁbrillation may be an indicator of increased LA pressures associated with diastolic dysfunction. A diastolic evaluation should always include an assessment of LA and RA volumes. The sonographer should assess LA size by panning and using slight rotational manipulation of the transducer with biplane images from the apical four-chamber and two-chamber views to “fully open” the LA area. LA volume measurement should be obtained at end systole, when the chamber is at its fullest. The LA volume is planimetered by placing the cursor at either the medial or the

Figure 18-1 Biplane left atrial (LA) area and volume are measured at end ventricular systole (maximum atrial area) from the apical four- and twochamber views. Depicted by arrows, trace from the lateral annulus outlining the atrium to the medial annulus using the automatic tracing feature to “close” the tracing at the annular level. Avoid including the area between the mitral annulus and the closed mitral leaflets as this will falsely increase the atrial measurement. RV, right ventricle; LV, left ventricle; LA, left atrum; RA, right atrium.

TABLE 18-1 STAGES OF DIASTOLIC DYSFUNCTION

NORMAL YOUNG

NORMAL ADULT

STAGE I DELAYED, IMPAIRED, OR ABNORMAL RELAXATION

E/A ratio

1–2

1–2

DT (msec) IVRT (msec) PV S/D ratio MVa / PVa duration PVs2 / PVd ratio AR (cm/sec) CMM (cm/sec) TDI (cm/sec) Anatomic abnormalities

<240 70–90 <1 ≥1

STAGE II PSEUDONORMAL FILLING

STAGE III RESTRICTIVE FILLING

<1.0

1–1.5 (reverses with Valsalva maneuver)

>1.5

150–240 70–90 ≥1 ≥1

≥240 >90 ≥1 ≥1 or <1

150–200 <90 <1 <1

<150 <70 <1 <1

1.5–2.0 (Doppler values similar to stage III except no change with preload reduction maneuvers) <150 <70 <1 <1

≥1 or <1

≥1

>>1

<1

<<1

<<1

<35 >55 >10 None

<35 >55 >8 None

<35 >45 <8 Normal or mildly enlarged LA

≥35 <45 <8 Mild to moderate LA enlargement, LVH, normal or abnormal EF

≥35 <45 <8 Severe LA enlargement, LV systolic dysfunction, MV or TV regurgitation

≥35 <45 <8 Severe LA enlargement, LV systolic dysfunction, MV or TV regurgitation with possible MV systolic regurgitation

STAGE IV IRREVERSIBLE RESTRICTIVE

From Bursi F, Weston SA, Redfield MM: Systolic and diastolic heart failure in the community. JAMA 2006:296;2209–2216. Yamada H, et al: Prevalence of left ventricular diastolic dysfunction by Doppler echocardiography: Clinical application of the Canadian consensus guidelines. J Am Soc Echocardiogr 2002;15:1238–1244. Garcia MJ, et al: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875.

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function SV too close to MV annulus

SV too far away from MV tips

LV Figure 18-2 A, Pulsed Doppler sample volume (SV) placed too far away from the mitral valve (MV) leaflet tips (49 cm/ sec) into the left ventricle demonstrating blunted “E” wave velocities with a thick course spectral envelope. B, Pulsed Doppler sample volume placed too close to the mitral annulus (60 cm/sec), resulting in blunted “E” wave velocities with a thick course spectral envelope as well. C, Pulsed wave Doppler sample volume correctly placed at the mitral valve leaflet tips of left ventricular inflow with a Doppler spectral display of 70 cm/sec. Strive for the highest obtainable velocity signals. Note the clean spectral envelope of panel C as compared with panels A and B.

Perfect!

LV

LV

LA

LA

LA

E

E 49 cm/sec

E 60 cm/sec A

70 cm/sec A

A

A

various patterns represent increasing degrees of LV diastolic impairment. LV ﬁlling patterns are easily recognized. The sonographer is able to record transmitral velocity using PW Doppler. The routine measurements performed are the early diastolic (E) and atrial contraction (A) peak velocities, as well as early ﬁlling deceleration time.17 The sonographer should obtain these by using color Doppler as a guide to align the pulsed Doppler cursor parallel with the center of the LV inﬂow. Attention must be given to appropriate sizing and placement of the Doppler sample volume box between the tips of the mitral valve in the middle of the color Doppler velocity map. Placing the sample volume box too far into the left ventricle or too close to the mitral annulus will result in underestimated LV inﬂow Doppler velocities (Fig. 18-2). Using a sample volume box that is too large is likely to produce a coarse velocity proﬁle due to spectral broadening from wall motion artifact, thus yielding an incorrect velocity recording. A low ﬁlter setting is required as well to allow the operator to obtain timing information at the zero-velocity baseline. The sonographer should adjust sample volume at 1–2 mm, velocity ﬁlter at 200 Hz, sweep speed at 50–100 mm/sec, and optimize the Doppler gain. The sonographer should then measure the peak E- and A-wave velocities, as well as the E-wave deceleration time (Fig. 18-3). To measure mitral A-wave duration, place the sample volume box approximately 5 mm closer to the mitral annulus and collect additional pulsed Doppler waveforms. The same Doppler settings previously described are recommended. The A-wave duration is a measure of time that must be taken from the beginning to the end of the A wave using the leading-edge-to-leadingedge approach (Fig. 18-4).

Isovolumic Relaxation Time Isovolumic relaxation time (IVRT) is a measure of time (in milliseconds) from the onset of the aortic valve closure spike artifact to the onset of the mitral valve opening spike artifact (Figs. 18-5 and 18-6).17 The IVRT is obtained from the apical ﬁve-chamber view by aligning the Doppler beam midway between the LV inﬂow and the LV outﬂow (see Fig. 18-5). Using PW

B

C

Decel

E A

Figure 18-3 Example of measurement of peak velocities E (early filling) and A (atrial contribution) and E-wave deceleration time from the slope of peak “E” to baseline. Note that deceleration time is measured from peak E wave following the descent to the zero baseline. Be careful not to include signal noise. BPM, beats per minute.

Doppler, the sample volume is adjusted to 3–4 mm and placed midway between the mitral valve leaﬂet tips and the LV outﬂow tract until both the aortic valve closure and the mitral valve opening spikes are visualized above and below the zero-Doppler baseline. Alternatively, continuous wave (CW) Doppler may be used if the operator is unable to obtain clear aortic valve closure and mitral valve opening spikes. The velocity ﬁlter setting should be adjusted at 200–400 Hz, the chart speed at 100 mm/sec, and Doppler gain optimized. An IVRT interval that is prolonged is representative of impaired relaxation, while an IVRT that is short may be indicative of increased LA pressure.

Pulmonary Venous Flow Pulmonary venous (PV) ﬂow occurs during both systole and diastole, as well as with atrial contraction (see Chapter 10). Systolic PV ﬂow occurs while the mitral valve is closed. Diastolic PV ﬂow occurs while the mitral valve is open. While in the apical

217

218

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

A E

RV

LV

RA

LA

A Dur

Figure 18-4 Example of measurement of atrial duration (A Dur). Move sample volume approximately 5 mm nearer to the mitral annulus from the peak left ventricular inflow velocities measurements. This technique results in a smaller E wave and a slightly better defined A wave, making clearer visualization of the onset of the A wave and mitral valve closure. Measure the A-wave duration time from these two points.

four-chamber view, one can assess PV ﬂow using PW Doppler. The right upper PV is most frequently visualized and accessible from the transthoracic echo examination.17 Color Doppler should be used as a guide to ﬁnd the strongest PV ﬂow signal, which has been described as appearing like a candle ﬂame. The sample volume box should be placed approximately 1–2 cm into the pulmonary vein to obtain the purest forward-ﬂow Doppler signal (Fig. 18-7). The sonographer must take care to ensure that the sample volume box is indeed in the pulmonary vein and not in the left atrium or at the junction of the left atrium and the pulmonary vein, or the resulting signal will be contaminated by other blood ﬂow velocities. The Doppler sample volume box should be adjusted to 3–4 mm in size, and the Doppler ﬁlter should be set to 200 Hz to allow full visualization of the spectral Doppler signal to the zero baseline. Sweep speed is then adjusted to 50–100 mm/sec. There are several components of the PV Doppler waveform. These components are PVs1, PVs2, PVd, and PVa. PVs1 occurs during early systolic ﬁlling and is representative of LA relaxation. PVs2 occurs during late systolic ﬁlling and is representative of LA compliance and pressure. PVd occurs during diastolic ﬁlling and is representative of LV ﬁlling properties. Finally, PVa represents atrial reversal and is representative of ﬂow reversal due to atrial contraction. PVs1 and PVs2 are commonly merged. PVs1 is more likely to be observed with a slower heart rate. The sonographer measures peak PVs1, PVs2, and PVa velocities as well as PVar duration (Fig. 18-8).

Figure 18-5 Place the Doppler cursor between the mitral and aortic valves panning between apical four- and five-chamber views to obtain isovolumic relaxation time. Adjust Doppler filter and gain settings to optimize the aortic valve closure and mitral valve opening spike artifacts.

IVRT 60 MV Flow

40 20 cm/s

AoV Flow

-20 -40 -60 75 BPM

Figure 18-6 Measure isovolumic relaxation time (IVRT) from the end of aortic valve (AoV) closure to the beginning of mitral valve (MV) opening.

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

Color M-Mode Evaluation of Left Ventricular Inflow As described earlier in this chapter, CMM is a useful tool in that it provides an instant display of the LV ﬁlling pattern. CMM can be used to measure the rate of propagation of LV peak ﬁlling velocity during early diastole, with representative “E” and “A” CMM propagation signals or waves that represent distance/time (velocity). CMM propagation velocity (Vp) is reduced with impaired LV relaxation and may be used to diﬀerentiate restriction from constriction, as well as normal from pseudonormal diastolic function.12,17–19 To obtain a quality CMM examination of LV ﬁlling, begin with an apical four-chamber view and avoid foreshortening the apex. Then reduce the two-dimensional depth to approximately 16 cm or at least to a depth that includes the entire left ventricle and a portion of the left atrium. Finally, adjust the color sector to ﬁt over the entire LV chamber, including the mitral valve annulus. Reducing the color sector maximizes the color frame rate and provides a better-quality CMM. Place the CMM cursor through the center of the LV ﬂow, aligned as parallel as possible to the direction of the inﬂow jet (Fig. 18-9). One of the most common errors in obtaining a CMM is incorrect placement of the cursor. The sonographer should align it with the aliasing color of mitral inﬂow, being conscientious not to cut oﬀ the tips of the E and A waves. Attention to detail will make the diﬀerence between accurate and inaccurate waveforms and subsequent measurements.

LV RV

RA LA

Figure 18-7 Pulmonary venous (PV) flow may be visualized using two-dimensional color Doppler guided imaging to depict the “flame” appearance of forward PV flow. The Doppler sample volume is placed approximately 1–2 cm into the right upper pulmonary vein (RUPV).

0.8 S1

LV

S2 0.6

D AR dur

0.4 RV

0.2

[m/s]

-0.2 AR -0.4

0

49 HR

Figure 18-8 Pulsed wave Doppler spectral display of pulmonary vein flow with correct sample volume placement. Clear distinction of pulmonary vein flow systolic (S1, S2), diastolic (D), and atrial reversal (AR) is demonstrated. Measure the peak S, D, and AR velocities as well as the AR duration.

Figure 18-9 Use two-dimensional color Doppler to guide placement for the highest-velocity signals. Place the M-mode cursor in left ventricular (LV) flow propagation, demonstrating appropriate alignment of M-mode cursor.

219

220

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function Keep in mind that the left ventricle ﬁlls from the base in a lateral direction as blood ﬂow propagates toward the apex. It is important to avoid crossing the myocardial boundary regions. The sonographer needs to set the color gain just at subsaturation and proceed to CMM display. He or she should adjust the color velocity scale for color aliasing by shifting the baseline up so that it is in the 30–40 cm/sec range, or approximately 70% of the aliasing velocity from the zero baseline (Fig. 18-10).19 The CMM sweep should be recorded at a speed of 100 mm/sec. The goal is to obtain the longest column of color from the base of the mitral annulus to the LV apex with an edge of uniform color during early ﬁlling. Measure the Vp slope starting from the aliasing velocity during early ﬁlling from the mitral valve plane to 4 cm into the LV cavity as illustrated in Figure 18-11. Ideally ﬁve or six high-quality consecutive cardiac cycles should be averaged. Normal CMM has a vertical slope with distinct “E” and “A” waves that resemble conventional PW Doppler E and A waves of ventricular ﬁlling.

color two-dimensional—and can be collected from either the longitudinal apical images (to collect annular velocities from the apical four- and two-chamber views with spectral Doppler data) or short-axis images (to collect myocardial Doppler velocities from 2D color) (Fig. 18-12). Color myocardial TDI data can be collected from the apical views as well. A diastolic echocardiographic assessment includes TDI data. The sonographer begins with an apical four-chamber view, initiates TDI mode, and places a 5 mm sample volume on the lateral mitral annulus. This can be repeated at the medial mitral annulus. The right ventricular free wall annulus also can be interrogated using TDI.21 Attention should be given to ensure proper placement of the Doppler sample volume on the annulus, avoiding the basal segments of the ventricular myocardium (Figs. 18-13 and 18-14).

Tissue Doppler Imaging Tissue Doppler imaging (TDI) is a modality that measures myocardial velocity, in contrast to traditional Doppler, which measures blood ﬂow velocity. While in the TDI mode, the ultrasound system is programmed to amplify and display low-velocity signals generated by the myocardium and to ﬁlter out higher-velocity signals generated by blood ﬂow. This is the opposite of the traditional use of Doppler imaging to measure blood ﬂow, where lower-velocity signals generated by the myocardium are suppressed and only the high-velocity signals from moving blood are displayed. TDI is a sensitive tool in the assessment of diastolic function in that it can diﬀerentiate normal from pseudonormal diastolic dysfunction. TDI spectral waveforms mimic diastolic and systolic patterns of conventional ventricular ﬁlling and ventricular outﬂow pulsed Doppler ﬂow signals in that it includes two diastolic (E′ and A′) peaks and one systolic (S′) peak.17,20,21 TDI can be displayed in the same three formats as conventional Doppler—(1) pulsed (spectral display), (2) CMM, and (3) +58

+42

–58 cm/sec

–68 cm cm/sec

Figure 18-10 Diagram depicting color Doppler baseline before and after adjustment for color M-mode.

Figure 18-11 Example of color M-mode of left ventricular (LV) inflow propagation velocity (Vp). Measure Vp from the intersection of the anterior mitral valve leaflet M-mode extending along the first edge of uniform color or aliasing velocity approximately 4 cm into the left ventricle. Schematic diagram in upper left corner represents color M-mode measurement of LV inflow propagation. E, early LV filling; A, late filling or atrial contribution.

Figure 18-12 Example of tissue Doppler image displayed from the short-axis view used to collect myocardial Doppler velocities from twodimensional color images.

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

Right Ventricular Inflow PW Doppler assessment of right ventricular (RV) inﬂow is performed while in the apical four-chamber view to obtain information on RV diastolic function. This is obtained by using color Doppler to ﬁnd the highest RV inﬂow velocity (Fig. 18-15). Next, a PW Doppler cursor is aligned parallel with the center of the RV color Doppler inﬂow. The sonographer may need to move the transducer slightly more medial to obtain correct alignment. The two-dimensional image in this slightly oﬀ axis view may not be aesthetically pleasing; however, the Doppler signal will be more accurate. The Doppler cursor must not cross the LV apex, as this will result in a blunted Doppler signal (Fig. 18-16). The sample volume box should be adjusted at 1–2 mm and placed between the tips of the tricuspid valve. The velocity ﬁlter is set to approximately 200 Hz, and the Doppler gain optimized to display a clean spectral envelope. Some respiratory variation (up to 15%) is normal and commonly observed in the RV outﬂow pattern.17 The chart speed is set at 50–100 mm/sec. A biphasic Doppler spectral

display that includes an E and A wave during the diastolic phase should be obtained. The peak E- and A-wave velocities are measured, as well as RV inﬂow deceleration time (Fig. 18-17). The sonographer should avoid sampling the RV inﬂow by crossing the LV apex. This will result in unreliable Doppler data (Fig. 18-18).

Hepatic Veins Pulsed Doppler assessment of the hepatic venous (HV) ﬂow is obtained from the short-axis subcostal view. Color Doppler is used to guide the transducer and cursor placement to locate the highest ﬂow velocity (Fig. 18-18A). The sonographer should place the sample volume in the center of the highest ﬂow velocity so that it is parallel with ﬂow and approximately 2–3 cm into the hepatic vein beyond the junction of the inferior vena cava (IVC).

Correct SV placement

LV

RV

RV

LV RV

LV a′

RA

LA e′

A A

B

B

Figure 18-13 Example of tissue Doppler with a 5 mm sample volume (SV) correctly placed at the lateral mitral annulus. Note that early left ventricular (LV) filling is represented by e′ wave and late LV filling or atrial contribution is represented by a′ wave. Measure the peak e′ and a′.

Figure 18-15 A, Correct pulsed wave Doppler cursor and sample volume placement. B, Use of color Doppler guided cursor placement. Note that the cursor crosses the right apex and is parallel with right ventricular inflow and that the sample volume is appropriately placed at the tricuspid valve leaflet tips.

Incorrect SV placement

LV

Figure 18-14 Example of incorrectly placed tissue Doppler sample volume (SV) near the lateral mitral annulus. Note that the SV was placed in the left ventricular (LV) basal lateral wall segment rather than at the lateral mitral annulus. This results in a tissue Doppler velocity signal that is blunted, yielding an inaccurate estimation of tissue velocity.

RA

A

a′ LA

e′

B

221

222

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function 0

SV Angle 0º Dep 9.6 cm Size 1.0 mm Freq 2.0 MHz WF Low Dop 68% Map 3 Prf 2500 Hz

+67.3

5 10 15

-67.3 cm/s

70 60 50 40 30 20 10 cm/s -10 -20 51 BPM

RV E LV A Decel

A

B

Figure 18-16 Example of correct pulsed wave spectral Doppler cursor alignment and correct sample volume placement at the tips of the tricuspid valve leaflets, resulting in the clean “E” and “A” Doppler waveforms.

1.0.65 A

E

The sonographer should adjust the sample volume at 1–3 mm, optimize the Doppler gain, and adjust the sweep speed to 50– 100 cm/sec. The systolic (S) and diastolic (D) ﬁlling components, as well as venous reversal (VR) and atrial reversal (AR), are displayed and measured (see Fig. 18-18B). It is common to observe mild respiratory variation in the HV Doppler proﬁle in normal patients.17

Inferior Vena Cava A diastolic echocardiographic examination includes an M-mode interrogation of the IVC to determine its diameter and to rule out plethora. The IVC is generally best visualized while in the short-axis subcostal view. The two-dimensional depth is reduced to improve visualization. The M-mode cursor is placed so that it crosses and is perpendicular to the IVC. Once in M-mode, the gain is optimized and the sweep speed is recorded at 25–50 cm/ sec. Several regular respiratory cycles should be included during M-mode interrogation. The patient is instructed, “Take several quick, short sniﬀs, as if you have a stuﬀy nose,” while the sonographer records the IVC diameter via M-mode sweep (Fig. 18-19A). This maneuver allows the sonographer to observe and evaluate the IVC for collapse during quick forceful inspirations. A lack of 50% collapse of the IVC during the “sniﬀ ” test is considered IVC plethora (see Fig. 18-19B).

0.5

LV

RV

[m/s] -0.5

0.0 -0.5

A

-1.0 78 HR

B

Figure 18-17 Incorrect pulsed wave Doppler cursor placement of right ventricular inflow with the Doppler cursor crossing the left ventricular apex, resulting in blunted peak E and A waves.

A

HV

IVC

A

Col 84% Map 1 WF High PRF 4000 Hz Flow Opt: FR 30 20 10 cm/s -10 -20 -30 -40 -50

AR VR

D S

B

Figure 18-18 A, Example of color Doppler guided cursor placement of hepatic vein flow. B, Pulsed wave spectral Doppler of hepatic vein flow demonstrating measurement of peak S (systolic) and D (diastolic) waves, VR (venous reversal), and AR (atrial reversal.)

B Figure 18-19 A, Normal response to the “sniff ” test with M-mode representation of inferior vena cava (IVC) diameter during “sniffing” maneuver. The double arrow illustrates the IVC diameter at end expiration as compared with the change in diameter during the sniff test. The IVC is considered plethoric if during the sniff test it collapses only minimally or does not collapse at all, indicating increased right atrial pressures. B, Abnormal response to the sniff test with M-mode representation of IVC diameter during “sniffing” maneuver. Note minimal or no IVC collapse during the test.

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

Superior Vena Cava The SVC ﬂow is obtained by positioning the patient ﬂat on his or her back without a pillow for head support. The patient is then asked to extend his or her chin slightly up and to the left. This position helps to better expose the SVC for transducer placement and subsequent Doppler assessment. The transducer is placed in the right supraclavicular fossa (Fig. 18-20A). Using color Doppler as a guide, the sonographer should search for a vertical blue column of color ﬂow, indicating blood ﬂow toward the right atrium via the SVC (see Figs. 18-20B and 18-20C). The PW Doppler cursor is placed in the center of the blue, parallel to the highest ﬂow velocity. The sample volume size is adjusted to 4–5 mm and the sample volume placed at approximately 5–8 cm in depth (close to the junction of the SVC and the right atrium, although well into the SVC). The Doppler ﬁlter is set at 200 Hz and the Doppler gain optimized. The sonographer should use a sweep speed of 50–100 cm/sec to collect and measure peak S and D waves, as well as AR (see Fig. 18-20D). As with other right-heart Doppler evaluations, it is common to observe respiratory variation in the SVC Doppler proﬁle.

Sonographic Approach to Imaging Strain, Strain Rate, and Torsion When a stress is imposed on myocardial muscle, it will deform, or change shape and often change volume. Deformation is deﬁned as a change in shape due to an applied force. This can be the result of pulling, pushing, or twisting. The change in shape as a result of imposing a stress is referred to as strain.22,23 Strain in echo Doppler is deﬁned as the change in length of the myocardial ﬁber. Strain imaging is derived from TDI (one-dimensional strain) or from speckle tracking (two-dimensional strain). Strain occurs in radial and longitudinal directions. The myocardial muscle shortens and thickens during ventricular contraction. Negative strain is demonstrated by myocardial muscle shortening in the circumferential and longitudinal dimensions, and positive strain is demonstrated by thickening or lengthening in the radial direction. Strain imaging is particularly useful to assess geometric changes of LV function. Strain rate is the measure of deformation of myocardial muscle over time.22,23 LV torsion is a measure of energy and is used to

understand the energy expended during the cardiac cycle, in both systolic and diastolic phases. The deﬁnition of torsion is to twist or turn. Torsion imaging, also known as torsional deformation, is used to measure the energy expended throughout systole and diastole.24–26 As the ventricles contract and relax, the myocardium thickens and thins in the radial, circumferential, and longitudinal directions. At the same time, the ventricles move in a twisting or coiling (torsion) motion. The respiratory cycle further contributes to cardiac motion by translating the heart in the chest cavity without aﬀecting strain. Strain imaging requires additional skill and understanding of Doppler principles pertinent to optimization of strain Doppler data (Table 18-3). Keep in mind that the heart is moving in multiple directions during the course of the cardiac cycle. Special attention to detail will help avoid collection of inaccurate data. The sonographer can avoid common pitfalls by incorporating technical tips in the strain image examination to improve Doppler data quality.23 One must bear in mind that strain measurement is angle dependent. The sonographer must acquire the data by aligning the LV walls as much as possible along the insonation angle (Fig. 18-21). Sometimes, it is necessary to separately image two opposing LV walls. Finally, one has to take care to maximize the acquisition frame rate: with TDI, one should strive to acquire the data at 60–100 fps. Strain may also be displayed by speckle tracking (see Fig. 18-22), where multiple natural acoustic speckles are automatically tracked in the two-dimensional image.27 Speckle tracking images are not derived from TDI, so images are often easier to acquire because they are not angle dependent. Speckle tracking can be obtained from the basal, mid-, and apical shortaxis levels of the left ventricle, where the resulting 18 segments can be displayed as a bull’s-eye diagram (Fig. 18-23). Table 18-2 provides a summary that may be used as a pocket guide for quick reference.

TOOLS USED TO ASSIST THE SONOGRAPHER IN GAINING ADDITIONAL INFORMATION Respirometer A respirometer is a useful tool in the evaluation of diastolic function. While not necessary, it is recommended and can enhance the interpretation of a diastolic examination by providing respiratory VR

20 2

AR

10 SVC Color Doppler

4

cm/s -10 -20

D

-30 -40 -50

SVC

-60

S

-70

A

B

C

D

Figure 18-20 A, Transducer placement at the right supraclavicular fossa for interrogation of superior vena cava (SVC) flow. B, 2D image of SVC. C, 2D color flow Doppler guided cursor placement in the SVC. The sonographer should obtain solid blue color demonstrating flow away from the transducer. D, Typical SVC pulsed wave Doppler spectral display demonstrating measured peak S, D, and AR velocities.

223

224

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function TABLE 18-2 DIASTOLIC EXAM: COLLECTING AND MEASURING LEFT- AND RIGHT-HEART PARAMETERS

OBSERVATION

VIEW

MODALITY

AV groove LA size (volume/ area) LV inflow

PLAX A4Ch and A2Ch

2D 2D

A4Ch

PWD

A-wave duration

A4Ch

PWD

PV flow

A4Ch

PWD

LV inflow CMM

A4Ch

CMM

IVRT

Between A4Ch and A5Ch

PWD or CWD

MV lateral annulus MV medial annulus

A4Ch A4Ch

TDI TDI

RV inflow

A4Ch

PWD

HV

Subcostal SAX

PWD

TV free wall annulus IVC

A4Ch

TDI

Subcostal SAX

2D guided M-mode

SVC

Right supraclavicular fossa

PWD

Strain

Apical Views

Strain rate

Apical Views

Torsion

SAX and Apical Views

TDI or 2D speckle tracking TDI or 2D speckle tracking TDI or 2D speckle tracking

SAMPLE VOLUME PLACEMENT OR CURSOR PLACEMENT OR FRAMES/SEC

SAMPLE VOLUME SIZE (mm)

VELOCITY FILTER (Hz)

SWEEP SPEED (mm/sec)

SV between mitral valve leaflet tips SV 5 mm nearer to mitral annulus than where sampled for LV inflow SV 1–2 cm into pulmonary vein Activate color Doppler in LV. Cursor placement in highest velocity color signal. Activate M-mode Cursor placement intermediate between LV inflow and LV outflow SV lateral mitral annulus SV medial mitral annulus

1–2

200

50 or 100

1–2

200

50 or 100

3–4

200

50 or 100

Between tricuspid valve leaflet tips 2–3 cm into hepatic vein beyond junction of IVC SV free wall annulus

Left Heart

100

200–400

50 or 100

5 5

100 100

50 or 100 50 or 100

1–2

200

50 or 100

3–4

200

50 or 100

5

100

50 or 100

Right Heart

Place M-mode cursor perpendicular to IVC SV 5–8 cm depth and close to the junction of the right atrium

25 or 50 3–4

200

50 or 100

Strain Imaging

cycle timing information in relation to other dynamics inﬂuencing intracardiac pressure, as described in detail in Chapter 15. To collect accurate respiratory timing information, the nasal thermistor must be place appropriately in the patient’s nostril (Fig. 18-24). Once the thermistor is comfortably placed, the sonographer should perform a practice maneuver by instructing the patient to inhale and exhale through the nose. The sonographer must observe the respiratory signal on the screen display and adjust the gain enough to ensure that inhalation and exhalation are recognized. He or she should then identify positive and negative deﬂections of the respiratory waveform to ensure correct interpretation. Upon completion of use, the nasal thermistor should be cleaned with alcohol prep pads and allowed to air dry. Alternatively, electrodes placed on the chest wall can detect respiratory variation by motion of the chest wall with breathing.

60–100 frames/sec 60–100 frames/sec 60–100 frames/sec

Doppler Enhanced Contrast Echocardiography Myocardial contrast echocardiography (MCE) is an excellent tool for optimizing LV endocardial borders in technically diﬃcult cases; however, it can also be used to enhance a diastolic Doppler evaluation. It is particularly helpful in improving PV Doppler signals if the sonographer is struggling with an examination. Because contrast is used for LV opaciﬁcation (LVO), it is important to allow the contrast eﬀect to visually dissipate in order to avoid Doppler signal blooming or overcompensation in the Doppler spectral signal. After contrast administration, the sonographer should continue with the image examination until 2D visualization of contrast eﬀect subsides (which can take up to 5 minutes), then proceed with the PV Doppler evaluation (Fig. 18-25). In most cases, the two-dimensional contrast eﬀect will appear to have disappeared; however, there will still be an

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

Base

A

Figure 18-21 A, Correctly aligned versus B, incorrectly aligned left ventricular wall segments. C, Upper panel is an example of the color M-mode display of strain rate values in the left ventricular (LV) septum. Lower panel represents strain rate obtained in the middle of the LV septum (represented by the green line). Note that the S, E, and A waves appear like mirrored images of the septal tissue velocities. If the transducer is not aligned correctly with the LV septum, peak values of strain rate waves will be decreased (represented by the yellow line).

Apex

S

B

C

-2 -9 -10 Figure 18-22 Example of two-dimensional speckle tracking longitudinal strain.

Figure 18-23 Example of two-dimensional speckle tracking representing all 18 segments in a bull’s-eye diagram.

9 3

-5

E

A

225

226

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function TABLE 18-3 TO OPTIMIZE STRAIN IMAGE DATA, THE THE FOLLOWING TECHNIQUES SHOULD BE EMPLOYED To optimize Doppler velocity signal, avoid reverberation artifacts, and minimize signal noise

To avoid underestimation To avoid angle dependence To avoid respiratory drift and angle changes

Include harmonic image mode Use an appropriate pulse repetition frequency to avoid aliasing Use a narrow sector to improve spatial resolution Ensure that the sample volume tracks within the myocardium throughout the entire cardiac cycle and avoid tracking the left ventricular blood pool Select a high frame rate (greater than 100 frames per second) Align the axis of cardiac motion with the scan lines Acquire strain data at end expiration

From Marwick TH: Measurement of strain and strain rate by echocardiography: Ready for prime time? J Am Coll Cardiol 2006;47:1313–1327.

S

D

AR

A

S D

B

AR

Figure 18-25 A, A technically difficult pulmonary venous (PV) Doppler signal. B, The improved contrast enhanced PV Doppler signals.

(Fig. 18-26). Clinically these techniques can enhance or suppress cardiac sounds and murmurs. LV ﬁlling patterns are known to have preload dependence and alterations in preload indices and can be useful in detecting increased ﬁlling pressures. Attention must be paid to the mitral A wave, as it will increase during maneuvers due to increased ﬁlling pressures (Fig. 18-27). Close attention should also be given to the relationship between the Doppler and the respiratory variation when evaluating patients with constrictive pericarditis versus restrictive cardiomyopathy (see Chapter 24). Reducing preload with an upright positioning maneuver should be done if needed. If mitral E-wave respiratory variation greater than 25% is not present in a patient with suspected constriction, this may be secondary to a marked increase in LA pressure. Reduction of preload, as with upright sitting positioning, may bring out this respiratory variation.

Valsalva Maneuver Figure 18-24 Demonstration of appropriate placement of the nasal thermistor, resulting in an accurate respiratory signal display that can be superimposed on the spectral Doppler display.

adequate amount of contrast to enhance the Doppler signal to yield reproducible high-quality Doppler waveforms. The risks and beneﬁts of administering echo contrast must always be considered and the decision to give echo contrast must be made by a physician on a case-by-case basis.28

Maneuvers Techniques of manipulation may be performed to aid in the assessment of ﬁlling pressures and subsequently of diastolic function during an echocardiographic examination.8,13 Valsalva, postural changes, isometric exercise, and respiration are maneuvers that can be used to temporarily alter cardiac hemodynamics

The mitral E/A ratio alone does not diﬀerentiate normal from pseudonormal ﬁlling patterns. This is where the Valsalva maneuver is indicated. It is probably the most useful maneuver and is achieved by straining against a closed glottis for 10–15 seconds after deep inspiration. Intrathoracic pressure should be elevated to about 40 mmHg. The Valsalva maneuver can also be particularly helpful when determining reversible from irreversible restrictive ﬁlling patterns. The Valsalva maneuver can be performed by either having the patient blow into a tube connected to a dial sphygmomanometer (Fig. 18-28) or by bearing down. Performed incorrectly, the maneuver will result in equivocal data. It is the sonographer’s responsibility to thoroughly explain the Valsalva maneuver to the patient and then to conduct a practice session to coach the patient on how to fully participate in the maneuver with expectations of full compliance. The sonographer should explain to the patient that prior to actually recording it he or she will ﬁrst practice the

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function

Figure 18-26 Demonstration of the Valsalva effect on heart rate, blood pressure, and left ventricular filling pressures. In this example, the A wave increases in velocity during Valsalva and returns to baseline upon release of Valsalva. Heart rate and blood pressure return to baseline as well.

Figure 18-27 A, Note the increasing A-wave response to the Valsalva maneuver while pulsing left ventricular inflow. B, Note the relationship of the E and A waves as they return to baseline peak velocities once Valsalva effect subsides.

maneuver once or twice while the sonographer checks the placement of the cursor and the sample volume. If using the sphygmomanometer, the patient should be instructed to exert enough forward airﬂow to increase the gauge to approximately 40 mmHg. The sonographer should use the following analogies to help the patient understand what a Valsalva maneuver should feel like:

Figure 18-28 Example of a patient “blowing” into the sphygmomanometer tube to achieve a Valsalva effect.

“Bear down as if you were going to have a bowel movement.” “Push as if you were pushing a lawn mower up a big hill.” “Simulate the act of blowing up a large balloon.” The patient’s abdomen should be observed for veriﬁcation of active contraction of abdominal muscles. The sonographer’s hand should be placed on the abdomen to ensure adequacy of strain.

227

228

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function The jugular veins are examined to conﬁrm distention of strain phase. An adequate amount of expiratory eﬀort is needed to cause physiologic changes. The sonographer should strive for about a 40 mmHg change from baseline. Though not mandatory, a manometer is most commonly used during research protocols to document the exact measurement and change in expiratory eﬀort from baseline. Contraindications to performing Valsalva are unstable angina or recent myocardial infarction, severe valvular disease, recent transient ischemic attack or stroke, and uncontrolled hypertension.

Isometric Hand Exercise Isometric exercise such as a sustained handgrip is used to increase afterload. The patient should be instructed to squeeze rolled towels or tennis balls simultaneously in a squeeze/release, squeeze/ release pattern and continue performing it until the maneuver yields an adequate response. The patient should not hold his breath or perform Valsalva while doing isometric exercise. Physiologically, the hemodynamic eﬀects of an isometric handgrip are related to decreased vagal tone and increased sympathetic tone. In a patient with normal diastolic function, performing an isometric handgrip causes increased heart rate, blood pressure, cardiac output, and venous reversal. Individual response depends on the amount of exercise, baseline LV function, and baseline hemodynamic state. In patients with baseline LV dysfunction, isometric exercise will increase LV ﬁlling pressures.

Respiratory Maneuvers Respiratory changes are divided into two categories: those that increase with inspiration due to increased venous reversal and those that increase with expiration due to decreased lung volume. Physiologically, during deep inspiration, intrathoracic pressure decreases, causing increased venous reversal while augmenting right-heart preload, which increases RV stroke volume. During deep expiration, lung volume decreases as air leaves the lungs, and the heart moves closer to the thoracic wall. PV ﬂow enters the left atrium secondary to increased intrathoracic pressures. Vascular resistance is not solely a result of respiration but depends on the position of the patient. A supine position increases venous reversal; a standing position decreases venous reversal; sitting or standing accentuates respiratory induced changes. Right-sided velocities increase with inspiration, and left-sided velocities decrease with inspiration. Ischemic heart disease and arrhythmias are contraindicated for respiratory maneuvers. As mentioned, a respirometer is a useful tool in the assessment of timing Doppler data during the respiratory cycle to determine respiratory induced changes. Doppler data should be recorded during inspiration and expiration to better deﬁne the respiratory eﬀect on intracardiac chamber ﬁlling pressures. A respirometer is particularly useful in evaluating respiratory variation to help differentiate between constriction and restriction, for assessing pericardial eﬀusion, and for ruling out IVC plethora. A nasal thermistor is appropriately placed, and the cable is connected to the respirometer port of the ultrasound system. Some ultrasound systems incorporate a respiratory sensing device in the echocardiographic leads. The respirometer signal is displayed as a cine wave superimposed on the echo Doppler images. When using a nasal thermistor, the patient is asked to breath through the nose. The sonographer should always test the respirometer by ﬁrst practicing to demonstrate the inspiration and expiration signal on the screen.

Figure 18-29 Demonstration of image evaluation during upright sitting position maneuver.

Postural Maneuvers Postural changes, such as sitting or standing from a supine position, decrease venous reversal (Fig. 18-29). Physiologically, gravity causes pooling in the venous beds of the legs, decreasing venous reversal. RV and LV stroke volumes also fall, causing hypotension. This in turn causes reﬂex tachycardia and an increase in vascular resistance.

Leg Raising Maneuver Passive leg raising is the opposite of those maneuvers described earlier in this chapter, causing increased intra-abdominal pressure, venous reversal, stroke volume, cardiac output, and central aortic pressure (Fig. 18-30). This will cause reﬂex bradycardia, as in phase IV of the Valsalva maneuver.

Figure 18-30 Demonstration of image evaluation during leg elevation maneuver.

SUMMARY AND FUTURE DIRECTIONS Echocardiography is the workhorse of cardiac imaging and requires skillful sonographers. Echocardiography provides a diagnostic examination that is noninvasive, portable, and able to be repeated multiple times without risk to the patient while yielding unique functional and hemodynamic information. The cardiac sonographer plays an extremely important role in the diagnosis of diastolic heart disease. In-depth knowledge regarding cardiac

Chapter 18 • Sonographer’s Perspective of Evaluating Diastolic Function hemodynamics and Doppler principles and high-quality imaging skills are required to yield useful clinical data. The growing heart failure epidemic necessitates the demand for competent sonographers who are a critical part of the diagnostic team. Newer technology is being developed that will enhance the information yielded from a diastolic exam, allowing for earlier recognition of impaired diastolic dysfunction. Advances in imaging strain, strain rate, torsion, and tissue or speckle tracking will provide the sonographer with more sensitive and accurate tools; however, this necessitates advanced levels of training and education and should always be consistently practiced. Formal education through medical diagnostic training curricula as well as continuing education programs must include core training in diastolic heart failure assessment by echocardiography.

ABBREVIATIONS 2D A2Ch A4Ch A5Ch ALAX AoV AR CO CMM CWD E/A EF DT HV HR ITP IVC IVRT LA LV LVH MV MVa / PVa PLAX PP PSAX PV PV S/D PVs2 / PVd PWD RA RV SV SVC TDI TV VR

two-dimensional apical 2-chamber apical 4-chamber apical 5-chamber apical long axis aortic valve atrial reversal cardiac output color M-mode continuous wave Doppler LV inﬂow E and LV inﬂow A ratio ejection fraction deceleration time hepatic vein heart rate intrathoracic pressure inferior vena cava isovolumetric relaxation time left atrial left ventricular left ventricular hypertrophy mitral valve mitral valve A wave and pulmonary vein A wave ratio parasternal long axis pulse pressure parasternal short axis pulmonary venous pulmonary vein systolic / diastolic ratio pulmonary vein systolic peak 2 and pulmonary vein diastolic pulsed wave Doppler right atrial right ventricular sample volume superior vena cava tissue Doppler imaging tricuspid valve venous reversal

REFERENCES 1. Barker HB, Mullooly JP, Getchell W: Changing incidence and survival for heart failure in a well-deﬁned older population, 1970–1974 and 1990– 1994. Circulation 2006;113:799–804.

2. Gutierrez C, Blanchard DG: Diastolic heart failure: Challenges of diagnosis and treatment. Am Fam Physician 2004;69:2609–2616. 3. Appleton CP, Jensen JL, Hatle LK, et al: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal ﬂow velocity recordings. J Am Soc Echocardiogr 1997:10:271–292. 4. Rosamond W, Flegal K, Friday G, et al: Heart disease and stroke statistics—2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115: e69–e171. 5. Bursi F, Weston SA, Redﬁeld MM, et al: Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–2216. 6. Hawkins NM, Wang D, McMurray JJ, et al: Prevalence and prognostic implications of electrocardiographic left ventricular hypertrophy in heart failure: Evidence from the CHARM programme. Heart 2007;93:59–64. 7. Galderisi M: Diastolic dysfunction and diabetic cardiomyopathy: Evaluation by Doppler echocardiography. J Am Coll Cardiol 2006;48: 1548–1551. 8. Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246–270. 9. Appleton CP, Jensen JL, Hatle LK, et al: Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal ﬂow velocity recordings. J Am Soc Echocardiogr 1997:10:271–292. 10. Vasan RS, Benjamin EJ: Diastolic heart failure—no time to relax. N Engl J Med 2001;344:56–59. 11. Maurer MS, Spevack D, Burkhoﬀ D, et al: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44: 1543–1549. 12. Quiñones MA: Assessment of diastolic function. Prog Cardiovasc Dis 2005;47:340–355. 13. Mottram PM, Marwick TH: Assessment of diastolic function: What the general cardiologist needs to know. Heart 2005;91:681–695. 14. Garcia MJ: Comprehensive echocardiographic assessment of diastolic function. Heart Failure Clin 2006;2:163–178. 15. Oh JK, Hatle L, Tajik AJ, et al: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 16. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantiﬁcation: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantiﬁcation Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 17. Quiñones MA, Otto CM, Stoddard M, et al: Recommendations for quantiﬁcation of Doppler echocardiography: A report from the Doppler Quantiﬁcation Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15: 167–168. 18. Gilman G, Nelson TA, Hansen WH, et al: Diastolic function: A sonographer’s approach to the essential echocardiographic measurements of left ventricular diastolic function. J Am Soc Echocardiogr 2007;20:199–209. 19. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875. 20. Ho CY, Solomon SD: A clinician’s guide to tissue Doppler imaging. Circulation 2006;113:e396–e398. 21. Dokainish H, Sengupta R, Patel R, et al: Usefulness of right ventricular tissue Doppler imaging to predict outcome in left ventricular heart failure independent of left ventricular diastolic function. Am J Cardiol 2007;99:961–965. 22. Abraham TP, Nishimura RA: Myocardial strain: Can we ﬁnally measure contractility? J Am Coll Cardiol 2001;37:731–734. 23. Marwick TH: Measurement of strain and strain rate by echocardiography: Ready for prime time? J Am Coll Cardiol 2006;47:1313–1327. 24. Galderisi M. Can technical limitations of strain rate imaging be overtaken by particular arrangements? J Am Coll Cardiol 2006;48:1729. 25. Notomi Y, Setser RM, Shiota T, et al: Assessment of left ventricular torsional deformation by Doppler tissue imaging: Validation study with tagged magnetic resonance imaging. Circulation 2005;111:1141–1147. 26. Notomi Y, Lysyansky P, Setser RM, et al: Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol 2005;45:2034–2041. 27. Perk G, Tunick PA, Kronzon I: Non-Doppler two-dimensional strain imaging by echocardiography—from technical considerations to clinical applications. J Am Soc Echocardiogr 2007;20:234–243. 28. FDA online: Available at http://www.fda.gov/

229

DOUGLAS S. LEE, MD, PhD RAMACHANDRAN S. VASAN, MD, DM

19

Hypertension and Valvular Heart Disease INTRODUCTION PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN HYPERTENSION Mechanical Considerations Cellular and Molecular Bases of Left Ventricular Diastolic Dysfunction in Hypertension Clinical Basis of Hypertensive Heart Disease

PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN VALVULAR DISEASE Acute Aortic Insufficiency Chronic Aortic Insufficiency Aortic Stenosis Acute Mitral Regurgitation Chronic Mitral Regurgitation Mitral Stenosis FUTURE RESEARCH

INTRODUCTION Hypertension and valve disease are key risk factors for heart failure. Uncontrolled hypertension results in left ventricular (LV) remodeling, often with an increase in LV mass. Valve disease is associated with pressure or volume overload of the left ventricle, depending on its etiology. Signiﬁcant valve disease is associated with LV remodeling, usually with LV hypertrophy (LVH). The pattern of LV remodeling and its severity vary depending on the nature, severity, and chronicity of valve disease. LV remodeling is a fundamental substrate for overt heart failure. Thus, an overlap exists between the pathophysiology of LV remodeling in hypertensive heart disease and severe valve disease. The hypertrophic response in patients with valve disease results from the activation of biological pathways that also play a key role in the evolution of hypertensive heart disease. LV diastolic impairment occurs in patients with hypertension or valve disease, even in those without evidence of LVH or systolic dysfunction. Cases of heart failure due to hypertension and valve disease both frequently manifest with a preserved LV ejection fraction. When heart failure occurs in association with a normal LV ejection fraction but with concomitant LV diastolic ﬁlling abnor-

malities, the term diastolic heart failure (DHF) has been used.1,2 In cases of heart failure on the basis of hypertension, blood pressure control may lead to amelioration or resolution of abnormal LV diastolic function, and therefore may change the natural progression to hypertension-associated DHF.3–6 In the case of valve disease, medical management and/or surgical correction of the condition is associated with resolution of heart failure and LV diastolic dysfunction. In this chapter, we discuss pathophysiologic and clinical considerations in DHF due to hypertension or valvular heart disease. Although valvular heart disease constitutes an exclusion in some deﬁnitions of DHF,7 we employ a broader view by examining these conditions in the context of the syndrome of heart failure with preserved LV systolic function.

PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN HYPERTENSION Mechanical Considerations Hypertension increases the load on the left ventricle, with a resultant increase in LV mass (referred to as hypertrophy). The LV 233

Chapter 19 • Hypertension and Valvular Heart Disease 160

Laplace’s law: Wall stress = p × r/2 × h.

120

Hypertension and Left Ventricular Mass Systolic blood pressure is an important determinant of LV mass in hypertension.15 LV mass (LVM), in grams, is calculated by echocardiography using the following equation16:

25

50

75

100

125

150

125

150

125

150

LV volume (ml)

A 160

120

80

40

0 0

25

50

75

100

LV volume (ml)

B 160

120

80

40

0

LVM = 39.95 + 14.61 × height (m2.7) + 0.65 × SW (grams-meters/beat) − 17.17 × sex, where male sex is assigned a value of 1 and female sex is assigned a value of 2. An inappropriately increased LV mass was deﬁned as an observed to predicted ratio of LV mass greater than approximately 1.3. Such individuals, who have inappropriately increased LV mass that exceeds the compensatory needs for a given workload, have been found to exhibit further abnormalities of systolic and diastolic function. These abnormalities include delayed LV relaxation with prolonged isovolumic relaxation time (IVRT), increased myocardial stiﬀness, and mild systolic dysfunction of the midwall and LV chamber (see the section “Echocardiographic Features of Hypertensive Left Ventricular Hypertrophy”).27

40

0

LVM (g) = 1.04 × [(IVS + LVEDD + PWT)3 − LVEDD3] − 13.6, where IVS = thickness of interventricular septum, LVEDD = LV end diastolic dimension, and PWT = posterior wall thickness. Indexed for body surface area, an LV mass index greater than 131 g/m2 for men and greater than 100 g/m2 for women represents LVH.15 Other cutpoints for LVH have also been suggested, indexing for height raised to a power.17–19 LVH is one of the most common causes of isolated diastolic dysfunction and is an important independent risk factor for heart failure.20–22 The patterns of diastolic ﬁlling and its relation to LV pressure in chronic hypertension are shown in Figure 19-1. Early diastolic ﬁlling abnormalities in hypertension correlate with increased LV mass.23–26 In hypertensive individuals, observed LV mass may be signiﬁcantly greater than that which is predicted based on demographic, clinical, and hemodynamic factors (e.g., systolic blood pressure, stroke volume, sex, height). For instance, de Simone et al. calculated predicted LV mass as27:

80

0

LV pressure (mmHg)

To normalize wall stress in the presence of pressure overload, LV wall thickness increases, and this concept is applicable to both hypertension and valvular disease. Initially, this response to increased wall tension occurs with thickening of the LV walls within the “normal” range. However, progression toward an abnormal increase in LV wall thickness occurs with prolonged exposure. The development of LVH is not only load dependent but multifactorial and may be inﬂuenced by endocrine, autocrine, paracrine, and genetic factors. It is of interest that both blood pressure and LV mass exhibit familial aggregation and are heritable quantitative traits.8–11 Additionally, familial aggregation of LV diastolic measures12,13 and left atrial (LA) size14 (a marker of diastolic dysfunction) has also been reported, suggesting that LV diastolic dysfunction in response to stressors such as pressure overload may be modulated in part by genetic inﬂuences and shared environmental factors.

LV pressure (mmHg)

response to increased load is to normalize wall tension. According to Laplace’s law, wall stress is deﬁned by its relationship with pressure (p), chamber radius (r), and wall thickness (h), thus:

LV pressure (mmHg)

234

0

25

50

75

100

LV volume (ml)

C Figure 19-1 Ventricular systolic and diastolic pressure-volume loops associated with heart failure (HF) with normal ejection fraction (normal conditions shown in black). A, Diastolic HF that is not due to hypertensive etiology, with normal end systolic pressure-volume relationship (ESPVR), an upward and left-shifted end diastolic pressure-volume relationship (EDPVR), and normal or low blood pressure (red loop). B, Pressure-volume loops of HF with normal ejection fraction and chronic hypertension (note elevated blood pressure). ESPVR is elevated and EDPVR is shifted upward and to the left (blue loop). C, Same as B, except that ESPVR is normal or near-normal and EDPVR is normal or shifted to the right (green loop). (From Maurer J et al: Left heart failure with a normal ejection fraction: Identification of different pathophysiologic mechanisms. J Card Failure 2005;11:177.)

Chapter 19 • Hypertension and Valvular Heart Disease Regression of increased LV mass is correlated with reduction particularly in systolic blood pressure and parallels similar changes in the electrocardiogram (ECG).28 In patients with regression of LVH on ECG with treatment, there is regression of LV mass.29

Hypertension and Left Ventricular Geometry The eﬀect of hypertension on LV diastolic dysfunction is also partly dependent on LV geometry (see the section “Echocardiographic Features of Hypertensive Left Ventricular Hypertrophy”), a phenotype deﬁned on the basis of presence versus absence of LVH, and the relative wall thickness (RWT). The RWT has been calculated as: RWT = 2 × PWT/LVEDD. The RWT is considered to be increased if greater than 0.42.30,31 Alternatively, RWT has also been calculated as: RWT = (IVS + PWT)/LVEDD and is considered increased if greater than 0.45.32 In those without LVH, normal LV geometry is represented by normal LV mass and normal RWT, whereas concentric LV remodeling is deﬁned by normal LV mass and increased relative wall thickness. Concentric remodeling represents the early adaptive changes to decrease LV wall tension in response to an increase in pressure overload. In the presence of LVH, LV geometry may be concentric or eccentric. Concentric hypertrophy occurs when RWT is increased and LVH is present, often in the presence of reduced ventricular internal dimensions. Eccentric hypertrophy is characterized by ventricular enlargement and an increase in LV mass, where wall tension is increased by virtue of an increase in radius so that RWT is normal.

Hypertensive Overload and Left Ventricular Diastolic Dysfunction In hypertension, ventricular hypertrophy occurs to compensate for elevated wall stress and increased ventricular stiﬀness, and impaired LV relaxation may ensue.33 Impairment in LV relaxation decreases early LV ﬁlling, and the atrial contribution to ventricular ﬁlling increases. In hypertensive states, due to increased afterload from vascular or valvular etiologies, increased LV chamber stiﬀness may result from an increase in myocyte hypertrophy and/or alterations in the cardiac interstitium. An increase in LV stiﬀness or reduction in ventricular compliance results in increased LV diastolic pressure for any degree of ventricular preload, and subsequent pulmonary venous congestion with symptoms of dyspnea. In adult patients with diastolic,24 isolated systolic,25 borderline isolated systolic,34 and combined systolic and diastolic hypertension,35 as well as in children with hypertension,36 an abnormal diastolic ﬁlling pattern characterized by impaired early diastolic ventricular ﬁlling with an enhancement in late diastolic ﬁlling (due to atrial systole) has been reported, indicating subnormal LV relaxation with normal ventricular compliance.37 A prolonged IVRT has also been demonstrated in hypertensive persons.38 Possible contributing factors for the LV diastolic dysfunction observed in hypertensive patients include myocardial ﬁbrosis and increased LV mass (see the sections “Cellular and Molecular Basis of Left Ventricular Diastolic Dysfunction in Hypertension” and

“Clinical Epidemiology of Hypertensive Heart Disease”) although they do not always accompany hypertension.39,40 An indication that diastolic dysfunction may be present in the context of the pressure-overloaded ventricle is the identiﬁcation of LVH or an abnormal increase in LV mass. Although diastolic ﬁlling abnormalities often occur when LV mass is increased, ventricular hypertrophy is not a requisite for LV diastolic dysfunction, which may also occur at an earlier stage in hypertensive patients without overt LVH. Early diastolic ﬁlling abnormalities in hypertension correlate with increased LV mass.23–26 As noted previously, LVH is one of the most common causes of isolated LV diastolic dysfunction and is an important independent risk factor for heart failure.20–22 Myocardial ﬁbrosis with increased interstitial collagen deposition is another mechanism underlying LV diastolic dysfunction in hypertensive subjects. There is a strong relation between LV stiﬀness and myocardial collagen content41,42 and plasma levels of ﬁbrosis markers43 in hypertensive persons. Improvement of LV diastolic function during antihypertensive treatment is related to regression in myocardial collagen content.41,42 This may indicate that LV mass is determined mainly by loading conditions, whereas myocardial ﬁbrosis and LV diastolic dysfunction may be the consequence of the detrimental eﬀects of neurohormonal activation. The hypothesis that LVH and myocardial ﬁbrosis are regulated independently of each other, and to some extent of blood pressure, is supported by limited experimental evidence.44–46

Left Atrial Function in Hypertension Compensatory changes in the left atrium reﬂect functional changes due to LVH that occur as a result of hypertensive load. Because the impairment in LV relaxation decreases early LV ﬁlling, the contribution of the left atrium to ventricular ﬁlling in later diastole increases. These changes may operate under the Frank-Starling principle, to prevent marked changes in mean LA pressure that can occur with elevated LV diastolic pressure or with an increase in LA preload.47,48 Increases in LA size and systolic force have been associated with aging, and both have been suggested as a compensatory response to age-related reduction of ventricular relaxation.49,50 LA systolic force (LASF), can be calculated echocardiographically as: LASF = 0.53 × MOA × (peak A velocity)2, where MOA = mitral oriﬁce area. The degree of change in LA size and systolic force in the pressure- or volume-overloaded left ventricle is highly dependent on the degree of LV diastolic dysfunction, reﬂected by an impairment of active ventricular relaxation.51 A change in LA size over time is not a feature of “normal aging.”52 The left atrium enlarges in response to changes in LV ﬁlling patterns that characterize abnormal LV relaxation, with a reduction in the emptying volume from the left atrium to the left ventricle and a reduced ﬂow from the pulmonary veins into the left ventricle in early diastole.52,53 The left atrium may compensate by an increase in its size, an augmentation of active contraction, and an increase in late diastolic emptying.52–54 Therefore, LA size or volume is an indicator of LV diastolic dysfunction in patients without valve disease or atrial ﬁbrillation. In one study, patients with an LA volume index of less than 27 ml/m2 had a similar future risk of atrial ﬁbrillation or heart failure as those with normal LV diastolic ﬁlling.55

235

236

Chapter 19 • Hypertension and Valvular Heart Disease Impaired LA contractility arising from a loss of LA systolic force or atrial arrhythmia will result in a further reduction in LV preload, a decrease in cardiac output, and increased LA pressure. Hypertension is associated with LA enlargement, depression of LA contractile function, and an increased risk for atrial ﬁbrillation,56,57 all of which can precipitate overt heart failure in patients with underlying LV diastolic dysfunction.58

Effect of Associated Metabolic Risk Factors on Left Ventricular Diastolic Function in Hypertension The concomitant presence of other cardiovascular disease risk factors can worsen the impairment of LV diastolic function in hypertension.59 Metabolic factors such as dyslipidemia and dysglycemia may be important in this regard. Indices of LV mass and diastolic function have been correlated with lipid proﬁle.60 Additionally, elevated glucose levels, insulin resistance, and hyperinsulinemia have been associated with LV diastolic dysfunction in hypertensive patients.61–64 The development of LV diastolic dysfunction with elevated glucose levels in persons with and without diabetes has been reported in hypertensive patients, and even slight elevations in fasting glucose levels have been reported to aﬀect LV diastolic function.65 Experimental treatment interventions with thiazolidinediones and insulin-sensitizing agents have been found to inhibit cardiac hypertrophy and improve LV diastolic function. These eﬀects are thought to be mediated in part by activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ).66–68 Additionally, these treatments may decrease cardiac ﬁbrosis by inhibiting collagen synthesis, mediated by a decrease in the ratio of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).69,70

Effect of Obesity on Left Ventricular Diastolic Function in Hypertension Obesity may also modulate the development of LV diastolic ﬁlling abnormalities in hypertensive patients. In a study of lean (body mass index [BMI] <25 kg/m2), overweight (BMI 26– 29 kg/m2), and obese (BMI >30 kg/m2) persons with hypertension, LV mass itself and LV mass indexed to height increased progressively with higher BMI.71,72 The LA diameter, which reﬂects LA diastolic ﬁlling abnormalities, is also signiﬁcantly increased in obese individuals.72 An increasing trend of E-wave deceleration time and IVRT with increasing BMI has been observed, and the E/A ratio was signiﬁcantly lower in overweight and obese versus lean hypertensive individuals.71 When those with normal and abnormal LV diastolic function were compared, the major diﬀerences were older age and higher LV mass in the latter group.71

Aortic Stiffness and Left Ventricular Diastolic Dysfunction in Hypertension Among hypertensive patients, aortic stiﬀness has been identiﬁed as a predictor of cardiovascular mortality and all-cause death.73 Aortic stiﬀness has been closely linked with DHF in hypertension and may contribute to the pathophysiology and progression of diastolic dysfunction: Patients with DHF have stiﬀ, large arteries and increased blood pressure lability.74–76 Mechanisms of increased aortic stiﬀness in hypertension include hemodynamic stress caused by high pressure in the arterial walls, structural

alterations in the vasculature, and atherosclerotic disease.77 However, hypertension may increase aortic stiﬀness even in the absence of coronary artery disease.78 LV diastolic function in hypertension is associated with indices of aortic stiﬀness and may be even further increased by the coexistence of other conditions, such as diabetes.78 Given the associations demonstrated in early studies, evaluation of aortic stiﬀness may take on greater importance in future studies of DHF. Evaluation of aortic stiﬀness includes assessment of aortic strain and distensibility, which are aortic elasticity parameters and can be calculated as: Aortic strain (%) = (AoSD − AoDD) × 100/AoDD Distensibility (cm2/dyne) = 2 × aortic strain/(SBP − DBP), where AoSD = aortic systolic diameter, AoDD = aortic diastolic diameter, dyne = dynamic measurement, SBP = systolic blood pressure, and DBP = diastolic blood pressure.78,79 Aortic strain and distensibility were related positively with E/A ratio and inversely with deceleration time and IVRT in one study.78 Although other factors, such as age, sex, blood pressure, and LVH, may also inﬂuence arterial compliance, analyses adjusted for these variables suggest a signiﬁcant independent relationship between arterial compliance and LV diastolic dysfunction.80 Pulse wave velocity (PWV) is a measure of large artery stiﬀness, based on the principle that PWV is inversely related to the elasticity of the vascular wall and directly related to arterial stiﬀness. PWV is calculated by dividing the pulse transmission time, in milliseconds, typically from carotid to femoral arteries by the distance traveled by the pulse wave using body surface measurements.81 The augmentation index (AI) is a manifestation of the early return of the reﬂected wave from the periphery to the heart during systole, when the heart is ejecting blood. Both increased PWV and AI increase with greater arterial stiﬀness and increase cardiac afterload. Prior studies have reported that LV concentric remodeling and hypertrophy are associated with vascular stiﬀness in hypertensive patients.82,83 Even in those with recently diagnosed hypertension without evidence of LVH, there is demonstrable increased aortic stiﬀness that occurs concurrently with the presence of LV diastolic dysfunction.84 Aortic stiﬀness is associated not only with indices of LV diastolic dysfunction, but with the occurrence of heart failure with normal LV ejection fraction.85 Despite what we have discussed, it is not known whether these ﬁndings indicate a causal mechanistic link between DHF and vascular stiﬀness or simply the coexistence of systemic changes in hypertension. A number of potential mechanisms link aortic stiﬀness in hypertensive patients with diastolic dysfunction (Fig. 19-2)80: 1. It is possible that increased aortic stiﬀness may increase afterload, resulting in LV changes, including ventricular hypertrophy and delayed LV relaxation.86 2. Increased vascular stiﬀness is associated with a higher velocity of transmission of the pulse wave ejected by the left ventricle, and early return of reﬂected waves may augment the amplitude of the central aortic pressure wave. This would further increase LV afterload and central pulse pressure.87 3. The reduction in central aortic diastolic pressure may also reduce coronary perfusion, which, coupled with ventricular hypertrophy, may increase subendocardial ischemia.

Chapter 19 • Hypertension and Valvular Heart Disease Aortic stiffening

↓ Central aortic DBP

↑ Central aortic SBP

↓ Coronary perfusion

↑ LV afterload

Myocyte hypertrophy

Subendocardial ischemia

Impaired relaxation

Myocardial fibrosis

Diastolic dysfunction Figure 19-2 Pathophysiological pathways through which aortic stiffness may contribute to the development of diastolic dysfunction. DBP, diastolic blood pressure; SBP, systolic blood pressure. (From Mottram et al: Relation of arterial stiffness to diastolic dysfunction in hypertensive heart disease. Heart 2005;91:1551.)

The association of arterial stiﬀness and LV diastolic dysfunction may also be modulated by sex, since there may be diﬀerential degrees of concentric remodeling with increased afterload in women versus men and a higher prevalence of DHF in women.88,89 In a large community-based study, age and female sex were associated with the vascular elastance index (Ea) normalized to body surface area,90 calculated as: Ea = Pes/SV, where Pes = end systolic pressure and SV = stroke volume.91 Similar associations were observed for age, female sex, and LV diastolic elastance (Ed),90 calculated as: Ed = E/E′, where, E = early mitral inﬂow diastolic ﬁlling velocity and E′ = mitral annular early diastolic velocity measured by tissue Doppler.92–94 It was speculated that the ventricular-vascular stiﬀening proﬁles may contribute to DHF.90 Genetic and environmental factors may also inﬂuence the development of aortic stiﬀness. Arterial stiﬀness is increased in those with a parental history of essential hypertension95 and also varies according to race.96 Polymorphism of the GNB3 gene, which encodes the G protein β3 subunit, has been associated with increased PWV and AI.97 Although regular resistance and aerobic exercise programs do not aﬀect PWV,98 a regimen of intensive, long-term blood pressure control may decrease arterial stiﬀness.99

Cellular and Molecular Bases of Left Ventricular Diastolic Dysfunction in Hypertension A number of cellular processes regulate or aﬀect LV diastolic function. In myocytes, relaxation of the ventricle is dependent on calcium (Ca2+) traﬃc that is inﬂuenced by the activity of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2) and its regulator, phospholamban.100,101 Dephosphorylation of phospholamban reduces SERCA2 activity, resulting in impaired relaxation, and in contrast, phosphorylation has a lusitropic eﬀect.102 Neuro-

hormonal factors also contribute to LV diastolic dysfunction. Angiotensin II acts via the angiotensin II type 1 (AT1) receptor to stimulate myocardial atrial natriuretic peptide (ANP) gene expression, endothelin (ET-1) production, and collagen accumulation. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce DHF, presumably partly via the inhibition of this mechanism.103 Blockade of the AT1 receptor may improve LV diastolic function by a decrease in myocardial stiﬀness, an increase in SERCA expression, promotion of phosphorylation of phospholamban, and attenuation of the prolongation of Tau (τ, the time constant of LV relaxation).104,105 A number of other prohypertrophic factors may contribute to the development of LV diastolic dysfunction. Pathways that may alter LV hypertrophic remodeling include guanosine 3′,5′-cyclic monophosphate (cGMP) and phosphodiesterase-5A (PDE5A) signaling.106,107 Sildenaﬁl, an inhibitor of cGMP catabolism and a PDE5A inhibitor, prevented the development of myocyte and cardiac hypertrophy and reversed preexisting hypertrophy in an animal model.108 The ET-1 pathway may also contribute to the pathogenesis of LV diastolic dysfunction and DHF. The ETA receptor mediated an increase in myocardial stiﬀness in hypertensive animal models,109 and upregulation of myocardial ET-1 is present in hypertrophied ventricles that transition to progressive LV diastolic dysfunction.110 Signaling pathways activated in hypertension include members of the mitogenactivated protein kinase (MAPK) superfamily (the p38 MAPK, the extracellular regulated kinases [ERK] and c-Jun kinases), the gp130 family (the JAK/STAT pathway), and the calcineurin pathway.111 The transition from compensated LVH to heart failure occurs by remodeling processes, which may involve myocardial ﬁbrosis, myocyte degeneration, autophagic cell death, oncosis, an increase in length, and reduction in cross-sectional area.112,113 Abnormal collagen deposition and accumulation may contribute to increased LV stiﬀness in DHF. These interstitial changes are mediated by excessive collagen synthesis and an increase in the ratio of type I to type III collagen subtypes.104,114 In patients with hypertension, greater turnover of type III collagen was associated with increased LV mass and impairment of diastolic function.115 DHF is associated with reduced TIMP gene expression and increased MMP-2 and MMP-9 activity.116 In patients with hypertension, circulating TIMP-1 levels correlated with indices of LV diastolic ﬁlling, including E′, which is an indicator of load-independent early diastolic relaxation and ventricular wall movement in early diastole.117

Clinical Basis of Hypertensive Heart Disease Epidemiology Hypertension is a prevalent condition with signiﬁcant implications for the development of heart failure. Data from the Framingham Heart Study found that hypertension often preceded the onset of heart failure in those in the third to sixth decades of life.118 Since the incidence of hypertension and heart failure both increase with age, the coexistence of these conditions in later years may be of even greater importance.119 In a study of the transition from hypertension to congestive heart failure, hypertension was present in 91% of new heart failure cases.120 The risk of heart failure was increased twofold in men and threefold in women, and the population attributable risk associated with hypertension was 39% in men and 59% in women.120 Survival after the onset of

237

238

Chapter 19 • Hypertension and Valvular Heart Disease hypertensive heart failure was poor, with only 24% of men and 31% of women surviving 5 years.120 A common precursor of DHF is a condition referred to as hypertensive hypertrophic cardiomyopathy of the elderly.121 This term refers to elderly patients who frequently are female, have systolic hypertension, and present with marked ventricular hypertrophy, a supernormal LV ejection fraction, and a propensity for developing pulmonary edema.

Clinical Presentation Diastolic dysfunction due to hypertension may be asymptomatic, may manifest as exercise intolerance, or may present acutely with the clinical syndrome of decompensated heart failure with preserved LV ejection fraction. Thus, LV diastolic dysfunction that occurs in concert with hypertension and associated LVH may have an insidious course. Some hypertensive persons with LVH are asymptomatic under resting conditions but may experience exertional dyspnea due to a relative inability to augment their LV end diastolic volume upon exercise.122 The decreased cardiac output arising from LV diastolic ﬁlling abnormalities may result in symptoms of “fatigue.” There may be a slow progression of exercise intolerance, and ﬁnally rest symptoms may develop.123 At the other end of the spectrum, some patients present with severe uncontrolled hypertension and acute pulmonary edema, which can be reversed by lowering blood pressure.124,125 Clinically, it is diﬃcult to reliably distinguish acute decompensated heart failure on the basis of LV diastolic dysfunction from primarily systolic heart failure.126,127 The pathophysiologic bases for these abnormalities are (1) the increased left-sided ﬁlling pressures arising as a result of impaired LV relaxation and (2) subsequent pulmonary interstitial edema. Patients may also present with evidence of myocardial ischemic symptoms, which may or may not be associated with signiﬁcant epicardial coronary stenosis. In patients with hypertension and LVH, an increase in wall tension decreases subendocardial perfusion. Therefore, patients with hypertensive heart failure may develop ischemic symptoms in the presence of normal epicardial coronary arteries on angiography.128 It is highly likely that patients with hypertensive LV diastolic dysfunction may also develop ischemic symptoms from epicardial coronary artery disease, particularly in the setting of an adverse coronary risk proﬁle, since hypertension is an important component of atherosclerotic disease risk.

Echocardiographic Features of Hypertensive Left Ventricular Hypertrophy Mitral Inflow Parameters The diastolic properties of the left ventricle are often estimated in clinical practice by Doppler indices of early and late peak ﬂow velocities, the latter representing atrial contraction. In hypertensive LVH, the ratio of early to late peak ﬂow velocities (E/A ratio) is reduced as the LV relaxation phase is prolonged.129,130 The E/A ratio in the hypertensive condition is a reﬂection of LV active relaxation, myocardial passive stiﬀness, and LA work needed for diastolic LV ﬁlling.131–134 Hypertensive patients have their diastolic function signiﬁcantly inﬂuenced by the presence of LVH compared with such patients without increased LV mass and compared with normotensive patients. In hypertensive patients with LVH in particular, there is a decrease in E/A ratio of mitral inﬂow velocities, an increase

in E-wave deceleration time, an increase in IVRT, and an increase in the ratio of the magnitude of motion due to atrial systole relative to total diastolic atrioventricular plane displacement (AVLA/AV-mean) (Fig. 19-3A).135 Measures of LV wall thickness (including interventricular wall thickness and posterior wall thickness), relative wall thickness, and blood pressure are inversely associated with LV diastolic function, independent of blood pressure. Thus, the E/A ratio and the IVRT exhibit a linear pattern of correlation with blood pressure, interventricular septum thickness, relative wall thickness, and LV mass index (see Fig. 19-3B).135 Stepwise regression analysis of the determinants of LV diastolic function suggests that age, systolic blood pressure, heart rate, and relative wall thickness are signiﬁcant predictors of both the E/A ratio and the E-wave deceleration time, with model R2 of 0.43 and 0.23, respectively. Among these factors, age and systolic blood pressure explain most of the variation in E/A ratio and E-wave deceleration time. Predictors of IVRT are relative wall thickness, systolic blood pressure, and age, in decreasing order of importance (model R2 0.22).135 In addition to the eﬀects of LV mass, LV geometry also has an eﬀect on ventricular diastolic function, as noted previously. Hypertensive patients with concentric LVH manifest echocardiographically with a lower transmitral peak E velocity, prolonged E deceleration, increased IVRT, and an increase in LA size and systolic force, in comparison with those with a normal LV geometry.136–138 In contrast, those with eccentric LV geometry have diﬀerent diastolic properties—in particular, an attenuation of the delay in LV relaxation.49 In eccentric LV geometry, the association with abnormal LA structure and function is also attenuated, further suggesting that LA changes are a reﬂection of impaired LV ﬁlling in myocardial hypertrophic states. LV diastolic ﬁlling abnormalities (e.g., prolonged IVRT and E deceleration time, lower E/A ratio) are also associated with greater propensity to a reduction in midwall fractional shortening, a subtle abnormality of ventricular contractile function.139,140 Limitations of Mitral Inflow Parameters Although the most common method for evaluation of diastolic function in hypertension is derived from transmitral ﬂow velocities using pulsed-wave (PW) Doppler echocardiography, there are a number of potential limitations to this approach. The E/A ratio, which is widely adopted as an index of diastolic function, is subject to “pseudonormalization” with increasing age.141 Additionally, mitral inﬂow parameters are dependent on changes in preload, afterload, and contractility. Interpretation of transmitral ﬂow may be aided by information obtained from pulmonary venous ﬂow velocities. The normal pulmonary venous ﬂow consists of forward ﬂow during systole (S wave) and diastole (D wave) and retrograde ﬂow during atrial systole (AR). The S/D pulmonary venous ﬂow velocity ratio is increased in isolated relaxation abnormality conditions and is decreased, together with increased retrograde ﬂow, during atrial contraction (AR) as LV diastolic compliance abnormalities advance.142 PW tissue Doppler imaging (TDI) measured in the myocardium and at the mitral annulus in systole and diastole may be a better method to identify load-independent changes in LV relaxation. These TDI measures correlate with τ, the time constant of isovolumic relaxation; and early studies suggest that the early (Em) and late (Am) tissue Doppler waves at the mitral annulus may change directionally in response to antihypertensive treatment.143 The Em/Am ratio, a global TDI index of diastolic dysfunction, tracked with the reduction in LV mass that occurred with ACE inhibitor therapy in hypertensive patients.143,144

Chapter 19 • Hypertension and Valvular Heart Disease *** **

1.8

*

***

1.4 E/A ratio

E/A ratio

1.8

1.0

1.4 1.0

0.6 *

0.6

* E-dec (msec)

250 200

250 200 150

***

***

150

130

IVRT (msec)

IVRT (msec)

150

110 90 0.65 ***

AV-LA/AVmean (%)

0.35 HT without LVH

Effects of Treatment Hypertension Treatment Hypertension is a key risk factor for the development of cardiovascular disease. Studies have found that systolic blood pressure and pulse pressure, which are both highly correlated, are major predictors of heart failure.146–149 By comparison, diastolic blood pressure was not found to be a risk factor for future heart failure. In the Systolic Hypertension in the Elderly Program (SHEP), which was designed to reduce blood pressure in those with systolic hypertension, one of the major cardiovascular endpoints was the reduction of heart failure events.150 Treatment of hypertension has been shown in multiple randomized trials to reduce cardiovascular events irrespective of age at treatment initiation.151 Reduction in systolic blood pressure has been proposed as the primary mechanism by which these beneﬁts occur, since neither the change nor the achieved diastolic blood

130 110

0.65

0.45

Color M-mode Doppler echocardiography, which evaluates all velocities along a scan line aligned with mitral inﬂow, may also be used to supplement information from transmitral ﬁlling patterns.145 The velocity of ﬂow propagation (Vp) into the left ventricle can be determined by the slope of the color wave front. A left ventricle with normal relaxation demonstrates rapid ﬂow propagation, whereas a slowly relaxing ventricle is associated with blunted ﬂow propagation.

*

90

*

0.55

NT

A

**

300

150

AV-LA/AV-mean (%)

Figure 19-3 A, Evaluation of left ventricular (LV) diastolic function in normotensives (NT, n = 38), hypertensive patients without LV hypertrophy (HT without LVH, n = 38), and hypertensive patients with LV hypertrophy (HT with LVH, n = 114). E/A ratio, ratio of peak early (E) and peak of late (A) mitral inflow velocities; E-dec, Ewave deceleration time; IVRT, isovolumic relaxation time; AV-LA/AV-mean, ratio of the magnitude of motion due to atrial systole to the total diastolic atrioventricular plane displacement. Mean and standard deviations are shown. *p < 0.05, **p < 0.01, ***p < 0.001. B, Evaluation of LV diastolic function in those with normal geometry (normal, n = 63), LV remodeling (LV remod, n = 13), eccentric LV hypertrophy (Ecc LVH, n = 47), and concentric LV hypertrophy (Conc LVH, n = 64). (From Muller-Brunotte R et al: Blood pressure and left ventricular geometric pattern determine diastolic function in hypertensive myocardial hypertrophy. J Hum Hypertens 2003;17:841–849.)

E-dec (msec)

300

HT with LVH

*

0.55 0.45 0.35

B

Normal LV remod Ecc LVH Conc LVH

pressure correlate with the beneﬁcial eﬀects of hypertension treatment.151 Reduction of Cardiac Fibrosis Cardiac ﬁbrosis in hypertensive patients has been identiﬁed as a potential contributor to LV stiﬀness. ACE inhibitors and AT II receptor antagonists may regress myocardial ﬁbrosis and decrease LV stiﬀness in hypertension.152,153 Aldosterone antagonism also has a prominent eﬀect on inhibiting cardiac ﬁbrosis, which improves diastolic function and decreases LV stiﬀness.154 Aldosterone antagonism also may improve subtle abnormalities in systolic function that may be present in hypertensive patients with preserved ejection fractions (>50%) and diastolic dysfunction, including increases in strain rate, peak systolic strain, and cyclic variation of integrated backscatter.154

PATHOPHYSIOLOGY AND CLINICAL RELEVANCE OF DIASTOLIC DYSFUNCTION IN VALVULAR DISEASE Valvular heart disease may contribute to the syndrome of heart failure with preserved systolic function. However, it is important to delineate with patient history, physical examination, and cardiac imaging studies whether the syndrome is attributable to severe or to symptomatic valvular disease, since the management principles

239

240

Chapter 19 • Hypertension and Valvular Heart Disease diﬀer. One of the primary diﬀerences is the potential for surgical correction of valve disease, which can alleviate the underlying structural cause of heart failure. The natural history of severe aortic or mitral valve lesions has been well described, and a wide array of surgical options is available. It is recognized that DHF has been deﬁned by an absence of signiﬁcant valvular heart disease.7 It is also relatively uncommon as an underlying etiology for the syndrome of heart failure with preserved LV function. In elderly patients, aged 65 years and older, who were hospitalized for heart failure and met the Framingham diagnostic criteria for congestive heart failure, less than 10% with preserved systolic function had severe aortic or mitral valvular disease.155 However, the left-sided valvular lesions largely share features of LV diastolic dysfunction and/or hypertrophy with hypertensive DHF and therefore merit discussion in this chapter alongside the topic of hypertension. We will here describe the features of left-sided valvular disease as they pertain to heart failure syndromes with potential for diastolic dysfunction. We have limited the scope of this section to a discussion of the more commonly occurring conditions of acute or chronic regurgitation or stenosis of the mitral and aortic valves.

Acute Aortic Insufficiency Acute aortic insuﬃciency may be the underlying cause in some cases of heart failure with preserved systolic function. Unlike chronic aortic insuﬃciency, where the ventricle may undergo enlargement and eccentric hypertrophy, the left ventricle does not have the opportunity to accommodate a sudden increase in preload from the regurgitant volume. Therefore, the widened pulse pressure and the myriad of signs and symptoms of chronic aortic insuﬃciency are not present in the acute setting. Instead, there is an increase in LV end diastolic pressure and a decrease in forward cardiac output and stroke volume; consequently, a drop in blood pressure may be observed. In acute aortic insuﬃciency, the left ventricle operates at the high end of the pressure-volume relationship (Fig. 19-4C). In the setting of acute aortic insuﬃciency, overt pulmonary edema may be partly attenuated by preclosure of the mitral valve, which occurs due to the regurgitant jet and increase in LV pressures during the diastolic ﬁlling phase.

A

B

Chronic aortic insuﬃciency is often observed clinically in the context of LV enlargement and eccentric hypertrophy. Chronic volume overload results in increases in myocyte length and LV volume, thereby accommodating the increased regurgitant volume. Despite larger end diastolic volumes, LV compliance remains normal, so that LV end diastolic pressure is not elevated. The increased stroke volume accompanied by an increase in systolic force, via the Frank-Starling mechanism, results in an elevation of systolic blood pressure and a widened pulse pressure. The ﬁlling pressures in chronic aortic insuﬃciency are decreased, and therefore pulmonary congestive symptoms may be minimal to none. As LV dilation progresses, the ventricle operates on a higher segment of the pressure-volume curve, with minimal symptomatic burden. In chronic aortic insuﬃciency, there may be elevated afterload; and in response to increased wall tension, there may be initial concentric followed by eccentric hypertrophy.156,157 The concentric hypertrophy that develops may have an adverse eﬀect on LV diastolic function, which could result in development of congestive symptoms.158 The adverse eﬀect of increased afterload in chronic severe aortic regurgitation is illustrated by the association of systolic hypertension (deﬁned as a systolic blood pressure >140 mmHg) with increased risk of cardiovascular events, including heart failure onset.159,160 The adverse eﬀects of systolic hypertension in aortic regurgitation remained even after accounting for other risk factors, including age, gender, diastolic blood pressure,

DIASTOLIC DYSFUNCTION

Left ventricular volume

Left ventricular volume

Chronic Aortic Insufficiency

Pressure

NORMAL

Pressure

Pressure

SYSTOLIC DYSFUNCTION

Infective endocarditis or a structurally compromised native or prosthetic aortic valve is a common underlying etiology for acute aortic insuﬃciency. Medical therapy targeted at the underlying condition, such as treatment with antibiotics, may be required. Other medical therapies are generally temporizing measures, and emergency surgery is often required. Vasodilators may unload the left ventricle to increase forward ﬂow but may compromise diastolic coronary perfusion. Pressor agents that increase blood pressure by increasing peripheral vasoconstriction may worsen the degree of aortic regurgitation. Avoidance of bradycardia may also decrease aortic runoﬀ time and ameliorate acute aortic insuﬃciency. The intra-aortic balloon pump is contraindicated because it may exacerbate the degree of aortic insuﬃciency.

Left ventricular volume

C

Figure 19-4 Left ventricular pressure-volume loops in systolic and diastolic dysfunction. A, In systolic dysfunction, LV contractility is depressed, the end systolic pressure-volume relationship (ESPVR) is displaced downward and to the right (black arrow), and the end diastolic pressure is normal (open arrow). B, Normal left ventricular pressure-volume loop. C, In diastolic dysfunction, the diastolic pressure-volume relationship is shifted upward and to the left (black arrow), there is diminished capacity to fill at low left atrial pressures, and the end diastolic pressure is elevated (open arrow). (From Aurigemma G: Diastolic heart failure. NEJM 2004;351:1097.)

Chapter 19 • Hypertension and Valvular Heart Disease LV diastolic dimension, and LV ejection fraction at rest.160 Changes in the extracellular matrix may engender an increase in LV stiﬀness that is observable in chronic aortic insuﬃciency as well.161 Treatment for chronic aortic insuﬃciency may require surgery. The primary management issue is the timing of surgical intervention, which is inﬂuenced by the natural history of the condition, prevention of often irreversible myocardial damage, and technical considerations at surgery. In relatively asymptomatic individuals with preserved LV ejection fraction, nifedipine delayed time to surgery, which was indicated on the basis of symptoms or LV systolic dysfunction.162 However, there are relatively few trials of medical therapy in this condition. Once symptoms develop, surgical therapy is generally indicated, because prognosis worsens dramatically after symptom onset.163 Undue delay of surgery once symptoms have developed may lead to worsened LV function and poor surgical outcome.

Aortic Stenosis Hemodynamically signiﬁcant aortic valve obstruction increases LV pressure and increases the LV work to eject blood out of the narrowed valve. By Laplace’s law, an increase in ventricular pressure leads to an increase in LV wall thickness to maintain wall stress. However, ventricular hypertrophy leads to LV diastolic ﬁlling abnormalities and increased chamber stiﬀness, resulting in the need for increased ﬁlling pressure to attain any given ventricular volume when compared with the nonhypertrophied state. Ventricular hypertrophy in chronic aortic stenosis may also be accompanied by subendocardial ischemia. Chronically, ongoing aortic valve obstruction leads to a decline in LV systolic and diastolic function and potentially a reduction in the transaortic valve gradient, due to reduced LV ejection fraction. Patients with aortic valvular stenosis frequently present with heart failure symptoms with a normal LV ejection fraction, suggesting an important role of diastolic dysfunction in the pathogenesis of the symptoms.164 In the pressure-overloaded heart of aortic stenosis, myocardial ﬁbrosis occurs, and there are increased levels of enzymes that reﬂect greater collagen deposition.165,166 In aortic stenosis, there is an increase in collagen synthesis relative to collagen degradation, procollagen endopeptidase, and lysine and proline hydroxylases, compared with controls without valve disease.167 Expression of TIMPs and MMPs are increased in patients with aortic stenosis compared with controls, and increased TIMP/MMP ratios have been noted in humans.167 Increased TIMPs can stimulate ﬁbroblast growth and may have a direct stimulatory eﬀect on collagen production by cardiac ﬁbroblasts.168,169 As noted previously, the diastolic dysfunction in hypertensive LVH and chronic aortic stenosis are parallel in many aspects. However, one very important diﬀerence is the impact of surgical intervention on LV systolic and diastolic function. Aortic valve surgery relieves LV pressure overload and decreases afterload. In patients with systolic dysfunction due to severe aortic stenosis without concomitant cardiomyopathy, LV ejection fraction may return to normal. In patients with dominant aortic stenosis, replacement of the aortic valve has been demonstrated to decrease LV mass.170,171 In dominant aortic insuﬃciency, aortic valve surgery decreases both LV dimension and mass.172 The beneﬁcial eﬀects of surgery may be measurable as early as one week after the procedure.173 The degree of reverse LV remodeling after aortic valve replacement is partly dependent on the type of valve employed. In the case of the pulmonary autograft or Ross procedure, the relative stenosis is

small and the eﬀective oriﬁce area large. Although signiﬁcant regression of LV mass may be realized with such surgical procedures, incomplete reversal of LVH may occur, particularly in patients with elevated blood pressure, smokers, and those with high presurgical LV mass index at baseline.174 The abnormalities of LV diastolic dysfunction that were present in aortic stenosis may also be reversed after surgical relief of valvular obstruction, but this may occur over a period of years after the procedure. Reduction in LV diastolic stiﬀness and normalization of relaxation are accompanied by reduction of interstitial ﬁbrosis.175

Acute Mitral Regurgitation Acute mitral regurgitation may also present as heart failure with preserved systolic function. In acute mitral regurgitation, there is acute volume overload of the left atrium and left ventricle, which have not accommodated to the regurgitant volume by chamber enlargement. As a result of mitral regurgitation, forward cardiac output is also reduced, resulting in the potential for lowered systemic blood pressure and an increase in peripheral resistance, which may further increase regurgitation. There is an acute rise in LA and LV diastolic pressures, leading to pulmonary congestion. The ejection fraction may be supranormal because of the increased stretch of ventricular myocytes arising from an increase in LV volume. In acute mitral regurgitation, medical therapy with arterial vasodilators may decrease afterload and also diminish regurgitant volume.176 However, hypotension may be present, limiting the use of vasodilators, and in some cases, an intra-aortic balloon pump may be required as a bridge to surgical repair of the structurally abnormal mitral valve. The intra-aortic balloon pump may decrease afterload while maintaining mean arterial blood pressure in such cases. In acute, severe mitral regurgitation due to a ﬂail leaﬂet, mortality rate was high with medical therapy and markedly increased in those who even transiently had New York Heart Association class III or IV symptoms. Surgical correction was associated with a signiﬁcant reduction in mortality rate.177 In asymptomatic individuals with perhaps less severe degrees of mitral regurgitation, the best management strategy is not elucidated. Uncorrected mitral regurgitation may lead to eccentric hypertrophy with progressive chamber enlargement and a decrease in LV ejection fraction, which may render later surgical correction untenable. There may also be an increased risk of sudden death in such individuals.178,179

Chronic Mitral Regurgitation In chronic, severe mitral regurgitation, there is an increase in ventricular preload that over time may lead to the development of eccentric hypertrophy. Enlargement of the LV chamber and increased wall thickness are accompanied by LA enlargement. Initially, chronic mitral regurgitation is compensated by chamber enlargement, and the patient may be asymptomatic. LV diastolic function is altered in chronic mitral regurgitation: Early diastolic ﬁlling is enhanced, τ remains unchanged, but chamber stiﬀness decreases.180–182 The enhanced diastolic function returns to normal after mitral valve replacement.182 The major clinical issue is deciding whether surgical intervention is required, while systolic function is still relatively preserved and ventricular dilation is minimized. A regurgitant fraction of 40%–50% may be an indication that surgery will ultimately be required, since mitral

241

242

Chapter 19 • Hypertension and Valvular Heart Disease valve repair that can reduce this fraction to less than 35% reversed myocardial dysfunction in an animal model.183 Once symptoms develop, even if mild, the prognosis of mitral regurgitation worsens.177 Additionally, if LV ejection fraction decreases below 60% or if the LV end diastolic dimension is greater than 45 mm, there is worsened prognosis,184,185 and surgery is warranted. Valve repair or replacement should be performed, and ideally the former is the preferred procedure because preservation of the subvalvular apparatus improves LV ejection fraction and decreases the likelihood of development of symptomatic heart failure postoperatively.186–189

Mitral Stenosis Mitral stenosis causes pulmonary congestion by inhibiting ﬁlling of the left ventricle across the stenosed oriﬁce. LA and pulmonary venous pressures become elevated, and cardiac ﬁlling and output are decreased. Subsequently, pulmonary hypertension may develop. Factors aﬀecting LV ﬁlling in mitral stenosis are an increased pulmonary driving pressure and elevated LA pressure. Intrinsic LV diastolic dysfunction, therefore, does not contribute to this syndrome of heart failure with preserved LV function. Medical management consists primarily of diuretics and slowing of heart rate, to maximize the period available for diastolic LV ﬁlling. Surgical intervention with mitral balloon valvulotomy or valve replacement may be required if symptoms are uncontrolled by medical management.

FUTURE RESEARCH Investigations into the role of hypertension in DHF should include studies of pathophysiology, longitudinal analyses, and treatment. The relative importance of risk factors and prognostic factors for systolic and diastolic heart failure is also not elucidated. It is unknown, for example, whether hypertension is more (or equally) important for the development of diastolic versus systolic heart failure. Such studies are needed to develop preventative strategies and improve treatment for the condition. It is conceivable that hypertension will be an important risk factor in both types of heart failure, given the association of hypertension with increased LV mass and its role as a coronary disease risk factor. The relative importance of systolic blood pressure, pulse pressure, and other measures of vascular stiﬀness in determining future DHF risk, and their interactions with other known cardiovascular risk factors, require further research. Ventricular-vascular coupling in the setting of vascular stiﬀness and LV diastolic dysfunction has not been delineated adequately. In particular, causality has not been determined but may be important if therapeutic targets are to be identiﬁed. The sex-related diﬀerences in incidence of DHF and vascular stiﬀness have been described, but further study may provide greater insights into the mechanisms of DHF and vascular stiﬀness. The transition from preclinical disease to clinically overt DHF has not been well characterized. Thus, the factors that promote transition from a state of compensated hypertrophy to DHF have not been determined. This is of importance because targeting the driving pathway for this transition may enable prevention with early, speciﬁc treatment strategies. Furthermore, the factors that determine whether a hypertensive patient remains in a state of

LV diastolic dysfunction or progresses to systolic heart failure have not been described adequately. The primary treatment strategy for diastolic dysfunction in hypertensive patients is blood pressure control. However, the signiﬁcant degree of cardiac ﬁbrosis in DHF may present a therapeutic target to improve LV diastolic dysfunction. Whether LV diastolic dysfunction and stiﬀness can be reversed signiﬁcantly, and whether this translates into a clinical eﬀect (such as reduced symptom burden or improved outcome), may provide valuable insights. Valvular heart diseases with a signiﬁcant component of cardiac ﬁbrosis may also represent a potential therapeutic target of antiﬁbrotic regimens. Ultimately, the clinical eﬀectiveness of such novel therapies targeted toward decreasing ventricular stiﬀness will need to be tested in controlled clinical trials. More study is required in the longitudinal follow-up of preclinical hypertrophic states with evidence of LV diastolic dysfunction but without overt heart failure. It is known that once the initial onset of heart failure has occurred, the prognostic outlook is grim. Greater eﬀorts are needed to study these patients and possibly prevent DHF. One area of investigation may be in the setting of LVH and LV diastolic dysfunction, whether “how” blood pressure is reduced is more important than the “magnitude” of blood pressure reduction. For example, would drugs that target putative myoproliferative pathways (e.g., ACE inhibitors, angiotensin receptor blockers) be better preventatively than antihypertensive agents that are not pathophysiologically speciﬁc? Additionally, it is unknown whether diﬀerent degrees of diastolic dysfunction at baseline should be treated diﬀerently. Speciﬁcally, it is unknown whether more severe degrees of diastolic dysfunction in hypertensive patients should be treated more aggressively using multimodality drug therapy. It is also unknown how such patients should be followed longitudinally. To this end, echocardiography and other imaging studies can identify the presence of LV diastolic dysfunction, but whether these modalities can be used serially to assess progress over time has not been determined. REFERENCES 1. Vasan RS, Levy D: Deﬁning diastolic heart failure: A call for standardized diagnostic criteria. Circulation 2000;101:2118–2121. 2. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 3. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. 4. Fouad-Tarazi FM, Liebson PR: Echocardiographic studies of regression of left ventricular hypertrophy in hypertension. Hypertension 1987;9: II65–II68. 5. Smith VE, White WB, Meeran MK, Karimeddini MK: Improved left ventricular ﬁlling accompanies reduced left ventricular mass during therapy of essential hypertension. J Am Coll Cardiol 1986;8:1449–1454. 6. Schulman SP, Weiss JL, Becker LC, et al: The eﬀects of antihypertensive therapy on left ventricular mass in elderly patients. N Engl J Med 1990;322:1350–1356. 7. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;112: e154–e235. 8. Grandi AM, Poletti L, Tettamanti F, et al: Left ventricular anatomy and function in normotensive young adults with hypertensive parents. Study at rest and during handgrip. Am J Hypertens 1995;8:154–159.

Chapter 19 • Hypertension and Valvular Heart Disease 9. Kuznetsova T, Staessen JA, Olszanecka A, et al: Maternal and paternal inﬂuences on left ventricular mass of oﬀspring. Hypertension 2003; 41:69–74. 10. Garner C, Lecomte E, Visvikis S, et al: Genetic and environmental inﬂuences on left ventricular mass. A family study. Hypertension 2000;36: 740–746. 11. Levy D, DeStefano AL, Larson MG, et al: Evidence for a gene inﬂuencing blood pressure on chromosome 17: Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. Hypertension 2000;36:477–483. 12. Bielen E, Fagard R, Amery A: The inheritance of left ventricular structure and function assessed by imaging and Doppler echocardiography. Am Heart J 1991;121:1743–1749. 13. Tang W, Arnett DK, Devereux RB, et al: Sibling resemblance for left ventricular structure, contractility, and diastolic ﬁlling. Hypertension 2002;40: 233–238. 14. Palatini P, Amerena J, Nesbitt S, et al: Heritability of left atrial size in the Tecumseh population. Eur J Clin Invest 2002;32:467–471. 15. Levy D, Anderson KM, Savage DD, et al: Echocardiographically detected left ventricular hypertrophy: Prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988;108:7–13. 16. Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977;55:613–618. 17. Daniels SR, Kimball TR, Morrison JA, et al: Indexing left ventricular mass to account for diﬀerences in body size in children and adolescents without cardiovascular disease. Am J Cardiol 1995;76:699–701. 18. de Simone G, Daniels SR, Devereux RB, et al: Left ventricular mass and body size in normotensive children and adults: Assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992;20: 1251–1260. 19. Lauer MS, Anderson KM, Larson MG, Levy D: A new method for indexing left ventricular mass for diﬀerences in body size. J Am Coll Cardiol 1994;74:487–491. 20. Aronow WS, Ahn C, Kronzon I, Koenigsberg M: Congestive heart failure, coronary events and atherothrombotic brain infarction in elderly blacks and whites with systemic hypertension and with and without echocardiographic and electrocardiographic evidence of left ventricular hypertrophy. Am J Cardiol 1991;67:295–299. 21. Gardin JM, McClelland R, Kitzman D, et al: M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (The Cardiovascular Health Study). Am J Cardiol 2001;87:1051–1057. 22. Gottdiener JS, Arnold AM, Aurigemma GP, et al: Predictors of congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2000;35:1628–1637. 23. Bonaduce D, Breglio R, Conforti G, et al: Myocardial hypertrophy and left ventricular diastolic function in hypertensive patients: An echo Doppler evaluation. Eur Heart J 1989;10:611–621. 24. Inouye I, Massie B, Loge D, et al: Abnormal left ventricular ﬁlling: An early ﬁnding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120–126. 25. Pearson AC, Gudipati C, Nagelhout D, et al: Echocardiographic evaluation of cardiac structure and function in elderly subjects with isolated systolic hypertension. J Am Coll Cardiol 1991;17:422–430. 26. Ren JF, Pancholy SB, Iskandrian AS, et al: Doppler echocardiographic evaluation of the spectrum of left ventricular diastolic dysfunction in essential hypertension. Am Heart J 1994;127:906–913. 27. de Simone G, Kitzman DW, Palmieri V, et al: Association of inappropriate left ventricular mass with systolic and diastolic dysfunction: The HyperGEN study. Am J Hypertens 2004;17:828–833. 28. Verdecchia P, Angeli F, Gattobigio R, et al: Does the reduction in systolic blood pressure alone explain the regression of left ventricular hypertrophy? J Hum Hypertens 2004;18(Suppl 2):S23–S28. 29. Okin PM, Devereux RB, Liu JE, et al: Regression of electrocardiographic left ventricular hypertrophy predicts regression of echocardiographic left ventricular mass: The LIFE study. J Hum Hypertens 2004;18:403– 409. 30. Reichek N, Devereux RB: Reliable estimation of peak left ventricular systolic pressure by M-mode echographic-determined end-diastolic relative wall thickness: Identiﬁcation of severe valvular aortic stenosis in adult patients. Am Heart J 1982;103:202–203. 31. Ganau A, Devereux RB, Roman MJ, et al: Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol 1992;19:1550–1558.

32. Krumholz HM, Larson M, Levy D: Prognosis of left ventricular geometric patterns in the Framingham Heart Study. J Am Coll Cardiol 1995;25: 879–884. 33. Hess OM, Ritter M, Schneider J, et al: Diastolic stiﬀness and myocardial structure in aortic valve disease before and after valve replacement. Circulation 1984;69:855–865. 34. Sagie A, Benjamin EJ, Galderisi M, et al: Echocardiographic assessment of left ventricular structure and diastolic ﬁlling in elderly subjects with borderline isolated systolic hypertension (The Framingham Heart Study). Am J Cardiol 1993;72:662–665. 35. Fouad FM, Slominski JM, Tarazi RC: Left ventricular diastolic function in hypertension: Relation to left ventricular mass and systolic function. J Am Coll Cardiol 1984;3:1500–1506. 36. Snider AR, Gidding SS, Rocchini AP, et al: Doppler evaluation of left ventricular diastolic ﬁlling in children with systemic hypertension. Am J Cardiol 1985;56:921–926. 37. Devereux RB: Left ventricular diastolic dysfunction: Early diastolic relaxation and late diastolic compliance. J Am Coll Cardiol 1989;13:337– 339. 38. Andren B, Lind L, Hedenstierna G, Lithell H: Left ventricular diastolic function in a population sample of elderly men. Echocardiography 1998;15:433–450. 39. Volders PG, Willems IE, Cleutjens JP, et al: Interstitial collagen is increased in the non-infarcted human myocardium after myocardial infarction. J Mol Cell Cardiol 1993;25:1317–1323. 40. Brilla CG, Pick R, Tan LB, et al: Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 1990;67:1355–1364. 41. Brilla CG, Funck RC, Rupp H: Lisinopril-mediated regression of myocardial ﬁbrosis in patients with hypertensive heart disease. Circulation 2000;102:1388–1393. 42. Diez J, Querejeta R, Lopez B, et al: Losartan-dependent regression of myocardial ﬁbrosis is associated with reduction of left ventricular chamber stiﬀness in hypertensive patients. Circulation 2002;105:2512–2517. 43. Lindsay MM, Maxwell P, Dunn FG: TIMP-1: A marker of left ventricular diastolic dysfunction and ﬁbrosis in hypertension. Hypertension 2002; 40:136–141. 44. Jalil JE, Doering CW, Janicki JS, et al: Fibrillar collagen and myocardial stiﬀness in the intact hypertrophied rat left ventricle. Circ Res 1989; 64:1041–1050. 45. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium. Fibrosis and renin- angiotensin-aldosterone system. Circulation 1991; 83:1849. 46. Yamamoto K, Masuyama T, Sakata Y, et al: Myocardial stiﬀness is determined by ventricular ﬁbrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc Res 2002;55:76–82. 47. Stott DK, Marpole DG, Bristow JD, et al: The role of left atrial transport in aortic and mitral stenosis. Circulation 1970;41:1031–1041. 48. Braunwald E, Frahm CJ, Ross JJ: Studies on Starling’s law of the heart. V. Left ventricular function in man. J Clin Invest 1961;40:1882–1890. 49. Cioﬃ G, Mureddu GF, Stefenelli C, de Simone G: Relationship between left ventricular geometry and left atrial size and function in patients with systemic hypertension. J Hypertens 2004;22:1589–1596. 50. Mattioli AV, Sansoni S, Lucchi GR, Mattioli G: Serial evaluation of left atrial dimension after cardioversion for atrial ﬁbrillation and relation to atrial function. Am J Cardiol 2000;85:832–836. 51. Chinali M, de Simone G, Liu JE, et al: Left atrial systolic force and cardiac markers of preclinical disease in hypertensive patients: The Hypertension Genetic Epidemiology Network (HyperGEN) Study. Am J Hypertens 2005;18:899–905. 52. Thomas L, Levett K, Boyd A, et al: Compensatory changes in atrial volumes with normal aging: Is atrial enlargement inevitable? J Am Coll Cardiol 2002;40:1630–1635. 53. Triposkiadis F, Tentolouris K, Androulakis A, et al: Left atrial mechanical function in the healthy elderly: New insights from a combined assessment of changes in atrial volume and transmitral ﬂow velocity. J Am Soc Echocardiogr 1995;8:801–809. 54. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284–1289. 55. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial ﬁbrillation and congestive heart failure in patients >/= 65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004; 93:54–58. 56. Barbier P, Alioto G, Guazzi MD: Left atrial function and ventricular ﬁlling in hypertensive patients with paroxysmal atrial ﬁbrillation. J Am Coll Cardiol 1994;24:165–170.

243

244

Chapter 19 • Hypertension and Valvular Heart Disease 57. Benjamin EJ, Levy D, Vaziri SM, et al: Independent risk factors for atrial ﬁbrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271:840–844. 58. Shah PM, Pai RG: Diastolic heart failure. Curr Probl Cardiol 1992;17:781–868. 59. de Simone G, Palmieri V, Bella JN, et al: Association of left ventricular hypertrophy with metabolic risk factors: The HyperGEN study. J Hypertens 2002;20:323–331. 60. Horio T, Miyazato J, Kamide K, et al: Inﬂuence of low high-density lipoprotein cholesterol on left ventricular hypertrophy and diastolic function in essential hypertension. Am J Hypertens 2003;16:938–944. 61. Watanabe K, Sekiya M, Tsuruoka T, et al: Eﬀect of insulin resistance on left ventricular hypertrophy and dysfunction in essential hypertension. J Hypertens 1999;17:1153–1160. 62. Nagano N, Nagano M, Yo Y, et al: Role of glucose intolerance in cardiac diastolic function in essential hypertension. Hypertension 1994;23: 1002–1005. 63. Jain A, Avendano G, Dharamsey S, et al: Left ventricular diastolic function in hypertension and role of plasma glucose and insulin. Comparison with diabetic heart. Circulation 1996;93:1396–1402. 64. Liu JE, Palmieri V, Roman MJ, et al: The impact of diabetes on left ventricular ﬁlling pattern in normotensive and hypertensive adults: The Strong Heart Study. J Am Coll Cardiol 2001;37:1943–1949. 65. Miyazato J, Horio T, Takishita S, Kawano Y: Fasting plasma glucose is an independent determinant of left ventricular diastolic dysfunction in nondiabetic patients with treated essential hypertension. Hypertens Res 2002;25:403–409. 66. Yamamoto K, Ohki R, Lee RT, et al: Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes. Circulation 2001;104:1670–1675. 67. Asakawa M, Takano H, Nagai T, et al: Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo. Circulation 2002;105:1240–1246. 68. Zhu P, Lu L, Xu Y, Schwartz GG: Troglitazone improves recovery of left ventricular function after regional ischemia in pigs. Circulation 2000; 101:1165–1171. 69. Laviades C, Varo N, Fernandez J, et al: Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998;98:535–540. 70. Lindsay MM, Maxwell P, Dunn FG: TIMP-1: A marker of left ventricular diastolic dysfunction and ﬁbrosis in hypertension. Hypertension 2002;40: 136–141. 71. Parrinello G, Licata A, Colomba D, et al: Left ventricular ﬁlling abnormalities and obesity-associated hypertension: Relationship with overproduction of circulating transforming growth factor beta1. J Hum Hypertens 2005;19:543–550. 72. Krishnan R, Becker RJ, Beighley LM, Lopez-Candales A: Impact of body mass index on markers of left ventricular thickness and mass calculation: Results of a pilot analysis. Echocardiography 2005;22:203–210. 73. Laurent S, Boutouyrie P, Asmar R, et al: Aortic stiﬀness is an independent predictor of all–cause and cardiovascular mortality in hypertensive patients. Hypertension 2001; 37:1236–1241. 74. Hundley WG, Kitzman DW, Morgan TM, et al: Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802. 75. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and arterial stiﬀening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720. 76. Kitzman DW, Little WC, Brubaker PH, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 77. Blacher J, Asmar R, Djane S, et al: Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999;33: 1111–1117. 78. Eren M, Gorgulu S, Uslu N, et al: Relation between aortic stiﬀness and left ventricular diastolic function in patients with hypertension, diabetes, or both. Heart 2004;90:37–43. 79. Lacombe F, Dart A, Dewar E, et al: Arterial elastic properties in man: A comparison of echo-Doppler indices of aortic stiﬀness. Eur Heart J 1992;13:1040–1045. 80. Mottram PM, Haluska BA, Leano R, et al: Relation of arterial stiﬀness to diastolic dysfunction in hypertensive heart disease. Heart 2005;91: 1551–1556.

81. Breithaupt-Grogler K, Ling M, Boudoulas H, Belz GG: Protective eﬀect of chronic garlic intake on elastic properties of aorta in the elderly. Circulation 1997;96:2649–2655. 82. Roman MJ, Ganau A, Saba PS, et al: Impact of arterial stiﬀening on left ventricular structure. Hypertension 2000;36:489–494. 83. Palmieri V, Bella JN, Roman MJ, et al: Pulse pressure/stroke index and left ventricular geometry and function: The LIFE Study. J Hypertens 2003; 21:781–787. 84. Tsiouﬁs C, Chatzis D, Dimitriadis K, et al: Left ventricular diastolic dysfunction is accompanied by increased aortic stiﬀness in the early stages of essential hypertension: A TDI approach. J Hypertens 2005;23:1745– 1750. 85. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and arterial stiﬀening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720. 86. Leite-Moreira AF, Correia-Pinto J, Gillebert TC: Afterload induced changes in myocardial relaxation: A mechanism for diastolic dysfunction. Cardiovasc Res 1999;43:344–353. 87. O’Rourke MF: Diastolic heart failure, diastolic left ventricular dysfunction and exercise intolerance. J Am Coll Cardiol 2001;38:803–805. 88. Krumholz HM, Larson M, Levy D: Sex diﬀerences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993;72:310–313. 89. Aurigemma GP, Gaasch WH: Gender diﬀerences in older patients with pressure-overload hypertrophy of the left ventricle. Cardiology 1995; 86:310–317. 90. Redﬁeld MM, Jacobsen SJ, Borlaug BA, et al: Age- and gender-related ventricular-vascular stiﬀening: A community-based study. Circulation 2005; 112:2254–2262. 91. Kelly RP, Ting CT, Yang TM, et al: Eﬀective arterial elastance as index of arterial vascular load in humans. Circulation 1992;86:513–521. 92. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular ﬁlling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 93. Dokainish H, Zoghbi WA, Lakkis NM, et al: Optimal noninvasive assessment of left ventricular ﬁlling pressures: A comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation 2004;109:2432– 2439. 94. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 95. Yasmin, Falzone R, Brown MJ: Determinants of arterial stiﬀness in oﬀspring of families with essential hypertension. Am J Hypertens 2004;17: 292–298. 96. Zion AS, Bond V, Adams RG, et al: Low arterial compliance in young African-American males. Am J Physiol Heart Circ Physiol 2003;285: H457–H462. 97. Nurnberger J, Opazo SA, Mitchell A, et al: The T-allele of the C825T polymorphism is associated with higher arterial stiﬀness in young healthy males. J Hum Hypertens 2004;18:267–271. 98. Stewart KJ, Bacher AC, Turner KL, et al: Eﬀect of exercise on blood pressure in older persons: A randomized controlled trial. Arch Intern Med 2005;165:756–762. 99. Ichihara A, Hayashi M, Koura Y, et al: Long-term eﬀects of intensive bloodpressure lowering on arterial wall stiﬀness in hypertensive patients. Am J Hypertens 2003;16:959–965. 100. Luo W, Grupp IL, Harrer J, et al: Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res 1994;75:401–409. 101. Kadambi VJ, Ball N, Kranias EG, et al: Modulation of force-frequency relation by phospholamban in genetically engineered mice. Am J Physiol 1999;276:H2245–H2250. 102. Wegener AD, Simmerman HK, Lindemann JP, Jones LR: Phospholamban phosphorylation in intact ventricles. Phosphorylation of serine 16 and threonine 17 in response to beta-adrenergic stimulation. J Biol Chem 1989;264:11468–11474. 103. Kim S, Yoshiyama M, Izumi Y, et al: Eﬀects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure. Circulation 2001;103:148–154. 104. Sakata Y, Yamamoto K, Mano T, et al: Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix. J Hypertens 2003;21: 1737–1745.

Chapter 19 • Hypertension and Valvular Heart Disease 105. Sakata Y, Yamamoto K, Mano T, et al: Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction. Cardiovasc Res 2003;57:757–765. 106. Knowles JW, Esposito G, Mao L, et al: Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deﬁcient mice. J Clin Invest 2001;107:975–984. 107. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA: Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003;93: 280–291. 108. Takimoto E, Champion HC, Li M, et al: Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005;11:214–222. 109. Yamamoto K, Masuyama T, Sakata Y, et al: Prevention of diastolic heart failure by endothelin type A receptor antagonist through inhibition of ventricular structural remodeling in hypertensive heart. J Hypertens 2002;20:753–761. 110. Iwanaga Y, Kihara Y, Hasegawa K, et al: Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation 1998;98:2065–2073. 111. Lips DJ, deWindt LJ, van Kraaij DJ, Doevendans PA: Molecular determinants of myocardial hypertrophy and failure: Alternative pathways for beneﬁcial and maladaptive hypertrophy. Eur Heart J 2003;24:883–896. 112. Hein S, Arnon E, Kostin S, et al: Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: Structural deterioration and compensatory mechanisms. Circulation 2003;107:984–991. 113. Peterson JT, Hallak H, Johnson L, et al: Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 2001;103:2303–2309. 114. Fielitz J, Hein S, Mitrovic V, et al: Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J Am Coll Cardiol 2001;37:1443–1449. 115. Olsen MH, Christensen MK, Wachtell K, et al: Markers of collagen synthesis is [sic] related to blood pressure and vascular hypertrophy: A LIFE substudy. J Hum Hypertens 2005;19:301–307. 116. Nishikawa N, Yamamoto K, Sakata Y, et al: Diﬀerential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation. Cardiovasc Res 2003;57:766–774. 117. Tayebjee MH, Lim HS, Nadar S, et al: Tissue inhibitor of metalloproteinase-1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertension. Eur J Clin Invest 2005;35:8–12. 118. Kannel WB, Castelli WP, McNamara PM, et al: Role of blood pressure in the development of congestive heart failure. The Framingham study. N Engl J Med 1972;287:781–787. 119. Vasan RS, Beiser A, Seshadri S, et al: Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA 2002;287:1003–1010. 120. Levy D, Larson MG, Vasan RS, et al: The progression from hypertension to congestive heart failure. JAMA 1996;275:1557–1562. 121. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985;312:277–283. 122. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic ﬁlling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. 123. Fouad-Tarazi FM: Left ventricular diastolic dysfunction in hypertension. Curr Opin Cardiol 1994;9:551–560. 124. Given BD, Lee TH, Stone PH, Dzau VJ: Nifedipine in severely hypertensive patients with congestive heart failure and preserved ventricular systolic function. Arch Intern Med 1985;145:281–285. 125. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344:17–22. 126. Thomas JT, Kelly RF, Thomas SJ, et al: Utility of history, physical examination, electrocardiogram, and chest radiograph for diﬀerentiating normal from decreased systolic function in patients with heart failure. Am J Med 2002;112:437–445. 127. Badgett RG, Lucey CR, Mulrow CD: Can the clinical examination diagnose left-sided heart failure in adults? JAMA 1997;277:1712–1719. 128. Houghton JL, Frank MJ, Carr AA, et al: Relations among impaired coronary ﬂow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensive patients without obstructive coronary artery disease. J Am Coll Cardiol 1990;15:43–51. 129. de Simone G, Greco R, Mureddu G, et al: Relation of left ventricular diastolic properties to systolic function in arterial hypertension. Circulation 2000;101:152–157.

130. Wachtell K, Smith G, Gerdts E, et al: Left ventricular ﬁlling patterns in patients with systemic hypertension and left ventricular hypertrophy (the LIFE study). Losartan Intervention For Endpoint. Am J Cardiol 2000; 85:466–472. 131. Stoddard MF, Pearson AC, Kern MJ, et al: Left ventricular diastolic function: Comparison of pulsed Doppler echocardiographic and hemodynamic indexes in subjects with and without coronary artery disease. J Am Coll Cardiol 1989;13:327–336. 132. Kuo LC, Quinones MA, Rokey R, et al: Quantiﬁcation of atrial contribution to left ventricular ﬁlling by pulsed Doppler echocardiography and the eﬀect of age in normal and diseased hearts. Am J Cardiol 1987;59: 1174–1178. 133. Bonow RO, Frederick TM, Bacharach SL, et al: Atrial systole and left ventricular ﬁlling in hypertrophic cardiomyopathy: Eﬀect of verapamil. Am J Cardiol 1983;51:1386–1391. 134. Channer KS, Jones JV: The contribution of atrial systole to mitral diastolic blood ﬂow increases during exercise in humans. J Physiol 1989;411: 53–61. 135. Muller-Brunotte R, Kahan T, Malmqvist K, Edner M: Blood pressure and left ventricular geometric pattern determine diastolic function in hypertensive myocardial hypertrophy. J Hum Hypertens 2003;17:841– 849. 136. Simek CL, Feldman MD, Haber HL, et al: Relationship between left ventricular wall thickness and left atrial size: Comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8:37–47. 137. Cioﬃ G, Stefenelli C: Comparison of left ventricular geometry and left atrial size and function in patients with aortic stenosis versus those with pure aortic regurgitation. Am J Cardiol 2002;90:601–606. 138. de Simone G, Kitzman DW, Chinali M, et al: Left ventricular concentric geometry is associated with impaired relaxation in hypertension: The HyperGEN study. Eur Heart J 2005;26:1039–1045. 139. Wachtell K, Papademetriou V, Smith G, et al: Relation of impaired left ventricular ﬁlling to systolic midwall mechanics in hypertensive patients with normal left ventricular systolic chamber function: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Am Heart J 2004;148:538–544. 140. Bella JN, Palmieri V, Liu JE, et al: Relationship between left ventricular diastolic relaxation and systolic function in hypertension: The Hypertension Genetic Epidemiology Network (HyperGEN) Study. Hypertension 2001;38:424–428. 141. Yamakado T, Takagi E, Okubo S, et al: Eﬀects of aging on left ventricular relaxation in humans. Analysis of left ventricular isovolumic pressure decay. Circulation 1997;95:917–923. 142. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 143. Di Bello V, Giorgi D, Pedrinelli R, et al: Left ventricular hypertrophy and its regression in essential arterial hypertension. A tissue Doppler imaging study. Am J Hypertens 2004;17:882–890. 144. Edner M, Jarnert C, Muller-Brunotte R, et al: Inﬂuence of age and cardiovascular factors on regional pulsed wave Doppler myocardial imaging indices. Eur J Echocardiogr 2000;1:87–95. 145. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998; 32:865–875. 146. Chen YT, Vaccarino V, Williams CS, et al: Risk factors for heart failure in the elderly: A prospective community-based study. Am J Med 1999;106:605–612. 147. Gottdiener JS, Arnold AM, Aurigemma GP, et al: Predictors of congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2000;35:1628–1637. 148. Haider AW, Larson MG, Franklin SS, Levy D: Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003;138:10–16. 149. Kostis JB, Lawrence-Nelson J, Ranjan R, et al: Association of increased pulse pressure with the development of heart failure in SHEP. Systolic Hypertension in the Elderly (SHEP) Cooperative Research Group. Am J Hypertens 2001;14:798–803. 150. Kostis JB, Davis BR, Cutler J, et al: Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA 1997;278:212–216. 151. Wang JG, Staessen JA, Franklin SS, et al: Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 2005;45:907–913.

245

246

Chapter 19 • Hypertension and Valvular Heart Disease 152. Brilla CG, Funck RC, Rupp H: Lisinopril-mediated regression of myocardial ﬁbrosis in patients with hypertensive heart disease. Circulation 2000;102:1388–1393. 153. Diez J, Querejeta R, Lopez B, et al: Losartan-dependent regression of myocardial ﬁbrosis is associated with reduction of left ventricular chamber stiﬀness in hypertensive patients. Circulation 2002;105:2512–2517. 154. Mottram PM, Haluska B, Leano R, et al: Eﬀect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558–565. 155. Pedersen F, Raymond I, Mehlsen J, et al: Prevalence of diastolic dysfunction as a possible cause of dyspnea in the elderly. Am J Med 2005;118:25–31. 156. Wisenbaugh T, Spann JF, Carabello BA: Diﬀerences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation. J Am Coll Cardiol 1984;3:916–923. 157. Taniguchi K, Nakano S, Kawashima Y, et al: Left ventricular ejection performance, wall stress, and contractile state in aortic regurgitation before and after aortic valve replacement. Circulation 1990;82:798–807. 158. Feiring AJ, Rumberger JA: Ultrafast computed tomography analysis of regional radius-to-wall thickness ratios in normal and volume-overloaded human left ventricle. Circulation 1992;85:1423–1432. 159. Spagnuolo M, Kloth H, Taranta A, et al: Natural history of rheumatic aortic regurgitation. Criteria predictive of death, congestive heart failure, and angina in young patients. Circulation 1971;44:368–380. 160. Supino PG, Borer JS, Herrold EM, et al: Prognostic impact of systolic hypertension on asymptomatic patients with chronic severe aortic regurgitation and initially normal left ventricular performance at rest. Am J Cardiol 2005;96:964–970. 161. Borer JS, Truter SL, Herrold EM, et al: The cellular and molecular basis of heart failure in regurgitant valvular diseases: The myocardial extracellular matrix as a building block for future therapy. Adv Cardiol 2002;39:7–14. 162. Scognamiglio R, Rahimtoola SH, Fasoli G, et al: Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994;331:689–694. 163. Klodas E, Enriquez-Sarano M, Tajik AJ, et al: Surgery for aortic regurgitation in women. Contrasting indications and outcomes compared with men. Circulation 1996;94:2472–2478. 164. Dineen E, Brent BN: Aortic valve stenosis: Comparison of patients with to those without chronic congestive heart failure. Am J Cardiol 1986;57:419–422. 165. Krayenbuehl HP, Hess OM, Monrad ES, et al: Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement. Circulation 1989;79:744–755. 166. Villari B, Campbell SE, Hess OM, et al: Inﬂuence of collagen network on left ventricular systolic and diastolic function in aortic valve disease. J Am Coll Cardiol 1993;22:1477–1484. 167. Heymans S, Schroen B, Vermeersch P, et al: Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac ﬁbrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 2005;112:1136–1144. 168. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ Res 2003; 92:827–839. 169. Lovelock JD, Baker AH, Gao F, et al: Heterogeneous eﬀects of tissue inhibitors of matrix metalloproteinases on cardiac ﬁbroblasts. Am J Physiol Heart Circ Physiol 2005;288:H461–H468. 170. Monrad ES, Hess OM, Murakami T, et al: Time course of regression of left ventricular hypertrophy after aortic valve replacement. Circulation 1988;77:1345–1355.

171. Pantely G, Morton M, Rahimtoola SH: Eﬀects of successful, uncomplicated valve replacement on ventricular hypertrophy, volume, and performance in aortic stenosis and in aortic incompetence. J Thorac Cardiovasc Surg 1978;75:383–391. 172. Roman MJ, Klein L, Devereux RB, et al: Reversal of left ventricular dilatation, hypertrophy, and dysfunction by valve replacement in aortic regurgitation. Am Heart J 1989;118:553–563. 173. Djavidani B, Schmid FX, Keyser A, et al: Early regression of left ventricular hypertrophy after aortic valve replacement by the Ross procedure detected by cine MRI. J Cardiovasc Magn Reson 2004;6:1–8. 174. Duebener LF, Stierle U, Erasmi A, et al: Ross procedure and left ventricular mass regression. Circulation 2005;112:I415–I422. 175. Villari B, Vassalli G, Monrad ES, et al: Normalization of diastolic dysfunction in aortic stenosis late after valve replacement. Circulation 1995;91: 2353–2358. 176. Yoran C, Yellin EL, Becker RM, et al: Mechanism of reduction of mitral regurgitation with vasodilator therapy. Am J Cardiol 1979;43: 773–777. 177. Ling LH, Enriquez-Sarano M, Seward JB, et al: Clinical outcome of mitral regurgitation due to ﬂail leaﬂet. N Engl J Med 1996;335:1417–1423. 178. Grigioni F, Enriquez-Sarano M, Ling LH, et al: Sudden death in mitral regurgitation due to ﬂail leaﬂet. J Am Coll Cardiol 1999;34:2078– 2085. 179. Carabello BA: Sudden death in mitral regurgitation: Why was I so surprised? J Am Coll Cardiol 1999;34:2086–2087. 180. Corin WJ, Murakami T, Monrad ES, et al: Left ventricular passive diastolic properties in chronic mitral regurgitation. Circulation 1991;83:797– 807. 181. Zile MR, Tomita M, Nakano K, et al: Eﬀects of left ventricular volume overload produced by mitral regurgitation on diastolic function. Am J Physiol 1991;261:H1471–H1480. 182. Zile MR, Tomita M, Ishihara K, et al: Changes in diastolic function during development and correction of chronic LV volume overload produced by mitral regurgitation. Circulation 1993;87:1378–1388. 183. Nagatsu M, Ishihara K, Zile MR, et al: The eﬀects of complete versus incomplete mitral valve repair in experimental mitral regurgitation. J Thorac Cardiovasc Surg 1994;107:416–423. 184. Enriquez-Sarano M, Tajik AJ, Schaﬀ HV, et al: Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation 1994;90:830–837. 185. Wisenbaugh T, Skudicky D, Sareli P: Prediction of outcome after valve replacement for rheumatic mitral regurgitation in the era of chordal preservation. Circulation 1994;89:191–197. 186. Enriquez-Sarano M, Schaﬀ HV, Orszulak TA, et al: Valve repair improves the outcome of surgery for mitral regurgitation. A multivariate analysis. Circulation 1995;91:1022–1028. 187. Rozich JD, Carabello BA, Usher BW, et al: Mitral valve replacement with and without chordal preservation in patients with chronic mitral regurgitation. Mechanisms for diﬀerences in postoperative ejection performance. Circulation 1992;86:1718–1726. 188. David TE, Uden DE, Strauss HD: The importance of the mitral apparatus in left ventricular function after correction of mitral regurgitation. Circulation 1983;68:II76–II82. 189. Sarris GE, Cahill PD, Hansen DE, et al: Restoration of left ventricular systolic performance after reattachment of the mitral chordae tendineae. The importance of valvular-ventricular interaction. J Thorac Cardiovasc Surg 1988;95:969–979.

HSUAN-HUNG CHUANG, MBBS FILIPPOS TRIPOSKIADIS, MD RANDALL C. STARLING, MD, MPH

20

Dilated Cardiomyopathy and Cardiac Transplantation INTRODUCTION PATHOPHYSIOLOGY Diastolic Dysfunction in Dilated Cardiomyopathy Diastolic Dysfunction in the Transplanted Heart CLINICAL RELEVANCE Prognostic Significance of Left Ventricular

Diastolic Dysfunction in Dilated Cardiomyopathy Prognostic Significance of Right Ventricular Diastolic Dysfunction in Dilated Cardiomyopathy Impact on Treatment Strategies in Dilated Cardiomyopathy FUTURE RESEARCH

INTRODUCTION Dilated cardiomyopathy (DCM) is a heterogeneous disease of the myocardium that is characterized by left ventricular (LV) or biventricular dilatation and systolic dysfunction. In the classiﬁcation of the World Health Organization/International Society and Federation of Cardiology Task Force, DCM in its primary (e.g., idiopathic, familial) and secondary forms (most commonly ischemic, hypertensive, valvular, alcohol-related, or viral or autoimmune in origin) is the most common cause of the clinical syndrome of heart failure (HF).1 Familial DCM accounts for approximately 20% to 35% of DCM cases and has been linked to a diverse group of loci and genes.2 The reported annual incidence of the primary form of DCM varies between ﬁve and eight cases per 100,000 population3,4; true incidence is likely underestimated, since many asymptomatic cases remain unrecognized. Primary DCM can occur at any age but is ﬁrst seen mostly between the ages of 20 and 50 years.5,6

Blacks and males have a 2.5-fold increase in risk compared with Caucasians and females. The natural history of DCM is often progressive, and the clinical picture at the time of diagnosis can vary widely, with the most common initial manifestation being HF in 75% to 85% of patients.6–8 Echocardiography plays an essential role in the diagnosis and the follow-up of DCM. A portion of patients fortunately experience recovery of function and “reverse remodeling,” which can be documented with serial echocardiographic examinations.

PATHOPHYSIOLOGY Diastolic Dysfunction in Dilated Cardiomyopathy In patients with DCM, there are abnormalities in the LV systolic pressure-volume (P-V) relationship, which are almost always associated with changes in the diastolic portion of that relationship. Indeed, nearly all patients with systolic dysfunction have 247

248

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation impaired relaxation and variable decreases in ventricular compliances.9 LV diastolic dysfunction may lead to an increase in LV diastolic pressure and greatly inﬂuence the symptomatic status and outcome of patients.10 Despite improved treatment, the mortality rate in DCM remains high, accounting for 10,000 deaths annually in the United States.3 Diastolic function has traditionally been evaluated by cardiac catheterization with direct measurement of ﬁlling pressures and relaxation. This invasive approach, describing LV ﬁlling pressures, compliance, and relaxation as major determinants of LV diastolic function, is neither feasible nor suitable for routine evaluation. The development and validation of several noninvasive Doppler echocardiographic techniques that are relatively load independent have made echocardiography the clinical standard for the assessment of LV diastolic function.

Pathomorphology and Pathogenesis of Dilated Cardiomyopathy DCM is heterogeneous in its morphology. Common to the whole group is a poorly contracting dilated LV with a normal or reduced LV wall thickness. The lack of an increase in LV wall thickness often masks a signiﬁcant increase in LV mass. The histological changes are variable and nonspeciﬁc, including (a) increased myocyte diameter and nuclear size, (b) myoﬁbrillary loss, (c) focal myocyte apoptosis and death, (d) increase in interstitial Tlymphocytes/macrophages, and (e) interstitial ﬁbrosis.11 The pathogenesis of DCM remains uncertain despite intense research. Four basic mechanisms have been hypothesized, including familial and genetic factors, chronic viral infection of the myocardium and other cytotoxic insults, immune abnormalities leading to cellular and humorally mediated myocyte damage, and metabolic, energetic, and contractile abnormalities.12,13 With the onset of failure of the heart’s intrinsic mechanisms for sustaining a reasonable ejection fraction (EF) (e.g., contractile protein and excitation-contraction coupling mechanisms, cellular remodeling, bioenergetics), the cardiac remodeling process gradually becomes maladaptive. This is compounded by the eﬀects of endogenous bioactive chemicals (e.g., hormones, neurotransmitters, cytokines) and cell loss via myocyte apoptosis or necrosis compounds, which alter the expression of genes regulating contractility, contributing to the progressive myocardial dysfunction in DCM.

below approximately 30%.15 To maintain cardiac output, relaxation begins to prolong, becomes more afterload dependent, and eventually leads to elevation in LV end diastolic pressure (LVEDP).16 Thus, while the diastolic P-V relationship may reﬂect a more compliant chamber, the other abnormal diastolic indices support the conclusion that all patients with systolic HF and elevated diastolic pressures in fact have combined systolic and diastolic HF (Fig. 20-1).10 Alternatively, some patients may have only a modest decrease in LV EF and a modest increase in end diastolic volume, but a marked increase in LVEDP and a diastolic P-V relationship, reﬂecting decreased chamber compliance. Conversely, improvement in systolic function following treatment often leads to concomitant improvement in relaxation, especially if these changes are mediated through the β-adrenergic pathways.

Echocardiographic Indices of Left Ventricular Diastolic Dysfunction Abnormal ventricular contractility and dilatation are the hallmarks of DCM. Although DCM is usually a diﬀuse process, LV dysfunction can exist independently of concomitant right ventricular (RV) involvement in some patients. The early opening of mitral valve leaﬂets on M-mode echocardiography (the so-called C-hump) may reﬂect a high LVEDP. A large body of literature has accrued describing the various Doppler echocardiographic techniques in assessment of diastolic function. These techniques can be used alone or in combination, but most of them are dependent on heart rate, preload, and afterload. The LV ﬁlling or transmitral ﬂow pattern remains the starting point. The pulmonary venous ﬂow signal should always be sought as an adjunct to the mitral inﬂow pattern. These have been described in great detail in Chapters 2, 10, and 18. Brieﬂy, most patients can be categorized into one of the three patterns based on the following Doppler indices and timing (Fig. 20-2): ❒

❒

Diastolic Dysfunction and the Pressure-Volume Relationship In patients with DCM and systolic HF, the abnormalities in the P-V relationship occur during systole, including decreased LV EF, stroke volume, and stroke work. As diastolic function is critically important to systolic function and is linked to it symbiotically, virtually all patients with symptomatic HF have abnormalities in diastolic function. Conversely, as diastolic function worsens and ﬁlling pressures increase, systolic function is aﬀected by the FrankStarling mechanism. This is often called the “yin and yang” of cardiac function. Ventricular diastole involves the complex interplay of numerous components, including LV relaxation, diastolic suction, stiﬀness or compliance of the myocardium, pericardial restraint, ventricular interaction, and atrial contribution.14 LV relaxation is related to the time constant of intracavitary pressure decay during isovolumic relaxation, whereas LV compliance and stiﬀness are related more to the local slope of the diastolic P-V curve. LV relaxation remains relatively intact until LV EF falls

❒

Impaired relaxation (IR) pattern. Intracardiac pressures are unaﬀected, but less eﬀective suction from LV relaxation results in a delayed and diminished left atrial (LA)-to-LV early diastolic pressure gradient. This is characterized by long isovolumic relaxation time (IVRT), prolonged deceleration time (DT) of the early diastolic E wave, a high late diastolic A-wave velocity, and a decreased E/A ratio. Pseudonormal (PN) pattern. Increased LA pressure oﬀsets the reduced ﬂow related to impaired relaxation. Transmitral ﬂow pattern appears normal in terms of E/A ratio and DT. Restrictive ﬁlling (RF) pattern. LV distensibility is reduced because of increased intrinsic stiﬀness or decreased operating compliance, and LA pressure is increased. The elevated LA pressure results in an increased E velocity. The decrease in mid-to-late diastolic distensibility produces a more rapid transmitral pressure equilibration, creating a “dip-andplateau” eﬀect. This is characterized by short IVRT, high E velocity and short DT, and reduced A velocity. This pattern can be further stratiﬁed into “reversible” and “irreversible” subgroups with loading manipulations, resulting in incremental prognostic value.17,18

Because the majority of patients with DCM are studied while on medications, drug eﬀects must also be considered. A study by Makhoul et al.19 demonstrated a direct relationship between changes in pulmonary capillary wedge pressure (PCWP) induced by intravenous isosorbide dinitrate and the transmitral E/A ratio.

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation LV PRESSURE-VOLUME LOOP

LV pressure (mmHg)

LV pressure (mmHg)

LV PRESSURE-VOLUME LOOP

LV pressure (ml/m2)

A

LV volume (ml/m2)

Normal Systolic HF NYHA class III–IV Systolic HF following treatment

B

Normal Combined systolic and diastolic HF NYHA class III–IV Combined systolic and diastolic HF after treatment

Figure 20-1 Pressure-volume (P-V) loops in A, systolic heart failure (HF) and B, combined systolic and diastolic HF. A normal left ventricular (LV) P-V loop is shown on the left side of the curve (red loop). Systolic HF manifests as an increase in LV end diastolic volume and a reduction in stroke volume. LV end diastolic pressure (LVEDP) is increased. As a result, the diastolic portion of the curve simply shifts to the right, along the same P-V relationship (green loop). This returns to an intermediate state following treatment (blue loop). In panel B, illustrating combined diastolic and systolic HF, the LVEDP is elevated. Owing to a decrease in LV distensibility, whereby a higher diastolic pressure is necessary to achieve the same diastolic volume, there is a significant upward shift of the diastolic P-V relationship. This is in contrast to pure diastolic HF, where there is only an upward shift in P-V relationship, but no change in LV end diastolic volume. (Modified from Zile MR et al: New concepts in diastolic dysfunction and diastolic heart failure: Part I. Diagnosis, prognosis, and measurements of diastolic function. Circ 2002;105:1387–1393.)

Diastolic

Normal

Mild DD

Moderate DD

Severe DD

Function

Normal Impaired relaxation Pseudonormal Reversible restrictive Fixed restrictive E A

Mitral inflow

E Mitral inflow after Valsalva

A

Sa DTI mitral annulus Aa Ea Pulmonary venous flow

S E

LV relaxation

Normal

Impaired

Impaired

Impaired

Impaired

LV compliance

Normal

Normal to ↓

↓↓

↓↓↓

↓↓↓↓

Atrial pressure Tau

Normal

Normal ↑

↑↑ ↑

↑↑↑ ↑↑

↑↑↑↑ ↑↑↑

Figure 20-2 Doppler parameters in progressive diastolic dysfunction. DD, diastolic dysfunction; TDI, tissue Doppler imaging; LV, left ventricle; E, early diastolic velocity (cm/sec); A, late diastolic velocity (cm/sec); Sa, myocardial systolic velocity (cm/sec); Ea, myocardial early diastolic velocity (cm/sec); Aa, myocardial late diastolic velocity. (Modified from Redfield MM et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202.)

249

250

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation The initial high E/A ratio, typical of the RF pattern, was reduced by more than 50% after administration of nitrates in nearly all patients with New York Heart Association class IV HF. In addition to analysis of ﬁlling pattern, the mean LA pressure (MLAP) may be accurately predicted from the DT of the pulmonary venous diastolic (DTD) ﬂow slope, using the following regression equation20: MLAP = 53.236 − [0.302 DTD] + [0.000484 (DTD2)]. Other echocardiographic indices of diastolic function pertaining to DCM include rate of LV pressure decline, the Tei index, color kinesis, and ﬂow propagation velocity (Vp). Rate of LV Pressure Decline This can be obtained by tracing the deceleration phase of the mitral regurgitation Doppler spectral signal and applying the Bernoulli equation to obtain the instantaneous pressure gradient between the left ventricle and the left atrium. This derivative of Tau (τ) from the velocity curve, validated in human studies as a standard for assessment of active relaxation, is not applicable to those cases of DCM without a complete mitral regurgitant envelope. The Tei Index This is a combined myocardial performance index (isovolumic contraction time plus IVRT divided by ejection time) that may be more eﬀective for analysis of global cardiac dysfunction than for systolic and diastolic measures alone. Although it may be a sensitive indicator of overall cardiac dysfunction in patients with mild to moderate HF,21 it has variable prognostic signiﬁcance in both adults and children with DCM22–24 (see Chapter 16). Color Kinesis Color kinesis is an echocardiographic technique based on acoustic quantiﬁcation that allows color encoding of endocardial motion in real time.25–27 The regional LV ﬁlling properties can be derived from segmental analysis of diastolic color kinesis images. Increased diastolic asynchrony has been found in patients with DCM and severe mitral regurgitation, which are known to adversely aﬀect global diastolic function.28–30 However, this technique is dependent on the quality of two-dimensional images and may be aﬀected by signiﬁcant cardiac translation and/or rotation. Flow Propagation Velocity This method oﬀers a glance at diﬀerent intrinsic LV properties that determine LV ﬁlling, such as geometry and LV synchrony. The color M-mode velocity propagation of early diastolic ﬂow correlates with intraventricular pressure gradients and has been proposed as a load-independent indicator of LV diastolic function. Brun et al. were the ﬁrst to show that Vp is related to LV relaxation.31 The progressive decrease of Vp runs in parallel with the increase of τ, irrespective of rising ﬁlling pressure.32 It is therefore free of pseudonormalization, unlike transmitral ﬂow. Compared with the brisk Vp in normal patients, there is often signiﬁcantly delayed propagation and prolongation of the duration of inﬂow in patients with DCM.33 In fact, continuous apical ﬂow can be visualized in 25% of DCM. The ratio of E/Vp is a widely used index in the estimation of ﬁlling pressure. Coelho et al. found that in patients with severe LV dysfunction, Vp correlated closely with E/A ratio, IVRT, DT, and the Tei index.34 In a heterogeneous group comprising normal, ischemic, and dilated hearts,35 PCWP was calculated as: PCWP = [5.27 × E/Vp] + 4.6 (mmHg).

Reported positive and negative predictive values for E/Vp greater than 1.5 to predict PCWP greater than 12 mmHg were 93% and 70%, respectively. Correlation between E/Vp and PCWP outperformed correlations with maximal E and E/A, independent of LV EF (see Chapter 11).

Tissue Doppler Imaging Early diastolic LV longitudinal expansion, as represented by mitral annular velocity (Ea), and late diastolic mitral annular velocity (Aa) correspond fairly to the E and A waves on mitral inﬂow. Although Ea has been suggested as being less load sensitive than mitral inﬂow variables, this remains debatable.36,37 Ea is often reduced to less than 8 cm/sec in the RF pattern. Blunting of the magnitude of Ea correlates closely with diastolic dysfunction established invasively.36 Tissue Doppler imaging (TDI) may even be of value in the presence of atrial ﬁbrillation, where there is no A wave. The ratio of transmitral peak inﬂow E velocity to Ea has also been shown to correlate signiﬁcantly with invasively derived mean PCWP using a regression equation, Mean PCWP = 1.24 (E/Ea) + 1.9 (mmHg), and shows better correlation with LVEDP (r = 0.87) than do other Doppler variables38,39 (see Chapter 12). As a general clinical guideline, an E/Ea ratio greater than 10 is predictive of a mean PCWP above 15 mmHg with a sensitivity and speciﬁcity of 92% and 80%, respectively. The interval between the onset of mitral E and annular Ea by TDI (TE–Ea) has also been used to estimate LV ﬁlling pressure and correlate with τ.40 It has been proposed that PCWP is closely related to IVRT/TE–Ea. In fact, IVRT/ TE–Ea less than 2 was found to have a sensitivity of 91% and a speciﬁcity of 89% for detecting PCWP greater than 15 mmHg in other disease states.41 However, the cutoﬀ limit for this index in DCM requires further evaluation. Finally, it is noteworthy that TDI may reveal subtle abnormalities of systolic and diastolic function in asymptomatic relatives of patients with familial DCM with LV enlargement and preserved LV EF and therefore may help predict those who will go on to develop clinical DCM.41

Diastolic Dysfunction in the Transplanted Heart With advances in surgical techniques and immunosuppression, the survival rate following orthotropic heart transplantation (OHT) signiﬁcantly exceeds that of medical therapy for advanced HF. However, the transplanted heart does not provide the recipient with normal cardiac function, as posttransplant cardiac physiology and hemodynamics diﬀer signiﬁcantly from those in healthy subjects. Despite anticipated 1- and 5-year survival rates of 90% and 70%, respectively, acute and chronic allograft rejections have remained major determinants of patient outcome. Other important perioperative issues are persistently elevated pulmonary hypertension and RV dysfunction. As acute rejection is initially asymptomatic, regular rejection surveillance is obligatory. For detecting allograft rejection and monitoring immunosuppressive treatment, clinical and laboratory examinations, along with endomyocardial biopsies (EMBs), are conducted following a predetermined time schedule. Despite the inherent limitations and complications associated with biopsy, current noninvasive surveillance methods, though preferable, have yet to match EMBs in terms of sensitivity and speciﬁcity. These limitations have fueled the continuing challenge

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation to develop noninvasive methods to detect acute rejection and to monitor response to therapy. Serial echocardiography, with each individual patient serving as his or her own control, appears to be most promising.

Surgical Techniques and Physiology of the Transplanted Heart It is important to recognize the expected anatomical and physiological changes of a transplanted heart. For more than 30 years, OHT has been performed mostly with biatrial anastomoses, a technique ﬁrst described by Lower and Shumway.42,43 Using this technique, systemic and pulmonary venous communications between the donor and recipient hearts are simpliﬁed with biatrial anastomoses. The downside of this technique includes enlargement of the atria with abnormal geometry; asynchronous contraction of the donor and recipient atria with alteration in ventricular ﬁlling; tendency for thrombus formation, arrhythmias, and conduction disturbances in 10%–30% of patients; and residual atrioventricular valve regurgitation.44–47 More recently, bicaval and total techniques to improve cardiac anatomy, physiology, and postoperative outcome have gained popularity.48 The bicaval technique consists of complete excision of the recipient atria and direct anastomoses of the left and right pulmonary veins and the inferior and superior vena cavae.49 This technique reconstitutes atrial geometry with the theoretical advantage of preserving atrial contractility and reduction in valvular regurgitation.50 There is also less sinus node dysfunction and reduced need for chronic pacemaker post-OHT. Immediately after OHT, the heart is relatively noncompliant, with signiﬁcantly elevated ﬁlling pressures and abnormal LV isovolumic relaxation.51,52 The early postoperative noncompliance is attributed to factors such as ischemic myocardial injury, high peripheral vascular resistance, denervation, donor-recipient size mismatch, interaction between donor and recipient atria, allograft rejection, preexistent recipient pulmonary hypertension, and volume overload.53–57 Long-term studies of OHT recipients suggest that these hemodynamics remain mildly abnormal months after the procedure,58,59 while others with an initial RF pattern may become nonrestrictive in the ﬁrst 6 weeks after OHT.60 Young et al. showed that abnormal PCWP and right atrial (RA) and pulmonary artery pressures improved markedly during the fourth to eighth weeks.61 The average PCWP was 19 mmHg immediately after OHT and improved to 12 mmHg at 4–8 weeks. In contrast, Greenberg et al. demonstrated that LV ﬁlling pressures improved but never completely normalized.58 At 1 year after OHT, PCWP and RA and pulmonary artery pressures were elevated in comparison with age-matched controls. Likewise, Valantine et al. found that up to 15% of patients exhibited restrictive physiology at 6 years post-OHT.62 The functional signiﬁcance is that although the exercise capacity of OHT recipients usually improves in comparison with their pretransplant status, this is only about 60%– 70% of that found in healthy subjects.63,64 The LVEDP during exercise is often normal or elevated in comparison with control subjects, suggestive of a leftward shift of the P-V curve, which is consistent with diastolic dysfunction.65

Alterations in Diastolic Function During Allograft Rejection The noninvasive evaluation of the transplanted heart, particularly echocardiographic measures of diastolic function, has become an

integral part of long-term follow-up. Changes in myocardial structure caused by rejection-induced edema, lymphocyte inﬁltration, increased mass, and myocardial necrosis have been shown to compromise myocyte function, resulting in increased myocardial stiﬀness and abnormal relaxation.66–68 With mild or even early rejection, two-dimensional echocardiographic changes are subtle and are not accurate or reproducible enough. Pathophysiologically, rejection-induced myocardial edema manifested by an echocardiographically discernible increase in wall thickness is a rather late event. During episodes of rejection, restrictive physiology of the allograft becomes more prominent. Commonly cited Doppler changes in acute rejection include (1) decreased pressure half-time of the early diastolic E wave, (2) decreased IVRT, and (3) increased E velocity. Using the patient as his or her own baseline, a signiﬁcant change—deﬁned as greater than 20% for E velocity and greater than 15% for pressure half-time or IVRT—is fairly consistent with rejection.67,69 Valantine et al. evaluated 64 patients undergoing hemodynamic and Doppler echocardiographic studies as part of the routine follow-up 1–13 years after OHT.70 Ten patients were found to have strikingly abnormal (restrictive) transmitral ﬂow patterns. This group had a higher incidence of rejection as the only identiﬁable clinical diﬀerence. RF pattern was associated with impaired systolic performance, and there was correlation between transtricuspid (RV IVRT) and transmitral (LV IVRT) ﬂow patterns and degree of rejection. Barba et al. studied 56 OHT recipients 6 weeks postoperatively and found that during acute rejection, LV wall thickness signiﬁcantly increased compared with negative biopsies, while IVRT and pressure half-time signiﬁcantly decreased.71 However, the increase in mitral E velocity was signiﬁcantly associated with only severe rejection. The progressive shortening of IVRT as a marker of graft rejection showed a high sensitivity (85%) and low speciﬁcity (57%). In another prospective study, Berwing et al. reported that parameters of systolic function such as percent fractional shortening and systolic wall thickness of the posterior wall remained without signiﬁcant changes at moderate (grade 2) and severe (grade 3) rejections.72 The same is valid for relaxation parameters such as maximum velocity of posterior wall reduction (in terms of peak thinning rate [PTR]), the time interval of end systole to maximum velocity of posterior wall reduction (tESPTR), and IVRT. Although LV ﬁlling parameters such as mitral E velocity increased signiﬁcantly from 73.3 + 15.2 cm/sec in the rejection-free interval (grade 0) to 103.9 + 15.0 cm/sec at grade 2 rejection and 101.1 + 9.2 cm/sec at grade 3 rejection, these parameters are too insensitive to diagnose or exclude a moderate or severe acute rejection in the individual case. Analyses of transmitral Doppler and pulmonary venous ﬂow velocity have not lived up to their promise to detect rejection-related diastolic dysfunction for two main reasons. Firstly, transmitral Doppler indices are inﬂuenced by variables other than ventricular diastolic function, such as age, heart rate, and, most importantly, ventricular loading conditions.73 Pulmonary venous ﬂow velocities are particularly variable, even in individuals without heart disease. Secondly, denervation of the transplanted heart, with its lack of autonomic regulation and the usual sinus tachycardia, leads to a form of RF ﬁlling pattern that amounts to diastolic dysfunction in the absence of acute rejection.74 TDI and Vp measurements appear promising in allowing earlier and more accurate detection of LV dysfunction in the transplanted heart. Derumeaux et al. found values for sensitivity and speciﬁcity of 92% using mitral annular Ea velocity during mild or moderate and severe rejection.75 With increasing rejection grade, Ea decreased

251

252

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation signiﬁcantly. Puleo et al. tested 121 OHT recipients who underwent TDI at the time of EMB surveillance.68 These investigators found a signiﬁcant decrease in mitral annular Ea at the inferior wall during moderate allograft rejection but no change in peak systolic velocity in comparison with nonrejecting allograft recipients, with a sensitivity of 76% and a speciﬁcity of 88%. In 78 OHT recipients (among whom 75 histological analyses revealed no signiﬁcant rejection), Mankad et al. found a reduction in posterior wall peak systolic and diastolic velocity gradients with rejection, as well as a reduction in mitral annular systolic Sa and diastolic Ea velocities, with a sensitivity of 93% and a speciﬁcity of 71%.76 Dandel et al. also reported that in all patients with acute rejection, a signiﬁcant reduction in Ea velocity was obtained from the basal LV posterior wall in the short axis. They suggested that absence of such a change could practically exclude acute transplant rejection. In 91.7% of cases, the pulsed Doppler ﬁndings reverted completely during antirejection therapy within 65 hours.77 Stengel et al. found that late diastolic mitral annular Aa velocity and mitral annular systolic Sa velocity were higher in patients with rejection grade less than 3A compared with those of 3A or greater (Aa, 8.8 cm/sec vs. 7.7 cm/sec; Sa, 19.3 cm/sec vs. 9.3 cm/sec). Sensitivity and speciﬁcity of Aa less than 8.7 cm/ sec in predicting signiﬁcant allograft rejection were 82% and 53%, respectively.78 Unlike ﬁndings in other studies, neither early diastolic mitral annular Ea velocity nor Vp was associated with the histological degree of allograft rejection, though there was a trend toward lower Ea values during episodes of rejection. Although an Aa velocity can reliably exclude severe rejection, the fact that the best threshold of an Aa velocity less than 9 cm/sec falsely detected rejection in almost 50% of cases indicates that it is not speciﬁc enough and that the pathophysiological problem of restriction to allograft LV ﬁlling impairs the reliability of any tool assessing diastolic function during the early rejection process. In our own series at the Cleveland Clinic, Sun et al. noted that in pericardial eﬀusion, with IVRT less than 90 msec and mitral inﬂow E/A ratio greater than 1.7, the diameter of the inferior vena cava and the duration of pulmonary venous reversal were independently associated with rejection by multivariate analysis. However, no single predictor or combination of predictors was powerful enough to eliminate surveillance EMB.79 Palka et al. analyzed TDI-derived early diastolic indices of LV and RV function.80 They found that signiﬁcant diﬀerences in the late isovolumic relaxation myocardial velocity gradient, as well as diﬀerences in timing between onsets of mitral E and mitral annular Ea waves and between mitral and tricuspid annular Ea, might help identiﬁcation of those with acute rejection, with a sensitivity and speciﬁcity greater than 0.80. They attributed these diﬀerences to altered early diastolic untwisting of the oblique LV ﬁbers and the delay in early diastolic RV relaxation. More reﬁned approaches to ultrasonic tissue characterization appear promising, since they may detect interstitial edema early in the course of rejection. Preferential adherence of intercellular adhesion molecule-1–targeted microbubbles may also oﬀer a noninvasive imaging technique for detection of acute rejection that may be characterized by endothelial dysfunction.

CLINICAL RELEVANCE Prognostic Significance of Left Ventricular Diastolic Dysfunction in Dilated Cardiomyopathy Although the overall prognosis of DCM patients is most clearly related to the severity of LV systolic dysfunction, it alone is insuf-

ﬁcient to predict symptoms, exercise tolerance, or outcome or to identify those who may beneﬁt the most from OHT, particularly when the LV EF falls under 25%.81–85 Combination of available clinical, laboratory, hemodynamic, electrophysiological, and functional parameters for each individual may more accurately predict survival.86–88 Doppler-derived diastolic abnormalities have shown additional prognostic values.89–93 An RF ﬁlling pattern is common in patients (37%–58%) with DCM and is associated with elevated LVEDP and PCWP, more atrioventricular valvular regurgitation and symptoms, and markedly depressed biventricular systolic function.86,89–91,94–96 Studies by Xie et al. and Werner et al. have shown the RF pattern to predict a higher mortality rate in patients with systolic dysfunction.89,92 Both series found that patients with a DT less than 140 msec and an E/A ratio greater than 2.0 had a 2-year survival rate of approximately 50%, compared with those without this pattern, who had a survival rate of greater than 90%. This was independent of the degree of mitral regurgitation, often found in these DCM patients. Whalley et al. attempted to further distinguish the prognostic implication of the PN ﬁlling pattern in 115 HF patients with mixed etiologies.97 The one-year follow-up results showed that (1) all-cause mortality in RF, PN, and IR patterns was 37.5%, 23.4%, and 17.4%, respectively; (2) hospital readmission for HF in the three patterns was 40.7%, 30.9%, and 15.2%, respectively; and (3) death/HF hospital readmission was 62.9%, 47.6%, and 26.1%, respectively. These data are consistent with the notion that the PN pattern reﬂects a less advanced disease state compared with the RF pattern in the continuum of diastolic dysfunction. Dini et al. reported that the difference in duration of pulmonary venous ﬂow and mitral ﬂow at atrial contraction (ARd-Ad) provided an incremental prognostic value to predict outcome in HF patients.98 The index of ARd-Ad has been shown to directly reﬂect LVEDP.99 They found that patients with a nonrestrictive pattern and ARd-Ad greater than 30 msec had an intermediate prognosis between patients with a restrictive pattern (worse) and those with a nonrestrictive pattern and ARd-Ad less than 30 msec (better) in terms of survival and event rates. Exercise tolerance is often reduced in DCM, and resting PCWP as well as resting LA volume and systolic function correlate with and inﬂuence peak oxygen consumption (VO2) and exercise capacity.39,100–102 Abnormal ventilatory response has been shown to correlate with M-mode IVRT. Studies by Vanoverschelde et al. and Xie et al. have demonstrated a clear relationship between LV ﬁlling pattern and functional class.91,103 Patients with increased transmitral E wave or shortened DT, or both, had poorer treadmill performance compared with those who had an IR pattern. This is consistent with the notion that the RF pattern represents increased preload and abnormal LV compliance. Hansen et al. evaluated the incremental value of transmitral ﬂow patterns to peak VO2, as obtained by cardiopulmonary exercise testing, in determining the prognosis of patients with systolic dysfunction (LV EF <40%).104 In this study of 311 consecutive patients (of which 223 had DCM) evaluated for OHT, independent predictors of mortality were transmitral ﬂow pattern, peak VO2, and LV end diastolic diameters. In patients with an RF pattern, peak VO2 was lower (13.2 ± 4.2 ml/min/kg) than in those without an RF pattern (16.6 ± 5.8 ml/min/kg, p < 0.0001). In patients with peak VO2 less than 14 ml/min/kg body weight, the outcome was markedly poorer in the presence of the RF pattern compared with its absence (2-year survival rate, 52% vs. 80%). Similarly, despite peak VO2 greater than 14 ml/ min/kg, the outcome was less favorable in the presence of the RF

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation pattern (2-year survival rate, 80% vs. 94%) (Fig. 20-3). The severity of diastolic dysfunction is thus closely related to survival. However, one must keep in mind that even though the RF pattern has prognostic value, there is substantial overlap of ﬁlling indices between survivors and nonsurvivors. Although Dopplerderived diastolic function may have important prognostic information for the patient groups as a whole, it may not be applicable to an individual patient. Others have attempted to use TDI data to predict exercise capacity, though results have been conﬂicting, possibly related to diﬀerent patient subsets and treatment strategies. Some have found that mitral annular Ea velocity was not better at predicting exercise capacity than was conventional

100

Non-RFP

Survival (%)

80

Total 60

RFP

40

20 p = 0.005 0 0

1

2

3

34 20 14

6 4 3

t (years) Total Non-RFP RFP

n = 140 n = 61 n = 79

84 45 41

A 100

Non-RFP Total

80 Survival (%)

RFP 60

Prognostic Significance of Right Ventricular Diastolic Dysfunction in Dilated Cardiomyopathy The presence of RV dilatation and systolic dysfunction is known to signiﬁcantly worsen the prognosis of patients with DCM, and several echocardiographic RV systolic parameters, such as tricuspid annular plane systolic excursion (TAPSE) less than 14 and peak systolic tricuspid annular velocity (Sa) less than 10.8 cm/sec, have been shown to possess independent prognostic power106–109 (see Chapter 14). RV diastolic dysfunction is also common, but less is known about its prognostic impact.110,111 The peak early diastolic velocity (EaTri) and peak late velocity (AaTri) of the tricuspid annulus, as well as their ratio EaTri /AaTri, may be used. Signiﬁcant decrease in EaTri and EaTri /AaTri were found in disease states including DCM.111 These velocities are also dependent on age112 and RV systolic function,113 with an inverse relationship to RV ﬁlling pressures. The RV EaTri /AaTri ratio was signiﬁcantly correlated to the LV Ea/Aa ratio, and there is no pseudonormalization of EaTri during progressive increase in RV ﬁlling pressure, indicating that these parameters are not load dependent.113 Yu et al. examined RV Doppler ﬁlling parameters and deﬁned RV diastolic dysfunction by a shortening of DT of the transtricuspid early diastolic E wave to less than 143 msec, and by a reversal in EaTri /AaTri.114 They showed that the presence of RV diastolic dysfunction signiﬁcantly predicted cardiac morbidity, including nonfatal hospitalization for HF or angina, but no mortality. Meluzin et al. evaluated the prognostic impact of combination of RV systolic and diastolic function in 177 consecutive patients with symptomatic HF due to ischemic or idiopathic DCM and mean LV EF of 23%.115 Over a mean follow-up of 16 months, RV systolic and diastolic functions were found to be independent predictors of event-free survival on multivariate analysis. The survival pattern was, however, determined mainly by the EaTri value, with EaTri of less than 8.9 cm/sec predicting a high risk of cardiacrelated death irrespective of RV systolic function.

40

Impact on Treatment Strategies in Dilated Cardiomyopathy

20 p = 0.03

0 0

1

2

3

41 31 10

7 4 4

t (years) Total Non-RFP RFP

E-wave velocity.105 In contrast, mitral annular Aa velocity correlated signiﬁcantly with peak VO2, whereas transmitral A velocity did not reﬂect exercise capacity. Aa velocity might be a better marker of LA function, reﬂecting the adaptive capacity of the left atrium to compensate for increased diastolic volume and LV ﬁlling pressures.

n = 125 n = 82 n = 43

86 62 25

B Figure 20-3 Mitral inflow patterns provide prognostic information incremental to that of peak VO2 in patients with ischemic or dilated cardiomyopathy. The outcome is significantly poorer in the presence of a restrictive filling pattern (RFP) than in its absence, both in A, patients with peak VO2 ≤14 ml/min/kg and in B, patients with peak >14 ml/min/kg. (Modified from Hansen A et al: Prognostic value of Doppler echocardiographic mitral inflow patterns: Implications for risk stratification in patients with chronic congestive heart failure. J Am Coll Cardiol. 2001;37:1049–1055.)

Therapies targeting the interruption of persistent neurohormonal activation have formed the cornerstone in the management of DCM and HF over the last decade. These therapies, directly or indirectly, play an inﬂuential role in the improvement of diastolic function. There is growing evidence that beta blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers, as well as nitric oxide donors, can be beneﬁcial. Patients with DCM and HF have elevated circulating and tissue concentrations of angiotensin II, which may promote hypertrophy, apoptosis, interstitial ﬁbrosis, ventricular and vascular remodeling, and secretion of aldosterone. Aldosterone itself promotes ﬁbroblast proliferation and collagen deposition, leading to an increase in passive stiﬀness of the ventricles and the arterial bed, and thus ventricular ﬁlling and arterial compliance.116 Thus various inhibitors of the renin-angiotensin-aldosterone system

253

254

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation have all been found to have salutary eﬀects on improving diastolic function. Beta blocker therapy is now recommended for all but the most advanced cases of symptomatic systolic HF. In addition to the improvement of systolic function, beta blockers have been shown to lengthen diastole and aﬀect neurohormonal activation, thereby improving outcome.117 Capomolla et al. reported improvement in diastolic ﬁlling following therapy with carvedilol, with concomitant signiﬁcant reduction in eﬀective regurgitant oriﬁce area and mitral regurgitation.118 Similar ﬁndings were reported by Andersson et al. among the patients enrolled in the Metoprolol in Dilated Cardiomyopathy (MDC) study.119 The authors reported a good correlation between decrease in heart rate and prolongation of DT at 3 months in the metoprolol group. Although short-term studies did not reveal any change in chamber stiﬀness, Kim et al. found a reduction in chamber stiﬀness after a longer follow-up period of 6 months.120 This is not unexpected, as, unlike the improvement in relaxation and contractility that can occur over a shorter duration,121 a longer treatment period with beta blockers would be necessary before any signiﬁcant change in geometry and chamber stiﬀness, as the regression of hypertrophy and interstitial remodeling is a slower process.121,122 In those with mild to moderate LV dysfunction, beta blockers seem to improve exercise capacity through improvement in LV compliance and diastolic function. Likewise, the beneﬁts have recently been demonstrated in those with moderate to severe LV dysfunction. Therapy can be tailored to the individual patient with the use of noninvasive hemodynamic information obtained. For example, there is diastolic ventricular interaction in DCM patients with the RF pattern,123 and volume unloading in this setting allows for increased LV ﬁlling. Such patients generally receive signiﬁcant symptomatic beneﬁt from diuretics and venodilator therapy. On the other hand, patients with normal or only mildly elevated ﬁlling may have further deterioration of cardiac output with the use of diuretics and preload reduction. In such patients, management should be directed at optimizing cardiac output with afterload reduction using ACE inhibitors and/or other vasodilators. Studies are ongoing to ascertain the value of this noninvasive hemodynamically based or echo-guided management of HF.

FUTURE RESEARCH Although much is known about the mechanisms underlying diastolic dysfunction in HF, many basic issues remain to be resolved. Clinically relevant diastolic dysfunction integrates abnormalities emanating from sarcomere, extracellular matrix, vasculature, and various cardiac structures. Much work is still needed to clarify which abnormalities are the most meaningful as primary clinical targets for therapeutic intervention. Disparities among various echocardiographic parameters of diastolic function may not be uncommon. Overall Doppler ﬂow measurements are operator dependent and more prone to measurement errors, though in some cases there is genuine disparity. In addition, patient’s age must be considered, as it has a signiﬁcant inﬂuence on mitral inﬂow, pulmonary vein, mitral annular TDI, and propagation velocity. Other methods of noninvasive quantiﬁcation of diastolic dysfunction, including myocardial characterization using ultrasonic backscatter, need further evaluation. The “holy grail” of diastolic dysfunction is to ﬁnd that loadindependent parameter that can be reliably used to monitor disease progression and evaluation of response to therapy. The

clinical applications of TDI in the assessment of LV diastolic function, loading conditions, and synchronization have moved from the experimental lab to clinical practice. Further advances, particularly in strain and strain rate imaging, will establish the use of this technique to quantify LV systolic and diastolic function. In the ﬁeld of advanced HF therapeutics, biventricular pacing has been shown to alleviate symptoms eﬀectively, improve cardiac function, and reverse LV remodeling (see Chapter 29). Studies have shown that systolic asynchrony, but not QRS complex duration, is a better predictor of acute hemodynamic, echocardiographic, or clinical response. Similar to systolic asynchrony, diastolic asynchrony also occurred in more than 40% of DCM patients with narrow QRS complexes and in about 70% of those with wide QRS complexes. Another observed predictor of diastolic asynchrony is the degree of diastolic dysfunction, as illustrated by the negative correlation with mitral annular Ea velocity. Since cardiac output is dependent on both systolic emptying and diastolic ﬁlling, systolic and diastolic asynchrony may cause additive hemodynamic compromise in the failing heart. This relationship between diastolic asynchrony and cardiac resynchronization therapy needs further evaluation. The mean survival rate for DCM was approximately 50% at 5 years, but this has improved with the advent of neurohormonal blockade. When all other treatment options prove unsuccessful and the patient is deemed to have end-stage HF, OHT may be considered. Because the supply of donor organs is limited and many of those on the waiting list die before ﬁnding a donor, risk stratiﬁcation in individual patients is important; Doppler-derived information on diastolic function may thus aid in better prognostication and selection of patients likely to beneﬁt the most from OHT. Lastly, mild hemodynamic abnormalities characterize the transplanted heart. Early recognition of acute rejection episodes in cardiac allograft recipients remains a major challenge during follow-up after OHT. Echocardiography cannot supplant invasive methods for monitoring acute rejection but is a useful adjunct for surveillance and monitoring of allograft function after OHT. Protocols now combine routine biopsies with supplemental biopsy in the event of echocardiographic evidence of acute restrictive physiology.124 Recently gene expression proﬁling (GEP) has been utilized in heart transplant recipients to determine a state of quiescence and to exclude signiﬁcant cardiac allograft rejection.125 New algorithms are currently being evaluated in clinical trials to determine whether GEP combined with echocardiography can reduce the need for invasive monitoring with EMB. REFERENCES 1. Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Deﬁnition and Classiﬁcation of Cardiomyopathies. Circulation 1996;93:841–842. 2. Maron BJ, Towbin JA, Thiene G, et al: Contemporary deﬁnitions and classiﬁcation of the cardiomyopathies: An American Heart Association Scientiﬁc Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807–1816. 3. Gillum RF: Idiopathic cardiomyopathy in the United States, 1970–1982. Am Heart J 1986;111:752–755. 4. Codd MB, Sugrue DD, Gersh BJ, et al: Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 1989;80:564–572.

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 5. Johnson RA, Palacios I: Dilated cardiomyopathies of the adult (ﬁrst of two parts). N Engl J Med 1982;307:1051–1058. 6. Komajda M, Jais JP, Reeves F, et al: Factors predicting mortality in idiopathic dilated cardiomyopathy. Eur Heart J 1990;11:824–831. 7. Sugrue DD, Rodeheﬀer RJ, Codd MB, et al: The clinical course of idiopathic dilated cardiomyopathy. A population-based study. Ann Intern Med 1992;117:117–123. 8. Diaz RA, Obasohan A, Oakley CM: Prediction of outcome in dilated cardiomyopathy. Br Heart J 1987;58:393–399. 9. Sutherland GR, Lange A, Palka P, et al: Does Doppler myocardial imaging give new insights or simply old information revisited? Heart 1996;76: 197–199. 10. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 11. Williams RS: Apoptosis and heart failure. N Engl J Med 1999;341:759– 760. 12. Zisman LS, Asano K, Dutcher DL, et al: Diﬀerential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart. Circulation 1998;98:1735–1741. 13. Davies CH, Davia K, Bennett JG, et al: Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation 1995;92:2540–2549. 14. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 15. Eichhorn EJ, Willard JE, Alvarez L, et al: Are contraction and relaxation coupled in patients with and without congestive heart failure? Circulation 1992;85:2132–2139. 16. Eichhorn EJ, Hatﬁeld B, Marcoux L, et al: Functional importance of myocardial relaxation in patients with congestive heart failure. J Card Fail 1994;1:45–56. 17. Pozzoli M, Traversi E, Cioﬃ G, et al: Loading manipulations improve the prognostic value of Doppler evaluation of mitral ﬂow in patients with chronic heart failure. Circulation 1997;95:1222–1230. 18. Capomolla S, Pinna GD, Febo O, et al: Echo-Doppler mitral ﬂow monitoring: An operative tool to evaluate day-to-day tolerance to and eﬀectiveness of beta-adrenergic blocking agent therapy in patients with chronic heart failure. J Am Coll Cardiol 2001;38:1675–1684. 19. Makhoul N, Hasanein J, Dagan T, et al: Doppler diastolic transmitral ﬂow patterns in severe heart failure: Response to controlled changes in ﬁlling pressure using intravenous isosorbide dinitrate. Cardiology 1994;85: 235–243. 20. Kinnaird TD, Thompson CR, Munt BI: The deceleration time of pulmonary venous diastolic ﬂow is more accurate than the pulmonary artery occlusion pressure in predicting left atrial pressure. J Am Coll Cardiol 2001;37:2025–2030. 21. Bruch C, Schmermund A, Marin D, et al: Tei-index in patients with mildto-moderate congestive heart failure. Eur Heart J 2000;21:1888– 1895. 22. Dujardin KS, Tei C, Yeo TC, et al: Prognostic value of a Doppler index combining systolic and diastolic performance in idiopathic-dilated cardiomyopathy. Am J Cardiol 1998;82:1071–1076. 23. Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664. 24. McMahon CJ, Nagueh SF, Eapen RS, et al: Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: A prospective clinical study. Heart 2004;90:908–915. 25. Lang RM, Vignon P, Weinert L, et al: Echocardiographic quantiﬁcation of regional left ventricular wall motion with color kinesis. Circulation 1996;93:1877–1885. 26. Vandenberg BF, Oren RM, Lewis J, et al: Evaluation of color kinesis, a new echocardiographic method for analyzing regional wall motion in patients with dilated left ventricles. Am J Cardiol 1997;79:645–650. 27. Bednarz J, Vignon P, Mor-Avi VV, et al: Color kinesis: Principles of operation and technical guidelines. Echocardiography 1998;15:21–34. 28. Godoy IE, Mor-Avi V, Weinert L, et al: Use of color kinesis for evaluation of left ventricular ﬁlling in patients with dilated cardiomyopathy and mitral regurgitation. J Am Coll Cardiol 1998;31:1598–606. 29. Vignon P, Mor-Avi V, Weinert L, et al: Quantitative evaluation of global and regional left ventricular diastolic function with color kinesis. Circulation 1998;97:1053–1061. 30. Gaasch WH, Blaustein AS, Bing OH: Asynchronous (segmental early) relaxation of the left ventricle. J Am Coll Cardiol 1985;5:891–897.

31. Brun P, Tribouilloy C, Duval AM, et al: Left ventricular ﬂow propagation during early ﬁlling is related to wall relaxation: A color M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 32. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular ﬁlling ﬂow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27:365–371. 33. Jacobs LE, Kotler MN, Parry WR: Flow patterns in dilated cardiomyopathy: A pulsed-wave and color ﬂow Doppler study. J Am Soc Echocardiogr 1990;3:294–302. 34. Coelho L, Pires R, Costa M, et al: Mitral ﬂow propagation velocity assessed with M-mode color Doppler in patients with dilated cardiomyopathy. Rev Port Cardiol 2001;20:39–44. 35. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular ﬁlling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 36. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 37. Yalcin F, Kaftan A, Muderrisoglu H, et al: Is Doppler tissue velocity during early left ventricular ﬁlling preload independent? Heart 2002;87:336–339. 38. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527–1533. 39. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular ﬁlling pressures: A comparative simultaneous Dopplercatheterization study. Circulation 2000;102:1788–1794. 40. Garcia MJ, Rodriguez L, Ares M, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–114. 41. Rivas-Gotz C, Khoury DS, Manolios M, et al: Time interval between onset of mitral inﬂow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation: Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470. 42. Lower RR, Shumway NE: Studies on orthotopic homotransplantation of the canine heart. Surg Forum 1960;11:18–19. 43. Shumway NE, Lower RR, Stofer RC: Transplantation of the heart. Adv Surg 1966;2:265–284. 44. Leyh RG, Jahnke AW, Kraatz EG, et al: Cardiovascular dynamics and dimensions after bicaval and standard cardiac transplantation. Ann Thorac Surg 1995;59:1495–1500. 45. Sievers HH, Leyh R, Jahnke A, et al: Bicaval versus atrial anastomoses in cardiac transplantation. Right atrial dimension and tricuspid valve function at rest and during exercise up to thirty-six months after transplantation. J Thorac Cardiovasc Surg 1994;108:780–784. 46. Deleuze PH, Benvenuti C, Mazzucotelli JP, et al: Orthotopic cardiac transplantation with direct caval anastomosis: Is it the optimal procedure? J Thorac Cardiovasc Surg 1995;109:731–737. 47. Triposkiadis F, Starling RC, Haas GJ, et al: Timing of recipient atrial contraction: A major determinant of transmitral diastolic ﬂow in orthotopic cardiac transplantation. Am Heart J 1993;126:1175–1181. 48. Dreyfus G, Jebara V, Mihaileanu S, et al: Total orthotopic heart transplantation: An alternative to the standard technique. Ann Thorac Surg 1991;52:1181–1184. 49. Blanche C, Valenza M, Czer LS, et al: Orthotopic heart transplantation with bicaval and pulmonary venous anastomoses. Ann Thorac Surg 1994;58: 1505–1509. 50. Laske A, Carrel T, Niederhauser U, et al: Modiﬁed operation technique for orthotopic heart transplantation. Eur J Cardiothorac Surg 1995;9: 120–126. 51. Hausdorf G, Banner NR, Mitchell A, et al: Diastolic function after cardiac and heart-lung transplantation. Br Heart J 1989;62:123–132. 52. Paulus WJ, Bronzwaer JG, Felice H, et al: Deﬁcient acceleration of left ventricular relaxation during exercise after heart transplantation. Circulation 1992;86:1175–1185. 53. Skowronski EW, Epstein M, Ota D, et al: Right and left ventricular function after cardiac transplantation. Changes during and after rejection. Circulation 1991;84:2409–2417. 54. Frist WH, Stinson EB, Oyer PE, et al: Long-term hemodynamic results after cardiac transplantation. J Thorac Cardiovasc Surg 1987;94:685–693. 55. Braith RW, Mills RM Jr, Wilcox CS, et al: Fluid homeostasis after heart transplantation: The role of cardiac denervation. J Heart Lung Transplant 1996;15:872–880.

255

256

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 56. Valantine HA, Appleton CP, Hatle LK, et al: Inﬂuence of recipient atrial contraction on left ventricular ﬁlling dynamics of the transplanted heart assessed by Doppler echocardiography. Am J Cardiol 1987;59: 1159–1163. 57. McClurken JB, Todd BA, Mather PJ, et al: Recipient-donor atrial synchronization beneﬁts acute hemodynamics after orthotopic heart transplantation. J Heart Lung Transplant 1996;15:368–370. 58. Greenberg ML, Uretsky BF, Reddy PS, et al: Long-term hemodynamic follow-up of cardiac transplant patients treated with cyclosporine and prednisone. Circulation 1985;71:487–494. 59. Verani MS, George SE, Leon CA, et al: Systolic and diastolic ventricular performance at rest and during exercise in heart transplant recipients. J Heart Transplant 1988;7:145–151. 60. St Goar FG, Gibbons R, Schnittger I, et al: Left ventricular diastolic function. Doppler echocardiographic changes soon after cardiac transplantation. Circulation 1990;82:872–878. 61. Young JB, Leon CA, Short HD 3rd, et al: Evolution of hemodynamics after orthotopic heart and heart-lung transplantation: Early restrictive patterns persisting in occult fashion. J Heart Transplant 1987;6:34–43. 62. Valantine HA, Appleton CP, Hatle LK, et al: A hemodynamic and Doppler echocardiographic study of ventricular function in long-term cardiac allograft recipients. Etiology and prognosis of restrictive-constrictive physiology. Circulation 1989;79:66–75. 63. Mandak JS, Aaronson KD, Mancini DM: Serial assessment of exercise capacity after heart transplantation. J Heart Lung Transplant 1995; 14:468–478. 64. Stevenson LW, Sietsema K, Tillisch JH, et al: Exercise capacity for survivors of cardiac transplantation or sustained medical therapy for stable heart failure. Circulation 1990;81:78–85. 65. Kao AC, Van Trigt P 3rd, Shaeﬀer-McCall GS, et al: Allograft diastolic dysfunction and chronotropic incompetence limit cardiac output response to exercise two to six years after heart transplantation. J Heart Lung Transplant 1995;14:11–22. 66. Sagar KB, Hastillo A, Wolfgang TC, et al: Left ventricular mass by M-mode echocardiography in cardiac transplant patients with acute rejection. Circulation 1981;64:II217–II220. 67. Amende I, Simon R, Seegers A, et al: Diastolic dysfunction during acute cardiac allograft rejection. Circulation 1990;81:III66–III70. 68. Puleo JA, Aranda JM, Weston MW, et al: Noninvasive detection of allograft rejection in heart transplant recipients by use of Doppler tissue imaging. J Heart Lung Transplant 1998;17:176–184. 69. Seacord LM, Miller LW, Pennington DG, et al: Reversal of constrictive/ restrictive physiology with treatment of allograft rejection. Am Heart J 1990;120:455–459. 70. Valantine HA, Fowler MB, Hunt SA, et al: Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection. Circulation 1987;76:V86–V92. 71. Barba J, Gomez JA, Abecia AC, et al: Changes in diastolic function in heart rejection: Role of Doppler echocardiography. Rev Esp Cardiol 1992;45: 652–656. 72. Berwing K, Friedl A, Schaper J, et al: Doppler and echocardiography parameters in detection of acute graft rejection after heart transplantation. Z Kardiol 1994;83:225–233. 73. Seiler C, Aeschbacher BC, Meier B: Quantitation of mitral regurgitation using the systolic/diastolic pulmonary venous ﬂow velocity ratio. J Am Coll Cardiol 1998;31:1383–1390. 74. Hausmann B, Muurling S, Stauch C, et al: Detection of diastolic dysfunction: Acoustic quantiﬁcation (AQ) in comparison to Doppler echocardiography. Int J Card Imaging 1997;13:301–310. 75. Derumeaux G, Douillet R, Redonnet M, et al: Detection of acute rejection of heart transplantation by Doppler color imaging. Arch Mal Coeur Vaiss 1998;91:1255–1262. 76. Mankad S, Murali S, Kormos RL, et al: Evaluation of the potential role of color-coded tissue Doppler echocardiography in the detection of allograft rejection in heart transplant recipients. Am Heart J 1999;138:721–730. 77. Dandel M, Hummel M, Muller J, et al: Reliability of tissue Doppler wall motion monitoring after heart transplantation for replacement of invasive routine screenings by optimally timed cardiac biopsies and catheterizations. Circulation 2001;104:I184–I191. 78. Stengel SM, Allemann Y, Zimmerli M, et al: Doppler tissue imaging for assessing left ventricular diastolic dysfunction in heart transplant rejection. Heart 2001;86:432–437. 79. Sun JP, Abdalla IA, Asher CR, et al: Non-invasive evaluation of orthotopic heart transplant rejection by echocardiography. J Heart Lung Transplant 2005;24:160–165.

80. Palka P, Lange A, Galbraith A, et al: The role of left and right ventricular early diastolic Doppler tissue echocardiographic indices in the evaluation of acute rejection in orthotopic heart transplant. J Am Soc Echocardiogr 2005;18:107–115. 81. Franciosa JA, Park M, Levine TB: Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 1981;47:33–39. 82. Ikram H, Williamson HG, Won M, et al: The course of idiopathic dilated cardiomyopathy in New Zealand. Br Heart J 1987;57:521–527. 83. Franciosa JA, Wilen M, Ziesche S, et al: Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1983;51:831–836. 84. Griﬃn BP, Shah PK, Ferguson J, et al: Incremental prognostic value of exercise hemodynamic variables in chronic congestive heart failure secondary to coronary artery disease or to dilated cardiomyopathy. Am J Cardiol 1991;67:848–853. 85. Saxon LA, Stevenson WG, Middlekauﬀ HR, et al: Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1993;72:62–65. 86. Fuster V, Gersh BJ, Giuliani ER, et al: The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981;47:525–531. 87. Kuhn H, Becker R, Fischer J, et al: The etiology, course and prognosis of dilated cardiomyopathy. Z Kardiol 1982;71:497–508. 88. Romeo F, Pelliccia F, Cianfrocca C, et al: Determinants of end-stage idiopathic dilated cardiomyopathy: A multivariate analysis of 104 patients. Clin Cardiol 1989;12:387–392. 89. Xie GY, Berk MR, Smith MD, et al: Prognostic value of Doppler transmitral ﬂow patterns in patients with congestive heart failure. J Am Coll Cardiol 1994;24:132–139. 90. Pinamonti B, Di Lenarda A, Sinagra G, et al: Restrictive left ventricular ﬁlling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: Clinical, echocardiographic and hemodynamic correlations and prognostic implications. Heart Muscle Disease Study Group. J Am Coll Cardiol 1993;22:808–815. 91. Vanoverschelde JL, Raphael DA, Robert AR, et al: Left ventricular ﬁlling in dilated cardiomyopathy: Relation to functional class and hemodynamics. J Am Coll Cardiol 1990;15:1288–1295. 92. Werner GS, Schaefer C, Dirks R, et al: Prognostic value of Doppler echocardiographic assessment of left ventricular ﬁlling in idiopathic dilated cardiomyopathy. Am J Cardiol 1994;73:792–798. 93. St Goar FG, Masuyama T, Alderman EL, et al: Left ventricular diastolic dysfunction in end-stage dilated cardiomyopathy: Simultaneous Doppler echocardiography and hemodynamic evaluation. J Am Soc Echocardiogr 1991;4:349–360. 94. Shen WF, Tribouilloy C, Rey JL, et al: Prognostic signiﬁcance of Dopplerderived left ventricular diastolic ﬁlling variables in dilated cardiomyopathy. Am Heart J 1992;124:1524–1533. 95. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 96. Takenaka K, Dabestani A, Gardin JM, et al: Pulsed Doppler echocardiographic study of left ventricular ﬁlling in dilated cardiomyopathy. Am J Cardiol 1986;58:143–147. 97. Whalley GA, Doughty RN, Gamble GD, et al: Pseudonormal mitral ﬁlling pattern predicts hospital re-admission in patients with congestive heart failure. J Am Coll Cardiol 2002;39:1787–1795. 98. Dini FL, Michelassi C, Micheli G, et al: Prognostic value of pulmonary venous ﬂow Doppler signal in left ventricular dysfunction: Contribution of the diﬀerence in duration of pulmonary venous and mitral ﬂow at atrial contraction. J Am Coll Cardiol 2000;36:1295–1302. 99. Rossvoll O, Hatle LK: Pulmonary venous ﬂow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993;21:1687–1696. 100. Packer M: Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure. Circulation 1990;81:III78– III86. 101. Franciosa JA, Leddy CL, Wilen M, et al: Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure. Am J Cardiol 1984;53:127–134. 102. Triposkiadis F, Trikas A, Pitsavos C, et al: Relation of exercise capacity in dilated cardiomyopathy to left atrial size and systolic function. Am J Cardiol 1992;70:825–827. 103. Xie GY, Berk MR, Smith MD, et al: Relation of Doppler transmitral ﬂow patterns to functional status in congestive heart failure. Am Heart J 1996;131:766–771.

Chapter 20 • Dilated Cardiomyopathy and Cardiac Transplantation 104. Hansen A, Haass M, Zugck C, et al: Prognostic value of Doppler echocardiographic mitral inﬂow patterns: Implications for risk stratiﬁcation in patients with chronic congestive heart failure. J Am Coll Cardiol 2001;37:1049–1055. 105. Witte KK, Nikitin NP, De Silva R, et al: Exercise capacity and cardiac function assessed by tissue Doppler imaging in chronic heart failure. Heart 2004;90:1144–1150. 106. Meluzin J, Spinarova L, Dusek L, et al: Prognostic importance of the right ventricular function assessed by Doppler tissue imaging. Eur J Echocardiogr 2003;4:262–271. 107. Ghio S, Recusani F, Klersy C, et al: Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000;85:837–842. 108. Ghio S, Gavazzi A, Campana C, et al: Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183–188. 109. de Groote P, Millaire A, Foucher-Hossein C, et al: Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948–954. 110. Yu CM, Sanderson JE, Chan S, et al: Right ventricular diastolic dysfunction in heart failure. Circulation 1996;93:1509–1514. 111. Meluzin J, Spinarova L, Bakala J, et al: Pulsed Doppler tissue imaging of the velocity of tricuspid annular systolic motion; a new, rapid, and non-invasive method of evaluating right ventricular systolic function. Eur Heart J 2001;22:340–348. 112. Kukulski T, Hubbert L, Arnold M, et al: Normal regional right ventricular function and its change with age: A Doppler myocardial imaging study. J Am Soc Echocardiogr 2000;13:194–204. 113. Nageh MF, Kopelen HA, Zoghbi WA, et al: Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol 1999;84:1448–1451, A8. 114. Yu HC, Sanderson JE: Diﬀerent prognostic signiﬁcance of right and left ventricular diastolic dysfunction in heart failure. Clin Cardiol 1999;22: 504–512.

115. Meluzin J, Spinarova L, Hude P, et al: Combined right ventricular systolic and diastolic dysfunction represents a strong determinant of poor prognosis in patients with symptomatic heart failure. Int J Cardiol 2005;105: 164–173. 116. Weber KT: Aldosterone in congestive heart failure. N Engl J Med 2001;345:1689–1697. 117. Eichhorn EJ, Bedotto JB, Malloy CR, et al: Eﬀect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure. Improvements in hemodynamic, contractile, and diastolic performance with bucindolol. Circulation 1990;82:473–483. 118. Capomolla S, Febo O, Gnemmi M, et al: Beta-blockade therapy in chronic heart failure: Diastolic function and mitral regurgitation improvement by carvedilol. Am Heart J 2000;139:596–608. 119. Andersson B, Caidahl K, di Lenarda A, et al: Changes in early and late diastolic ﬁlling patterns induced by long-term adrenergic beta-blockade in patients with idiopathic dilated cardiomyopathy. Circulation 1996;94:673–682. 120. Kim MH, Devlin WH, Das SK, et al: Eﬀects of beta-adrenergic blocking therapy on left ventricular diastolic relaxation properties in patients with dilated cardiomyopathy. Circulation 1999;100:729–735. 121. Hall SA, Cigarroa CG, Marcoux L, et al: Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 1995;25:1154–1161. 122. Lowes BD, Gill EA, Abraham WT, et al: Eﬀects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure. Am J Cardiol 1999;83:1201–1205. 123. Atherton JJ, Moore TD, Thomson HL, et al: Restrictive left ventricular ﬁlling patterns are predictive of diastolic ventricular interaction in chronic heart failure. J Am Coll Cardiol 1998;31:413–418. 124. Burgess MI, Bhattacharyya A, Ray SG: Echocardiography after cardiac transplantation. J Am Soc Echocardiogr 2002;15:917–925. 125. Starling RC, Pham M, Valantine H, et al: Molecular testing in the management of cardiac transplant recipients: Initial clinical experience. J Heart Lung Transplant 2006;25:1389–1395.

257

CRAIG R. ASHER, MD ALLAN L. KLEIN, MD

21

Primary Restrictive, Infiltrative, and Storage Cardiomyopathies INTRODUCTION PATHOPHYSIOLOGY CLINICAL RELEVANCE Primary Restrictive Cardiomyopathies Infiltrative Cardiomyopathies Storage Cardiomyopathies FUTURE RESEARCH

“A classiﬁcation serves to bridge the gap between ignorance and knowledge.” J. F. Goodwin1

INTRODUCTION Historically, restrictive cardiomyopathies were among the three primary forms of idiopathic heart muscle disease characterized by the World Health Organization as “restrictive ﬁlling and reduced diastolic volume of either or both ventricles with normal or nearnormal systolic function.”2,3 This early grouping of cardiomyopathies highlighted the readily evident morphological and functional features of these disorders, which were largely of unknown cause. With advances in diagnostic testing (biochemistry, genetics, immunology, and pathology) and cardiac imaging techniques (echocardiography, computed tomography [CT], magnetic resonance imaging [MRI]), the etiology of many cardiomyopathies can now be identiﬁed. The most recent classiﬁcation proposal of the American Heart Association (AHA) deﬁnes primary (involving predominantly the heart) and secondary (related to systemic disorders) cardiomyopathies.4 Using this new classiﬁcation, except for primary restrictive cardiomyopathy, the entity of “restrictive

cardiomyopathy” no longer exists, and most inﬁltrative and storage disorders are considered speciﬁc secondary cardiomyopathies (i.e., amyloid cardiomyopathy). From the point of view of the clinician, however they are compiled, these are disorders in which diastolic dysfunction is at least initially the predominant pathophysiological derangement. They are rare diseases, generally with a poor prognosis and often presenting with advanced right- or left-sided heart failure. Much of the data regarding these diseases are based on observational retrospective studies from tertiary centers with little prospective and randomized information. Although a cardiologist will often initiate testing, a multidisciplinary team of geneticists, pathologists, radiologists, hematologists, and oncologists is often required to reﬁne the diagnosis and determine management strategies. Since inﬁltrative and storage cardiomyopathies occur as part of a multisystem disorder, treatments with chemotherapeutic agents, stem cells, and enzyme replacement are increasingly becoming options. This chapter will review primary restrictive cardiomyopathy and the most prevalent forms of inﬁltrative and storage disorders encountered among patients surviving into adulthood. A practical approach to diagnosis, diﬀerentiation, and exclusion of other, more common disorders with similar pathophysiology and structural appearance will be presented along with current treatment options.

PATHOPHYSIOLOGY Most primary restrictive cardiomyopathies are characterized by at most mild degrees of increased wall thickness on gross inspection.5–7 Cardiac biopsy will distinguish whether at the cellular level there is myocyte hypertrophy (increased myocte diameter and nuclear area), endocardial and interstitial ﬁbrosis (increased collagen to muscle ratio), or both (Fig. 21-1).8,9 Exclusion of ﬁber disarray, inﬂammation, eosinophilia, lymphocytes, amyloid or iron deposits, and pericardial disease via light and electron micros259

260

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies

Figure 21-1 Idiopathic restrictive cardiomyopathy in a 63-year-old woman. Left panel: Gross specimen, shown in four-chamber format, demonstrating prominent biatrial enlargement with normal-sized ventricles. Right panel: Light microscopy showing marked interstitial fibrosis (light pink areas) (hematoxylin and eosin; magnification ×120). (From Ammash NM et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496.)

copy is required to distinguish primary restrictive diseases. Absence of an endocardial ﬁbrotic shell with extension into the myocardium excludes endomyocardial disease. Structural characteristics of primary restrictive cardiomyopathies include (a) biatrial enlargement, (b) nondilated or reduced left ventricular (LV) cavity size, and (c) normal or mild wall thickness.10 The pathogenesis of diastolic impairment may be secondary to myocyte abnormalities, including abnormal calcium handling, accumulation of desmin (a cytoskeletal component), myocyte hypertrophy, and extracellular matrix interstitial ﬁbrosis with proliferation of collagen ﬁbers and elastic elements.11–13 A marked increase in stiﬀness of the myocardium or endocardium causes the ventricular pressure to rise dramatically with only small changes in volume, causing an upward shift of the LV pressurevolume relationship and a “dip and plateau” or “square root” hemodynamic pattern.14 Both ventricles are aﬀected by the process, but usually the pressures are higher on the left than the right, which may reﬂect the relatively decreased compliance of the left ventricle compared with the right ventricle. Secondary inﬁltrative and storage cardiomyopathies result from the presence of myocardial cellular or extracellular substances that impair diastolic function. In inﬁltrative diseases, there is localization to the interstitium (between myocardial cells), as with cardiac amyloidosis; whereas in storage disorders, the deposits are within cells, as with hemochromatosis and Fabry’s disease.15 The inﬁltrative and storage cardiomyopathies may have heterogeneous morphological and hemodynamic ﬁndings, depending on the speciﬁc underlying process and the stage of disease, which often involves LV dysfunction, increased wall thickness, and nonrestrictive diastolic ﬁlling patterns.

CLINICAL RELEVANCE Primary Restrictive Cardiomyopathies Case 1 A 23-year-old woman presents to her family physician complaining of fatigue, exercise intolerance, muscle aches, and dyspnea

with exertion. No other past medical history (PMH) is present. Family history is signiﬁcant for an aunt with hypertrophic cardiomyopathy (HCM). On examination, she is found to be tachycardic. The cardiac exam is notable for an elevated jugular venous pressure of 10 cm H2O, an S3 gallop, and 1+ lower extremity pitting edema. An electrocardiogram (ECG) shows ﬁrst-degree atrioventricular (AV) block with a P-R interval of 240 msec. A chest x-ray (CXR) shows mild pulmonary congestion. Brain natriuretic peptide (BNP) level is 750 pg/ml, and the creatine phosphokinase (CPK) level is 280 units/L. An echocardiogram shows normal LV and RV size and function, with moderately dilated atria, stage 3 diastolic dysfunction (restrictive ﬁlling pattern), E/E′ of 15, and a delayed color M-mode slope of 35 cm/ sec. Cardiac MRI shows normal pericardial thickness and reduced tissue signal intensity. Subsequent cardiac catheterization is notable for pressures (mmHg) as follows: right atrial, 15; right ventricular end diastolic, 17; left ventricular end diastolic, 24; pulmonary artery systolic pressure, 55; pulmonary capillary wedge pressure, 25; and cardiac index, 2.3 L/min/m2. Cardiac biopsy conﬁrms idiopathic restrictive cardiomyopathy and excludes speciﬁc inﬁltrative and storage diseases. Diagnosis Primary (or idiopathic) restrictive cardiomyopathy is a rare disorder of advanced diastolic impairment, often leading to biventricular diastolic heart failure and sudden cardiac death. It was ﬁrst described by Benotti et al. in nine patients with heart failure, elevated RV and LV ﬁlling pressures, normal systolic function, and dip-and-plateau hemodynamic tracing.16 In children, the disease is more common in females, and the prognosis is worse compared with adults.17,18 Familial autosomal dominant transmission and the association with skeletal myopathies (predominantly distal) and heart block have been reported in several generations of families.8,19,20 Other associations include family members with HCM and Noonan’s syndrome.21 Genetic linkage analysis studies have shown mutations in cardiac troponin-I (TNNI3) and defects in genes coding for myocyte desmin accumulation in patients with restrictive cardiomyopathy.22 The clinical signs and symptoms of primary restrictive cardiac disease relate closely to the degree of left atrial (LA) hypertension required to compensate for reduced ventricular ﬁlling.5,23 Initially, there is exercise intolerance and fatigue, progressing to dyspnea with minimal eﬀort. Exertional chest pain is usually absent. Atrial ﬁbrillation is common due to the atrial enlargement. Ventricular arrhythmias or heart block are commonly present in advanced cases and are often the causes of death. Symptoms of proximal or distal myopathy may be present. Cardiac examination may reveal pulmonary congestion, jugular venous distention with a prominent X and Y descent, an S3 depending on the ﬁlling characteristics, hepatomegaly, ascites, peripheral edema, and anasarca in advanced cases.5,10 Kussmaul’s sign can be detected, while apical retraction (as in constrictive pericarditis) is not seen. Laboratory testing may provide supportive information. BNP levels are elevated proportional to the level of ﬁlling pressures and stage of diastolic dysfunction. Elevated BNP levels also may aid in excluding constrictive physiology.24 CPK levels may be elevated with concomitant myopathy. No data are available on troponin levels in patients with idiopathic restrictive cardiomyopathy. Echocardiography is often the ﬁrst-line test and may be virtually diagnostic.25,26 Atrial enlargement with nondilated ventricles with near normal systolic function is uniformly present on echo-

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies cardiography. Mild LV dysfunction may develop among patients with advanced disease requiring transplantation. Generally, if hypertrophy is present, it is mild. The pathophysiological ﬁndings of advanced diastolic dysfunction are evident with a comprehensive echocardiographic Doppler study (elevated ﬁlling pressures ± restrictive physiology). Restrictive physiology may not be present, depending on the stage of disease and loading conditions, but abnormal diastolic function should be evident by evaluation of mitral and tricuspid inﬂow patterns, pulmonary and hepatic venous ﬂows, and isovolumic relaxation time (IVRT).27,28 Tissue Doppler echocardiography (TDE) E and A annular velocities are low, with mitral E/E annular ratios elevated consistent with high ﬁlling pressures.29 Concomitantly, the color M-mode propagation slope is slow.29 TDE and color M-mode, along with pulsed Doppler ﬂow patterns with a respirometer, can help distinguish restrictive from constrictive physiology. MRI and CT may be useful to exclude increased pericardial thickness, septal bounce, or conical compression.30,31 Cine MRI may show abnormal ﬁlling patterns in early and advanced stages of restrictive cardiomyopathy similar to echocardiography. MRI is capable of distinguishing tissue characteristics and shows a diﬀuse reduction in signal intensity due to ﬁbrosis in idiopathic restrictive cardiomyopathy, with more speciﬁc patterns in other inﬁltrative processes like amyloidosis or hemochromatosis.31 Cardiac catheterization is often used as a conﬁrmatory test. Using strict criteria, either right- or left-sided ﬁlling pressures are elevated, with a typical dip-and-plateau RV and LV ﬁlling pattern and an “M”- or “W”-shaped venous ﬁlling pattern with prominent X and Y descents.6 LV diastolic pressures are greater than 5 mmHg more than RV ﬁlling pressures. Cardiac index is reduced, and pulmonary artery pressure is greater than 50 mmHg in most patients with a ratio of RV systolic to diastolic pressure greater than 1/3. Often RV endomyocardial biopsy is done at the same time as hemodynamic assessment and importantly excludes other speciﬁc etiologies.7,32

Texas Children’s Hospital found that predictors of sudden death included female sex, chest pain, syncope, and ischemia on Holter monitor. The annual mortality rate was 7%, with sudden death occurring in 28% of patients.34 Predictors of poor outcome in the pediatric population include age, female sex, ischemic manifestations, decreased cardiac index, pulmonary venous congestion, and elevated pulmonary vascular resistance.8,18,35,36 Beta blockers are the primary therapy to reduce the risk of sudden death. Additional medical therapy includes diuretics for symptomatic relief and consideration of antiplatelet agents or anticoagulation, due to the high risk of atrial ﬁbrillation and embolism reported in some series.33 Vasodilators should be used cautiously unless LV dysfunction is present, since they may cause hypotension. Pacemakers are often required for heart block. Implantable cardioverter-defrillators are recommended for any patients with ischemic manifestations, along with listing for transplantation.34 Transplantation can substantially improve survival and is usually required within 4 years of diagnosis, optimally before pulmonary vascular resistance is irreversibly high.37 Heartlung transplantation is an option for some children.37 When concomitant skeletal myopathy is present, the beneﬁts of transplantation may be partial. Idiopathic restrictive cardiomyopathy may also be diagnosed in adults after exclusion of secondary causes of restrictive physiology (Fig. 21-2). A large series of 94 patients (mean age, 64 years) was identiﬁed from 1979 to 1996 at the Mayo Clinic, with typical structural and hemodynamic features of restrictive cardiomyopathy.38 At follow-up of 68 months, 50% of patients had died, primarily from cardiac causes, and 4 required heart transplantation. Using multivariate analysis, predictors of death included male sex, LA dimension greater than 60 mm, age older than 70 years, and advanced New York Heart Association class (Fig. 21-3).

Management The prognosis of idiopathic restrictive cardiomyopathy depends most on the age of the patient and presenting hemodynamic factors. Although variable, the course is usually progressive and generally poor among the pediatric population, with survival rates of less than 50% over 2 years.17,33 A serial study of 18 children (9 male; mean age, 4.3 years) evaluated over a course of 31 years at

Using the most recent AHA classiﬁcation, cardiac amyloidosis is the most important inﬁltrative cardiomyopathy in adults. Sarcoidosis has been recategorized as a secondary inﬂammatory disorder.4 The exceedingly rare inﬁltrative disorders—Gaucher’s, Hurler’s, and Hunter’s diseases—are familial defects in metabolism that involve multiple systems, including the heart, and will not be discussed in this chapter.

Infiltrative Cardiomyopathies

Diastolic dysfunction Restrictive physiology

Primary restrictive (Predominant cardiac involvement)

Figure 21-2 Algorithm with differential diagnosis of restrictive physiology determined either by cardiac catheterization or echocardiogram. TR, tricuspid regurgitation; RV, right ventricular; MR, mitral regurgitation.

Secondary restrictive

End stage other primary cardiomyopathy (Predominant cardiac involvement)

End stage other secondary cardiomyopathy (Systemic involvement)

“Restrictive-like diastolic filling” (catheterization/echocardiogram)

• Severe TR (right side) • RV dysfunction (right side) • Severe MR • Constriction • Atrial fibrillation

261

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 100

100 79%

60

45% Women

44%

40 20

p = 0.033 0

1

2

3

4

A

5

6

7

8

9

60

I

40

II

20

27% Men

0

p = 0.007

80 Survival

Survival

80

III IV

0

10

0

1

2

3

4

B

Years

5

6

7

8

9

10

Years

100

100 78% 47% No

51%

60 40 20

80 Survival

80 Survival

262

29% Yes

p = 0.026

69%

60

20

0

42% No

33%

40

11% Yes

p = 0.027

0 0

C

1

2

3

4

5

6

7

8

9

10

Years

0

D

1

2

3

4

5

6

7

8

9

10

Years

Figure 21-3 Kaplan-Meier survival curves in relation to A, sex; B, New York Heart Association functional class (I or II); C, pulmonary venous congestion; and D, left atrial dimension >60 mm. (From Ammash NM et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496.)

Cardiac Amyloidosis Case 2 A 44-year-old man presents to a cardiologist for a second opinion regarding amyloid cardiomyopathy. He complains of dyspnea with exertion, orthopnea, orthostasis, abdominal distention, and lower extremity swelling and numbness. No other PMH is present. The man is African American. Family history is signiﬁcant for his father and brother, who died in their forties with cardiomyopathy. On examination, he appears cachectic and has a supine blood pressure of 96/64 and upright 80/68 mmHg. The cardiac exam is notable for jugular venous distention to the jaw. There is S3 gallop, reduced intensity heart sounds and a moderate apical regurgitant murmur. There is ascites and 3+ lower extremity pitting edema. An ECG shows low voltage in the limb leads and an intraventricular conduction delay. CXR shows a globular heart silhouette and mild pulmonary congestion. BNP level is 4000 pg/ml. An echocardiogram shows severe biventricular increased wall thickness with moderately impaired systolic function. The atria are dilated and the pulmonary artery pressure is 60 mmHg. There is moderate mitral regurgitation. There is stage 2 diastolic dysfunction (pseudonormal ﬁlling pattern), E/E′ of 18, with a delayed color M-mode slope of 40 cm/sec. There is a moderate-sized pericardial eﬀusion. Serum and urine electrophoresis with immunoﬁxation and bone marrow biopsy shows no evidence of abnormal immunoglobulin. A laboratory analysis shows a mutation in transthyretin (TTR) protein, conﬁrming the diagnosis of familial TTR amyloidosis. Etiology and Classification Cardiac amyloidosis is the prototype of inﬁltrative cardiomyopathies and the most frequently encountered in clinical practice.39–41 There are several types of cardiac amyloidoses, each with its own clinical presentations, treatment strategies, and prognosis (Table 21-1).39 Amyloidosis is a multisystem disease in which

linear, nonbranching, aggregated protein ﬁbrils with a cross-β pleated conﬁguration are deposited in various organs of the body, including the heart.42 Within the heart, the amyloid particles can inﬁltrate the myocardium (atria and ventricles), valves, pericardium, conduction system, and coronary arteries.41 The ﬁbrils deposit between cells (interstitial), with a replacement of the normal tissue structures. When stained with Congo red, this material shows apple-green birefringence under a polarizing microscope. Alcian blue can also be used to diagnose amyloid.39,43 Amyloidosis can be classiﬁed by the type of protein deposited. The primary type is the most common form, occurring in 85% of patients with ﬁbrils composed of kappa or lambda immunoglobulin light chains (AL type for amyloid light chain), often associated with a plasma cell dyscrasia such as multiple myeloma.39,43 There may be extracellular deposition of amyloid protein in the kidney, heart, liver, nerves, skin, and tongue, resulting in tissue damage and organ malfunction.42 The most common manifestations include nephrotic syndrome or renal failure, congestive heart failure, sensorimotor peripheral neuropathy, and orthostatic hypotension. Nearly half of patients have cardiac involvement, including congestive heart failure; however, the heart is involved in most all patients by pathological examination.43 Death from cardiac involvement secondary to congestive heart failure or arrhythmia occurs in greater than 50% of patients with systemic amyloidosis.44,45 Familial amyloidosis results from the production of a mutant pre-albumin protein (i.e., TTR), and there are diﬀerent types, which present with cardiomyopathy, neuropathy, or nephropathy.46 TTR is made up of 125 pairs of amino acids, and more than 100 mutations have been recognized.47 This type of amyloidosis is important to recognize because liver transplantation may be lifesaving, though optimally it should be performed before cardiac involvement has occurred. Laboratory testing should be performed to test for TTR if a family history is present or there is

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies TABLE 21-1 MAJOR FORMS OF AMYLOIDOSIS CARDIAC INVOLVEMENT

OTHER ORGAN INVOLVEMENT

ASSOCIATED DISORDERS

TREATMENT

Immunoglobulin light chain (λ, κ)

Common

Plasma cell dyscrasias (e.g., multiple myelomas)

Chemotherapy; cardiac transplant if isolated cardiac

AA (secondary)

Nonimmunoglobulin, serum protein A

Rare

Liver, kidney, nervous system, gastrointestinal tract, skin Kidney

Underlying disease

ATTR (familial)

Nonimmunoglobulin, transthyretin Nonimmunoglobulin, transthyretin

Common

Nervous system

Inflammatory diseases (e.g., rheumatoid arthritis, familial Mediterranean fever, tuberculosis) None

Common

None

Congestive heart failure

Nonimmunoglobulin, atrial natriuretic peptide

Common

None

Atrial fibrillation

TYPE

PROTEIN

AL (primary)

SSA (senile)

AANP (atrial)

Liver transplant if no cardiac involvement Supportive treatment for congestive heart failure Supportive treatment for atrial fibrillation

Modified from Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.

no evidence of AL type amyloid on biopsy. In familial amyloidosis, cardiac involvement occurs in 28% of patients at the time of diagnosis; however, it usually presents later in the course of the disease and is less ominous prognostically compared with AL (primary) amyloidosis.46 Peripheral neuropathy may be the presenting feature, but cardiac manifestations may subsequently predominate.48 The disease was reported over 30 years ago in a Danish family but has also been described in several other families of diﬀerent ethnic origin and has an autosomal dominant expression.49,50 Cardiac failure or cardiac arrhythmia is responsible for the deaths in over 50% of patients.46 Familial amyloidosis has been reported in African Americans as a cause of heart failure secondary to a mutation in TTR isoleucine-122 (substitution for valine).51 This mutation has been found in nearly 4% of African Americans in the United States and in approximately one-quarter of elderly patients with cardiac amyloidosis. Senile systemic amyloidosis (SSA) occurs in elderly men from the production of a wild-type TTR and has been associated with congestive heart failure without signiﬁcant noncardiac involvement.52,53 Survival is reasonably good relative to AL amyloid or other etiologies of congestive heart failure.52,54 There may be extensive deposits in the heart producing congestive heart failure, or there may be minor deposits in the atria with no symptoms. The prevalence of senile amyloid at autopsy appears to be highest in African Americans. It is important to diﬀerentiate senile cardiac amyloidosis from immunoglobulin-derived amyloidosis (AL type) and familial amyloidosis because the treatment regimens diﬀer. The favorable prognosis of SSA relative to AL is concordant with the accumulating evidence that light chains are responsible for toxicity and poor outcome in AL amyloidosis.55 Secondary amyloidosis (AA type) is rare, with the ﬁbrils consisting of protein A, a nonimmunoglobulin acute phase reactant resulting from a multitude of chronic inﬂammatory conditions (e.g., tuberculosis, familial Mediterranean fever, rheumatoid arthritis, inﬂammatory bowel disease).56 Cardiac involvement is unusual in secondary amyloidosis, with renal manifestations being predominant.57 Isolated atrial amyloidosis is often found limited to the atria at autopsy in the elderly and derives from atrial

natriuretic peptide.58 It is more common in females and seems to be associated with the presence of atrial ﬁbrillation.59,60 Clinical Presentation Cardiac amyloidosis may present with a spectrum of disease severity. In the nonfamilial forms, it generally aﬀects males over age 30.44,61 In early cardiac amyloidosis, patients may be asymptomatic, while those with advanced disease will have the typical evidence of restrictive cardiomyopathy with severe right-heart failure, ascites, and peripheral edema.62,63 Left-heart failure is a less common manifestation. Additional symptoms include chest pain, presyncope/syncope, and sudden cardiac death. Chest pain resembling angina pectoris may be present despite normal epicardial coronary arteries due to partial obliteration of the distal coronary arteries by amyloid inﬁltration or intramyocardial vessels.64,65 Orthostatic hypotension occurs in 10%–15% of patients secondary to amyloid inﬁltration of the autonomic nervous system, with symptoms of syncope, diarrhea, lack of sweating, and impotence.42,66 Renal involvement with nephrotic syndrome and adrenal disease may aggravate postural hypotension. Syncope may be due to postural hypotension or supraventricular or ventricular arrhythmias. Other symptoms may be attributable to peripheral neuropathy, macroglossia, or carpal tunnel syndrome.39,67 Physical examination may reveal signs of cardiac cachexia in advanced disease. Low cardiac output may cause decreased blood pressure, and orthostatic hypotension may still occur. Macroglossia, periorbital edema, petechia, and bruising may be evident on general examination.39 The cardiac exam may reveal an S4 (very early disease) or S3 (advanced disease) on auscultation from either the right or the left heart.68 Mitral and tricuspid valvular regurgitation may also be present, though usually not severe. There is often evidence of biventricular heart failure with predominant right-heart failure.63 The jugular venous pulse will be elevated with a prominent X and Y descent, and hepatomegaly, ascites, and peripheral edema will be present, especially in the advanced disease.39 Neurological examination may reveal ﬁndings consistent with peripheral neuropathy.

263

264

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies The cardiac silhouette on CXR is usually enlarged in patients with advanced disease with evidence of pulmonary congestion or pericardial eﬀusion.69 The electrocardiogram typically has low voltage in the limb leads and shows a pseudoinfarction pattern with Q waves simulating a myocardial infarction in the precordial leads (∼50% of patients).70,71 More speciﬁcally, patients with cardiac amyloidosis have a low ratio of electrocardiographic voltage to LV wall thickness.72 However, the usefulness of this ratio is limited by the presence of coexisting diseases that may result in reduced voltage. Arrhythmias, especially atrial ﬁbrillation, are common, and sick-sinus syndrome may be present.39 AV conduction defects may be present, especially in familial amyloidosis associated with myopathy, though right and left bundle branch block is uncommon.73 Ventricular arrhythmias are not as common as expected and are not often the cause of sudden cardiac death in nonfamilial forms.74 Echocardiography Two-dimensional and Doppler echocardiography are the procedures of choice for diagnosis, serial follow-up, and prognostic determination of patients with cardiac amyloidosis,75–82 which gives a distinctive appearance on two-dimensional echocardiography and is associated with abnormal LV and RV diastolic function. The ﬁndings of a normal or small LV cavity size with markedly thickened myocardium associated with a highly abnormal texture often described as “granular sparkling” in appearance is the classical presentation (Fig. 21-4). Other disorders that cause increased LV wall thickness must be considered (Fig. 21-5). The sparkling appearance is thought to be due to the acoustic mismatch between the highly reﬂective amyloid deposits in the endocardium, myocardium, and pericardium and the normal tissue.83,84 Moreover, autopsy and clinical biopsy series have demonstrated the presence of amyloid ﬁbrils in the myocar-

dium at the site of the sparkling echoes. However, the speciﬁcity of this ﬁnding is reduced with improved echocardiographic imaging techniques, including harmonic imaging. Global LV systolic function is usually preserved in early disease, whereas systolic function is usually impaired in advanced disease. The interatrial septum and valve leaﬂets are thickened. Both atria are enlarged, and small to moderate pericardial eﬀusions are usually present.80,82

Figure 21-4 Apical four-chamber view of patient with cardiac amyloidosis demonstrating severe increased wall thickness of the left and right ventricles, dilated atria, and a pericardial effusion. The myocardium has a “granular sparkling” appearance caused by hyperrefractile amyloid particles intermixed with normal myocardium.

↑ LV wall thickness

Hypertrophy

Primary

• Hypertrophic CM • LV noncompaction

Cardiomyopathy

Secondary

Physiological

Athlete’s heart

Myocardial

Pathological

• HTN • ESRD

Valvular

• AS • AR

Endomyocardial

Secondary

• EMF/Loffler’s • Carcinoid • Radiation

Storage

Inflammatory

Infiltrative

• Fabry’s • Hemochromatosis • Glycogen storage

Sarcoidosis

Amyloidosis

Primary

Idiopathic restrictive

Figure 21-5 Algorithm with differential diagnosis of increased left ventricular (LV) wall thickness. CM, cardiomyopathy; HTN, hypertension; ESRD, end-stage renal disease; AS, aortic stenosis; AR, aortic regurgitation; EMF, endomyocardial fibrosis.

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Cardiac amyloidosis has traditionally been considered to require a restrictive pattern of ventricular ﬁlling. However, a spectrum of LV ﬁlling abnormalities using pulsed-wave Doppler echocardiography is detected in patients with cardiac amyloidosis.68,77,85 In a study of 53 patients with the classic echocardiographic features of cardiac amyloidosis, those with advanced disease demonstrated a mean LV wall thickness greater than 15 mm and a “restrictive” physiology pattern of LV ﬁlling.68 Furthermore, in serial studies of individual patients, the “impaired relaxation” pattern gradually evolved into a “restrictive” pattern through a “pseudonormal,” or intermediate, phase in the progression of the disease.77 The mechanism for this serial change in LV ﬁlling pattern is thought to be the gradual decrease in the compliance of the left ventricle with progressive deposition of amyloid ﬁbrils in the myocardium, leading to loss of myocardial cells from pressure necrosis.86 When the duration of the pulmonary venous atrial reversal wave is longer than the mitral A-wave duration, ﬁlling pressures are elevated and the disease is advanced with restrictive physiology.87 Eventually the pulmonary atrial reversal wave may be lost due to atrial involvement of amyloid inﬁltration. RV diastolic impairment also may occur in patients with cardiac amyloidosis.76 The RV ﬁlling pattern is often similar to that of the left ventricle or may be less advanced. In early cases, there is an RV free wall thickness of less than 7 mm and abnormal relaxation. In advanced cases, the RV wall is greater than 7 mm in thickness, with restrictive physiology present. The systolic forward ﬂows by Doppler echocardiography in the superior vena cava and hepatic vein are also decreased with advanced disease, and the diastolic ﬂow is increased compatible with restrictive physiology. Newer diagnostic techniques, including TDE, strain and strain rate, and two-dimensional strain imaging, have been utilized to characterize early systolic dysfunction in patients with cardiac amyloidosis before the onset of congestive symptoms or reduced LV ejection fraction.88,89 Using these methods, it has been shown that there are diﬀerences between the longitudinal basal peak systolic strain rate and strain among amyloid patients with no cardiac involvement, cardiac involvement and no symptoms, and cardiac involvement with symptoms (Figs. 21-6 and 21-7).89 This ﬁnding allows for detection of patients with early amyloid heart disease to be targeted for therapy. Other Diagnostic Tools Cardiac amyloidosis can be diagnosed noninvasively antemortem in most cases from the typical features obtained from the history, examination, ECG, and echocardiogram. However, conﬁrmatory testing is needed before treatment is initiated, and further classiﬁcation of the subtype of amyloid is necessary. Serum and urine protein immunoﬁxation and electrophoresis are recommended to assess for the secretion of a monoclonal protein associated with a plasma cell dyscrasia.39,43,44,66,90 Although some patients with AL amyloid will have multiple myeloma, a greater proportion may have unassociated monoclonal gammopathies of uncertain signiﬁcance. In 10% of cases, there is no monoclonal protein secreted (nonsecretory primary amyloidosis). Laboratory testing of antisera against TTR, the kappa and lambda light chains, and protein A in biopsy or blood samples can be performed. A serum free–light chain assay is available to assess the ratio of kappa-to-lambda free light chains and may be more sensitive than immunoﬁxation.43,91 A positive serum immunoﬁxation plus an abnormal kappa/lambda ratio are highly sensitive to diagnose AL amyloidosis.90

Noncardiac sites of biopsy can include the bone marrow, fat pad, rectum, gingiva, kidney, and liver, though fat aspirate may detect amyloidosis in most patients (>70%).44,92,93 If the echocardiogram is not diagnostic or the fat pad aspirate is negative and cardiac amyloidosis is still suspected, an endomyocardial biopsy can be performed to make the diagnosis. A conﬁrmatory cardiac biopsy may be particularly important if there are other confounding causes of increased LV mass, such as LV hypertrophy (LVH) or HCM. The presence of low electrocardiographic voltage favors a diagnosis of amyloidosis rather than hypertensive or

Figure 21-6 Color-coded map of myocardial long-axis strain recorded from the ventricular septum. Top left image is from the apical four-chamber view, with a bar representing a key to the color-coding. The numbers on the ventricular septum correspond to the numbers on the map; the apical septal strain is represented on the top part of the map, and the base is represented on the bottom. A, Recording from a normal subject. Immediately after the onset of systole (arrow indicates R wave), there is a brief light blue vertical line, representing isovolumic systole, followed by a broad, uniform orange/red-coded band, representing ventricular contraction. This is followed by early relaxation in blue, diastasis in green, and a late diastolic relaxation in a second blue area. B, Strain map from a patient with cardiac amyloid, heart failure, and a mildly reduced ejection fraction. The arrow again represents the onset of the QRS complex. There is almost no longitudinal motion in any portion of the septum, with the large area of green representing absent motion and the brief patches of color representing slight elongation in late diastole (light blue). Systolic longitudinal motion at the base and a brief, reduced contraction in midsystole near the apical septum are yellowish orange. (From Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.)

265

266

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies hypertrophic cardiomyopathy; however, endomyocardial biopsy may be necessary in some cases to give a deﬁnitive diagnosis because of the grim prognostic implications of a diagnosis of cardiac amyloidosis.94 Although systolic anterior motion (SAM) of the mitral valve on echocardiogram is thought to be patho-

Figure 21-7 Speckle tracking image of a patient with advanced cardiac amyloidosis showing decreased longitudinal systolic strain. Top left image is from the apical four-chamber view with a bar representing a key to the color-coding varying from −20% to 20%. Each apical segment is color coded. The global strain is −4.3%. Lower right image shows the actual peak systolic strain values for each segment. For example, the basal septum has a peak strain of −1% (n = −20%). The apical segments have greater peak systolic strain values. Top right image (graph) and lower right image (anatomic M-mode) show decreased peak systolic strain over the cardiac cycle. All the segments in different colors show decreased systolic strain. Basal and midventricular segments have the worst systolic strain, while the apical segment has the best systolic strain.

pneumonic of hypertrophic cardiomyopathy, it has also been recognized in a series of patients with cardiac amyloidosis.95 MRI can be used to identify the increased myocardial thickness and small LV cavity in cardiac amyloidosis. It can be used to demonstrate the lack of increased pericardial thickening with the ancillary ﬁndings of biatrial enlargement and inferior vena cava dilatation, similar to echocardiography. Myocardial wall thickening due to hypertrophy or amyloid inﬁltration may be distinguishable.96–98 A pattern of global and subendocardial late gadolinium enhancement and speciﬁc features of T-1 blood pool kinetics are seen in patients with suspected amyloidosis.99 Subendocardial late enhancement involves the right and left ventricles, including the septum, causing the so-called zebra appearance of the septum (Fig. 21-8). This subendocardial late enhancement matches the deposition of amyloid seen histologically. The sensitivity of this ﬁnding in a series of 30 patients with echocardiographic features of amyloid was 69%. Nuclear medicine techniques have been used to diagnose cardiac amyloidosis, including technetium-99m pyrophosphate scintigraphy and imaging of indium-labeled antimyosin antibodies, though the reported sensitivities of these techniques are low.100–102 However, a recent small study with technetium-99m dicarboxypropane diphosphonate (DPD) was 100% speciﬁc for diﬀerentiating TTR amyloid from AL type.103 Figure 21-9 shows the diagnostic evaluation of suspected amyloidosis. Prognosis The prognosis of cardiac amyloidosis is generally poor, but it depends on the type of disease, with AL (primary) amyloidosis having the worst prognosis.43,44,46,57,61,104 In a serial study of over 800 patients with primary amyloidosis over a 10-year period, the median survival was 2.1 years and less than 6 months once congestive heart failure had occurred.104 Several prognostic indicators have been determined (Table 21-2). Mean LV wall thickness and

Figure 21-8 Cardiovascular magnetic resonance (CMR) image of a patient with systemic AL amyloidosis. Top row shows diastolic frames from cines (vertical long axis, horizontal long axis, and short axis, respectively), showing a thickened left ventricle (LV) and pleural effusion (Pl eff ) and pericardial effusion (Pc eff ) (arrows) associated with heart failure. Bottom row shows late gadolinium enhancement images in the same planes. The CMR sequence forces the myocardium remote from the pathology to be nulled (black) such that the abnormal region is enhanced. In cardiac amyloidosis, however, the region of greatest abnormality is enhanced, as the entire myocardium is affected with amyloid infiltration, and the result is diffuse global subendocardial enhancement (straight arrows). The endocardium of the right ventricle (RV) is also heavily loaded with amyloid, and therefore the septum in the horizontal long-axis view shows biventricular subendocardial enhancement with a dark midwall (zebra appearance; dotted arrows). The right ventricular free wall is also enhanced (curved arrow). Note that the blood pool is dark, which does not occur in other reported conditions, including abnormal gadolinium handling in these patients. LA, left atrium; RA, right atrium. (From Maceira AM et al: Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–193.)

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Suspected cardiac amyloidosis (e.g. heart failure with typical echocardiogram)

Careful physical exam seeking other potential organ involvement (e.g. proteinuria, periorbital purpura)

Biopsy of selected cardiac or non-cardiac tissue

Biopsy positive: amyloidosis confirmed

Where feasible, special stains such as immunogold

Special stains unavailable

Serum and urine IFE, FLC assay, bone marrow biopsy

One or (usually) more positive

All negative

Genetic testing for mutant TTR or ApoA1

Amyloid type confirmed

TTR

AL amyloidosis

Positive

Negative

Familial

Probably SSA

Therapy as below Quantify light chains (as baseline for follow-up) and exclude concomitant myeloma

Genetic testing for mutant TTR

Positive

Negative

Familial amyloidosis Supportive therapy. Assess for liver transplant and need for cardiac transplant.

SSA Supportive therapy.

AL amyloidosis Chemotherapy and supportive therapy.

Figure 21-9 Flow diagram outlining the evaluation of a patient with suspected cardiac amyloidosis. Clinical evaluation may reveal clues that strengthen the likelihood of amyloidosis, but a tissue diagnosis is mandatory. Although special staining of the biopsy may confirm the type of amyloid, further workup of AL amyloid is required to exclude myeloma and to quantify free light chains. If the biopsy stains positive for transthyretin (TTR), further testing is needed to determine whether this is a wild type or mutant. ApoA1, apolipoprotein A1; IFE, immunofixation electrophoresis; FLC, free–light chain assay; SSA, senile systemic amyloidosis. (From Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060.)

267

268

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies TABLE 21-2 ECHOCARDIOGRAPHIC/LABORATORY PROGNOSTIC DETERMINANTS IN AMYLOIDOSIS Left ventricular wall thickness ≥15 mm Right ventricular wall thickness >7 mm Mitral inflow deceleration time ≤150 msec Left ventricular dysfunction Right ventricular enlargement Abnormal Tei index >0.77 ↑ Troponin level ↑ Brain natriuretic peptide level

LV impairment have been suggested as useful variables in assessing the degree of cardiac involvement and prognosis. In a study of 132 patients with biopsy-proven amyloidosis, those with a mean wall thickness of 15 mm had a median survival of 0.4 year compared with 2.4 years for those with a mean wall thickness of 12 mm.80 Doppler echocardiography has also been shown to be useful in prognostic stratiﬁcation of patients with cardiac amyloidosis. Patients with a deceleration time of the mitral early ﬁlling wave at a baseline study of no greater than 150 msec had signiﬁcantly reduced survival compared with those whose deceleration time was greater than 150 msec (1-year probability of survival, 49% vs. 92%; p < 0.001).78 Bivariate analysis showed that the combination of a shortened deceleration time of no greater than 150 msec and an increased mitral E/A ratio were stronger predictors of cardiac death than were two-dimensional variables of mean LV wall thickness and fractional shortening. A Doppler echocardiographic derived parameter, the Tei index, combining systolic and diastolic performance, has been determined to have signiﬁcant prognostic importance in cardiac amyloidosis (see Chapter 16 in this volume).105 RV enlargement and LV dysfunction have also been identiﬁed as independent predictors of poor outcome among patients with primary amyloidosis.45,79 Both elevated troponin and BNP levels have been associated with a poorer prognosis.106 Treatment The mainstay of treatment is relief of symptoms, though eﬀorts are being undertaken to suppress the principal disease process. The deﬁnitive treatment for cardiac amyloidosis (AL type) involves antiplasma cell therapy that stops production of light chains and includes alkylating agents, such as melphalan and prednisone.39,104 Few randomized trials of chemotherapy have shown beneﬁt in AL amyloidosis.107,108 A trial of 100 patients with primary amyloidosis using melphalan, prednisone, and colchicine showed improvement of systemic disease when the major features were not cardiac or renal.108 A subsequent trial randomized 220 patients to colchicine, melphalan, prednisone, or combined therapy. A median duration of survival of 17–18 months occurred in the regimens including melphalan, with only 15% of patients surviving for at least 5 years. Colchicine has also been used to prevent amyloidosis associated with familial Mediterranean fever; however, there is no evidence that it halts the progression of amyloid deposition in primary amyloidosis.104 Various dosing regimens of melphalan have been used with modest success, including among patients with cardiac disease without signiﬁcant LV dysfunction or advanced heart failure.109 Chemotherapy has been associated with

a high morbidity and mortality in patients with advanced cardiac disease. Autologous stem cell transplantation has shown favorable results, mostly in patients without cardiac disease or early cardiac involvement, and is the treatment of choice for AL amyloidosis.110,111 The toxicity of blood cell transplantation, however, limits its use to a minority of patients. Diuretics are the main drugs used to treat the cardiac symptoms. Avoidance of digoxin has been suggested because of concern for digoxin binding to amyloid ﬁbrils and the risk of arrhythmias, although the data to support this recommendation are mostly experimental or anecdotal.112 With careful monitoring, digoxin has been used for heart rate control in patients with atrial ﬁbrillation.61 Patients with cardiac amyloidosis may also be very sensitive to the negative inotropic eﬀects of calcium-channel blockers, either because of their abnormal binding to amyloid ﬁbrils or because of their vasodilator eﬀects.113 Vasodilator agents such as angiotensin converting enzyme (ACE) inhibitors or angiotensin II inhibitors are poorly tolerated, with a risk of signiﬁcant hypotension.39 Pacemakers may be useful to treat symptomatic high AV block. Anticoagulation should be considered because of the risk of thrombus formation with atrial amyloid involvement and atrial standstill, even among patients in sinus rhythm.114,115 Cardiac transplantation is generally not performed in patients with AL type amyloid, since systemic involvement of other organs is usually present and may progress.116–120 It has been considered in select patients without extracardiac disease (<5% of cases), since the transplanted heart is usually not clinically aﬀected.119,120 In this situation, heart transplantation is coupled to chemotherapy and stem cell transplantation. Liver transplantation has been performed for the familial type (TTR variant), since the circulating TTR is produced in the liver.121–123 Thus, the new liver will replace the variant TTR with a normal TTR. Ideally, this is performed before cardiac involvement occurs. Nonsteroidal antiinﬂammatory drugs, such as Diﬂunisal, that can stabilize TTR and prevent the formation of amyloid are being evaluated.124 There is no speciﬁc treatment for the senile type of amyloid, though usually patients can be managed medically.

Storage Cardiomyopathies There has been a growing recognition that cardiac storage disorders often go unrecognized and may be frequent mimics of HCM.4,125,126 Intracellular accumulation of various substances within myocytes generally results from defects in genes coding for metabolic pathways. It is likely that the list of these disorders continues to expand rapidly. Currently, primary cardiomyopathies due to PRKAG2 and LAMP2 proteins have been described, and secondary cardiomyopathies include Fabry’s, Pompe’s, and Nieman-Pick diseases and hemochromatosis.4 Fabry’s disease and the primary cardiomyopathies will be discussed, since they are most prevalent in adults. Hemochromatosis, though more likely to manifest as a dilated cardiomyopathy, will also be reviewed.

Fabry’s Disease Case 3 A 48-year-old man presents with dyspnea on exertion. He has been diagnosed with nonobstructive HCM. There is a family history of Fabry’s disease. On cardiac examination, there is a moderate intensity ejection murmur that is unchanged with Valsalva. ECG shows a short P-R interval and LVH. Echocardio-

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies gram shows severe symmetric hypertrophy (interventricular septum, 1.9 cm; posterior wall, 1.8 cm). There is no SAM of the mitral valve or the LV outﬂow tract gradient at rest or with exercise echocardiogram. A laboratory test for alpha-galactosidase shows levels less than 10% of normals. Genetic testing conﬁrms Fabry’s disease with a mutation in the gene coding for alphagalactosidase. An endomyocardial biopsy shows inclusion bodies in the sarcoplasmic reticulum. The patient is referred for enzyme replacement therapy. Etiology and Presentations Fabry’s disease is a rare X-linked recessive disorder of metabolism due to gene mutations coding for alpha-galactosidase. This defect results in a deﬁciency in the enzyme alpha-galactosidase A that leads to accumulation of glycosphingolipids, the most common of which is globotriaosylceramide, Gb(3), in lysosomes.127 Although described decades ago, isolated cardiac manifestations have not been widely recognized until the past decade, and enzyme replacement therapy has only recently become available.128,129 Fabry’s disease most severely aﬀects homozygous males, with generally milder symptoms occurring in females.130–133 Abnormal deposition of glycolipid occurs in the cardiovascular system (myocardium, valves, conduction system, blood vessels), nerves, skin, and kidney.134 Lysosomal inclusions are seen by electron microscopy with vacuolization of myocytes, endothelial and smooth muscle cells with a concentric lamellar conﬁguration.133 The noncardiac manifestations of Fabry’s disease include angiokeratoma, acroparesthesias, hypohidrosis, and corneal opacities.132 Among children in the European Fabry Outcome Survey (FOS), the most frequent symptoms were acroparesthesias, altered temperative sensitivity, gastrointestinal eﬀects, vertigo, tinnitus, and fatigue.135Adults may present with renal failure and stroke, though cardiac-related symptoms alone may occur, including dyspnea, chest pain, syncope, and congestive heart failure.136 Recent studies have shown that Fabry’s disease may be the cause of LVH in 4%–6% of men with late-onset HCM.130,131 Furthermore, 12% of

females (mean age, 51.5 years) with late-onset hypertrophy were demonstrated to have Fabry’s disease by endomyocardial biopsy, despite electrocardiographic and echocardiographic appearances of HCM (Fig. 21-10).132 Among female patients with Fabry’s disease screened for LVH in one study, 63% had evidence of concentric or eccentric hypertrophy, suggesting cardiac involvement.133 In the same study, among females older than 45 years of age with Fabry’s, hypertrophy was evident in all patients. The diagnosis of Fabry’s disease in adults is ﬁrst suspected by ﬁndings on the ECG and echocardiogram. The ECG may show AV block and a short P-R interval with evidence of LVH.137 Cardiac manifestations described by echocardiography include increased aortic dimension, mitral regurgitation with mitral valve prolapse, and increased LV wall thickness.138–143 Although most often the pattern of increased LV wall thickness is concentric hypertrophy or remodeling, asymmetric hypertrophy has been described.132 The systolic function is usually preserved. SAM of the mitral valve has been described.142 Diastolic function, though typically abnormal, is usually not restrictive.144 The diagnosis of Fabry’s disease can be conﬁrmed in hemizygous males by detection of reduced levels of leukocyte alphagalactosidase levels.136 Heterozygous females may have normal or mildly decreased levels, and therefore tissue biopsy or gene testing of aﬀected tissue for diagnosis may be required.132 Eﬀorts have been made to use diﬀerent imaging modalities to screen patients with LVH for Fabry’s disease, including echocardiography and MRI, since treatment to reduce the accumulation of cardiac inﬁltration with glycolipid has become available.144–146 Echocardiographic screening of mutation-positive patients for Fabry’s disease, though negative for LVH, has shown reduced tissue Doppler systolic, E-annular, and A-annular velocities compared with controls.144 MRI has also shown abnormalities in patients with Fabry’s plus LVH with reduced radial and longitudinal strain and strain rate relative to controls and improvement in strain and strain rate with concomitant reduction in wall thickness with treatment.147 MRI studies show a mildly increased

Figure 21-10 Fabry’s cardiomyopathy. A, 12-lead electrocardiogram showing signs of left ventricular (LV) hypertrophy and ST-segment depression with giant negative T waves in precordial leads, suggesting apical hypertrophic cardiomyopathy. B, End diastolic (left) and end systolic (right) echocardiographic apical four-chamber view showing severe wall hypertrophy and cavity obliteration of ventricular apex. C, LV angiography in right anterior oblique (30˚) view showing massive apical hypertrophy of LV. D, LV endomyocardial biopsy showing normal cells (arrows) intermingled with cells containing glycolipid inclusion vacuoles (arrowheads) (hematoxylin and eosin; ×200). (From Chimenti C et al: Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 2004;110:1047–1053.)

269

270

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies signal intensity of the myocardium but no speciﬁc pattern except a tendency toward posterior-basal late enhancement with gadolinium.147,148 Reduction in radial and longitudinal strain determined echocardiographically in patients with Fabry’s disease shows a correlation between hypertrophy and late enhancement by MRI.149 Thus far, the most accurate and promising ﬁnding to distinguish LVH due to hypertension and HCM from Fabry’s cardiomyopathy is the presence of a binary appearance of the LV endocardium border.145 In one study, the sensitivity and speciﬁcity of this ﬁnding was 94% and 100%, respectively. The ﬁnding is demonstrated histologically by compartmentalization of glycosphingolipids to the endocardium (Fig. 21-11). Once cardiac involvement with Fabry’s disease has been conﬁrmed, treatment with enzyme replacement (recombinant human alpha-galactosidase A) can be initiated. Several studies have demonstrated a reduction in LVH and improvement in cardiac function with galactose infusion therapy.147,150,151

liver function tests.125,126 The clinical course progresses rapidly, with premature death. PRKAG2 has a less ominous prognosis. There is a dominant inheritance pattern and lack of noncardiac involvement, with patients surviving to adulthood, though often with arrhythmias and conduction disease.125 A study of 50 unselected patients (mean age, 6 years) with the diagnosis of HCM who underwent gene analysis for LAMP2 found 2 (4%) with mutations. Both of these patients had WolﬀParkinson White syndrome and skeletal myopathy.126 A similar study of 75 unselected patients with HCM found 3 (4%) with LAMP2 or PRKAG2 mutations.125 The same investigators performed a subgroup analysis of 24 patients with LVH and preexcitation and found 11 with mutations in LAMP2 or PRKAG2 with associated ﬁndings of LAMP2, including male sex, severe hypertrophy, early onset of HCM, preexcitation, and elevated liver and muscle enzymes. An algorithm for the diagnosis of patients with suspected LAMP2 or PRKAG 2 mutations is proposed in Figure 21-12.

Glycogen Storage Disorders

Hemochromatosis

Two gene mutations (PRKAG2 and LAMP2) causing glycogen storage disease have recently been recognized as primary cardiomyopathies mimicking HCM.125,126 PRKAG2 codes for a regulatory gene for cyclic adenosine monophosphate (cAMP)–activated protein kinase, and LAMP2 (also called Danon’s disease) codes for a lysosome membrane protein.4 Neither of these diseases is associated with myocyte disarray or interstitial ﬁbrosis, but rather glycogen-rich vacuoles. Additional gene mutations aﬀecting nonsarcomeric proteins involved in metabolism are likely to be discovered. Danon’s disease occurs as an X-linked gene aﬀecting male children younger than 20 years of age, though females are usually detected as adults. Noncardiac manifestations include skeletal myopathy, mental retardation, behavioral changes, and ocular abnormalities.125,126 Cardiac manifestations include early onset of HCM, preexcitation, and elevated creatine kinase, troponins, and

Case 4 A 50-year-old man is undergoing consideration for liver transplantation due to primary hemochromatosis. He has no known cardiac disease and no cardiac risk factors. On examination, his skin is bronze. The cardiac examination is notable for a positive S4 gallop. ECG shows low voltage in the limb leads. An echocardiogram shows normal LV size and function with abnormal diastolic function (stage 2 ﬁlling pattern) and reduced tissue Doppler systolic annular (6 cm/sec) and E-annular velocities (4 cm/sec). A cardiac MRI is done and shows abnormalities consistent with hemochromatosis. A cardiac biopsy conﬁrms iron overload in the myocardium. Etiology and Presentations Hemochromatosis is an iron storage disease that aﬀects the heart, pancreas, liver, gonads, joints, and skin.152 Primary idio-

Figure 21-11 Two-dimensional echocardiography in four-chamber apical view and left ventricular (LV) endomyocardial biopsy from two patients with Fabry’s disease cardiomyopathy (A, D and B, E, respectively) and a patient with hypertrophic cardiomyopathy (C, F). Comparison of the three echocardiographic frames reveals the presence of a binary appearance of the LV endocardial border in the two Fabry patients (A, B). This echocardiographic finding reflects glycosphingolipid compartmentalization involving a thickened endocardium (End) with enlarged and engulfed smooth muscle cells (SMC), a subendocardial empty space (SES), and a prominent involvement of subendocardial myocardial layer (SL), while the middle layer (ML) appears partially spared (D, E). The echocardiographic pattern is absent in hypertrophic cardiomyopathy (C), despite a similar thickening of the endocardium (F). (From Pieroni M et al: Fabry’s disease cardiomyopathy: Echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol 2006;47:1663–1671. )

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Unexplained left ventricular hypertrophy: is ventricular preexcitation present? No

Yes

Analyze sarcomere-protein genes; is mutation present?

Young, male patient prominent left ventricular voltage; massive hypertrophy? No

Yes

Hypertrophic cardiomyopathy

No

Analyze PRKAG2; is mutation present?

Yes

No

Measure alanine aminotransferase and creatine phosphokinase; elevated? Yes

Yes

No

Glycogen-associated cardiomyopathy

Analyze LAMP2; is mutation present? Yes

Cardiac Danon’s disease

No

Consider other glycogen storage disease

Figure 21-12 Algorithm for the diagnostic evaluation of patients with unexplained hypertrophy, where hypertrophic cardiomyopathy may not be the etiology. A family history of the dominant inheritance of left ventricular (LV) hypertrophy, unaccompanied by systemic manifestations or electrocardiographic findings of ventricular preexcitation, suggests hypertrophic cardiomyopathy; the identification of a sarcomeric mutation confirms the diagnosis. In young patients with echocardiographic findings of unexplained LV hypertrophy and electrocardiograms with prominent LV voltage and short P-R intervals, delta waves, or both, glycogen storage disease should be suspected. Dominant inheritance and an absence of systemic disease suggest the presence of glycogen-associated cardiomyopathy due to PRKAG2 mutations. Male sex and abnormalities in liver, musculoskeletal, or neurologic function suggest a diagnosis of Danon’s disease, although systemic manifestations can be modest or absent in the cardiac form of this disease. When the cause is not established by genetic analyses, a tissue biopsy and a biochemical study may be helpful. (From Arad M et al: Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005;352:362–372.)

pathic hemochromatosis is an autosomal recessive disorder related to the human leukocyte antigen on chromosome 6 that results in excessive iron absorption.152,153 It is the most common autosomal recessive disease in Caucasians.154 Both men and women are aﬀected in middle age (ﬁfties/sixties), with women usually presenting after menstruation has ceased.155 Secondary hemochromatosis results from hemoglobin synthesis abnormalities leading to ineﬀective erythropoiesis, chronic liver disease, excessive intake of iron, or multiple blood transfusions.153 Histologically, iron is deposited in the sarcoplasmic reticulum, mostly within the subepicardium and to a lesser extent the subendocardium of the myocardium.155 Interstitial iron is not seen, characterizing hemochromatosis as a storage, not an inﬁltrative, disorder.4 The ventricles and conduction system are most often aﬀected.155 The degree of myocardial iron correlates with the severity of cardiac dysfunction.156–159 Manifestations of cardiac involvement occur when there is a large amount of iron deposited over a long period of time. Onethird of patients manifest cardiac symptoms with evidence of congestive heart failure, supraventricular or ventricular arrhythmias, and conduction defects.152 Cardiac involvement is usually recognized after a noncardiac diagnosis is already known. Less often, patients will present with a cardiomyopathy of unknown etiology without known hemochromatosis. Laboratory tests will show an elevated serum ferritin and increased ratio of plasma iron

level to total iron binding capacity, urinary iron, liver iron, and saturation of transferrin.160 Cardiomegaly may be seen on CXR. Electrocardiographic ﬁndings have included arrhythmias, conduction disorders, and low voltage. Echocardiography is a useful noninvasive technique in the assessment of cardiac involvement in primary hemochromatosis, detecting clinically occult heart involvement, following patients serially, and assessing LV function after phlebotomy.156,161–163 A retrospective review from the Mayo Clinic described 19 patients with primary hemochromatosis and demonstrated that 7 (37%) had chamber dilatation and systolic dysfunction secondary to hemochromatosis, while 12 patients did not.157 Increased ventricular wall thickness was not evident in this cohort of patients. Patterns consistent with dilated or restrictive cardiomyopathy or mixed patterns have been described in patients with primary hemochromatosis, though the earliest ﬁnding is usually a restrictive pattern.155,159 Ventricular dysfunction and increased ventricular mass may normalize after successful phlebotomy.163–165 The presence of systolic dysfunction usually signiﬁes a poor prognosis.156 Manifestations of secondary hemochromatosis in the heart include increased LV wall thickness and mass, increased cavity dimension, and LA enlargement.166 Speciﬁc Doppler ﬁlling indexes and TDE are useful to diﬀerentiate patients with hereditary hemochromatosis from normal subjects and therefore may be useful for screening.167 Exercise radionu-

271

272

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies Figure 21-13 Middle-aged man with hemochromatosis developed congestive heart failure and a dilated cardiomyopathy. He was treated with deferoxamine and phlebotomy. A, Systolic frame illustrating systolic dysfunction. B, Mitral inflow pattern illustrating Stage 2 diastolic dysfunction. Thirteen months later, systolic frame illustrated normal systolic function (C), and mitral inflow pattern illustrated reversion to Stage 1 diastolic dysfunction (D).

.69

.69 PW:2MHz 1.0

m/s

A

B

1.0

1.6MHZ

C

D

clide cine angiography demonstrating exercise-related LV dysfunction in patients with normal baseline function has also been shown to be sensitive to detect preclinical disease.168 Other noninvasive tests, including CT and MRI, may be useful in demonstrating subclinical involvement of hemochromatosis (Fig. 21-13).169,170 The MRI may show a low myocardial signal on the cine gradient echo, consistent with myocardial iron deposition.169 Endomyocardial biopsy may be useful to exclude the diagnosis, especially when echocardiographic or clinical features are not evident.171 Treatment by repeat phlebotomies in primary hemochromatosis or the use of chelating agents (desferoxamine) in secondary hemochromatosis may result in improvement of cardiac involvement, making early diagnosis important.163–165 Thus, cardiac hemochromatosis is a potentially reversible form of cardiomyopathy. Heart transplantation may be considered when the heart involvement is life threatening, or combined heart and liver transplantation may be useful in patients with heart and liver failure.155,172–174

FUTURE RESEARCH The AHA 2006 reclassiﬁcation of cardiomyopathies has shifted the focus toward understanding the genetic and cellular causes of speciﬁc heart muscle diseases.4 Ultimately, the most eﬀective approach to early diagnosis and targeted treatment will be guided by knowledge of the basic underpinnings of the disease processes. Meanwhile, until these advances occur, echocardiography and MRI have risen to the forefront as noninvasive tests with the potential to detect preclinical myocardial disease and diﬀerentiate various disorders. These modalities have begun to uncover speciﬁc ﬁngerprints for each disease and should continue to be utilized during the evaluation and screening of cardiomyopathies. Most of the disorders discussed in this review continue to be associated with a poor prognosis and often are managed as pallia-

1.2 0.8 0.4 0.0 0.4 0.8 1.2 1.6

+ m / s –

tive diseases. Furthermore, over the past few decades, it is not readily evident to most physicians that progress has occurred. Advances in studying uncommon problems rely on reminding clinicians that treatment investigations are ongoing. Patients and their doctors should be encouraged to pursue evaluations at specialty referral centers, allowing them to receive the latest therapies and to be participants in prospective registries or clinical trials. Many of these centers, such as Amyloid or Fabry’s Cardiomyopathy Clinics, exist both nationally and internationally and are essential for promoting excellence in care and future research. At the present time, there is reason for modest optimism. Patients with idiopathic restrictive or amyloid cardiomyopathy without signiﬁcant noncardiac disease can be considered for cardiac or liver transplantation. Storage cardiomyopathies such as Fabry’s disease and hemochromatosis may be largely reversible with known accepted therapies. Amyloid cardiomyopathy still presents a diﬃcult challenge; however, a better recognition of non-AL forms of amyloid has allowed more patients to be eligible for treatment. Although at one time the diseases encompassed by the entity of “restrictive cardiomyopathy” were considered the topic of case presentations and few therapeutic options, in the future we anticipate earlier diagnosis, enhanced understanding of pathophysiological mechanisms, and increasing options for treatment and clinical research, with the ultimate goal of improved outcomes. REFERENCES 1. Goodwin JF: The frontiers of cardiomyopathy. Br Heart J 1982;48:11–18. 2. Report of the WHO/ISFC task force on the deﬁnition and classiﬁcation of cardiomyopathies. Br Heart J 1980;44:672–673. 3. Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the deﬁnition and classiﬁcation of cardiomyopathies. Circulation 1996;93:841–842. 4. Maron BJ, Towbin JA, Thiene G, et al: Contemporary deﬁnitions and classiﬁcation of the cardiomyopathies. Circulation 2006;113:1807–1816.

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 5. Kushawa SS, Fallon JT, Fuster V: Restrictive cardiomyopathy. N Engl J Med 1997;336:267–276. 6. Keren A, Popp RL: Assignment of patients into the classiﬁcation of cardiomyopathies. Circulation 1992;86:1622–1633. 7. Siegel RJ, Shah PK, Fishbein MC: Idiopathic restrictive cardiomyopathy. Circulation 1984;70:165–169. 8. Katritsis D, Wilmshurst PT, Wendon JA, et al: Primary restrictive cardiomyopathy: Clinical and pathologic characteristics. J Am Coll Cardiol 1991;18:1230–1235. 9. Angelini A, Calzolari V, Thiene G, et al: Morphologic spectrum of primary restrictive cardiomyopathy. Am J Cardiol 1997;80:1046–1050. 10. Ammash NM, Seward JB, Bailey KR, et al: Clinical proﬁle and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496. 11. Hirota Y: Restrictive cardiomyopathy, cardiac amyloidosis and hypereosinophilic heart disease. In Braunwald E (ed): Cardiomyopathies, myocarditis, and pericardial disease: Atlas of heart diseases, vol 2. Philadelphia, Current Medicine, 1995;5.1–5.15. 12. Zhang J, Kumar A, Stalker HF, et al: Clinical and molecular studies of a large family with desmin associated restrictive cardiomyopathy. Clin Genet 2001;59:248–256. 13. Hayashi T, Shimomura H, Terasaki F, et al: Collagen subtypes and matrix mettaloproteinase in idiopathic restrictive cardiomyopathy. Int J Cardiol 1998;64:109–116. 14. Abelmann WH, Lorell BH: The challenge of cardiomyopathy. J Am Coll Cardiol 1989;13:1219–1239. 15. Klein AL, Oh JK, Miller FA, et al: Two-dimensional and Doppler echocardiographic assessment of inﬁltrative cardiomyopathy. J Am Soc Echocardiogr 1988;1:48–59. 16. Benotti JR, Grossman W, Cohn PF: Clinical proﬁle of restrictive cardiomyopathy. Circulation 1980;61:1206–1212. 17. Lewis AB: Clinical proﬁle and outcome of restrictive cardiomyopathy in children. Am Heart J 1992;123:1589–1593. 18. Cetta F, O’Leary PW, Seward JB, et al: Idiopathic restrictive cardiomyopathy in childhood: Diagnostic features and clinical course. Mayo Clinic Proceedings 1995;70:634–640. 19. Fitzpatrick AP, Shapiro LM, Rickards AF, Poole-Wilson PA: Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy. Br Heart J 1990;63:114–118. 20. Ishiwata S, Nishiyama S, Seki A, et al: Restrictive cardiomyopathy and complete atrioventricular block and distal myopathy with rimmed vacuoles. Jpn Circ J 1993;57:928–933. 21. Cooke RA, Chambers JB, Curry PV: Noonan’s cardiomyopathy: A nonhypertrophic variant. Br Heart J 1994;71:561–565. 22. Mogensen J, Kubo T, Duque M, et al: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003;111:175–178. 23. Child JS, Perloﬀ JK: The restrictive cardiomyopathies. Cardiol Clin 1988;6:289–316. 24. Leya FS, Arab D, Joyal D, et al: The eﬃcacy of brain natriuretic peptide levels in diﬀerentiating constrictive pericarditis from restrictive cardiomyopathy. J Am Coll Cardiol 2005;45:1900–1902. 25. Klein AL, Asher CR: Diseases of the pericardium, restrictive cardiomyopathy and diastolic dysfunction. In Topol EJ, ed, Textbook of cardiovascular medicine, 2nd ed. Philadelphia, Lippincott-Raven 2004:595–646. 26. Leung DL, Klein AL: Restrictive cardiomyopathy: Diagnosis and prognostic implications. In Otto CM, ed, The practice of clinical echocardiography. Philadelphia, WB Saunders, 1996:473–493. 27. Klein AL, Cohen GI, Pietrolungo JF, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler transesophageal echocardiographic measurements of respiratory variations in pulmonary venous ﬂow. J Am Coll Cardiol 1993;22:1935–1943. 28. Hatle LK, Appleton CP, Popp RL: Diﬀerentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370. 29. Rajagopalan N, Garcia MJ, Rodriguez L, et al: Comparison of new Doppler echocardiographic methods to diﬀerentiate constrictive pericardial heart disease and restrictive cardiomyopathy. Am J Cardiol 2001;87:86–94. 30. Soler R, Rodriguez E, Remuinan C, et al: Magnetic resonance imaging of primary cardiomyopathies. J Comput Assis Tomo 2003;27:724–734. 31. Celletti F, Fattori R, Napoli G, et al: Assessment of restrictive cardiomyopathy of amyloid or idiopathic etiology by magnetic resonance imaging. Am J Cardiol 1999;83:798–801. 32. Hosenpud JD, Niles NR: Clinical, hemodynamic and endomyocardial biopsy ﬁndings in idiopathic restrictive cardiomyopathy. West J Med 1986;144:303–306.

33. Denﬁeld SW, Rosenthal G, Gajarski RJ, et al: Restrictive cardiomyopathies in childhood: Etiologies and natural history. Tex Heart Inst J 1997; 24:38–44. 34. Rivenes SM, Kearney DL, Smith EO, et al: Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation 2000;102:876–882. 35. Russo LM, Webber SA: Idiopathic restrictive cardiomyopathy in children. Heart 2005;91:1199–2002. 36. Weller RJ, Weintraub R, Addonizio LF, et al: Outcome of idiopathic restrictive cardiomyopathy in children. Am J Cardiol 2002;90:501–506. 37. Fenton MJ, Chubb H, McMahon AM, et al: Heart and heart-lung transplantation for idiopathic restrictive cardiomyopathy in children. Heart 2006;92:85–89. 38. Ammash NM, Seward JB, Bailey KR, et al: Clinical proﬁle and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496. 39. Falk RH: Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–2060. 40. Gertz MA, Rajkumar SV: Primary systemic amyloidosis. Curr Treat Options Oncol 2002;3:261–271. 41. Kholova I, Niessen HW: Amyloid in the cardiovascular system: A review. J Clin Pathol 2005;58:125–133. 42. Kyle RA, Greipp PR: Amyloidosis (AL): Clinical and laboratory features in 229 cases. Mayo Clin Proc 1983;58:665–683. 43. Kyle RA: Amyloidosis. Circulation 1995;91:12769–12771. 44. Gertz MA, Kyle RA: Primary systemic amyloidosis—a diagnostic primer. Mayo Clin Proc 1989;64:1505–1519. 45. Kyle RA, Gertz MA: Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45–59. 46. Gertz MA, Kyle RA, Thibodeau SN: Familial amyloidosis: A study of 52 North American–born patients examined during a 30-year period. Mayo Clin Proc 1992;67:428–440. 47. Connors LH, Lim A, Prokaeva T, et al: Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 2003;10:160–184. 48. Booth DR, Tan SY, Hawkins PN, et al: A novel variant of transthyretin, 59Thr—>Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation 1995;91:962–967. 49. Fredericksen T, Gotzsche H, Harboe N, et al: Familial primary amyloidosis with severe amyloid heart disease. Am J Med 1962;33:328–348. 50. Benson MD, Wallace MR, Tejada E, et al: Hereditary amyloidosis: Description of a new American kindred with late onset cardiomyopathy. Appalachian amyloid. Arth & Rheum 1987;30:195–200. 51. Jacobson DR, Pastore RD, Yaghoubian R, et al: Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;366:466–473. 52. Kyle RA, Spittell PC, Gertz MA, et al: The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 1996;101:395–400. 53. Olson LJ, Gertz MA, Edwards WD, et al: Senile cardiac amyloidosis with myocardial dysfunction. Diagnosis by endomyocardial biopsy and immunohistochemistry. N Engl J Med 1987;317:738–742. 54. Ng B, Connors LH, Davidoﬀ R, et al: Senile systemic amyloidosis presenting with heart failure: A comparison with light chain associated amyloidosis. Arch Intern Med 2005:165:1425–1429. 55. Liao R, Jain M, Teller P, et al: Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation 2001;104:1594–1597. 56. Dubrey SW, Cha K, Simms RW, et al: Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol 1996; 77:313–315. 57. Gertz MA, Kyle RA: Secondary systemic amyloidosis: Response and survival in 64 patients. Medicine 1991;70:246–256. 58. Pucci A, Wharton J, Arbustini E, et al: Atrial amyloid deposits in the failing human heart display both atrial and brain natriuretic peptide–like immunoreactivity. J Pathol 1991;165:235–241. 59. Goette A, Rocken C: Atrial amyloidosis and atrial ﬁbrillation: A genderdependent “arrhythmogenic substrate”? Eur Heart J 2004;25:1237–1241. 60. Rocken C, Peters B, Juenemann G, et al: Atrial amyloidosis: An arrhythmogenic substrate for persistent atrial ﬁbrillation. Circulation 2002; 106:2091–2097. 61. Gertz MA, Lacy MQ, Dispenzieri A: Amyloidosis. Hematol Oncol Clin North Am 1999;13:1211–1233. 62. Cueto-Garcia L, Tajik AJ, Kyle RA, et al: Serial echocardiographic observations in patients with primary systemic amyloidosis: An introduction to the concept of early (asymptomatic) amyloid inﬁltration of the heart. Mayo Clin Proc 1984;59:589–597.

273

274

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 63. Spyrou N, Foale R: Restrictive cardiomyopathies. Curr Opin Cardiol 1994;9:344–348. 64. Barth RF, Willerson JT, Buja LM, et al: Amyloid coronary artery disease, primary systemic amyloidosis and paraproteinemia. Arch Intl Med 1970;126:627–630. 65. Mueller PS, Edwards WD, Gertz MA: Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis. Am J Med 2000;109:181–188. 66. Bernardi L, Passino C, Porta C, et al: Widespread cardiovascular autonomic dysfunction in primary systemic amyloidosis: Does spontaneous hyperventilation have a compensatory role against postural hypotension? Heart 2002;88:615–621. 67. Rubinow A, Cohen AS: Skin involvement in generalized amyloidosis. A study of clinically involved and uninvolved skin in 50 patients with primary and secondary amyloidosis. Ann Intern Med 1978;88:781–785. 68. Klein AL, Hatle LK, Burstow DJ, et al: Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll of Cardiol 1989;13:1017–1026. 69. Shabetai R: Pathophysiology and diﬀerential diagnosis of restrictive cardiomyopathy. Cardiovasc Clin 1988;19:123–132. 70. Dubrey SW, Cha K, Skinner M, et al: Familial and primary (AL) cardiac amyloidosis: Echocardiographically similar diseases with distinctly diﬀerent clinical outcomes. Heart 1997;78:74–82. 71. Murtagh B, Hammill SC, Gertz MA, et al: Electrocardiographic ﬁndings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol 2005;95:535–537. 72. Carroll JD, Gaasch WH, McAdam KP: Amyloid cardiomyopathy: Characterization by a distinctive voltage/mass relation. Am J Cardiol 1982; 49:9–13. 73. Dubrey SW, Cha K, Anderson J, et al: The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 1998;91:141–157. 74. Falk RH, Rubinow A, Cohen AS: Cardiac arrhythmias in systemic amyloidosis: Correlation with echocardiographic abnormalities. J Am Coll Cardiol 1984;3:107–113. 75. Klein AL, Oh JK, Miller FA, et al: Two-dimensional and Doppler echocardiographic assessment of inﬁltrative cardiomyopathy. J Am Soc Echocardiogr 1988;1:48–59. 76. Klein AL, Hatle LK, Burstow DJ, et al: Comprehensive Doppler assessment of right ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;15:99–108. 77. Klein AL, Hatle LK, Taliercio CP, et al: Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;16:1135–1141. 78. Klein AL, Hatle LK, Taliercio CP, et al: Prognostic signiﬁcance of Doppler measures of diastolic function in cardiac amyloidosis. A Doppler echocardiography study. Circulation 1991;83:808–816. 79. Patel AR, Dubrey SW, Mendes LA, et al: Right ventricular dilation in primary amyloidosis: An independent predictor of survival. Am J Cardiol 1997;80:486–492. 80. Cueto-Garcia L, Reeder GS, Kyle RA, et al: Echocardiographic ﬁndings in systemic amyloidosis: Spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 1985;6:737–743. 81. Falk RH, Plehn JF, Deering T, et al: Sensitivity and speciﬁcity of the echocardiographic features of cardiac amyloidosis. Am J Cardiol 1987; 59:418–422. 82. Siqueira-Filho AG, Cunha CL, Tajik AJ, et al: M-mode and twodimensional echocardiographic features in cardiac amyloidosis. Circulation 1981;63:188–196. 83. Chiaramida SA, Goldman MA, Zema MJ, et al: Real-time cross-sectional echocardiographic diagnosis of inﬁltrative cardiomyopathy due to amyloid. J Clin Ultra 1980;8:58–62. 84. Chandrasekaran K, Aylward PE, Fleagle SR, et al: Feasibility of identifying amyloid and hypertrophic cardiomyopathy with the use of computerized quantitative texture analysis of clinical echocardiographic data. J Am Coll Cardiol 1989;13:832–840. 85. Chew C, Ziady GM, Raphael MJ, Oakley CM: The functional defect in amyloid heart disease. The “stiﬀ heart” syndrome. Am J Cardiol 1975;36:438–444. 86. St. John Sutton MG, Reichek N, Kastor JA, Giuliani ER: Computerized M-mode echocardiographic analysis of left ventricular dysfunction in cardiac amyloid. Circulation 1982;66:790–799. 87. Abdalla I, Murray RD, Lee JC, et al: Duration of pulmonary venous atrial reversal ﬂow velocity and mitral inﬂow A wave: New measure of severity of cardiac amyloidosis. J Am Soc Echocardiogr 1998;11:1125–1133.

88. Koyama J, Ray-Sequin PA, Davidoﬀ R, Falk RH: Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis. Am J Cardiol 2002;89:1067–1071. 89. Koyama J, Ray-Sequin PA, Falk RH: Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 2003;107:2446–2452. 90. Katzmann JA, Abraham RS, Dispenzieri A, et al: Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem 2005;51:878–881. 91. Abraham RS, Katzmann JA, Clark RJ, et al: Quantitative analysis of serum free light chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis. Am J Clin Pathol 2003;119:274–278. 92. Gertz MA, Lacy MQ, Dispenzieri A: Amyloidosis: Recognition, conﬁrmation, prognosis, and therapy. Mayo Clin Proc 1999;74:490–494. 93. Libbey CA, Skinner M, Cohen AS: Use of the abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med 1983;143: 1549–1552. 94. Ardehali H, Qasim A, Cappola T, et al: Endomyocardial biopsy plays a role in diagnosing patients with unexplained cardiomyopathy. Am Heart J 2004;147:919–923. 95. Oh JK, Tajik AJ, Edwards WD, et al: Dynamic left ventricular outﬂow tract obstruction in cardiac amyloidosis detected by continuous-wave Doppler echocardiography. Am J Cardiol 1987;59:1008–1010. 96. Sechtem U, Higgins CB, Sommerhoﬀ BA, et al: Magnetic resonance imaging of restrictive cardiomyopathy. Am J Cardiol 1987;59:480–482. 97. Von Kemp K, Beckers R, Vandenweghe J, et al: Echocardiography and magnetic resonance imaging in cardiac amyloidosis. Acta Cardiologica 1989;44:29–36. 98. Celletti F, Fattori R, Napoli G, et al: Assessment of restrictive cardiomyopathy of amyloid or idiopathic etiology by magnetic resonance imaging. Am J Cardiol 1999;83:798–801, A10. 99. Maceira AM, Joshi J, Prasad SK, et al: Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–193. 100. Hongo M, Fujii T, Hirayama J, et al: Radionuclide angiographic assessment of left ventricular diastolic ﬁlling in amyloid heart disease: A study of patients with familial amyloid polyneuropathy. J Am Coll Cardiol 1989;13:48–53. 101. Hongo M, Hirayama J, Fujii T, et al: Early identiﬁcation of amyloid heart disease by technetium-99m–pyrophosphate scintigraphy: A study with familial amyloid polyneuropathy. Am Heart J 1987;113:654–662. 102. Lekakis J, Nanas J, Moustafellou C, et al: Cardiac amyloidosis detected by indium-111 antimyosin imaging. Am Heart J 1992;124:1630–1631. 103. Perugini E, Guidalotti PL, Salvi F, et al: Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076–1084. 104. Gertz MA, Kyle RA: Amyloidosis: Prognosis and treatment. Semin Arthritis Rheum 1994;24:124–138. 105. Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–664. 106. Dispenzieri A, Kyle RA, Gertz MA, et al: Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet 2003; 361:1787–1789. 107. Kyle RA, Gertz MA, Greipp PR, et al: A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone and colchicine. N Engl J Med 1997;336:1202– 1207. 108. Skinner M, Anderson JJ, Simms R, et al: Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine alone. Am J Med 1996;100:290–298. 109. Palladini G, Perfetti V, Obici L, et al: Association of melphalan and highdose dexamethasone is eﬀective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplant. Blood 2004;103:2936–2938. 110. Skinner M, Sanchorawala V, Seldin DC, et al: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: An 8-year study. Ann Intern Med 2004;140:85–93. 111. Comenzo RL, Vosburgh E, Falk RH, et al: Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: Survival and responses in 25 patients. Blood 1998;91:3662– 3670. 112. Rubinow A, Skinner M, Cohen AS: Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981;63:1285–1288.

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 113. Pollak A, Falk RH: Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest 1993;104:618–620. 114. Willens HJ, Levy R, Kessler KM: Thromboembolic complications in cardiac amyloidosis detected by transesophageal echocardiography. Am Heart J 1995;129:405–406. 115. Plehn JF, Southworth J, Cornwell GG: Brief report: Atrial systolic failure in primary amyloidosis. N Engl J Med 1992;327:1570–1573. 116. Hosenpud JD, DeMarco T, Frazier OH, et al: Progression of systemic disease and reduced long-term survival in patients with cardiac amyloidosis undergoing heart transplantation. Follow-up results of a multicenter survey. Circulation 1991;84(5 Suppl):III338–343. 117. Dubrey S, Simms RW, Skinner M, Falk RH: Recurrence of primary (AL) amyloidosis in a transplanted heart with four-year survival. Am J Cardiol 1995;76:739–741. 118. Kpodonu J, Massad MG, Caines A, Geha AS: Outcome of heart transplantation in patients with amyloid cardiomyopathy. J Heart Lung Transplant 2005;24:1763–1765. 119. Dubrey SW, Burke MM, Hawkines PN, et al: Cardiac transplantation for amyloid heart disease: The United Kingdom experience. J Heart Lung Transplant 2004;23:1142–1153. 120. Pelosi F Jr, Capehart J, Roberts WC: Eﬀectiveness of cardiac transplantation for primary (AL) cardiac amyloidosis. Am J Cardiol 1997;79:532–535. 121. Suhr OB, Herlenius G, Friman S, Ericzon BG: Liver transplantation for hereditary transthyretin amyloidosis. Liver Transpl 2000;6:263–276. 122. Skinner M, Lewis LD, Jones LA, et al: Liver transplantation as treatment for familial amyloidotic polyneuropathy. Ann Intern Med 1994;120: 133–134. 123. Holmgren G, Ericzon BG, Groth CG, et al: Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993;341:1113–1116. 124. Miller SR, Sekijima Y, Kelly JW: Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. Lab Invest 2004;84:545–552. 125. Arad M, Maron BJ, Gorham JM, et al: Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005;352:362–372. 126. Yang Z, McMahon CJ, Smith LR, et al: Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation 2005;112:1612–1617. 127. Brady RO, Gal AE, Bradley RM, et al: Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deﬁciency. N Engl J Med 1967;276:1163–1167. 128. Von Scheidt W, Eng CM, Fitzmaurice TF, et al: An atypical variant of Fabry’s disease with manifestations conﬁned to the myocardium. N Engl J Med 1991;324:395–399. 129. Eng CM, Guﬀon N, Wilcox WR, et al: Safety and eﬃcacy of recombinant human alpha-galactosidase A—-replacement therapy in Fabry’s disease. N Engl J Med 2001;345:9–16. 130. Nakao S, Takenaka T, Maeda M, et al: An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 1995;333: 288–293. 131. Sachdev B, Takenaka T, Teraguchi H, et al: Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 2002;105:1407–1411. 132. Chimenti C, Pieroni M, Morgante E, et al: Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 2004;110:1047–1053. 133. Kampmann C, Baehner F, Whybra C, et al: Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol 2002;40:1668–1674. 134. Desnick RJ, Ioannou YA, Eng CM: Alpha-galactosidase A deﬁciency: Fabry disease. In Scriver CH et al (eds): The metabolic and molecular bases of inherited diseases. New York, McGraw-Hill 2001:3733–3774. 135. Ramaswami U, Whybra C, Parini R, et al: Clinical manifestations of Fabry disease in children: Data from the Fabry Outcome Survey. Acta Paediatr 2006;95:86–92. 136. Desnick RJ, Brady R, Barranger J, Collins AJ: Fabry disease, an underrecognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338–346. 137. Pochis WT, Litzow JT, King BG, Kenny D: Electrophysiologic ﬁndings in Fabry’s disease with a short PR interval. Am J Cardiol 1994;74:203–204. 138. Sakuraba H, Yanagawa Y, Igarashi T, et al: Cardiovascular manifestations in Fabry’s disease. A high incidence of mitral valve prolapse in hemizygotes and heterozygotes. Clin Genet 1986;29:276–283. 139. Bass JL, Shrivastava S, Grabowski GA, et al: The M-mode echocardiogram in Fabry’s disease. Am Heart J 1980;100:807–812.

140. Cohen IS, Fluri-Lundeen J, Wharton TP: Two dimensional echocardiographic similarity of Fabry’s disease to cardiac amyloidosis: A function of ultrastructural analogy? J Clin Ultra 1983;11:437–441. 141. Linhart A, Palecek T, Bultas J, et al: New insights in cardiac structural changes in patients with Fabry’s disease. Am Heart J 2000;139:1101– 1108. 142. Morimoto S, Sugiura A, Iwase M, et al: Relief of left ventricular outﬂow obstruction by cibenzoline in a patient with Fabry’s disease—a case report. Angiology 2006;57:241–245. 143. Goldman ME, Cantor R, Schwartz MF, et al: Echocardiographic abnormalities and disease severity in Fabry’s disease. J Am Coll Cardiol 1986;7: 1157–1161. 144. Pieroni M, Chimenti C, Ricci F, et al: Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation 2003;107:1978–1984. 145. Pieroni M, Chimenti C, De Cobelli F, et al. Fabry’s disease cardiomyopathy: Echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol 2006;47:1663–1671. 146. Matsui S, Murakami E, Takekoshi N, et al: Myocardial tissue characterization by magnetic resonance imaging in Fabry’s disease. Am Heart J 1989;117:472–474. 147. Weidemann F, Breunig F, Beer M, et al: Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: A prospective strain rate imaging study. Circulation 2003;108:1299– 1301. 148. Moon JC, Sachdev B, Elkington AG, et al: Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease: Evidence for a disease speciﬁc abnormality of the myocardial interstitium. Eur Heart J 2003;24: 2151–2155. 149. Weidemann F, Breunig F, Beer M, et al: The variation of morphological and functional cardiac manifestation in Fabry disease: Potential implications for the time course of the disease. Eur Heart J 2005;26:1221–1227. 150. Frustaci A, Chimenti C, Ricci R, et al: Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med 2001;345:25–32. 151. Kalliokoski RJ, Kantola I, Kalliokoski KK, et al: The eﬀect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease. J Inherit Metab Dis 2006;29:112–118. 152. Hauser SC: Hemochromatosis and the heart. Heart Dis Stroke 1993;2:487–491. 153. Buja LM, Roberts WC: Iron in the heart. Etiology and clinical signiﬁcance. Am J Med 1971;51:209–221. 154. Adams PC, Halliday JW, Powell LW: Early diagnosis and treatment of hemochromatosis. Adv Intern Med 1989;34:111–126. 155. Case Records of the Massachusetts General Hospital (Case 31–1994). N Engl J Med 1994;331:460–466. 156. Olson LJ, Baldus WP, Tajik AJ: Echocardiographic features in idiopathic hemochromatosis. Am J Cardiol 1987;60:885–889. 157. Olson LJ, Edwards WD, Holmes DR, et al: Endomyocardial biopsy in hemochromatosis: Clinicopathologic correlates in six cases. J Am Coll Cardiol 1989;13:116–120. 158. Olson LJ, Edward WD, McCall JT, et al: Cardiac iron deposition in idiopathic hemochromatosis: Histologic and analytic assessment of 14 hearts from autopsy. J Am Coll Cardiol 1987;10:1239–1243. 159. Dabestani A, Child JS, Henze E, et al: Primary hemochromatosis: Anatomic and physiologic characteristics of the cardiac ventricles and their response to phlebotomy. Am J Cardiol 1984;54:153–159. 160. Bonkovsky HL, Slaker DP, Bills EB, Wolf DC: Usefulness and limitation of laboratory and hepatic imaging studies in iron-storage disease. Gastroenterology 1990;99:1079–1091. 161. Candell-Riera J, Lu L, Seres L, et al: Cardiac hemochromatosis: Beneﬁcial eﬀects of iron removal therapy. An echocardiographic study. Am J Cardiol 1983;52:824–829. 162. Short EM, Winkle RA, Billingham ME: Myocardial involvement in idiopathic hemochromatosis. Morphologic and clinical improvement following venesection. Am J Med 1981;70:1275–1279. 163. Rivers J, Garrahy P, Robinson W, Murphy A: Reversible cardiac dysfunction in hemochromatosis. Am Heart J 1987;113:216–217. 164. Rahko PS, Salerni R, Uretsky BF: Successful reversal by chelation therapy of congestive cardiomyopathy due to iron overload. J Am Coll Cardiol 1986;8:436–440. 165. Easley RM Jr, Schreiner BF Jr, Yu PN: Reversible cardiomyopathy associated with hemochromatosis. N Engl J Med 1972;287:866–867. 166. Henry WL, Nienhuis AW, Wiener M, et al: Echocardiographic abnormalities in patients with transfusion-dependent anemia and secondary myocardial iron deposition. Am J Med 1978;64:547–555.

275

276

Chapter 21 • Primary Restrictive, Infiltrative, and Storage Cardiomyopathies 167. Palka P, Macdonald G, Lange A, Burstow DJ: The role of Doppler left ventricular ﬁlling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis. J Am Soc Echocardiogr 2002;15:884–890. 168. Leon MB, Borer JS, Bacharach SL, et al: Detection of early cardiac dysfunction in patients with severe beta-thalassemia and chronic iron overload. N Engl J Med 1979;21:1143–1148. 169. Blankenberg F, Eisenberg S, Scheinman MN, Higgins CB: Use of cine gradient echo (GRE) MR in the imaging of cardiac hemochromatosis. J Comput Assist Tomo 1994;18:136–138. 170. Niwano S, Yokoyama J, Niwano H, Aizawa Y: Images in cardiovascular medicine. Iron deposition in myocardium documented on standard computed tomography in cardiac hemochromatosis. Circulation 1998;97:2371.

171. Przybojewski JZ: Endomyocardial biopsy: A review of the literature. Cath & Cardiovasc Diag 1985;11:287–330. 172. Westra WH, Hruban RH, Baughman KL, et al: Progressive hemochromatotic cardiomyopathy despite reversal of iron deposition after liver transplantation. Am J Clin Path 1993;99:39–44. 173. Caines AE, Kpodonu J, Massad MG, et al: Cardiac transplantation in patients with iron overload cardiomyopathy. J Heart Lung Transplant 2005;24:486–488. 174. Ocel JJ, Edwards WD, Tazelaar HD, et al: Heart and liver disease in 32 patients undergoing biopsy of both organs, with implications for heart or liver transplantation. Mayo Clin Proc 2004;79:492–501.

22

ARUMUGAM NARAYANAN, MD GERARD P. AURIGEMMA, MD

Coronary Artery Disease INTRODUCTION PATHOPHYSIOLOGY Acute Ischemia Postinfarction Left Ventricular Remodeling CLINICAL RELEVANCE Diagnosis by Doppler Echocardiography FUTURE RESEARCH

INTRODUCTION While the importance of hypertension in the pathogenesis of diastolic dysfunction and diastolic heart failure is well known,1–6 relatively less attention has been paid to the interaction between coronary artery disease (CAD) and diastolic dysfunction. Accordingly, this chapter will be devoted to reviewing aspects of diastolic dysfunction in patients with coronary disease, with an emphasis on the role of Doppler echocardiography in elucidating aspects of the pathogenesis of heart failure. Diastolic heart failure is a condition characterized by signs and symptoms of heart failure, where “the dominant abnormality resides in diastole.”2 Cross-sectional and population-based studies indicate that at least one-third of all patients with congestive heart failure (CHF) have a normal or near-normal ejection fraction (EF) and that most have diastolic heart failure.1–3 The prevalence is highest in patients over age 75.1,2,7 Historically it has been assumed that the mortality rate of diastolic heart failure is less than that of systolic heart failure, ranging from 5% to 8% annually, compared with 10% to 15% in patients with systolic heart failure.2 However, recent data8–10 have challenged this notion. As is the case with systolic heart failure, the mortality rate of diastolic heart failure is directly related to age and the presence of coronary disease.2 The reported prevalence of diastolic heart failure depends not only on age, but on the diagnostic criteria used to deﬁne diastolic dysfunction, the etiology of the disease, and the methods and design of the particular study in question.2,7

The prevalence of coronary disease in patients who develop diastolic heart failure is high. This conclusion is based on data compiled from several types of studies: cross-sectional studies; randomized, placebo-controlled, clinical trials; and community-based studies. Gottdiener et al. studied over 5000 community-based individuals, age 65 or greater, enrolled in the multicenter Cardiovascular Health Study (CHS). These investigators tabulated incidence rates of heart failure over a 5-year period. Prevalent CAD was associated with more than a threefold higher rate of incident CHF (15.3% vs. 41%). Other predictors of CHF include other indicators of prevalent atherosclerotic disease, such as reduced ankle-brachial index, history of stroke, and increased levels of C-reactive protein. The populationattributable risk of prevalent CAD in this study was roughly equivalent to that of arterial hypertension, which itself is epidemiologically important.5–9 In a subsequent analysis of CHF by EF in the CHS database,11 prevalent coronary heart disease was present in 58% of patients with CHF and normal EF and in 78% of patients with CHF and reduced EF. Framingham Study investigators conﬁrmed the importance of CAD in patients with diastolic heart failure, using the concept of population-attributable risk. When adjusting for age and heart failure risk factors in proportional hazards regression models, hypertension accounted for 39% of cases in men and 59% of cases in women.5 Among hypertensive subjects, CAD (in this instance, a history of myocardial infarction) was associated with increased risk for CHF in both sexes.5 Similarly high rates of CAD have been reported in a survey of clinical characteristics of patients hospitalized in New York City with diastolic heart failure reported by Klapholz et al.,6 as well as those enrolled in the “Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity” (CHARM)–Preserved study, the only published randomized clinical trial to date of treatment for diastolic heart failure.12 In the study by Klapholz et al., roughly one half of patients hospitalized in New York City for CHF who had a normal EF had a history of CAD. In the CHARM study, roughly one ﬁfth had a prior coronary artery bypass graft; one half, myocardial infarction; and one quarter, angina.12 These data demonstrate the importance of coronary heart disease in the pathogenesis of diastolic heart failure. 277

278

Chapter 22 • Coronary Artery Disease the rate of LV pressure decline.16–17 This subject is reviewed in detail elsewhere.18

PATHOPHYSIOLOGY As is reviewed in Chapter 2 of this volume, diastolic function is determined by the passive elastic properties of the left ventricle and the process of active relaxation.1,2 Active relaxation is an energy-dependent process that is aﬀected by ischemia. By contrast, abnormal passive elastic properties are generally caused by a combination of increased myocardial mass and alterations in the extramyocardial collagen network.2 The eﬀects of impaired active myocardial relaxation, caused by acute ischemia, can lead to further stiﬀness. The interplay between this impaired relaxation and passive stiﬀness determines left ventricular (LV) ﬁlling pressure.2

Acute Ischemia It has been demonstrated that acute myocardial ischemia eﬀects changes in both global and regional LV diastolic properties.13 The results of these alterations include a slower LV pressure decay with a consequent slowing of diastolic ﬁlling. Acute changes in the passive properties of the left ventricle result in an upward shift in the diastolic pressure-volume relationship (Fig. 22-1). As a result, the LV diastolic pressure-volume relationship changes: Chamber compliance is reduced, the time course is altered, and diastolic pressure is elevated. Under these circumstances, a relatively small increase in central blood volume or an increase in venous tone or arterial stiﬀness can produce a substantial increase in ﬁlling pressures and may result in acute pulmonary edema.14 The slowed relaxation following acute ischemia or infarction may persist for days.15 However, a slower rate of LV pressure fall is not the only result of direct eﬀects of ischemia on myocardial relaxation. Ischemia may also aﬀect contractility, loading conditions, and may worsen nonuniformity, which may also act to slow

Diastolic pressure (mmHg)

30

Angina

20

10

Postinfarction Left Ventricular Remodeling The subject of postinfarction LV remodeling is complicated, and excellent reviews of this topic have been published.19–21 To summarize brieﬂy, myocardial infarction produces global and regional changes in ventricular function in both infarcted and noninfarcted regions, resulting in alterations in LV shape and geometry. The immediate changes following infarction involve mainly the infarcted region. Subsequently, over weeks to months, further changes occur, and these involve the noninfarcted region. This constellation of changes is known as ventricular remodeling. In the consensus paper by Cohn et al., LV remodeling is deﬁned as “changes in size, shape, and function of the heart after cardiac injury. [The process] . . . is inﬂuenced by hemodynamic load, neurohumoral activation, and other processes.”20 A review of the processes involved in LV remodeling make it clear that what may begin as an adaptive process can have maleﬁc consequences for LV diastolic function. During acute ischemia, injury, and the attendant reduction in systolic function, the region undergoing infarction may develop systolic expansion and perform a reduced amount of eﬀective work.18,20 Following a large myocardial infarction, LV end diastolic pressures remain elevated, and the volume of viable myocardium increases approximately 30% because of increases in both myocyte cell length and diameter.18 In some instances, the ventricle may undergo progressive infarct expansion, usually within the ﬁrst 24–72 hours.18–21 In part, this expansion and volume increase help to compensate for the reduction in eﬀective work via the Frank-Starling mechanism.18–21 Even in the absence of acute LV expansion, LV dilation may develop, usually over several months after myocardial infarction18–21 involving both the infarcted and the noninfarcted regions. Given the curvilinear diastolic pressure-volume relationship, lengthening/dilation of noninfarcted regions is associated with an increase in LV end diastolic pressure.18–21 High wall stresses and ventricular remodeling may provide the stimuli for deleterious changes and further remodeling.21 The signal for progressive remodeling in the postinfarction ventricle may be diastolic wall stress, with parallels between this process and what is observed in chronic volume overload due to valvular regurgitation.21 Myocyte hypertrophy and changes in the extracellular matrix also are part of the remodeling process.18–21

CLINICAL RELEVANCE Diagnosis by Doppler Echocardiography

Control

20

40

60

80

100

Diastolic volume (cc/m2) Figure 22-1 The acute effect of ischemia on the pressure-volume relationship. These data are taken from the study of a 60-year-old individual undergoing catheterization. The control diastolic pressure-volume relationship is shown. During the procedure, the patient developed angina; volume assessment and hemodynamic measures were repeated. As can be seen, the pressure-volume relationship shifted dramatically upward, so that at any given diastolic volume, the pressure during the angina episode is higher; note that the ejection fraction has not changed dramatically. (Figure courtesy of Dr. William H. Gaasch.)

Doppler echocardiography plays a critical diagnostic role in all patients with heart failure for a variety of reasons. First, diagnostically, it should be emphasized that the physical examination, electrocardiogram, and chest roentgenogram do not reliably distinguish diastolic from systolic heart failure. Second, an accurate EF determination is essential for the diagnosis of diastolic heart failure. Echocardiography can also rapidly exclude diagnoses such as acute mitral or aortic regurgitation or constrictive pericarditis, conditions also associated with signs and symptoms of heart failure and a normal EF. Finally, Doppler echocardiography can be used in many instances to reliably estimate ﬁlling pressures.

Chapter 22 • Coronary Artery Disease

General Principles As is reviewed in Chapter 5 of this volume, Doppler echocardiography measures the velocity of intracardiac blood ﬂow. Doppler transmitral ﬂow analysis has become the mainstay of the clinical assessment of diastolic function. In normal sinus rhythm, diastolic ﬂow from the left atrium to the left ventricle across the mitral valve occurs in two phases, denoted by two distinct waves: the E wave, which reﬂects early diastolic ﬁlling, and the A wave, in late diastole, which reﬂects atrial contraction. Because the velocity of blood ﬂow across the mitral valve depends on the transmitral pressure gradient, the E-wave velocity is inﬂuenced by both the rate of early diastolic relaxation and left atrial (LA) pressure. Alterations in the pattern of these velocities give insight into LV diastolic function and prognosis.22–25 As has been pointed out previously (see Chapter 10), standard mitral inﬂow patterns are extremely sensitive to loading conditions, particularly LA pressure. Stated another way, early diastolic ﬁlling rates might be increased by elevated LA pressure. Therefore, just as a “normal” (E > A) ﬁlling pattern does not necessarily indicate normal diastolic function, a reduced E-wave velocity and E/A ratio might be found in the presence of elevated ﬁlling pressures. As we have come to realize over the past decade, other data are necessary to give a complete picture of diastolic function. Such other data are

generally provided by pulmonary vein velocities26,27 and tissue Doppler analysis.25 Tissue Doppler techniques appear to be somewhat less sensitive to loading conditions than standard Doppler velocities (Fig. 22-2). It is important to bear in mind, in this connection, that the height of the transmitral E wave merely reﬂects the early diastolic LA-LV gradient. As is shown in Figure 22-3, it is possible that the E-wave height and E/A ratio may be low, not necessarily because of low LA pressure, but because of a protracted decline in LV diastolic pressure.28 As we will see, such a protracted decline in diastolic pressure may be caused by acute ischemia.

Acute Effects of Ischemia on Doppler Inflow Patterns There have been a number of studies of mitral inﬂow patterns in patients with acute myocardial ischemia (Table 22-1). Labovitz et al. studied functional changes by Doppler echocardiography in 32 patients during transient myocardial ischemia induced by percutaneous transluminal coronary angioplasty (PTCA).29 Ventricular ﬁlling during coronary occlusion showed signiﬁcant change, evident within 15 seconds of balloon occlusion; there was an acute decrease in peak E velocity as well as E/A ratio (Fig. 22-4A and B), with a return to baseline values within 15 seconds Diastolic dysfunction

LV pressure (mmHg)

50

Figure 22-2 A, End diastolic pressurevolume relationship (EDPVR) curves in normal, diastolic dysfunction, and remodeling groups. Inserted in the figure are the mitral inflow and tissue Doppler recordings for the three groups. The EDPVR is shifted left-upward for diastolic dysfunction compared with a right-downward shift for a heart that has remodeled. B, While mitral inflow velocity appears similar in all three groups, mitral annulus tissue Doppler early diastolic velocities are reduced in patients with diastolic dysfunction or remodeling. Two-dimensional echo shows completely normal cardiac structures for the normal subject at the center and increased wall thickness and LA enlargement but normal left ventricular size in the left panel, consistent with diastolic heart failure. On the right is displayed left ventricular (LV) enlargement typical of the remodeling heart. (A, Modified from Maurer MS, Spevack D, Burkhoff D, et al: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44:1543–1549. B, From Oh JK et al: Diastolic heart failure can be diagnosed by comprehensive twodimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506.)

Normal

40

Remodeling

30 20 10 0 0

A

50

100

150

LV volume (ml)

200

250

279

280

Chapter 22 • Coronary Artery Disease TABLE 22-1 TRANSMITRAL INFLOW (E AND A WAVES) IN ACUTE ISCHEMIA AUTHOR

NUMBER OF PATIENTS (n)

Labovitz et al.29 Snow et al.30

32 22

Iliceto et al.31

9

PATIENT POPULATION

E

A

E/A

AFF

DT

IVRT

Patients undergoing PTCA Patients in the unstable angina group who underwent elective PTCA* Patients with significant CAD who developed ischemic ECG changes with transesophageal atrial pacing

NA NA

NA NA

↓ ↔

NA ↔

NA ↓

NA ↓

↓

↑

↓

↑

NA

NA

*Doppler echocardiography performed 43 ± 27 hours after PTCA. E, early diastolic filling; A, atrial contraction in late diastole; E/A, ratio of E wave to A wave; AFF, atrial filling fraction; DT, deceleration time; IVRT, isovolumic relaxation time; PTCA, percutaneous transluminal coronary angioplasty; CAD, coronary artery disease; ECG, electrocardiogram.

LVP

LAP

MVF

Normal (1)

Impaired relaxation (2)

“Hyperabnormal relaxation” (3)

Figure 22-3 Schematic representation of simultaneous recordings of left ventricular pressure (LVP), left atrial pressure (LAP), and Doppler mitral flow velocity (MVF) in (1) a normal subject, (2) a patient with impaired relaxation without clinical heart failure, and (3) a patient with acute heart failure and a delayed relaxation. This figure illustrates that under certain conditions, such as acute ischemia, a low E/A ratio can be associated with elevated filling pressures. (From Bogaty P et al: New insights into diastolic dysfunction as the cause of acute leftsided heart failure associated with systemic hypertension and/or coronary artery disease. Am J Cardiol 2002;89:341–345.)

1.8 1.7 1.6 Baseline

E

Inflation

Recovery

1.5 1.4

A

1.3

1 m/sec– E/A

1.2 1.1 1.0 .9

V2

V2

.8

V2

.7 .6 .5

p < .001

0

A

B

Baseline

15 seconds

Figure 22-4 A, Simultaneous recording of pulsed Doppler left ventricular inflow velocities with accompanying electrocardiographic lead V2 during left anterior descending coronary occlusion/balloon inflation during percutaneous transluminal coronary angioplasty. There is a marked diminution in early (E) and the E/A ratio, which coincides with ST segment elevation induced by coronary occlusion. The flow profile returned to the baseline state in recovery. B, There was a significant decrease in the ratio of peak early to peak atrial diastolic velocities (E/A) by 15 seconds after coronary occlusion, with the E/A ratio falling in the vast majority of patients. (From Labovitz AJ et al: Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial ischemia produced by angioplasty. J Am Coll Cardiol 1987;10:748–755.)

Chapter 22 • Coronary Artery Disease following balloon deﬂation. The diastolic changes occurred prior to systolic and other clinical changes.29 Snow et al. prospectively evaluated 42 patients undergoing elective PTCA for severe ischemia (22 patients with unstable angina pectoris and 20 patients with post–acute myocardial infarction [AMI] ischemia).30 Doppler echocardiographic studies were performed before (8 ± 5 hours) and after (43 ± 27 hours) PTCA. Patients with severe ischemia (both the unstable angina and the postinfarction ischemia groups) showed abnormal diastolic ﬁlling patterns before PTCA, characterized by prolonged isovolumic relaxation time (IVRT) and mitral deceleration time (DT), decreased E/A peak velocity ratio, and increased atrial ﬁlling fraction (AFF). Following PTCA, IVRT and DT decreased in both groups; the decrease in IVRT was signiﬁcant. The E/A ratio increased, and AFF decreased in the post-AMI ischemia group at the same time.30 It is noteworthy that both studies demonstrated a reduced E/A ratio following acute ischemia, induced by either PTCA or the acute ischemia. The improvement in diastolic function and transmitral ﬂow velocities post-PTCA likely reﬂects early recovery of diastolic determinants, active ventricular relaxation, and compliance. These data may be interpreted in light of the hypothesis of Bogaty28: The reduced peak E is probably the result of reduced “driving pressure” between the left atrium and the left ventricle in

early diastole. It is conceivable that an acute ischemia–related reduction in peak E is more related to a slow decline in LV diastolic pressure than to reduced LA pressure. Iliceto et al.31 evaluated the eﬀect of atrial pacing-induced ischemia on Doppler-derived LV ﬁlling parameters in 17 patients with signiﬁcant CAD (Fig. 22-5A). The patients were divided into two groups on the basis of ischemic changes on electrocardiography (ECG) (ST depression ≥1.5 mm) immediately after cessation of atrial pacing. Group 1 (without ischemic changes) showed no signiﬁcant changes in LV ﬁlling variables, while group 2 (with ischemic changes) showed a signiﬁcant decrease in early peak ﬂow velocity from rest to postpacing, along with a compensatory increase in the atrial component of the mitral inﬂow velocities. As was observed in the studies headed by Labovitz and Snow, the E/A ratio decreased and the atrial fraction of the timevelocity integral increased in the group with manifest ischemia. The ﬁlling alterations gradually returned to baseline levels one minute after cessation of atrial pacing. The changes in LV ﬁlling occurring only in group 2 possibly reﬂect signiﬁcant ischemia noted by ECG changes and indicate that a threshold for these changes may exist (see Fig. 22-5B). In a more recent investigation using tissue Doppler imaging techniques, Donal and coworkers studied 28 consecutive patients with AMI involving either the left anterior descending or the right

PRE-AP E

POST-AP 17 th

POST-AP 1st Min

A

A GROUP 1

GROUP 2 1.5

1.0

1.0 E/A ratio

1.5

E/A ratio

Figure 22-5 A, Sequential recording of the transmitral flow velocities before atrial pacing, at the 3rd beat, the 17th beat, and 1 minute postatrial pacing (PAP), demonstrating changes with ischemia and recovery in a patient in group 2 (which developed ischemic electrocardiographic changes on pacing). The first panel at left shows normal left ventricular (LV) filling characteristics at rest before atrial pacing (PRE-AP). The next recording (second panel), at the 3rd postatrial pacing beat, shows a significant decrease in the early peak flow velocity, along with an increase in atrial peak flow velocity. At the 17th postatrial pacing beat (third panel), a gradual tendency toward recovery of the LV filling values is observed. At 1 minute after pacing (fourth panel), transmitral flow velocities are very similar to those of the 17th beat. B, Illustration comparing early/atrial (E/A) peak flow velocity ratio changes with atrial pacing in group 1 (no pacing-induced ischemia) and group 2 (pacing-induced ischemia). Early/atrial peak flow velocity ratio demonstrated a significant decrease in group 2 patients, without any significant change in group 1 patients, paralleling electrocardiographic ischemic changes. (From Iliceto S et al: Doppler echocardiographic evaluation of the effect of atrial pacing-induced ischemia on left ventricular filling in patients with coronary artery disease. J Am Coll Cardiol 1988;11:953–961.)

POST-AP 3rd

.5

.5

P: <.001

P: NS

B

Rest

Pacing

Rest

Pacing

281

282

Chapter 22 • Coronary Artery Disease coronary artery territory treated by primary PTCA.32 Echocardiographic studies were performed within 24 hours of angioplasty. A control group comprised 17 individuals with normal coronary angiography and transesophageal echocardiography. The authors recorded systolic (S), early diastolic (E), late diastolic (A), isovolumic contraction (IVC), and isovolumic relaxation (IVR) peak velocities by tissue Doppler. Not surprisingly, estimated LV ﬁlling pressures were signiﬁcantly higher in the two AMI groups compared with controls.32 The IVR peak velocities were signiﬁcantly lower in each of the two AMI populations compared with controls.32 The combination of IVC greater than 0 and IVR less than 1 separated ischemic from non-ischemic segments with 82% sensitivity and 85% speciﬁcity. Notably, among the two AMI groups, even non-ischemic segments or walls showed signiﬁcantly decreased velocities and displacements.32

Doppler Filling Profiles in Acute Myocardial Infarction Doppler echocardiography has been used to estimate prognosis in acute infarction (Table 22-2). Temporelli et al.33 showed that

DT was a strong prognostic marker both for LV remodeling and for survival following AMI (Fig. 22-6). A subset of 571 patients with conﬁrmed AMI and serial Doppler echo performed at 24 to 48 hours (baseline) from symptom onset, at hospital discharge, and at 6 months enrolled in the GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto) substudy formed the basis of the sample. Patients were assigned to two groups based on mitral DT, either restrictive (DT <130 msec) or nonrestrictive (DT >130 msec). During follow-up, the end diastolic volume index (EDVi) and the end systolic volume index (ESVi) increased, and percent of wall motion abnormality decreased in both groups. The magnitude of these changes was more pronounced in patients with a short DT compared with those with DT greater than 130 msec. A progressive impairment in EF was limited to patients with restrictive ﬁlling. LV dilation was twofold in the baseline restrictive ﬁlling group compared with the nonrestrictive ﬁlling group.33 By multivariate analysis, baseline EDVi and percent wall motion abnormality, along with predischarge persistent short DT, demonstrated a higher likelihood of severe late LV dilation (an increase in EDVi of more than 20%).33 These Doppler parameters also had prognostic importance. Follow-up at 4 years showed that

1.05

1.00

Survival (%)

0.95 p < 0.06 0.90

0.85 Baseline DT ≤130 msec (restrictive group) Baseline DT >130 msec (nonrestrictive group)

0.80

0.75 0

200

400

600

800

1000

1200

1400

1600

Time (days) 1.05

1.00

Survival (%)

0.95

0.90 p < 0.0003 0.85

Pre-discharge persistent short (≤130 msec) DT Pre-discharge prolonged (>130 msec) DT

0.80

0.75 0

200

400

600

800 Time (days)

1000

1200

1400

1600

Figure 22-6 Cumulative survival rates for all-cause mortality according to baseline and predischarge deceleration time (DT). The predischarge persistent short DT predicted a higher mortality. (From Temporelli PL et al: Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: Results of the GISSI-3 echo substudy. J Am Coll Cardiol 2004; 43:1646–1653.)

Chapter 22 • Coronary Artery Disease TABLE 22-2 PREDICTIVE VALUE OF DOPPLER ECHOCARDIOGRAPHIC PARAMETERS IN ACUTE MYOCARDIAL INFARCTION AUTHOR

NUMBER OF PATIENTS (n)

PATIENT POPULATION

Temporelli et al.33

571

AMI

PARAMETERS DT ≤130 msec predischarge persistent

FOLLOW-UP PERIOD 6 months

ENDPOINTS

RESULTS

Severe LV dilation and death from any cause

Severe dilation (>20%) was increased 1.6fold (patients with predischarge persistent restrictive filling vs. reversible restrictive filling; p < 0.04). All-cause mortality rate was 2.9-fold higher (patients with predischarge persistent restrictive filling vs. reversible restrictive filling; p < 0.0003). CHF was 1.4 times more common and NYHA class was higher; p < .01 (patients with restrictive LV filling vs. impaired relaxation). All 6 deaths were observed in patients with restrictive LV filling pattern. DT <170 msec was 2.4fold more often observed in patients with events than in patients without events; p < 0.001. E/e′ >10 was observed 13.2-fold more often in patients with events than in those without events; p < 0.0001. Two thirds of the deaths occurred in patients with E/e′ >15. Patients with E/e′ >15 were 2.2 times more likely to present with CHF; p < 0.001. Patients with E/e′ >15 had a 5.5-fold increase in indexed LV diastolic volume; p < .01.

4 years

Poulsen et al.34

58

First AMI (ST elevation)

DT ≤140 msec

12 months

In-hospital CHF or cardiac death

Naqvi et al.35

59

First AMI (ST elevation) who underwent primary PCI within 12 hours

DT <170 msec E/e′ ratio >10 of noninfarct–related mitral annulus

6 months

In-hospital events: cardiac death, CHF, sustained VT, or urgent surgical revascularization

Hillis et al.37

250

AMI

E/e′ ratio >15

13 months

All-cause mortality

Hillis et al.36

47

First AMI with TIMI grade III flow in infarctrelated coronary artery by angiography and akinesia of the arterial territory

E/e′ ratio >15

8 weeks

Remodeling (>15% increase in indexed LV end diastolic volume)

AMI, acute myocardial infarction; DT, deceleration time; LV, left ventricular; CHF, congestive heart failure; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; VT, ventricular tachycardia; TIMI, thrombolysis in myocardial infarction.

283

Chapter 22 • Coronary Artery Disease predischarge persistent restrictive ﬁlling (DT ≤130 msec) was the best predictor of mortality, compared with other clinical and Doppler echocardiographic variables.33 Poulsen et al. studied longitudinal changes and prognostic implications of LV diastolic function in patients with ﬁrst AMI and found similar results.34 They evaluated 58 consecutive patients admitted with ﬁrst AMI prospectively by two-dimensional and Doppler echocardiography, along with clinical evaluation on day 1 and day 5 and at 3 months and 12 months. The patients were classiﬁed into three groups based on the LV diastolic ﬁlling pattern at admission: normal, impaired relaxation, and pseudonormal/ restrictive patterns. CHF during hospitalization was noted more often in patients with the restrictive pattern than in patients with impaired relaxation at baseline (71% vs. 50%). Those with a restrictive pattern had more severe CHF by New York Heart Association class compared with normal and impaired relaxation ﬁlling patterns. Mitral E-wave DT less than 140 msec and age were determined as independent predictors of development of in-hospital CHF and cardiac death by multivariate regression analysis. Naqvi et al. evaluated 85 consecutive patients with a ﬁrst STelevation AMI, who underwent primary percutaneous coronary intervention (PCI) within 12 hours of hospital admission by echocardiography within 24 hours of primary PCI. The subjects were divided into two groups based on development (group A) or no development (group B) of in-hospital events, including cardiac death, CHF, sustained ventricular tachycardia (VT), and urgent surgical revascularization after primary PCI. Group A had restrictive mitral inﬂow and lower diastolic mitral annular Doppler tissue imaging (DTI) velocities, resulting in a high E/e′ (mitral inﬂow peak early velocity/mitral annular peak early velocity of the noninfarct annulus) ratio. Using peak early diastolic velocity of the lateral mitral annulus instead of the averaged peak early diastolic velocity of the non-infarcted annulus resulted in a higher E/e′ in group A versus B.35 The E/e′ ratio and mitral inﬂow E-wave DT were shown to be independent predictors of an in-hospital event on multivariate stepwise logistic regression analysis. E/e′ ratio less than 10 and a DT less than 170 msec were highly speciﬁc (98%) for absence of an in-hospital event. At the 6month follow-up echocardiographic assessment, baseline mitral inﬂow DT was the most important determinant of later LV EF. The E/e′ ratio (estimate of myocardial wall relaxation) and mitral inﬂow E-wave DT (estimate of global LV ﬁlling and relaxation) were superior to other echocardiographic parameters in determining in-hospital events and follow-up LV EF at 6 months.35 Hillis et al.36 examined the prognostic value of E/e′. The study group consisted of all 250 patients who had both Doppler transmitral ﬂow velocities and DTI performed among patients admitted for AMI at the Mayo Clinic with a clinically indicated echo during the index admission. Patients with E/e′ greater than 15 were older, more likely female, more likely to present with CHF, and more often had diabetes and a history of MI. These investigators found that patients with an E/e′ ratio greater than 15 had lower EF and a shorter DT. Twenty-nine patients died during a median follow-up period of 13 months, two thirds of whom had an E/e′ ratio greater than 15. After stratifying patients based on LV EF, E/e′ ratio of at least 15 predicted decreased survival in patients with an EF of 40% or greater. When DT was used to further delineate the groups, E/e′ ratio greater than 15 was a powerful predictor of mortality only in patients with DT greater than 140. The E/e′ ratio was the most powerful independent prognostic indicator of survival after AMI on stepwise multivariate analysis (Fig. 22-7). The E/e′ ratio more importantly

1.0

E/e′ ≤ 15

.9

Survival

284

.8

.7

.6

E/e′ > 15

.5 0 Number at risk 250

6

12

18

24

195

113

49

16

Duration of follow-up (months) Figure 22-7 Kaplan-Meier plot demonstrating decreased survival in patients with E/e′ ratio >15 compared with those with E/e′ ratio <15. (From Hillis GS et al: Noninvasive estimation of left ventricular filling pressure by E/e′ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360–367.)

complements the prognostic value of a combination of other clinical and echocardiographic parameters.36 The same researchers, in a more recent study, investigated the relationship between echocardiographic indices of acute and chronic LV ﬁlling pressures and dilation in 47 patients after their ﬁrst AMI.37 All patients demonstrated a patent infarct-related artery with a thrombolysis in myocardial infarction grade III ﬂow on coronary angiography and akinesia within this arterial territory on baseline echo. Patients were prospectively designated as remodeling (>15%) and nonremodeling (≤15%) groups based on the increase in indexed LV end diastolic volume at follow-up echocardiography at approximately 8 weeks. In this study, E/e′ was higher among the remodeling group, with a moderate correlation between basal E/e′ and changes in indexed LV diastolic volume (Fig. 22-8). Interestingly, LA volume index (LAVi) did not predict LV dilation. Both receiver operating characteristic (ROC) curve analysis and multivariate regression analysis conﬁrmed that E/e′ ratio greater than 15 was a strong predictor of remodeling, as deﬁned above. Finally, Sakata et al. investigated the prognostic value of Doppler transmitral ﬂow velocity patterns in AMI. Two hundred and six patients with ﬁrst AMI recruited to the study underwent two-dimensional and Doppler echocardiography on admission, and hemodynamic measurements (pulmonary capillary wedge pressure [PCWP] and cardiac index) were obtained by using a thermodilution catheter.38 The A-wave velocity was signiﬁcantly lower in nonsurvivors than in survivors. The E-wave velocity and the E/A ratio were signiﬁcantly higher, while DT was signiﬁcantly shorter in survivors with heart failure and nonsurvivors than in survivors without heart failure. Comparing patients with low A and those without a low A, the low A group had a signiﬁcantly higher frequency of mitral regurgitation, incidence of three-vessel coronary disease, PCWP, cardiogenic shock, and a higher mortality after angioplasty or thrombolytic therapy. Cardiac index and LV EF, on the other hand, were signiﬁcantly lower in the low A group. The low A was strongly associated with heart failure in the acute phase as well as in-hospital mortality. As

Chapter 22 • Coronary Artery Disease 120 E/E′ ≤ 15

LVEDV (ml/m2)

100

80

diography and tissue Doppler imaging, including deceleration time, E/E′ ratio, and E- and A-wave velocity, are associated with LV remodeling and predict acute in-hospital complications and cardiac mortality. Newer imaging modalities including speckle-strain imaging and three-dimensional echocardiography in association with biomarkers (BNP, MMP, TIMP) may provide additional information and improve understanding of diastolic function in coronary artery disease.

60

REFERENCES 40

20 120 E/E′ > 15

LVEDV (ml/m2)

100

80

60

40

20 Figure 22-8 Remodeling described by indexed left ventricular end diastolic volume (ml/m2) in patients with early transmitral flow velocity to early mitral annulus velocity ratio (E/E′) ≤15 compared with those with E/E′ >15. (From Hillis GS: Echocardiographic indices of increased left ventricular filling pressure and dilation after acute myocardial infarction. J Am Soc Echocardiogr 2006;19:450–456.)

a predictor of long-term mortality, the low A group had a signiﬁcantly higher mortality at 5 years. A shortened DT in the setting of an AMI likely reﬂects either worsened LV compliance or increased LV diastolic volume. An abnormality in compliance may serve to shift the LV pressurevolume curve upward and leftward. Such a shift in the diastolic pressure-volume relationship will lead to a more rapid equilibration of the transmitral pressure gradient and a shortened DT. In later stages of remodeling, the pressure-volume relationship may be shifted to the right. Progressive remodeling and chamber enlargement may be associated with a change in Doppler diastolic ﬁlling parameters. The addition of tissue Doppler imaging helps distinguish normal from pseudonormal ﬁlling patterns (similar to what is shown in Fig. 22-2) and provides pathophysiologic insight into diastolic function in progressive LV remodeling.

FUTURE RESEARCH Diastolic heart failure is increasingly being recognized by clinicians, and its role in the pathophysiology, diagnosis, and prognosis of ischemic heart disease is becoming better delineated. Diastolic function parameters as determined by Doppler echocar-

1. Aurigemma GP, Gaasch WH: Clinical practice. Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 2. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 3. Gottdiener JS, Arnold AM, Aurigemma GP, et al: Predictors of congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2000;35:1628–1637. 4. Vasan IRS, Benjamin EJ, Levy D: Prevalence, clinical features, and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol 1995;26:1565–1574. 5. Levy D, Larson MG, Vasan RS, et al: The progression from hypertension to congestive heart failure. JAMA 1996;275:1557–1562. 6. Klapholz M, Maurer M, Lowe AM, et al: Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: Results of the New York Heart Failure Registry. J Am Coll Cardiol 2004;43:1432–1438. 7. Redﬁeld MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 8. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355: 251–259. 9. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355: 260–269. 10. Aurigemma GP: Diastolic heart failure—a common and lethal condition by any name. N Engl J Med 2006;355:308–310. 11. Gottdiener JS, McClelland RL, Marshall R, et al: Outcome of congestive heart failure in elderly persons: Inﬂuence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med 2002;137:631–639. 12. Yusuf S, Pfeﬀer MA, Swedberg K, et al, for the CHARM Investigators and Committees: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781. 13. Carroll JC, Carroll EP: Exercise-induced angina pectoris In Gaasch WH, LeWinter MM (eds): Left ventricular diastolic dysfunction and heart failure. Philadelphia, Lea and Febiger, 1994:259–273. 14. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17–22. 15. Hess OM, Osakada G, Lavelle JF, et al: Diastolic myocardial wall stiﬀness and ventricular relaxation during partial and complete coronary occlusions in the conscious dog. Circ Res. 1983;52:387–400. 16. Pouleur H, Rousseau MF, van Eyll C, Charlier AA: Assessment of regional left ventricular relaxation in patients with coronary artery disease: Importance of geometric factors and changes in wall thickness. Circulation 1984;69:696–702. 17. Raya TE, Gay RG, Lancaster L, et al: Serial changes in left ventricular relaxation and chamber stiﬀness after large myocardial infarction in rats. Circulation 1988;77:1424–1431. 18. Rockman H, Lew WYW: Left ventricular remodeling and diastolic dysfunction in chronic ischemic heart disease. In Gaasch WH, LeWinter MM (eds): Left ventricular diastolic dysfunction and heart failure. Philadelphia, Lea and Febiger, 1994:306–324. 19. Pfeﬀer MA, Braunwald E: Ventricular remodeling after myocardial infarction. Circulation 1990;81:1161. 20. Cohn JN, Ferrari R, Sharpe N: Cardiac remodeling—concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 2000;35:569–582. 21. Opie LH, Commerford PJ, Gersh BJ, Pfeﬀer MA: Controversies in ventricular remodelling. Lancet 2006;367:356–367. Review.

285

286

Chapter 22 • Coronary Artery Disease 22. Aurigemma GP, Gottdiener JS, Shemanski L, et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 2001;37: 1042–1048. 23. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 24. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865–875. 25. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527–1533. 26. Appleton CP: Hemodynamic determinants of Doppler pulmonary venous ﬂow velocity components: New insights from studies in lightly sedated normal dogs. J Am Coll Cardiol 1997;30:1562–1574. 27. Tabata T, Thomas JD, Klein AL: Pulmonary venous ﬂow by Doppler echocardiography: Revisited 12 years later. J Am Coll Cardiol 2003;41:1243– 1250. Review. 28. Bogaty P, Mure P, Dumesnil JG: New insights into diastolic dysfunction as the cause of acute left-sided heart failure associated with systemic hypertension and/or coronary artery disease. Am J Cardiol 2002;89:341–345. 29. Labovitz AJ, Lewen MK, Kern M, et al: Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial ischemia produced by angioplasty. J Am Coll Cardiol 1987;10:748–755. 30. Snow FR, Gorcsan J 3rd, Lewis SA, et al: Doppler echocardiographic evaluation of left ventricular diastolic function after percutaneous transluminal coronary angioplasty for unstable angina pectoris or acute myocardial infarction. Am J Cardiol 1990;65:840–844.

31. Iliceto S, Amico A, Marangelli V, et al: Doppler echocardiographic evaluation of the eﬀect of atrial pacing-induced ischemia on left ventricular ﬁlling in patients with coronary artery disease. J Am Coll Cardiol 1988;11: 953–961. 32. Donal E, Raud-Raynier P, Coisne D, et al: Tissue Doppler echocardiographic quantiﬁcation. Comparison to coronary angiography results in acute coronary syndrome patients. Cardiovasc Ultrasound 2005; 3:10. 33. Temporelli PL, Giannuzzi P, Nicolosi GL, et al: Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: Results of the GISSI–3 echo substudy. J Am Coll Cardiol 2004;43:1646–1653. 34. Poulsen SH, Jensen SE, Egstrup K: Longitudinal changes and prognostic implications of left ventricular diastolic function in ﬁrst acute myocardial infarction. Am Heart J 1999;137:910–918. 35. Naqvi TZ, Padmanabhan S, Raﬁi F, et al: Comparison of usefulness of left ventricular diastolic versus systolic function as a predictor of outcome following primary percutaneous coronary angioplasty for acute myocardial infarction. Am J Cardiol 2006;97:160–166. Epub 2005 Nov 17. 36. Hillis GS, Ujino K, Mulvagh SL, et al: Echocardiographic indices of increased left ventricular ﬁlling pressure and dilation after acute myocardial infarction. J Am Soc Echocardiogr 2006;19:450–456. 37. Hillis GS, Moller JE, Pellikka PA, et al: Noninvasive estimation of left ventricular ﬁlling pressure by E/e’ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360–367. 38. Sakata K, Kashiro S, Hirata S, et al: Prognostic value of Doppler transmitral ﬂow velocity patterns in acute myocardial infarction. Am J Cardiol 1997;79:1165–1169.

SHEMY CARASSO, MD HARRY RAKOWSKI, MD

23 Hypertrophic Cardiomyopathy INTRODUCTION PATHOPHYSIOLOGY Molecular Level: Mutations and Calcium Economy Tissue Level: Hypertrophy, Fibrosis, and Disarray CLINICAL PRESENTATION AND PROGNOSIS Phenotypic Heterogeneity of Hypertrophic Cardiomyopathy Genotype/Phenotype Relations Origin of Symptoms

Prognosis Diagnosis Differential Diagnosis Identification of Subclinical Disease Clinical and Prognostic Correlates TREATMENT Medical Interventional Procedures FUTURE RESEARCH

INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a primary autosomaldominant disorder of the myocardium caused by mutations in several genes encoding cardiac contractile proteins (Fig. 23-1). Histopathologically it is associated with myocardial hypertrophy, ﬁber disarray, increased loose connective tissue, and ﬁbrosis, which are all thought to interfere with the generation of force and relaxation of the cardiac muscle (Fig. 23-2).1–5 Although HCM has been traditionally described as a hyperdynamic systolic disorder causing obstruction of the left ventricular outﬂow tract (LVOT), a large fraction of patients with HCM experience heart failure symptoms with a normal-appearing systolic function and without obstruction. This emphasizes the importance of myocardial relaxation and left ventricular (LV) ﬁlling in symptom generation in this disorder. The origin of diastolic dysfunction in HCM is multifactorial, with changes at the molecular, myocardial tissue, and global LV levels.

PATHOPHYSIOLOGY Molecular Level: Mutations and Calcium Economy The mutations related to HCM result in the production of abnormal myocardial sarcomeric proteins that have altered contraction

and relaxation characteristics. These include changes in the aﬃnity between the various contractile proteins and in the sensitivity to Ca2+, as well as in the eﬃciency of energy utilization (from ATP) and its expenditure.

Changes in Diastolic Calcium Levels Myosin Heavy Chain Mutations Mysosin heavy chain (MHC) mutations represent approximately 35% of HCM patients, and more than 50 diﬀerent point mutations have been described in families or probands with HCM. These are clustered in four particular locations in the S1 (head/rod junction) of the protein.6,7 The Arg403Gln has been extensively studied and is an example of a high-risk mutation. It lies close to the actin-binding interface7 and is a common severe mutation (100% penetrance and high incidence of sudden death). Its primary result is in reduction of ﬁlament sliding velocity and diminished rate of actin-activated myosin-ATPase activity, leading to a hypocontractile state.8–10 Diastolic function in patients with the Arg403Gln mutation is often impaired, with an end diastolic pressure (EDP) greater than 15 mmHg in most patients.11 Studies in mice12 showed two forms of diastolic dysfunction during inotropic stimulation: an increase in EDP and a slower maximal rate of relaxation (−dP/dt). The most direct explanation for impaired relaxation in αMHC403/+ hearts is that the 287

288

Chapter 23 • Hypertrophic Cardiomyopathy

Figure 23-1 Mutations in HCM. Cardiac contraction occurs when calcium binds the troponin complex (subunits C, I, and T) and α-tropomyosin, making possible the myosin-actin interaction. Actin stimulates ATPase activity in the globular myosin head and results in the production of force along actin filaments. Cardiac myosin binding protein C, arrayed transversely along the sarcomere, binds myosin and, when phosphorylated, modulates contraction. In hypertrophic cardiomyopathy, mutations may impair these and other protein interactions, result in ineffectual contraction of the sarcomere, and produce hypertrophy and disarray of myocytes. Percentages represent the estimated frequency with which a mutation on the corresponding gene causes hypertrophic cardiomyopathy. (From Spirito P, et al: The management of hypertrophic cardiomyopathy. N Engl J Med 1997;336:775–785.)

Figure 23-2 Pathology of hypertrophic cardiomyopathy. A, Gross pathology demonstrating asymmetric septal hypertrophy. B, Histopathology demonstrating fibrosis (thin arrows) and myocardial fiber disarray (thick arrows). Magnified figure shows normal myocardial architecture.

arginine-to-glutamine amino acid switch has slowed the kinetics of actin-myosin dissociation and led to prolonged activation of the thin ﬁlament.8 These observations indicate that the relaxation dysfunction is due to altered myosin binding kinetics. At high work loads, αMHC403/+ hearts reach an energetic state where sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) is unable to maintain the cytoplasm–sarcoplasmic reticulum Ca2+ gradient, causing diastolic Ca2+ overload12 due to a fall in the free energy stored in the high-energy phosphate bonds of ATP. Taken together, these observations indicate that the relaxation dysfunction is a primary consequence of altered myosin binding kinetics.

Changes in Sensitivity to Calcium Myosin Binding Protein C As with MHC, there are a large number of HCM-causing mutations (both missense and truncation mutations) aﬀecting variable regions of the protein.6 Myosin binding protein C (MyBPC) has modules responsible for binding to myosin ﬁlaments and to titin. MyBPC does not have a solely structural role but is also able to participate in regulatory signals, potentially in several pathways, linked through protein kinase cascades.13 In

young and adult homozygous cardiac-MyBPC knockout mice, isovolumic relaxation time (IVRT) was shown to be increased, indicating that relaxation was signiﬁcantly impaired.14 Skinned ﬁbers from LV papillary muscle from MyBPC mutant transgenic mice showed increased calcium sensitivity of force development and decreased maximum power compared with control ﬁbers.15 Cardiac Troponin T At least 10 mutations have been recognized in cardiac troponin T (cTnT), including missense, truncation, and deletion mutations. Their eﬀects include several aspects of increased function (higher sliding or shortening speed, higher Ca2+ aﬃnity) and decreased force (altered Ca2+ sensitivity, impairment of folding/ thin ﬁlament binding/sarcomere structure).16 Ca2+ sensitivity of force development increased moderately in some mutations and more dramatically in others. In one mutation, TnT(In16), both the activation and the inhibition of force were signiﬁcantly decreased, and the mutation substantially decreased the activation and inhibition of actin-Tm-activated myosin-ATPase activity. ATPase activation was also impaired by other TnT mutations. These observed changes in the Ca2+ regulation of force development would likely cause altered contractility and contribute to the development of HCM.17 The relaxation in these ﬁbers was also

Chapter 23 • Hypertrophic Cardiomyopathy signiﬁcantly impaired. One could speculate that this mutation could result in altered stoichiometry of the thin ﬁlament proteins and lead to dysfunctional interactions between the thick and thin ﬁlaments and change Ca2+-dependent interactions that would ultimately result in reduced activation and relaxation during muscle contraction.17 The data demonstrate that TnT can alter the rate of myosin cross-bridge detachment, and thus the troponin complex plays a signiﬁcant role in modulating muscle contractile performance.18 a-Tropomyosin Four HCM-related mutations are known, two of which change Ca2+ sensitive troponin binding, while the other two alter actin binding.6 In transgeneic mice, work performing ex vivo heart preparations demonstrated dramatically decreased rate of relaxation (−dP/dt) and increased diastolic and end diastolic pressures. Skinned ﬁber bundle measurements showed an increase in maximum tension and in Ca2+ sensitivity that corresponded to a slight increase in +dP/dt and slowing of relaxation as reﬂected in −dP/dt, respectively.19,20 Troponin I Five missense mutations were reported, along with a mutation causing the deletion of one codon. Troponin I (TnI) is the inhibitory component of the troponin complex and is involved in the Ca2+ regulation of muscle contraction in both skeletal and cardiac muscle.21 HCM TnI mutations result in (1) reduced inhibition of actin-tropomyosin–activated myosin ATPase by the troponin complex under relaxing conditions and (2) increased Ca2+ sensitivity of actin-tropomyosin–activated myosin ATPase regulation. These functional diﬀerences may manifest themselves in vivo as impairment of relaxation of cardiac muscle and may provide a hypertrophic stimulus leading to the disease state.21,22 Myosin Regulatory Light Chain Regulatory light chains (RLCs) play an important role in the maintenance of integrity of the thick ﬁlaments and their relaxed, ordered arrangement of myosin heads. Deltoid muscle biopsies from HCM patients with an RLC substitution mutation demonstrated increased calcium sensitivity and loss of relaxed order of thick ﬁlaments. The conformational change in peptide shape caused by the mutation may alter the degree to which the RLC can support the partially naked α-helical heavy chain core.13

Tissue Level: Hypertrophy, Fibrosis, and Disarray Microscopically, hypertrophy, ﬁbrosis, and myocardial ﬁber disarray are hallmarks of HCM,5–9 but they also exist in other forms of cardiac hypertrophy.23 Studies comparing hypertensive hypertrophy to HCM correlating histopathology ﬁndings to diastolic function showed that in both hypertensive and HCM patients, IVRT was signiﬁcantly longer, and the rapid ﬁlling volume index (RFVI) tended to be smaller than in the controls. While the mean myocyte size and percentage of myocardial interstitial ﬁbrosis did not diﬀer signiﬁcantly, quantitative disarray of myocytes in HCM was signiﬁcantly greater than that in hypertensive subjects. Multiple regression analysis showed that the percentage of ﬁbrosis was the most signiﬁcant factor related to diastolic LV dysfunction in hypertensive subjects, while disarray was the most signiﬁcant in HCM.23,24 In HCM patients, signiﬁcant positive correlations were observed between IVRT and wall thickness, diameter of

myocytes, and the percentage of ﬁbrosis, with negative correlations with disarray. There was a signiﬁcantly negative correlation between RFVI and wall thickness, and a signiﬁcantly positive correlation between RFVI and disarray. Multiple regression analyses showed that the diameter of myocytes, the percentage of ﬁbrosis, and disarray all correlated signiﬁcantly with IVRT (r = 0.821) and RFVI (r = 0.604). These results indicate that diastolic dysfunction in HCM is related to the degree of myocardial hypertrophy, increased interstitial ﬁbrosis, and especially myocardial disarrangement, including disorganization.23,24

Geometry Dynamic diastolic pressure-volume (P-V) curves measured during ﬁlling (PVRﬁll) in patients with HCM are often considerably shallower than would be anticipated if one assumed high chamber stiﬀness,25–27 and they markedly deviate from the passive end diastolic pressure-volume relationship (EDPVR) recorded during balloon catheter obstruction of inferior vena cava inﬂow. This is in contrast to the concordance of dynamic and passive curves in normal subjects, hypertensive hypertrophy, and dilated cardiomyopathy.27 The unusual behavior in HCM cannot be attributed directly to increased viscosity, enhanced pericardial constraint, or preload dependence of isovolumic relaxation. Regional heterogeneity of relaxation may play a role, but probably the major mechanism involves the end systolic distal chamber being virtually emptied, so that unfolding of the chamber in early diastole can accommodate substantial volumes by pure shape change without increasing the endocardial surface area and thus without stretching the myocardium.25,26 This may account for the fact that there was very little change in LV pressure during early ﬁlling in HCM hearts, yielding shallow PVRﬁll. This in turn may be directly related to the unique ﬁber and chamber architecture seen with HCM and possibly to enhanced ventricular interaction. These observations complicate the interpretation of diastolic P-V data in HCM, as well as conclusions regarding the inﬂuence of therapies based on analysis of single cardiac cycles.27

Ischemia In HCM, exercise-induced ischemia and reduced LV distensibility were demonstrated28,29 when studied by stress redistribution 201 Tl myocardial scintigraphy and biventricular cardiac catheterization and echocardiography at rest and during exercise. The LVEDP was signiﬁcantly increased in HCM patients with ischemia, while the end diastolic dimensions did not diﬀer from patients without it, indicating reduced LV diastolic distensibility.28 When LVEDP was measured serially,29 two distinct patterns were shown. In one, LVEDP steadily increased continuously throughout exercise. In contrast, in the second pattern, LVEDP exhibited biphasic changes rising until a critical heart rate was achieved, after which it declined. Importantly, the LVEDP at peak exercise in group 1 was similar to that at the critical heart rate in group 2 patients. Patients with this pattern had less exerciseinduced ﬁlling defects in 201Tl scintigraphy, suggesting a lower ischemic burden in this group. The biphasic pattern was lost with administration of a beta-blocker prior to exercise. The biphasic changes in LVEDP seen during exercise may be related to improved coronary microcirculation in response to betaadrenergic stimulation in patients with mild to moderate HCM.

289

290

Chapter 23 • Hypertrophic Cardiomyopathy

CLINICAL PRESENTATION AND PROGNOSIS Phenotypic Heterogeneity of Hypertrophic Cardiomyopathy The cardiac phenotype of HCM shows great diversity in the extent and pattern of hypertrophy, which may be asymmetric (involving mainly the interventricular septum, with or without LVOT obstruction), concentric, or apical,30 as well as in its penetrance.31,32 The clinical course is also very variable, especially in age of onset, existence of symptoms, disability, and predisposition to sudden death.33–35 With age, the hearts of aﬀected individuals undergo further remodeling, manifested by changes in the chamber size and the extent of hypertrophy. A small subset of aﬀected individuals progress to LV dilatation associated with end-stage heart failure (usually referred to as “burnt-out” HCM).36,37 Progression of HCM to the burnt-out phase of disease represents unfavorable remodeling characterized by loss of function; wall thinning and chamber dilatation cause combined systolic and diastolic dysfunction. Although this progression occurs in only about 10% of individuals with HCM, there is evidence that certain mutation populations are at greater risk for this clinical deterioration.37,38 In addition, the burnt-out phase of HCM may be evoked by a “second hit” in another gene, as has been reported in individuals with both sarcomere protein gene and mitochondrial mutations.

Genotype/Phenotype Relations Variability in the clinical course is explained in part by the diﬀerent roles that mutant proteins play in the sarcomere (see Fig. 23-2) and the eﬀect of the mutation on protein structure and function. The β-MHC gene was the ﬁrst to be identiﬁed as a cause of familial HCM, and almost 100 disease-causing mutations have been deﬁned to date that are responsible for about 35% of HCM cases.37 Most β-MHC mutations are located in the head and head/rod junction, and some of these mutations are recognized as causing severe hypertrophy that presents clinically early in life and demonstrate an increased risk for outﬂow obstruction, heart failure, and sudden death. Other β-MHC mutations may cause less severe clinical disease.37,39 MyBPC mutations (accounting for 15%–30% of HCM cases) are a leading cause of late-onset HCM and are generally associated with a good prognosis.31,32,40 TnT mutations (∼15% of HCM) generally cause less marked hypertrophy, with poor survival. Near-normal life expectancy has been reported with most α-tropomyosin (∼5% of HCM) and MyBPC mutations. Although this variation in clinical consequences most likely reﬂects diﬀerences in the biophysical properties of mutant and normal peptide, factors other than these structural changes can also inﬂuence disease expression. It has been demonstrated that the identical sarcomere mutation in diﬀerent populations can cause distinct hypertrophic morphologies and divergent clinical courses.41,42 Thus, although HCM-causing mutations can be identiﬁed, clinical diversity exists and is probably related to other genetic phenotypes, environment, gender, and acquired conditions. These data also raise the possibility that some (genetic or environmental or a combination of both) modiﬁers account for unfavorable cardiac remodeling and predisposition to adverse outcomes in HCM. Evaluation of candidate molecules as genetic modiﬁers of

HCM, particularly those that inﬂuence the extent of hypertrophy, including the renin-angiotensin-aldosterone axis, endothelin, and tumor necrosis factor (TNF), have shown conﬂicting results and appear only partially to explain the observed clinical diversity in the extent of hypertrophy in HCM. Polymorphisms within the angiotensin converting enzyme (ACE) gene have been reported to be associated with increased risk for sudden death.43,44 The complexities of deﬁning genetic modiﬁers in human HCM populations remain considerable, given the substantial heterogeneity of genetic causes that may independently inﬂuence hypertrophy.

Origin of Symptoms Symptoms leading to considerable disability in HCM patients are caused by obstruction (LVOT, RVOT, or LV midventricular), diastolic dysfunction with impaired relaxation and elevated ﬁlling pressures, coronary artery disease, independent mitral regurgitation (MR), and arrhythmia.45 Patients with obstructive HCM typically complain of dyspnea, angina, presyncope, syncope on exertion, or a combination thereof. Patients with nonobstructive HCM present with these symptoms less frequently, and usually the symptoms are milder. Congestive heart failure is uncommon in HCM in normal sinus rhythm, but it may be seen with severe obstruction to outﬂow or severe systolic or diastolic dysfunction, and of course it is common in the presence of atrial ﬁbrillation (AF). Patients with HCM and impaired relaxation, including those with apical HCM, develop progressive LA enlargement and AF, which results in severe hemodynamic deterioration because of the importance of atrial systole in the presence of impaired relaxation. Myocardial ischemia has been repeatedly demonstrated in both obstructive and nonobstructive HCM by means of ﬁxed and reversible thallium perfusion defects; by measurement of myocardial lactate production, particularly during rapid atrial pacing; and by positron emission tomography. Although the exact cause of the ischemia is in some doubt, it may be related to small-vessel disease with decreased vasodilator capacity. Other factors that could cause or contribute to ischemia are septal perforator artery compression, myocardial bridging, decreased coronary perfusion pressure, obstruction to LV outﬂow, and decreased capillary myocardial ﬁber ratio. Impaired relaxation of the myocardium during the isovolumic and rapid ﬁlling periods could impair coronary ﬁlling and result in ischemia. On the other hand, myocardial ischemia could act to impair relaxation by a number of mechanisms. Indeed, a vicious cycle may exist in HCM that relates diminished coronary perfusion and myocardial ischemia with impaired diastolic relaxation and vice versa. In about 20% of patients with subaortic obstruction in HCM, MR is to a variable extent independent of the systolic anterior motion, in which case other abnormalities of the mitral valve are present, such as anomalous papillary muscle attachment to the anterior leaﬂet, mitral valve prolapse, extensive anterior leaﬂet ﬁbrosis due to repeated mitral leaﬂet/septal contact, mitral annular calciﬁcation, and other, rarer abnormalities. These independent abnormalities of the mitral valve at times cause pansystolic MR, which is often anteriorly or centrally directed into the left atrium and is quite diﬀerent from the late-onset, posteriorly directed MR that is the result of anterior mitral leaﬂet systolic anterior motion.46 AF in the vast majority of cases of HCM is related to an increase in LA size (usually >50 mm). Obstructive HCM with

Chapter 23 • Hypertrophic Cardiomyopathy curve variables and mean LA pressure were not related in HCM patients, even when the extremes of age were excluded (Figs. 23-3 and 23-4).53 This may be due to a dominant inﬂuence of impaired relaxation on mitral inﬂow that overshadows the eﬀect of increased ﬁlling pressures.54 During left-heart catheterization, diastolic pressures before atrial contraction were weakly related to velocities of mitral or pulmonary venous ﬂow in HCM patients,54–57 whereas they correlated strongly with E/e′ and with E/Vp (e′ is the early diastolic longitudinal velocity recorded at the lateral mitral annulus; Vp is the ﬂow propagation velocity of ventricular ﬁlling).

concomitant MR is the most common cause of increased LA size and AF, but both systolic and diastolic dysfunction may also lead to signiﬁcant LA enlargement and atrial arrhythmias. The onset of AF in both obstructive and nonobstructive HCM may result in cardiac failure, syncope, and systemic emboli.

Prognosis In an unselected population followed prospectively,47 three distinctive modes of death were identiﬁed: (1) sudden and unexpected (51%; age 45 ± 20), (2) progressive heart failure (36%; age 56 ± 19), and (3) HCM-related stroke associated with AF (13%; age 73 ± 14). Sudden death was most common in young patients, whereas heart failure and stroke-related deaths occurred more frequently in midlife and beyond. However, neither sudden nor heart failure–related death showed a disproportionate age distribution. Stroke-related death did occur disproportionately in older patients, 91% of whom had AF and 64% of whom had LVOT obstruction. Even in patients with latent LVOT obstruction and apical HCM,48 the most frequent morbid event was AF. LA enlargement on baseline echo was identiﬁed as the only predictor of AF. Impaired LV relaxation in patients with HCM, including apical, has been previously proposed as a mechanism for progressive LA enlargement and subsequent AF.49–51 Thus, HCM patients appear to have a four- to sixfold greater likelihood of developing AF compared with the general population, and it will occur in about a third of them. AF prevalence increased progressively with age and LA size, which in turn is related to the degree of hypertrophy, severity of MR, and diastolic dysfunction. It is predominant in patients older than 60 years, but it is not rare in younger patients (<50 years), in whom it is associated with higher risk for clinical deterioration and HCM-related death.52

Left Atrial Volumes LA volumes have been previously shown to relate to LV ﬁlling pressures.58 A higher incidence of abnormal diastolic ﬁlling, a higher early diastolic velocity to early diastolic mitral annular velocity ratio, and a higher calculated LA pressure were found in HCM patients with an LA volume index (LAVI) of at least 34 m3/m2.51 Moreover, LA volumetric remodeling predicts exercise capacity in nonobstructive HCM and may reﬂect chronic LV diastolic burden. This simple, noninvasive measure of LA size may provide a long-term indication of the eﬀects of chronically elevated ﬁlling pressures in patients with HCM.59

Newer Doppler Echocardiographic Indices

Conventional Doppler Echocardiography

Myocardial Velocities by Tissue Doppler Imaging Patients with HCM demonstrate delayed and reduced longitudinal myocardial velocities and time-velocity integrals during early diastole.60 They also have lower velocities during atrial contraction and prolonged regional deceleration times and IVRTs. Larger changes in regional diastolic function were found in patients with mitral inﬂow E/A ratio below 1,60 and the diﬀerence in duration between mitral inﬂow and retrograde pulmonary venous ﬂow during atrial systole (Ar-A) correlates with elevated LA pressure54 and with abnormal collagen metabolism in patients with HCM.61

Mitral and Pulmonary Venous Flow Velocities Estimation of LV ﬁlling pressures by ﬂow Doppler echocardiographic methods is unreliable in HCM.53–57 Mitral ﬂow velocity

Myocardial Velocity Gradient A reduced myocardial velocity gradient (MVG), deﬁned as the diﬀerence in myocardial velocity between the endocardium and

Diagnosis

E DT=220 msec

E

E DT=220 msec A

DT=200 msec LV

A

Mean LAP 9 mmHg

Mean LAP 14 mmHg

Mean LAP 30 mmHg

DT 220; LAP 9

DT 220; LAP 14

DT 200; LAP 30

LV

Figure 23-3 Hypertrophic cardiomyopathy: deceleration time (DT) and mean left atrial pressure (LAP).53 Mitral inflow Doppler velocities and simultaneous left ventricular and LA pressure recordings are shown in three patients with similar transmitral early (E) and atrial (A) filling velocities and similar DT. Note that the mean LAPs are 9, 14, and 30 mmHg, respectively. This demonstrates the limitations of mitral inflow velocities in predicting LAP, since impaired relaxation overwhelms changes in filling pressures. (From Nishimura R, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226–1233.)

291

292

Chapter 23 • Hypertrophic Cardiomyopathy

E A

E¢

A

B Mitral E = 87 cm/sec A = 50 cm/sec E/A = 1.7 DT = 150 ms Annular = E′=8 cm/sec E/E′=10.9 Pulmonary vein PVS = 58 cm/sec PVD = 40 cm/sec PVAR = 50 cm/sec

S D

AR

C Figure 23-4 Mitral inflow and tissue annular velocities in apical hypertrophic cardiomyopathy (HCM). This patient with apical HCM complained of dyspnea on exertion and has Stage 2 diastolic dysfunction using mitral inflow and pulmonary vein flow velocities with a large atrial reversal. The use of E/E′ confirms an elevated LAP. A, Mitral inflow; B, Annular tissue velocities; C, Pulmonary venous velocities. Estimated LAP: 87/8 × 1.24 + 1.9 = 15 mmHg. DT, deceleration time; LAP, left atrial pressure.

the epicardium divided by myocardial wall thickness during diastole in HCM, reﬂects prolonged relaxation. It may also reﬂect an elevated LV EDP (Fig. 23-5).40,62 MVG is less aﬀected by preload alterations than by mitral inﬂow velocity pattern.63 During simultaneous LV pressures with tissue Doppler waveforms comparing HCM patients with controls, the peak negative MVG during rapid ﬁlling was lower in HCM, and a cutoﬀ value of 3.2/s discriminated well. HCM patients had higher EDPs (mean, 19.6 mmHg vs. 6.5 mmHg) and longer time constants of LV pressure decay (Tau, τ); MVG correlated inversely with both.62 In HCM patients, τ has been reported to inversely correlate with the myocardial peak early diastolic motion velocity.64 Echocardiographic Indices of Mechanical Dyssynchrony In HCM, longitudinal velocities around the LV base vary considerably, and a “heterogeneity index” (the average diﬀerence between individual velocity measurements and their means) can be calculated.65 Patients with HCM exhibit increased regional variations or asynchrony in the time to peak systolic velocity and in the duration of ejection.66 Diastolic function is also asynchronous, since patients with HCM have a high myocardial E/A heterogeneity index67 and more variation in the times from aortic valve closure to peak myocardial E velocity in diﬀerent segments.64 These observations are supported by a study of color kinesis in patients with HCM, using time curves of regional LV ﬁlling in a short-axis view.67 The percent ﬁlling fractions at 25%, 50%, and 75% of total ﬁlling were averaged for all segments in each patient, and the standard deviation of each mean was used as an “asynchrony index.” In subjects with HCM compared with con-

trols, asynchrony was increased in mid- and late diastole, and regional ﬁlling times were prolonged even in nonhypertrophied segments. Myocardial Strain and Strain Rate The assessment of myocardial muscle shortening (strain) and its rate are new tools in cardiac imaging. Strain may be evaluated noninvasively by tagging on magnetic resonance imaging (MRI) and by echocardiography.68–73 MRI studies have shown reduced longitudinal strain and early diastolic strain rate. Circumferential strain was less documented and was found to be either normal or slightly reduced in HCM.68,69 Strain rate imaging by tissue Doppler calculates velocity diﬀerences between two adjacent points to generate a strain rate/time curve, which is then integrated to calculate strain (Fig. 23-6). This method is restricted mostly to the evaluation of longitudinal indices by the alignment of the interrogation beam. By this method, longitudinal strain in patients has been shown to be reduced compared with controls.73 Newer methods analyze two-dimensional B-mode images by tissue tracking74–78 and allow for direct measurement of regional tissue displacement, shortening (strain) and strain rate both longitudinally and circumferentially and combining them into a three-dimensional model. Circumferential LV rotation can also be calculated. Our data77,78 are in support of the reduction of the longitudinal strain shown previously, while the circumferential strain was found to be increased. Longitudinal strain rate E was decreased by 23%, and circumferential strain rate E was increased by 37%, reﬂecting the decreased longitudinal strain and strain rate S and their increased circumferential values in HCM (Fig. 23-7A). Both longitudinal and circumferential strain rate

Chapter 23 • Hypertrophic Cardiomyopathy

Figure 23-5 Myocardial velocity gradients (MVGs) in hypertrophic cardiomyopathy (HCM) and athletes. Examples of Doppler myocardial M-mode images taken from the left ventricular (LV) posterior wall with calculated MVG. A, Male patient with HCM (age 36 years) with markedly hypertrophied LV posterior wall (1.9 cm). B, Male patient with HCM (age 23) with borderline LV posterior wall thickness (1.2 cm). C, Male athlete’s heart (age 25) with mild LV posterior wall hypertrophy (1.3 cm). Arrows show the peak values of the MVG and the normalized rate of the LV posterior wall systolic thickening during phases of the cardiac cycle. Asterisks indicate that MVG measured during right ventricular filling was markedly decreased in both HCM hearts (A and B) compared with the athlete’s heart (C). In contrast, the peak rate of wall thinning, assessed from a digitized grayscale M-mode image, did not show significant changes during right ventricular filling between the patient with HCM with borderline hypertrophy (B) and the athlete (C). AC, atrial contraction; RVF, rapid ventricular filling; VE, ventricular ejection. (From Palka P, et al: Differences in myocardial velocity gradient measured throughout the cardiac cycle in patients with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760–768.)

E/S ratio decreased signiﬁcantly, indicating impaired relaxation. Functional status (New York Heart Association class greater than I) was found to be related to decreased basal and midlongitudinal strain rate E. The LV twist angle (maximal instantaneous basal to apical angle diﬀerence) was similar, but time to peak twist was decreased by 13%, and untwist time (peak to trough twist) was lengthened by 16%, also implying delayed relaxation (see Fig. 23-7B).

Differential Diagnosis Hypertrophic Cardiomyopathy Versus Hypertensive Left Ventricular Hypertrophy Systolic velocities have been shown to be similarly reduced in HCM and hypertensive LV hypertrophy (LVH), with longer isovolumetric contraction and prolonged pre-ejection times in HCM compared with hypertensive patients. In HCM, the early diastolic velocity tends to be lower with increased heterogeneity of annular systolic velocities. Diastolic function is also more impaired in HCM, with lower velocities, higher heterogeneity, and longer IVRT.65,79 The MVG is also reduced in late diastole in HCM compared with hypertensive disease.62 These comparisons are somewhat confounded by younger mean age of HCM patients.

Hypertrophic Cardiomyopathy Versus Athlete’s Heart The discrimination between HCM and athlete’s heart is not trivial and may have signiﬁcant personal implications on an athlete’s career (ending it) and life (risking its end by sudden death). Patients with HCM have impaired systolic and diastolic function with both heterogeneity (of velocities) and dyssynchrony (of

timing of motion or contraction), whereas athletes have normal or supranormal function.65,79 Tissue Doppler is very helpful for discriminating between these conditions, and normal longitudinal function (mean systolic annular velocity <9 cm/sec)65 has a high negative predictive value. Individuals with HCM have lower diastolic velocities and prolonged isovolumetric relaxation.79 In one study, a value of less than 1 for the tissue Doppler E/A ratio was shown to be speciﬁc but not sensitive for diﬀerentiating HCM from athlete’s heart.80 A peak early diastolic MVG of at least 7 s−1 diﬀerentiated well between patients with HCM and athletes, in a young population (mean age 30) (see Fig. 23-6).40 In athlete’s heart, early diastolic velocity at the tricuspid annulus correlates with LV end diastolic diameter, inversely related to septal thickness.79 A tricuspid annular e velocity less than 0.16 m/sec diﬀerentiated between HCM and athlete’s heart with 89% sensitivity and 93% speciﬁcity.81

Identification of Subclinical Disease Subclinical disease implicates a negative phenotype with a positive HCM genotype. In a transgenic model of HCM,82 myocardial velocities were shown to be reduced. Systolic and early diastolic velocities were shown to be signiﬁcantly lower in subjects with HCM mutations, whether or not they had LVH when blindly compared with controls.83 A lateral annular systolic velocity less than 13 cm/sec had excellent sensitivity and speciﬁcity for identifying subjects with mutations but no LVH (see Table 23-1). In a similar study comparing controls and patients with proven βMHC mutations (with and without LVH), the mean myocardial early diastolic velocity was lower in patients with a mutation but no LVH,84 with a substantial overlap with the control group. In follow-up of 12 patients with β-MHC mutations (7 with MyBPC

293

294

Chapter 23 • Hypertrophic Cardiomyopathy

Figure 23-6 Reduced longitudinal strain in hypertrophic cardiomyopathy (HCM) by Doppler strain rate imaging. Different strain patterns in control patients and patients with HCM. Yellow, green, and red lines represent strain in basal, mid, and apical segments, respectively. A, Strain in healthy control. B, Strain in a patient with HCM. Note the lower maximal strain in HCM (8%) compared with normal (15%). (From Palka P, et al: Differences in myocardial velocity gradient measured throughout the cardiac cycle in patients with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760–768.)

mutations) but no LVH when ﬁrst examined, septal thickness and LV mass had increased after 2 years, and 6 patients met diagnostic criteria for HCM.85 These studies suggest that tissue Doppler may be very useful for early diagnosis or screening, but much larger studies are needed before clear diagnostic criteria can be proposed. Troponin T mutations present a major diagnostic challenge because of their very mild LVH and their high risk of sudden death. Tissue Doppler ﬁndings, especially diastolic velocities, may prove to be of prognostic value in future studies.

Clinical and Prognostic Correlates A high ratio of early diastolic mitral inﬂow velocity to mitral septal annular tissue velocity (E/E′) predicted death, cardiac arrest, or ventricular tachycardia in children observed for 26 months.86 Patients with HCM and LA enlargement had more serious cardiovascular events and demonstrated greater LVH, more diastolic dysfunction, and higher ﬁlling pressures.51 Early

diastolic velocities of lateral and septal annular motion were reduced in HCM compared with normal controls, and the E/E′ ratio correlated with symptomatic class and inversely with peak oxygen consumption.86,87 Our data also show that the clinical functional class77,78 is related to the early basal and midlongitudinal diastolic strain rate. The practical approach to echocardiographic assessment of diastolic function in HCM includes the combination of twodimensional, Doppler, and tissue Doppler information. Table 23-1 outlines this approach.

TREATMENT Medical Beta Blockers and Calcium Channel Blockers With symptoms it is conventional to initiate pharmacological therapy with negative inotropic drugs such as β-adrenergic

Chapter 23 • Hypertrophic Cardiomyopathy

Strain rate absolute value (%/s)

STRAIN RATE 4

Normal HCM

3.5 3 2.5 2 1.5 1 S

0.5

E

S

E

S

E

S

E

0 Base

Mid

Longitudinal

Apex

Circumferential

A TWIST ANGLE Twist

4.5

Normal HCM

Figure 23-7 Strain rate and twist by tissue strain imaging. A, Longitudinal and circumferential systolic and early diastolic strain rate in normal controls and hypertrophic cardiomyopathy (HCM) patients. Longitudinal systolic and diastolic strain rates are decreased in HCM, whereas circumferential strain rates are increased. Diastolic-to-systolic strain rate ratio is decreased in both planes. S and E denote peak systolic and early diastolic strain rates, respectively. B, Left ventricular twist (instantaneous base to apex rotation angle difference). Earlier systolic peak twist (solid arrows) and prolonged (dashed arrows) untwist are demonstrated in HCM patients.

Angle (degrees)

4

Flow Doppler

Pulmonary veins Tissue Doppler Multimodality

Mitral annular longitudinal velocity Left atrial pressure estimation

1.5

Untwist

0 0

20

40

60

80

100

Time (percent cycle length)

B

PARAMETERS LA dimension

Mitral inflow

2

0.5

A PRACTICAL APPROACH TO ECHOCARDIOGRAPHIC ASSESSMENT OF DIASTOLIC FUNCTION IN HYPERTROPHIC CARDIOMYOPATHY

Two-dimensional echo

3 2.5

1

TABLE 23-1

ECHOCARDIOGRAPHIC MODALITY

3.5

LA volume E A IVRT S D A reversal E′

( E′E × 1.24) + 1.9

LA, left ventricular; E, early diastolic filling; A, late atrial contraction; IVRT, isovolumic relaxation time; S, systolic; D, diastolic. From Nagueh et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. JACC 1997;30:1527–33.

blockers or verapamil, independent of whether outﬂow obstruction is present.88,89 Beta blockers relieve LVOT obstruction, and both beta blockers and verapamil inﬂuence ventricular diastolic function as well. Propranolol has been shown to shorten relaxation time in a dose-dependent fashion, up to its normalization at high dosages.90 LV diastolic stiﬀness in patients with HCM is not aﬀected by propranolol and verapamil.91,92 In tropomyosin (Tm)-mutated mice (E180G), diastolic dysfunction was abolished during β-blockade because propranolol eliminated the eﬀect of Tm to slow myocardial relaxation.93 Verapamil The eﬀect of verapamil on LVOT obstruction is less predictable, as it is also a potent vasodilator that can dangerously increase the outﬂow gradient.89 LV diastolic stiﬀness has been shown to remain unchanged in patients with HCM as with propranolol, and improved LV relaxation and mean diastolic ﬁlling were more consistent with verapamil than with beta blockers. Thus, the beneﬁcial eﬀect of verapamil on diastolic mechanics was found to be related to improved relaxation and diastolic ﬁlling rather than to changes in LV diastolic stiﬀness.91,92 L-Type Calcium Channel Blockers Diltiazem has been shown to normalize tissue Doppler peak systolic and early diastolic velocities at the lateral mitral annulus in asymptomatic patients with MyBPC mutations.94 In TnT mutant

295

296

Chapter 23 • Hypertrophic Cardiomyopathy mice stressed by isoproternol, severe diastolic heart failure and sudden death were prevented by pretreatment with diltiazem.95 Disopyramide A 1C anti-arrhythmic drug, disopyramide is a potent negative inotropic agent used in the treatment of obstructive HCM. Few studies have approached its eﬀect on diastolic function in HCM patients. Its main eﬀect seems to be improvement in ﬁlling (increased E, E/A ratio, decreased time interval from mitral valve opening to the O point in the apexcardiogram) that is related to the reduction of the LVOT gradient.96–98 Other Drugs Nicorandil, a potassium channel activator whose main eﬀect is anti-ischemic, has been shown to improve EDP during stress tests in HCM patients.99 Recent studies in animal models of HCM have shown that losartan and simvastatin can reverse the evolving cardiac phenotype.100,101 Aldosterone is a fundamental “molecular bridge” between enhanced collagen turnover in HCM and the cardiac phenotype.102 Therefore spironolactone might also be beneﬁcial but its potential beneﬁts remain unproven.

A

B

Interventional Procedures Septal ablation by alcohol and septal myectomy reduce Dopplerestimated τ, increase mitral annulus Ea velocity, and decrease pulmonary artery wedge pressure. Moreover, mitral inﬂow velocity propagation (Vp) assessed by color Doppler M-mode shows improvement of LV relaxation after septal reduction by increasing the intraventricular pressure gradient, or “suction,” during early diastole.103–105 Tissue Doppler strain rate imaging has shown normalization of diastolic dyssynchrony with septal ethanol ablation.106 Decreased afterload and an increased cardiac output due to the relief of the obstruction may lead to increased coronary ﬂow and improved myocardial perfusion,107 which may in turn beneﬁt LV relaxation. Also, the regression of hypertrophy and the changes in LV geometry that occur after septal reduction therapy, as shown in the present and previous studies,108,109 may also partially explain the improvement in diastolic function (Fig. 23-8).

C

D

FUTURE RESEARCH The origin of diastolic dysfunction in HCM is multifactorial. These factors range from molecular abnormalities in sarcomeric proteins and calcium metabolism and sensitivity, to tissue-level factors such as hypertrophy, ﬁbrosis, and disarray, to global ventricular geometric abnormalities and oxygen demand/supply mismatch. Symptoms in HCM are related to systolic obstruction and to the degree of diastolic dysfunction. Diastolic dysfunction leads to LA enlargement, which predisposes up to one third of patients to AF. AF decreases eﬀort tolerance dramatically in HCM patients, increases the risk of stroke, and is responsible for a large part of the morbidity and mortality in this disease. Conventional methods of assessing diastolic function (mitral inﬂow and pulmonary venous velocities) are of limited value in HCM. LA pressure assessment and LA volume have been shown to predict the severity of disease and outcome. Newer echocardiographic imaging methods, including two-dimensional speckle imaging to assess strain, strain rate, rotation, and untwisting, show promise in better understanding of the mechanical origin and degree of diastolic dysfunction and may be linked to prognosis.

Figure 23-8 Mitral inflow velocity and propagation velocity before and after septal ethanol ablation (SEA). Representative images of the improvement in color M-mode Doppler (CMM) and mitral inflow pulsed Doppler before (A and B, respectively) and after (C and D, respectively) SEA. Note increasing mitral velocity propagation (panel A vs. C) and normalization of restrictive mitral inflow (panel B vs. D) after the procedure. E and A denote early and late mitral inflow velocities, while Vp is the flow propagation.

REFERENCES 1. Teare D: Asymmetrical hypertrophy of the heart in young patients. Br Heart J 1958;20:1–8. 2. Ferrans VJ, Morrow AG, Roberts WC: Myocardial ultrastructure in idiopathic hypertrophic subaortic stenosis: A study of operatively excised left ventricular outﬂow tract muscle in 14 patients. Circulation 1972;45:769–792. 3. Pomerance A, Davies MJ: Pathological features of hypertrophic obstructive cardiomyopathy (HOCM) in the elderly. Br Heart J 1975;37:305–312. 4. Van Noorden S, Olsen EG, Pearse AG: Hypertrophic obstructive cardiomyopathy. A histological, histochemical and ultrastructural study of biopsy material. Cardiovasc Res 1971;5:118–131. 5. Maron BJ, Ferrans VJ, Henry WL, et al: Diﬀerences in distribution of myocardial abnormalities in patients with obstructive and nonobstructive asymmetric septal hypertrophy (ASH): Light and electron microscopic ﬁndings. Circulation 1974;50:436–446.

Chapter 23 • Hypertrophic Cardiomyopathy 6. Redwood CS, Moolman-Smook JC, Watkins H: Properties of mutant proteins that cause hypertrophic cardiomyopathy. Cardiovasc Res 1999;44:20–36. 7. Rayment I, Holden HM, Sellers JR, et al: Structural interpretation of the mutations in the beta-cardiac myosin. Proc Natl Acad Sci 1995;92: 3864–3868. 8. Sweeney HL, Straceski AJ, Leinwand LA, et al: Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J Biol Chem 1994;269:1603–1605. 9. Sata M, Ikebe M: Functional analysis of the mutations in the human cardiac β-myosin that are responsible for familial hypertrophic cardiomyopathy. J Clin Invest 1996;98:2866–2873. 10. Fujita H, Sugiura S, Momomura S-I, et al: Characterization of mutant myosins of Dictyostelium discoideum equivalent to human familial hypertrophic cardiomyopathy mutants. J Clin Invest 1997;99:1010– 1015. 11. Fananapazir L, Epstein ND: Genotype-phenotype correlations in hypertrophic cardiomyopathy. Circulation 1994;89:22–32. 12. Spindler M, Saupe KW, Christe ME, et al: Diastolic dysfunction and altered energetics in the αMHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Clin Invest 1998;101:1775–1783. 13. Levine RJ, Yang Z, Epstein ND, et al: Structural and functional responses of mammalian thick ﬁlaments to alterations in myosin regulatory light chains. J Struct Biol 1998;122:149–161. 14. Gautel M, Zuﬀardi O, Freiburg A, Labeit S: Phosphorylation switches speciﬁc for the cardiac isoform of myosin binding protein-C: A modulator of cardiac contraction? EMBO J 1995;14:1952–1960. 15. Yang Q, Sanbe A, Osinska H, et al: A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy. J Clin Invest 1998;102:1292–1300. 16. Tobacman LS, Lin D, Butters C, et al: Functional consequences of troponin T mutations found in hypertrophic cardiomyopathy. J Biol Chem 1999;274:28363–28370. 17. Szczesna D, Zhang R, Zhao J, et al: Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. J Biol Chem 2000;275:624–630. 18. Sweeney HL, Feng HS, Yang Z, Watkins H: Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: Insights into disease pathogenesis and troponin function. Proc Natl Acad Sci U S A 1998;95:14406–14410. 19. Prabhakar R, Boivin GP, Grupp IL, et al: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol 2001;33:1815–1828. 20. Bottinelli R, Coviello DA, Redwood CS, et al: A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. Circ Res 1998;82:106–115. 21. Elliott K, Watkins H, Redwood CS: Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy. J Biol Chem 2000;275:22069–22074. 22. Lang R, Gomes AV, Zhao J, et al: Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy. J Biol Chem 2002;277:11670–16678. 23. Ohsato K, Shimizu M, Sugihara N, et al: Histopathological factors related to diastolic function in myocardial hypertrophy. Jpn Circ J 1992;56: 325–333. 24. Sugihara N, Shimizu M, Suematsu T, et al: Early diastolic dysfunction of the left ventricle aﬀected by hypertrophy and abnormal histopathology in hypertrophic cardiomyopathy. J Cardiol 1990;20:71–81. 25. Sanderson JE, Gibson DG, Brown DJ, Goodwin JF: Left ventricular ﬁlling in hypertrophic cardiomyopathy: An angiographic study. Br Heart J 1977;39:661–670. 26. Gibson DG, Brown DG: Relation between diastolic left ventricular wall stress and strain in man. Br Heart J 1974;36:1066–1077. 27. Pak PH, Maughan L, Baughman KL, Kass DA: Marked discordance between dynamic and passive diastolic pressure-volume relations in idiopathic hypertrophic cardiomyopathy. Circulation 1996;94:52–60. 28. Isobe S, Izawa H, Takeichi Y, et al: Relationship between exercise-induced myocardial ischemia and reduced left ventricular distensibility in patients with nonobstructive hypertrophic cardiomyopathy. J Nucl Med 2003;44: 1717–1724. 29. Takeichi Y, Yokota M, Iwase M, et al: Biphasic changes in left ventricular end-diastolic pressure during dynamic exercise in patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:335–343. 30. Klues HG, Schiﬀers A, Maron, BJ: Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: Morphologic

31. 32.

33. 34. 35. 36. 37.

38. 39. 40. 41.

42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53.

54.

observations and signiﬁcance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol 1995;26:1699–1708. Niimura H, Bachinski LL, Sangwatanaroj S, et al: Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248–1257. Erdmann J, Raible J, Maki-Abadi J, et al: Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:322– 330. Abchee A, Marian AJ: Prognostic signiﬁcance of beta-myosin heavy chain mutations is reﬂective of their hypertrophic expressivity in patients with hypertrophic cardiomyopathy. J Invest Med 1997;45:191–196. Moolman JC, Corﬁeld VA, Posen B, et al: Sudden death due to troponin T mutations. J Am Coll Cardiol 1997:29:549–555. Maron BJ, Olivotto I, Spirito P, et al: Epidemiology of hypertrophic cardiomyopathy-related death: Revisited in a large non-referral-based patient population. Circulation 2000;102:858–864. Spirito P, Seidman CE, McKenna WJ, Maron, BJ: The management of hypertrophic cardiomyopathy. N Engl J Med 1997;336:775–785. Seidman CE, Seidman, JG: Hypertrophic cardiomyopathy. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The metabolic and molecular basis of inherited disease, 8th ed, vol 4. New York, McGraw-Hill, 2001:5433– 5418. Regitz-Zagrosek V, Erdmann J, Wellnhofer E, et al: Novel mutation in the alpha-tropomyosin gene and transition from hypertrophic to hypocontractile dilated cardiomyopathy. Circulation 2000;102:E112–E116. Roberts R, Sigwart U: New concepts in hypertrophic cardiomyopathy. Circulation 2001;104:2113–2116, 2249–2252. Harris SP, Bartley CR, Hacker TA, et al: Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res 2002;90:594–601. Fananapazir L, Epstein, ND: Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical β-myosin heavy chain gene mutations. Circulation 1994;89:22–32. Kimura A, Harada H, Park JE, et al: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16: 379–382. Marian AJ, Yu Q, Workman R, et al: Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet 1993;342:1085–1086. Lechin M, Quinones MA, Omran A, et al. Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. Circulation 1995;92:1808–1812. Wigle ED, Rakowski H, Kimball BP, Williams WG: Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation 1995;92: 1680–1692. Yu EH, Omran AS, Wigle ED, et al: Mitral regurgitation in hypertrophic obstructive cardiomyopathy: Relationship to obstruction and relief with myectomy. J Am Coll Cardiol 2000;36:2219–2225. Maron BJ, Olivotto I, Spirito P, et al: Epidemiology of hypertrophic cardiomyopathy-related death: Revisited in a large non-referral-based patient population. Circulation 2000;102:858–864. Eriksson MJ, Sonnenberg B, Woo A, et al: Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39: 638–645. Wigle ED, Sasson Z, Henderson MA, et al: Hypertrophic cardiomyopathy. The importance of the site and the extent of hypertrophy. A review. Prog Cardiovasc Dis 1985;28:1–83. Webb JG, Sasson Z, Rakowski H, et al: Apical hypertrophic cardiomyopathy: Clinical follow-up and diagnostic correlates. J Am Coll Cardiol 1990;15:83–90. Yang H, Woo A, Monakier D, et al: Enlarged left atrial volume in hypertrophic cardiomyopathy: A marker for disease severity. J Am Soc Echocardiogr 2005;18:1074–1082. Olivotto I, Cecchi F, Casey SA, et al: Impact of atrial ﬁbrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104: 2517–2524. Nishimura R, Appleton C, Redﬁeld M, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular ﬁlling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 1996;28:1226–1233. Nagueh SF, Lakkis NM, Middleton KJ, et al: Doppler estimation of left ventricular ﬁlling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99;254–261.

297

298

Chapter 23 • Hypertrophic Cardiomyopathy 55. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Col Cardiol 1997;30:1527–1533. 56. Yamamoto K, Nishimura RA, Chaliki HP, et al: Determination of left ventricular ﬁlling pressure by Doppler echocardiography in patients with coronary artery disease: Critical role of left ventricular systolic function. J Am Coll Cardiol 1997;30:1819–1826. 57. Nishimura RA, Abel MD, Hatle LK, Tajik AJ: Relation of pulmonary vein to mitral ﬂow velocities by transesophageal Doppler echocardiography: Eﬀect of diﬀerent loading conditions. Circulation 1990;81:1488–1497. 58. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular ﬁlling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. J Am Coll Cardiol 1993;22: 1972–1982. 59. Sachdev V, Shizukuda Y, Brenneman CL, et al: Left atrial volumetric remodeling is predictive of functional capacity in nonobstructive hypertrophic cardiomyopathy. Am Heart J 2005;149:730–736. 60. Severino S, Caso P, Galderisi M, et al.: Use of pulsed Doppler tissue imaging to assess regional left ventricular diastolic dysfunction in hypertrophic cardiomyopathy. Am J Cardiol 1998;82:1394–1398. 61. Lombardi R, Betocchi S, Losi MA, et al: Myocardial collagen turnover in hypertrophic cardiomyopathy. Circulation 2003;108:1455–1460. 62. Palka P, Lange A, Fleming AD, et al: Diﬀerences in myocardial velocity gradient measured throughout the cardiac cycle in patients with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760–768. 63. Kato T, Noda A, Izawa H, et al: Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;42:278– 285. 64. Shimizu Y, Uematsu M, Shimizu H, et al: Peak negative myocardial velocity gradient in early diastole as a noninvasive indicator of left ventricular diastolic function: Comparison with transmitral ﬂow velocity indices. J Am Coll Cardiol 1998;32:1418–1425. 65. Oki T, Mishiro Y, Yamada H, et al: Detection of left ventricular regional relaxation abnormalities and asynchrony in patients with hypertrophic cardiomyopathy with the use of tissue Doppler imaging. Am Heart J 2000;139:497–502. 66. Vinereanu D, Florescu N, Sculthorpe N, et al: Diﬀerentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001;88:53–58. 67. Cardim N, Castela S, Cordeiro R, et al: Tissue Doppler imaging assessment of long axis left ventricular function in hypertrophic cardiomyopathy. Rev Port Cardiol 2002;21:953–985. 68. Ito T, Suwa M, Imai M, et al: Assessment of regional left ventricular ﬁlling dynamics using color kinesis in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2004;17:146–151. 69. Young AA, Kramer CM, Ferrari VA, et al: Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy. Circulation 1994;90: 854–867. 70. Maier SE, Fischer SE, McKinnon GC, et al: Evaluation of left ventricular segmental wall motion in hypertrophic cardiomyopathy with myocardial tagging. Circulation 1992;86:1919–1928. 71. Rothfeld JM, LeWinter MM, Tischler MD: Left ventricular systolic torsion and early diastolic ﬁlling by echocardiography in normal humans. Am J Cardiol 1998;81:1465–1469. 72. Buchalter MB, Weiss JL, Rogers WJ, et al: Noninvasive quantiﬁcation of left ventricular rotational deformation in normal humans using magnetic resonance imaging myocardial tagging. Circulation 1990;81:1236–1244. 73. Yang H, Sun JP, Lever HM, et al: Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2003;16:233–239. 74. Notomi Y, Lysyansky P, Setser RM, et al: Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol 2005;45:2034–41. 75. Helle-Valle T, Crosby J, Edvardsen T, et al: New noninvasive method for assessment of left ventricular rotation: Speckle tracking echocardiography. Circulation 2005;112:3149–3156. 76. Vannan MA, Pedrizzetti G, Li P, et al: Eﬀect of cardiac resynchronization therapy on longitudinal and circumferential left ventricular mechanics by velocity vector imaging: Description and initial clinical application of a novel method using high-frame rate B-mode echocardiographic images. Echocardiography 2005;22:826–830.

77. Carasso S, Yang H, Vannan MA, et al: New concepts of myocardial mechanics in hypertrophic myocardiopathy. Paper presented at the meeting of the American College of Cardiology, June 2006, Atlanta, Georgia. 78. Carasso S, Yang H, Vannan MA, et al: A novel method of evaluating diastolic muscle mechanics septal hypertrophic cardiomyopathy. Paper presented at the meeting of the American College of Cardiology, June 2006, Atlanta, Georgia. 79. Cardim N, Longo S, Ferreira T, et al: Tissue Doppler imaging assessment of long axis left ventricular function in hypertensive patients with concentric left ventricular hypertrophy: Diﬀerential diagnosis with hypertrophic cardiomyopathy. Rev Port Cardiol 2002;21:709–740. 80. Cardim N, Oliveira AG, Longo S, et al: Tissue Doppler imaging: Regional myocardial function in hypertrophic cardiomyopathy and in athlete’s heart. J Am Soc Echocardiogr 2003;16:223–232. 81. Whyte GP, George K, Sharma S, et al: The upper limit of physiological cardiac hypertrophy in elite male and female athletes: The British experience. Eur J Appl Physiol 2004;16:154–161. 82. Nagueh SF, Kopelen HA, Lim DS, et al: Tissue Doppler imaging consistently detects myocardial contraction and relaxation abnormalities, irrespective of cardiac hypertrophy, in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2000;102:1346–1350. 83. Nagueh SF, Bachinski LL, Meyer D, et al: Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 2001;104:128–130. 84. Ho CY, Sweitzer NK, McDonough B, et al: Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–2997. 85. Nagueh SF, McFalls J, Meyer D, et al: Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 2003;108:395–398. 86. McMahon CJ, Nagueh SF, Pignatelli RH, et al: Characterisation of left ventricular diastolic function by tissue Doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation 2004:109. 87. Matsumura Y, Elliott PM, Virdee MS, et al: Left ventricular diastolic function assessed using Doppler tissue imaging in patients with hypertrophic cardiomyopathy: Relation to symptoms and exercise capacity. Heart 2002;87:247–251. 88. Maron BJ: Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287:1308–1320. 89. Wigle ED, Rakowski H, Kimball BP, Williams WG: Hypertrophic cardiomyopathy clinical spectrum and treatment. Circulation 1995;92: 1680–1692. 90. Bourmayan C, Razavi A, Fournier C, et al: Eﬀect of propranolol on left ventricular relaxation in hypertrophic cardiomyopathy: An echographic study. Am Heart J 1985;109:1311–1316. 91. Hess OM, Grimm J, Krayenbuehl HP: Diastolic function in hypertrophic cardiomyopathy: Eﬀects of propranolol and verapamil on diastolic stiﬀness. Eur Heart J. 1983;4(Suppl F):47–56. 92. Doiuchi J, Hamada M, Ito T, Kokubu T: Comparative eﬀects of calciumchannel blockers and beta-adrenergic blocker on early diastolic time intervals and A-wave ratio in patients with hypertrophic cardiomyopathy. Clin Cardiol 1987;10:26–30. 93. Michele DE, Gomez CA, Hong KE, et al: Cardiac dysfunction in hypertrophic cardiomyopathy mutant tropomyosin mice is transgene-dependent, hypertrophy-independent, and improved by β-blockade. Circ Res 2002;91:255–262. 94. McTaggart DR: Diltiazem reverses tissue Doppler velocity abnormalities in pre-clinical hypertrophic cardiomyopathy. Heart Lung Circ 2004;13: 39–40. 95. Westermann D, Knollmann BC, Steendijk P, et al: Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy. Eur J Heart Fail 2006;8:115–121. 96. Matsubara H, Nakatani S, Nagata S, et al: Salutary eﬀect of disopyramide on left ventricular diastolic function in hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 1995;26:768–775. 97. Sumimoto T, Hamada M, Ohtani T, et al: Eﬀect of disopyramide on left ventricular diastolic function in patients with hypertrophic cardiomyopathy: Comparison with diltiazem. Cardiovasc Drugs Ther 1992;6:425–428. 98. Sumimoto T, Hamada M, Ohtani T, Eﬀect of disopyramide on systolic and early diastolic time intervals in patients with hypertrophic cardiomyopathy. J Clin Pharmacol 1991;31:440–443. 99. Izawa H, Iwase M, Takeichi Y, et al: Eﬀect of nicorandil on left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy. Eur Heart J 2003;24:1340–1348.

Chapter 23 • Hypertrophic Cardiomyopathy 100. Lim DS, Lutucuta S, Bachireddy P, et al: Angiotensin II blockade reverses myocardial ﬁbrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 2001;103:789–791. 101. Patel R, Nagueh SF, Tsybouleva N, et al: Simvastatin induces regression of cardiac hypertrophy and ﬁbrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2001;104:317–324. 102. Tsybouleva N, Zhang L, Chen S, et al: Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation 2004;109:1284–1291. 103. Sitges M, Shiota T, Lever HM, et al: Comparison of left ventricular diastolic function in obstructive hypertrophic cardiomyopathy in patients undergoing percutaneous septal alcohol ablation versus surgical myotomy/myectomy. Am J Cardiol 2003;91:817–821. 104. Rovner A, Smith R, Greenberg NL, et al: Improvement in diastolic intraventricular pressure gradients in patients with HOCM after ethanol septal reduction. Am J Physiol 2003;285:H2492–H2499.

105. Park TH, Lakkis NM, Middleton KJ, et al: Acute eﬀect of nonsurgical septal reduction therapy on regional left ventricular asynchrony in patients with hypertrophic obstructive cardiomyopathy. Circulation 2002;106: 412–415. 106. Abraham TP, Nishimura RA, Holmes DR, et al: Strain rate imaging for assessment of regional myocardial function: results from a clinical model of septal ablation. Circulation 2002, 105:1403–1409. 107. Cannon RO III, McIntosh CL, Schenke WH, et al: Eﬀect of surgical reduction of left ventricular outﬂow obstruction on hemodynamics, coronary ﬂow, and myocardial metabolism in hypertrophic cardiomyopathy. Circulation 1989;79:766–775. 108. Mazur W, Nagueh SF, Lakkis NM, et al: Regression of left ventricular hypertrophy after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 2001;103:1492– 1496. 109. Quinones JA, DeLeon SY, Vitullo DA, et al: Regression of hypertrophic cardiomyopathy after modiﬁed Konno procedure. Ann Thorac Surg 1995;60:1250–1254.

299

TRACI L. JURRENS, MD NASER M. AMMASH, MD JAE K. OH, MD

24

Pericardial Diseases: Constriction and Pericardial Effusion INTRODUCTION PATHOPHYSIOLOGY Constrictive Pericarditis Versus Restrictive Cardiomyopathy Clinical Presentations and Physical Examination Findings Electrocardiogram and Brain Natriuretic Peptide

Echocardiography Chest X-ray, Computed Tomography, and Magnetic Resonance Imaging Treatment CLINICAL RELEVANCE SUMMARY AND FUTURE RESEARCH

INTRODUCTION Normal pericardium consists of an outer sac, the ﬁbrous pericardium; and an inner double-layered sac, the serous pericardium. The visceral layer of the serous pericardium, or epicardium, covers the heart and proximal great vessels. It is reﬂected to form the parietal pericardium, which lines the ﬁbrous pericardium (Fig. 24-1). The pericardium provides mechanical protection for the heart and lubrication to reduce friction between the heart and surrounding structures. The pericardium also has a signiﬁcant hemodynamic impact on the atria and ventricles. The nondistendible pericardium limits acute distention of the heart (see Chapter 2). Ventricular volume is greater at any given ventricular ﬁlling pressure with the pericardium removed than with the pericardium intact. The pericardium also contributes to diastolic coupling between two ventricles: The distention of one ventricle alters the ﬁlling of the other, an eﬀect that is important in the

pathophysiology of cardiac tamponade and constrictive pericarditis (CP). Ventricular interdependence within a normal pericardium is not noticeable clinically but becomes more marked when ﬁlling pressure becomes high or diastolic ﬁlling is limited. Among much pathology involving the pericardium, none is more fascinating than CP in terms of characteristic hemodynamics, clinical presentations, physical examination ﬁndings, and diﬃculty of diagnosis. This chapter will focus mainly on the underlying pathophysiology, clinical presentations, characteristic diagnostic features, various forms, and treatments of CP. Acute accumulation of pericardial eﬀusion results in sudden hemodynamic deterioration, as in cardiac rupture or hemopericardium. Detection of this acute cardiac tamponade is relatively easy by characteristic clinical setting (acute myocardial infarction, aortic dissection, or invasive cardiac procedure) and twodimensional echocardiographic ﬁndings of hemopericardium. This entity is not discussed in this chapter. Subacute or chronic 301

302

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion pericardial eﬀusion may create prominent right-heart failure, the presentation of which may be similar to CP; and not infrequently, CP presents with varying degrees of pericardial eﬀusion, including a presentation similar to cardiac tamponade, but hemodynamic abnormality persists after removal of pericardial eﬀusion. This condition is called eﬀusive-constrictive pericarditis and will be discussed at further length at the end of this chapter. Interest in the pericardium dates back to antiquity. Hippocrates mentioned the “smooth mantle surrounding the heart and containing a small amount of ﬂuid resembling urine.”1 In the 17thcentury, a Cornish clinician, John Mayow, described the gross appearance of CP in his patient’s heart as “nearly covered by car-

Figure 24-1 Normal pericardium consists of an outer sac, the fibrous pericardium, and an inner double-layered sac, the serous pericardium. The visceral layer of the serous pericardium, or epicardium, covers the heart and proximal great vessels. It is reflected to form the parietal pericardium, which lines the fibrous pericardium. The pericardium provides mechanical protection for the heart and lubrication to reduce friction between the heart and surrounding structures. The pericardium also has a significant hemodynamic impact on the atria and ventricles. The nondistendible pericardium limits acute distention of the heart. Ventricular volume is greater at any given ventricular filling pressure with the pericardium removed than with the pericardium intact. The pericardium also contributes to diastolic coupling between two ventricles: The distention of one ventricle alters the filling of the other, an effect that is important in the pathophysiology of cardiac tamponade and constrictive pericarditis. Ventricular interdependence becomes more marked at high ventricular filling pressures. Abnormalities of the pericardium can range from the pleuritic chest pain of pericarditis to marked heart failure and even death from tamponade or constriction. (Courtesy of William D. Edwards, MD).

A

B

tilage, adherent to its interior so that the blood could scarcely enter the ventricle,”1 illustrating diastolic ﬁlling abnormality of this disorder. Several hundred years passed before the ﬁrst publication mentioning the hemodynamics of CP appeared in 1946 from New York University. Cournand and Richards, who received the Nobel Prize for their work on cardiac catheterization, described the pressure tracing of CP in a 30-year-old patient, resembling right ventricular (RV) failure with “certain additional features.”2 The additional features include normal ventricular systolic pressure, low ventricular pulse pressure, a marked elevation of mean atrial and ventricular diastolic pressure, and the prominence of early diastolic dip in atrial and ventricular pressure. At that time, the hemodynamics of restrictive cardiomyopathy (RC) were not ﬁrmly established, and subsequently it was recognized that the hemodynamic features of CP were similar to those of RC.3 Sixty years later, the same hemodynamic criteria are still being used in most cardiac catheterization laboratories to diagnose CP, although the criteria lack speciﬁcity. More insights into the pathophysiology and unique hemodynamic features of CP have established more speciﬁc diagnostic criteria for constriction, which can be demonstrated by noninvasive two-dimensional Doppler echocardiography, as well as by invasive cardiac hemodynamic measurements. The diagnosis of CP is often overlooked, since ventricular systolic function is usually well preserved, and clinical manifestations can involve other organs, leading to investigation of noncardiac abnormalities before consideration of a pericardial disease. When discussing CP, it is impossible not to mention RC as well. Although CP and RC are two very diﬀerent entities, they appear similar superﬁcially. The hemodynamic end products of the constriction and restriction are almost identical, which makes their distinction diﬃcult if not impossible by a casual inspection of a patient’s hemodynamic status. It is essential to demonstrate features unique to each condition and that are not present in other conditions. This chapter will, therefore, also describe the similarities and diﬀerences between constriction and restriction in their clinical characteristics, hemodynamic proﬁles, and laboratory data.

PATHOPHYSIOLOGY CP is caused by noncompliant and usually (but not always) thickened pericardium (Fig. 24-2). The pericardium becomes abnormal because of damage from inﬂammation, radiation, trauma, or

Figure 24-2 A, Pathology specimen of typical constrictive pericarditis. The figure shows a thickened and fibrotic pericardium, which limits diastolic filling and can lead to heart failure despite normal systolic function. Since constriction is a curable entity, it should be considered in patients with heart failure and normal systolic function. B, Pathology specimen of idiopathic restrictive cardiomyopathy demonstrating prominent biatrial enlargement with normalsized ventricles. (A, Courtesy of William D. Edwards, MD; B, From Ammash NM et al: Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490–2496.)

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion an autoimmune process. A majority of patients with CP do have an underlying etiology, although this cannot be determined in a third of patients.4 In regions where tuberculosis is common, this is still the most frequent etiology for CP,5 but in the current era, previous cardiac surgery is the most common etiology in the United States,4 accounting for one third of surgically conﬁrmed cases of CP, followed by acute pericarditis, radiation, and collagen vascular disease. Therefore, CP should always be considered if a patient presents with heart failure, normal ejection fraction, and history of one of the associated conditions. In CP, the atria and inferior vena cava are enlarged secondary to limited ventricular ﬁlling and high ﬁlling pressure. Ventricular septal thickness is not increased but shows a characteristic motion with respiratory septal shift.

Constrictive Pericarditis Versus Restrictive Cardiomyopathy By deﬁnition, RC is a myocardial disease causing primarily diastolic dysfunction and heart failure similar to CP (see Chapter 21).6 RC can be idiopathic or secondary to inﬁltrative disease such as amyloidosis or sarcoidosis, or a storage disease such as Fabry’s disease. It has been also reported to occur secondary to hypereosinophilic syndrome, radiation, scleroderma, and medications such as chloroquine. Idiopathic or primary RC has distinct morphologic features that include nondilated, nonhypertrophied ventricles with biatrial enlargement (see Fig. 24-2B). On the other hand, left ventricular (LV) wall thickness in secondary RC is usually increased, and there may be an overlap with the nonobstructive form of hypertrophic cardiomyopathy. Despite the different pathophysiologic mechanisms of CP and RC, they share many similar hemodynamic ﬁndings when measured by cardiac catheterization. Both have increased atrial pressures and equalization of end diastolic pressures although the equalization is more common in CP.7 The “dip and plateau” pattern seen in ventricular diastolic pressure tracings has classically been associated with constriction. This ﬁnding, which reﬂects rapid early diastolic ﬁlling of the ventricles, followed by an abrupt cessation of ﬁlling in mid- and late diastole, is also found in RC, which is characterized by the noncompliant myocardium and limited ventricular ﬁlling during the mid- and late diastolic period. Therefore, there is a substantial overlap in hemodynamic features between CP and diastolic heart failure due to myocardial diseases. To distinguish one from the other condition, which is critical in providing an appropriate management, diagnostic features speciﬁc to a condition should be identiﬁed. There are two unique features in CP: (1) dissociation between intrathoracic and intracardiac pressures, which vary with respiration, and (2) increased interventricular coupling or dependence due to a relatively ﬁxed combined volume of the left and right ventricles within the constrictive pericardium. These unique features result in characteristic respiratory variation in diastolic ﬁlling, ventricular pressures, and Doppler velocities representing diastolic ﬁlling.8

Intrathoracic-Intracardiac Dissociation The dissociation between intrathoracic and intracardiac pressures in constriction causes respiratory variation in pressure diﬀerence between pulmonary capillary wedge pressure (PCWP) and LV diastolic pressure. This characteristic hemodynamic pattern is best illustrated by simultaneous pressure recordings from the left

Figure 24-3 Simultaneous pressure recordings from the left ventricle (LV) and pulmonary capillary wedge (PCW), together with mitral inflow velocity on a Doppler echocardiogram. The onset of the respiratory phase is indicated at the bottom. With the onset of expiration (Exp), PCW pressure increases much more than LV diastolic pressure, creating a large driving pressure gradient (large arrowhead). With inspiration (Insp), however, PCW pressure decreases much more than LV diastolic pressure, with a very small driving pressure gradient (three small arrowheads). These respiratory changes in the LV filling gradient are well reflected by the changes in the mitral inflow velocities recorded on Doppler echocardiography. (From Oh JK et al: The echo manual, 2nd ed, Lippincott Williams & Wilkins, 1999.)

ventricle and the pulmonary capillary wedge, together with mitral inﬂow velocities (Fig. 24-3). A thickened or inﬂamed pericardium prevents full transmission of the intrathoracic pressure changes that occur with respiration to the pericardial and intracardiac cavities, creating respiratory variations in the left-sided ﬁlling pressure gradient (the pressure diﬀerence between the pulmonary vein and the left atrium). With inspiration, intrathoracic pressure falls (3 to 5 mmHg normally), and the pressure in other intrathoracic structures (pulmonary vein, pulmonary capillaries) falls to a similar degree. This inspiratory pressure change is not fully transmitted to the intrapericardial and intracardiac cavities. As a result, the driving pressure gradient for LV ﬁlling decreases immediately after inspiration and increases with expiration.

Interventricular Dependence Diastolic ﬁlling (or distensibility) of the left and right ventricles is interdependent because the overall cardiac volume is relatively ﬁxed within the thickened or noncompliant (adherent) pericardium. Hence, reciprocal respiratory changes occur in the ﬁlling of both ventricles. With inspiration, decreased LV ﬁlling allows increased ﬁlling in the right ventricle. As a result, the ventricular septum shifts to the left, and tricuspid inﬂow E velocity and hepatic vein diastolic forward-ﬂow velocity increase (Fig. 24-4). With expiration, LV ﬁlling increases, causing the ventricular septum to shift to the right, which limits RV ﬁlling. Tricuspid inﬂow decreases and hepatic vein diastolic forward ﬂow decreases, with increased ﬂow reversals during diastole. Usually, diastolic forward-ﬂow velocity is higher than systolic forward-ﬂow velocity in the hepatic vein, which corresponds to the Y and X waves, respectively, of systemic venous pressure. It needs to be emphasized that the respiratory variation in ventricular ﬁlling is initiated from the left side, which is also evident from careful inspection of simultaneous pressure tracings from the left and right ventricles. In CP, the ﬂuctuation in the PCWP is more marked in parallel with intrathoracic pressure changes than ﬂuctuation in left atrial (LA) and LV diastolic pressure. Ventricular interdependence also

303

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion is observed in simultaneous recordings of LV and RV pressures. With inspiration, which induces less ﬁlling of the left ventricle, LV peak systolic pressure decreases; the opposite changes occur in the right ventricle, so that RV peak systolic pressure increases with inspiration.9 Their ejection time also varies with respiration in opposite directions in the left and right ventricles. This discordant pressure change between the ventricles in CP does not occur in RC (Fig. 24-5). Therefore, invasively or noninvasively, the diagnostic criteria of restriction and constriction should be based on the respiratory changes of ventricular ﬁlling and hemodynamic features instead of previously proposed criteria using the level of systolic RV pressure or equalization of ventricular end diastolic pressures, because

S D

PV

RV

Thickened pericardium

PCW

Inspiration

RV

LV

LV

R

A

A

LA

LA

HV

R

304

Expiration

IP Figure 24-4 Schematic diagram of differential ventricular filling varying with respiration. Pulmonary capillary wedge (PCW) pressure changes with respiration while intrapericardial (IP) or left ventricular (LV) diastolic pressure changes minimally with respiration. Diastolic filling (or distensibility) of the left and right ventricles is interdependent because the overall cardiac volume is relatively fixed within the thickened or noncompliant pericardium. Hence, reciprocal respiratory changes occur in the filling of both ventricles. With inspiration, decreased LV filling allows increased filling in the right ventricle. As a result, the ventricular septum shifts to the left, and tricuspid inflow E velocity and hepatic vein diastolic forward-flow velocity increase. With expiration, LV filling increases, causing the ventricular septum to shift to the right, which limits RV filling. Tricuspid inflow decreases, as does hepatic vein diastolic forward flow, with significant flow reversals during diastole. Usually, diastolic forward-flow velocity is higher than systolic forward-flow velocity in the hepatic vein, which corresponds to the Y and X waves, respectively, of systemic venous pressure. (From Oh JK et al: The echo manual, 2nd ed, Lippincott Williams & Wilkins, 1999.)

RCM

there is a large overlap of the hemodynamic values between constriction and restriction.8 If cardiac catheterization is performed for evaluation of CP, the discordant respiratory change between RV and LV pressures during inspiration should be looked for as a sign of interdependence of ventricular ﬁlling.9

Clinical Presentations and Physical Examination Findings Clinical presentations of CP are protean and nonspeciﬁc, but almost all patients do have symptoms and signs of heart failure. Dyspnea, edema, ascites, and fatigue are common symptoms. Less common symptoms, but important to remember, are chest pain, gastrointestinal adversities, hypotension with tamponade (eﬀusive-constrictive), arrhythmia, and right upper quadrant pain from hepatic congestion. Two thirds of the patients with CP do have an underlying etiology, as we have noted. On physical examination, jugular venous pressure ( JVP) is almost always elevated with rapid “y” descent. However, JVP rises further with inspiration in CP (which is called Kussmaul sign). Systemic and pulmonary venous congestion are parts of clinical presentations in both constriction and restriction. Ascites and hepatomegaly are more common in CP, and this may lead a physician to evaluate an abnormality in the liver or abdomen. Among patients who were referred to our medical center and found to have CP, more than a third of them had undergone a gastrointestinal procedure or liver biopsy or sometimes both prior to their referral. If JVP is found to be elevated in patients with hepatomegaly or ascites, right-heart failure as an underlying cardiac abnormality, including CP, should be strongly considered. Pulsus paradoxus may be present in patients with CP but is less common than in cardiac tamponade. Pulmonary venous congestion is more common in RC than in CP, and this is a poor prognostic sign. Characteristically, a third heart sound is heard in both constriction and restriction, and it is diﬃcult to distinguish them based on cardiac auscultation. The third heart sound corresponds to the time of the end of early rapid ﬁlling and the nadir of the “y” descent in atrial pressure tracings. In CP, this diastolic gallop sound is called a pericardial knock.

Electrocardiogram and Brain Natriuretic Peptide Electrocardiography is nonspeciﬁc for both CP and RC, although low QRS voltage in the setting of increased LV wall thickness strongly suggests cardiac amyloidosis. Brain natriuretic peptide (BNP) is usually elevated in patients with RC and relatively CONSTRICTION INSP

100

EXP

150

LV

LV 100

50

RV

50

0 mmHg

0

INSP

EXP

AV

Figure 24-5 Simultaneous recordings of left ventricular (LV) and right ventricular (RV) pressures in restrictive cardiomyopathy and constrictive pericarditis. Ventricular interdependence is shown with constriction. On inspiration, there is less filling of the left ventricle, so LV peak systolic pressure decreases. The opposite changes occur in the right ventricle during inspiration so that RV peak systolic pressure increases with inspiration. This causes a discordant pressure change between the left and right ventricles, as seen by the arrows pointing together. This change is not seen in restriction.

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion 3.25 3.00

Log10BNP (ng/L)

2.75 2.50 2.25 2.00 1.75 1.50 1.25 CP idiopathic

CP secondary

RCMP

Diagnosis Figure 24-6 Log 10 of brain natriuretic peptide (BNP) is compared in idiopathic constrictive pericarditis, secondary constrictive pericarditis, and restrictive cardiomyopathy. BNP is significantly lower in patients with idiopathic constrictive pericarditis than restrictive cardiomyopathy; however, BNP is not significantly different in patients with secondary constrictive pericarditis (previous cardiac surgery or radiation) compared with restrictive cardiomyopathy. A relatively normal BNP in the setting of elevated jugular venous pressure should alert the physician toward constrictive pericarditis. (From Babuin L et al: Brain natriuretic peptide levels in constrictive pericarditis and restrictive cardiomyopathy. JACC 2006;47:1489–1491.)

normal in CP,10–11 especially when constriction is idiopathic (Fig. 24-6). When constriction is related to coronary bypass surgery or radiation, BNP is higher than in idiopathic CP because of the underlying concomitant myocardial disease in those conditions.11 Therefore, relatively normal BNP in patients with clear evidence of heart failure suggests CP. The patients with cardiac amyloidosis usually have systemic amyloid with monoclonal gammopathy, positive fat aspirate, and other systemic manifestations of the disease. However, in a minority of patients, all these studies can be negative and may require RV endomyocardial biopsy for a deﬁnitive diagnosis.

Figure 24-7 M-mode echocardiogram of a patient with constrictive pericarditis. Ventricular septal motion is characteristically abnormal in patients with constrictive pericarditis due to the differential ventricular filling with respiration and increased interventricular dependence. The cardiac volume is relatively fixed within the noncompliant pericardium, thus diastolic filling of the left and right ventricles are reliant on each other. With inspiration, there is decreased filling of the left ventricle and increased filling in the right ventricle. To allow for this, the ventricular septum shifts to the left. With expiration, left ventricular (LV) filling increases, causing the ventricular septum to shift to the right, thus limiting right ventricular (RV) filling.

respiration and increased interventricular dependence (Fig. 24-7). Although the atria are generally larger in RC than in constriction, this feature cannot be used to diﬀerentiate one condition from the other. In RC, LA pressure is usually higher than right atrial (RA) pressure, and the atrial septum is curved toward the right atrium. The atrial septum has respiratory movement in patients with CP. The pericardial thickness is usually, but not always, increased in CP and can be measured by transthoracic and, better still, by transesophageal echocardiography (TEE).13 When calciﬁed, it appears as a bright echo dense structure, and when inﬂamed with edema, it appears as a dark soft tissue or a rind. The inferior vena cava, hepatic vein, and pulmonary veins are dilated in both RC and CP, unless patients are well treated with a diuretic agent. In constriction, the atrioventricular groove may be indented with their characteristic appearance.

Pulsed Doppler Echocardiography Two-Dimensional Echocardiography Ventricular dimensions and ejection fractions are usually normal in both CP and RC. Ventricular wall thickness can be increased in some secondary forms of RC and markedly increased in the cases of inﬁltrative cardiomyopathy. The most common inﬁltrative cardiomyopathy is cardiac amyloid, but rare conditions such as glycogen storage disease, hyperoxalosis, and hydroxychloroquine myopathy12 should be considered. The RV wall thickness is also characteristically increased in most inﬁltrative cardiomyopathy. When the myocardium is inﬁltrated by amyloid deposits, the valves, atrial wall, and ventricular walls are aﬀected, providing a characteristic granular or speckled appearance on echocardiography. Other forms of secondary restrictive cardiomyopathy can also have characteristic echocardiographic features, such as areas of myocardial thinning or unusual regional wall motion abnormalities that do not follow a coronary distribution in sarcoidosis or apical endocardial thickening due to thrombus deposition in hypereosinophilic syndrome. Ventricular septal motion is characteristically abnormal in patients with CP because of diﬀerential ventricular ﬁlling with

Since atrial and diastolic ﬁlling pressures are elevated in symptomatic patients with both CP and RC, mitral and tricuspid inﬂow velocities are expected to be restrictive, with E/A ratios greater than 1.5 and E-velocity deceleration times shorter than 160 msec. Additionally, in CP, there is a characteristic variation in mitral early diastolic E velocity with respiration.8,14 The variation in mitral E velocity is a result of preventing the full transmission of intrathoracic pressure change that occurs with respiration into intracardiac cavities. This unique feature of CP produces diagnostic Doppler echocardiographic recordings. Optimally, a respiratory variation of 25% or greater in the mitral inﬂow E velocity and increased diastolic ﬂow reversal with expiration in the hepatic vein need to be demonstrated to establish the diagnosis of CP (Fig. 24-8). This observation was initially based on the seven patients with CP.8 Further clinical observations, however, found that up to 50% of patients with CP demonstrate less than 25% of respiratory variation in mitral E velocity14 because of (a) mixed constriction and restriction, (b) marked increase of atrial pressures, or (c) more clinical experience of using twodimensional/Doppler echocardiography in the diagnosis of CP. If LA pressure is markedly increased, mitral valve opening occurs at a steep portion of the LV pressure curve, and the

305

306

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

A

Figure 24-9 In both restrictive cardiomyopathy and constriction, diastolic forward flow in the hepatic vein flow is accentuated. However, the diastolic flow reversals between the two are different, however. This figure shows hepatic vein flow in a patient with restrictive cardiomyopathy. Hepatic vein reversal is mostly during inspiration in restrictive cardiomyopathy due to the increase in systemic venous return with inspiration exceeding filling capacity of the diseased myocardium. Thus, both forward and reverse flow in the hepatic vein increase with inspiration and decrease with expiration. In constriction (see Fig. 24-8), the right ventricular (RV) cavity size increases with inspiration secondary to decreased left ventricular (LV) filling and ventricular septal shift to the left, resulting in little diastolic reversal on inspiration. During expiration, the RV cavity size decreases with the ventricular septal shift to the right, resulting in increased diastolic reversal on expiration.

B Figure 24-8 A, Mitral inflow velocity of a patient with constrictive pericarditis. Optimally, a respiratory variation of 25% or greater is seen in mitral inflow E velocity, as shown, where EI is the mitral inflow velocity on inspiration and Ee is the mitral inflow on expiration. This observation was based on a small number of patients with constrictive pericarditis.8 Larger observations indicate that up to 50% of patients with constrictive pericarditis have less than 25% respiratory variation in mitral E velocity.14 B, Pulsedwave Doppler recording of hepatic vein velocity in a patient with constrictive pericarditis. In constriction, right ventricular (RV) cavity size becomes larger during inspiration because of decreased left ventricular filling and the ventricular septal shift to the left, resulting in little diastolic flow reversals (arrowhead). With expiration, the right ventricle becomes smaller and the ventricular septum shifts to the right, resulting in increased diastolic flow reversal (arrow), as well as a decreased forward-flow velocity.

respiratory change has little eﬀect on the transmitral pressure gradient. In this case, Doppler echocardiographic examination may be repeated after an attempt to reduce preload (i.e., head-up tilt or sitting position).15 In any event, the lack of respiratory variation in mitral inﬂow velocities should not exclude the diagnosis of CP as long as mitral inﬂow is restrictive and other features of constriction are present. In contrast to myocardial disease, the deceleration time of mitral E velocity becomes shorter in CP, and shorter still with a reduced E velocity with inspiration. There is a corresponding respiratory variation in pulmonary venous diastolic forward-ﬂow velocities in CP while maintaining a larger forward-ﬂow velocity during diastole compared with systolic forward-ﬂow velocity as in RC. Respiratory variation in tricuspid inﬂow velocity is completely opposite to that of mitral inﬂow velocity. Hepatic vein ﬂow velocity has more predominant diastolic forward-ﬂow velocity and diastolic ﬂow reversals in both RC and constriction. However, in RC, hepatic vein diastolic ﬂow reversal is mostly during inspiration, when systemic venous return is increased and exceeds the ﬁlling capacity of the diseased myocardium. There-

fore, both forward and reversal ﬂows in the hepatic vein increase with inspiration and decrease with expiration and RC (Fig. 24-9). In constriction, RV cavity size becomes larger during inspiration because of decreased LV ﬁlling and the ventricular septal shift to the left, resulting in little diastolic ﬂow reversals. With expiration, however, the right ventricle becomes smaller with the ventricular septal shift to the right because of increased ﬁlling to the left ventricle, resulting in increased diastolic ﬂow reversal, as well as a decreased forward-ﬂow velocity (see Fig. 24-8B). This is completely paradoxical to respiratory phasic changes of hepatic venous ﬂow pattern seen in RC.7 This characteristic hepatic venous ﬂow velocity pattern in constriction has been observed even in the concomitant presence of atrial ﬁbrillation or with severe tricuspid valve regurgitation. The sensitivity of two-dimensional and Doppler echocardiography using these criteria for detecting constriction was found to be more than 80% and has been enhanced by additional tissue Doppler imaging (TDI) data.16 The respiratory variation of mitral inﬂow velocity is also observed in patients with increased respiratory eﬀort, as seen with severe chronic obstructive pulmonary disease, because the exaggerated pressure decrease in the thorax is not fully transmitted to the intracardiac cavities. Therefore, with inspiration, the LV ﬁlling pressure gradient decreases, as in CP, and increases with expiration. However, patients with increased respiratory eﬀort resulting in the respiratory variation of mitral inﬂow velocity have typical superior vena cava (SVC) ﬂow velocities that are not observed in patients with CP. Because of the marked intrathoracic pressure decrease with inspiration, there is an increase forward ﬂow from the SVC to the right atrium with inspiration,17 and the forward ﬂow is markedly reduced or even absent during the expiratory phase (Fig. 24-10). However, in CP, there is little respiratory change in RA pressure and the ﬂow from the SVC to the right atrium; therefore, respira-

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

Figure 24-10 Pulsed-wave Doppler and color M-mode recordings from the superior vena cava (SVC) in a patient with chronic obstructive lung disease, showing marked increase in SVC flow velocity with inspiration (arrows on left by pulsed-wave Doppler and arrowheads on right by color M-mode) and diminution with expiration. Patients with increased respiratory effort can also have respiratory variation of mitral inflow velocity, but they also have typical SVC flow velocities, which are not observed in patients with constrictive pericarditis. Patients with increased respiratory effort, such as in chronic obstructive pulmonary disease, have an exaggerated intrathoracic pressure decrease with inspiration causing an increased flow from the SVC to the right atrium. This flow is markedly reduced or absent during expiration. In constriction, however, there is little respiratory change in the right atrial pressure and the flow from the SVC to the right atrium; therefore, respiratory change in systolic forward-flow velocity in the SVC is usually <20 cm/sec in patients with constrictive pericarditis.

A

B

Figure 24-11 Tissue Doppler imaging (TDI) of mitral annulus to differentiate restriction from constriction. The lack of respiratory variation in mitral inflow velocities does not exclude the diagnosis of constrictive pericarditis, and other features of constriction should be looked for, such as hepatic vein velocity changes or early diastolic mitral septal annulus velocity (E′) of >7 cm/sec, especially when the mitral inflow profile indicates high filling pressure (i.e., restrictive filling with E/A ratio of >1.5 and deceleration time of <160 msec). The mitral annulus velocity E′ recorded by TDI has become a valuable Doppler parameter in the establishment of the diagnosis of constriction and in differentiating it from myocardial disease with restrictive filling. A, In myocardial disease, E′ is reduced (<7 cm/sec), since myocardial relaxation is abnormal. In constrictive pericarditis, it (and especially the septal annulus velocity) is relatively normal or even increased. B, This finding occurs because the constrictive pericardium limits ventricular filling by lateral expansion of the heart. Since myocardial relaxation is relatively well preserved in constriction (unless the myocardium is also involved, as seen in radiation injury to the heart), much of ventricular filling results instead from exaggerated longitudinal motion of the heart.

tory change in systolic forward-ﬂow velocity is usually less than 20 cm/sec in the SVC in patients with CP. TEE has also been shown to be helpful in the diﬀerentiation of occult CP from RC by Doppler interrogation of the pulmonary veins. Abdalla et al. found that rapid volume loading patients with occult constriction could enhance diastolic pressure equalization. Pulsed-Doppler TEE of the left or right pulmonary vein and mitral inﬂow performed after giving volume load can unmask a greater respiratory variation of diastolic ﬂow velocity in patients with CP.18

Tissue Doppler Imaging Mitral annulus velocity recorded by TDI has become a valuable Doppler parameter in establishing the diagnosis of constriction19,20 and in diﬀerentiating it from a myocardial disease or RC (Fig. 24-11). The application of this modality for the evaluation of diastolic function is reviewed at length in Chapter 12. All patients with myocardial disease have abnormal relaxation of the heart, which can be detected reliably by TDI, since early diastolic velocity (E′) of the mitral annulus has a good correlation with

307

308

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion myocardial relaxation. In myocardial disease, mitral septal annulus velocity is reduced (<7 cm/sec), since myocardial relaxation is abnormal, but in CP, mitral annulus velocity is relatively normal or even increased (see Fig. 24-11). It is related to the limitation of ventricular ﬁlling by lateral expansion of the heart due to the constrictive pericardium, and most ventricular ﬁlling is accomplished by exaggerated longitudinal motion of the heart. Myocardial relaxation is relatively well preserved in constriction unless the myocardium is also involved, as seen in radiation heart injury. The longitudinal motion, hence mitral septal annulus velocity, becomes more increased as the constriction gets worse with higher ﬁlling pressure, paradoxical to its change in myocardial disease. The phenomenon has been termed annulus paradoxus.21 The E/E′ ratio is therefore inversely proportional to PCWP, whereas E/E′ is positively related to PCWP in myocardial disease. More recently, Sohn et al. reported that E′ also varies with respiration.22 Strain imaging in CP is similar to that of normal individuals, but negative peak strain is markedly reduced in myocardial disease.23 Doppler myocardial velocity gradients (MVGs) measured from the posterior LV wall may be useful in discriminating constriction versus restriction. Palka et al. found that MVG was lower in restriction compared with constriction and normal controls during ventricular ejection and rapid ventricular ﬁlling.24

Doppler Echocardiographic Assessment in Patients with Atrial Fibrillation Although respiratory variations in mitral inﬂow Doppler velocities are helpful in diﬀerentiating constriction from restriction, atrial ﬁbrillation can make interpretation of respiratory variation in Doppler patterns diﬃcult. In patients with atrial ﬁbrillation, mitral valve E (MV-E) velocities and pulmonary vein diastolic (PVD) velocities become greater with longer ﬁlling intervals. Thus, one would expect in patients with atrial ﬁbrillation and CP that ﬁlling intervals would be an equally important factor in MVE and PVD velocities. On the other hand, constrictive physiology and hemodynamics should also aﬀect Doppler ﬂow velocities with respect to the respiratory cycle. Tabata et al. found a decrease in MV-E and PVD velocities after onset of inspiration, even during long ﬁlling intervals.25 The decrease in pressure gradient during inspiration reduces ﬂow from the pulmonary vein to the left ventricle, and despite the longer cardiac cycle length, the blood volume is not available to cause increased ﬂow during diastole. Conversely, there is an increase in velocities even during short ﬁlling intervals at the onset of expiration. Doppler velocities may need to be monitored for longer periods of time to appreciate the respiratory variations. Hepatic vein diastolic ﬂow reversal with expiration is an important Doppler ﬁnding in patients with constriction, especially when mitral inﬂow velocity is nondiagnostic, as it is in many patients. Occasionally, a temporary pacemaker may be required to regularize the patient’s rhythm to interpret the respiratory variation of Doppler velocities. Whether E′ velocity can distinguish constriction from restriction in patients with atrial ﬁbrillation requires further clinical observations.

Chest X-Ray, Computed Tomography, and Magnetic Resonance Imaging Chest x-ray ﬁndings can be helpful in a minority of patients. Biatrial enlargement is common, and pulmonary venous congestion as well as pleural eﬀusion may be seen in both RC and CP.

A calciﬁed pericardium (Fig. 24-12) is seen in 24% of patients with constriction and is best visualized from the lateral view.4 Pericardial calciﬁcation occurs more commonly over the right ventricle and diaphragmatic surface. Pericardial calciﬁcation in patients with heart failure strongly suggests CP, but its presence is not always indicative of symptomatic CP. Computed tomography (CT) and magnetic resonance imaging (MRI) can be used in the evaluation of constriction versus restriction.26–27 CT and MRI are the best imaging modalities to measure pericardial thickness and calciﬁcation (see Fig. 24-12). Gadolinium administration during MRI highlights the area of pericardial inﬂammation and is useful in identifying reversible components of increased pericardial thickness. Pericardial thickness exceeding 4 mm is highly suggestive of CP. However, a thickened pericardium, deﬁned as greater than 4 mm, is found in 72% and calciﬁcation in 25% of patients with surgically conﬁrmed constriction.13 Therefore, a normal appearance or normal thickness of the pericardium does not rule out CP. Cine imaging of CT and MRI can demonstrate the abnormal ventricular septal motion, a characteristic of CP. Patients who have had radiation or open-heart surgery may have patchy areas of thickened pericardium, as seen on imaging studies, but no hemodynamic compromise. Thus, CT and MRI can add information but should not be used alone in the diagnosis of constriction.

Treatment The diﬀerentiation of CP from RC is critical because the treatments are distinctly diﬀerent. While there is no cure for most myocardial diseases, CP is potentially curable by surgical pericardiectomy. A recent review of 135 patients with constriction found decreased perioperative mortality compared with earlier studies, but late survival was still inferior to that of age- and sex-matched controls.28 Long-term outcome was predicted by three variables: age, New York Heart Association (NYHA) functional class, and postradiation, with the last having the worst prognosis. Surgery alleviated or improved symptoms in a majority of late survivors, but one third eventually experienced new or recurrent NYHA class III or IV symptoms. In a subset with a recent onset (within 3 months) of CP, patients may respond to nonsteroidal antiinﬂammatory drugs (NSAIDs) or steroids. This “transient constriction” is not uncommon (see Case 4). Much eﬀusiveconstrictive pericarditis belongs to this category of transient constriction.

CLINICAL RELEVANCE Early reliable diagnosis of CP avoids unnecessary diagnostic investigations for other diseases, frequently noncardiac, and provides a potentially curable treatment for the condition. CP can present in a variety of forms, some of which may be treatable medically. Understanding of characteristic hemodynamics and diagnostic features will be able to diﬀerentiate heart failure due to myocardial dysfunction from that due to CP. These relevant clinical points will be discussed in this section using several case examples.

Case 1 A 58-year-old female was originally referred for evaluation of ascites. She complained of shortness of breath and abdominal

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion

A Figure 24-12 Typical chest x-ray (A) and CT (B) of constrictive pericarditis showing pericardial calcification (arrows). Pericardial calcification on chest x-ray is helpful but is present in only 25% of cases of constrictive pericarditis.13 It is best seen from the lateral view over the right ventricle and across the diaphragmatic surface of the heart. Pericardial calcification reflects chronicity of constrictive pericarditis and is associated with a higher surgical mortality. CT and MRI are the best imaging modalities to determine the thickness of the pericardium. However, a thickened pericardium, defined as greater than 4 mm, is found in 72% and calcification in 25% of patients with surgically confirmed constriction.13 Therefore, a normal appearance or normal thickness of the pericardium does not rule out constrictive pericarditis.

B

distention. At a diﬀerent institution, she underwent an extensive diagnostic evaluation that included multiple hepatic ultrasounds and a liver biopsy, the results of which were unremarkable. She described a pleuritic chest pain a few years prior to symptoms. On physical exam, she had elevation of her JVP with Kussmaul sign, and ascites was present. She was sent to cardiology for possible pericardial disease as a primary cause of symptoms. Echocardiogram revealed normal systolic function and characteristic mitral and hepatic inﬂow velocities for CP as described in this chapter. Subsequent left- and right-heart catheterization demonstrated marked elevation and equalization in diastolic ﬁlling pressures, as well as dissociation of intrathoracic and intracavitary pressures. She underwent pericardiectomy successfully and improved markedly. This case illustrates the diﬃculty in early detection and diagnosis of CP. Unless it is clinically suspected, no appropriate diagnostic procedure can be ordered or performed. This patient had markedly elevated JVP with Kussmaul sign, which should have alerted her physician to a possibility of cardiac pathology, even CP. Instead, her ascites was the main point of investigation, leading to various hepatic procedures. In our experience, almost a third of patients with an ultimate diagnosis of constriction

undergo noncardiac procedures, including liver biopsy, endoscopy, abdominal exploration, lymph node biopsy, etc. This case example points out the importance of assessing ﬁlling pressure in patients presenting with abdominal or gastrointestinal complaints. Gastrointestinal and hepatology colleagues are frequent referral physicians of their patients for an evaluation of CP, or at least a cardiac cause. It is also important to emphasize that echocardiography is usually the ﬁrst diagnostic study in such a clinical situation, and all sonographers and echocardiologists should be thoroughly familiar with echocardiographic diagnostic features of CP as described. It is possible that patients can proceed with pericardiectomy based on the diagnostic echocardiographic ﬁndings. When the diagnosis is not certain after echocardiography, but suggestive, or other physicians involved in patient care are not fully comfortable with an echocardiographic diagnosis of constriction, further imaging tests or cardiac catheterization may be performed.

Case 2 A 40-year-old male who underwent aortic valve replacement presented 5 years later with dyspnea on exertion and decreased

309

310

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion exercise tolerance. On physical examination, he had marked elevation of JVP with dramatic x and y descent. His lungs were clear and liver was enlarged. Echocardiogram showed typical respiratory variation of mitral inﬂow and hepatic vein velocities for CP. Mitral annulus early diastolic velocity was 15 cm/sec. Cardiac catheterization at a home hospital also showed hemodynamic changes consistent with CP. The CT scan, however, showed a normal-appearing pericardium. A few months later, the patient had a pericardiectomy. He had a thin and tightly adherent pericardium laterally and inferiorly with multiple areas of thickening. His symptoms improved after pericardiectomy. CT and MRI can be used in the evaluation of constriction versus restriction26–27 since their eﬃcacy is the best in imaging pericardial thickness and calciﬁcation. This case also illustrates the diagnostic importance of measuring mitral annulus velocity by TDI. If a patient has heart failure, and E′ is greater than 8 cm/sec, CP should be strongly considered and conﬁrmed by other characteristic Doppler features, such as restrictive mitral inﬂow with or without respiratory variation and hepatic vein Doppler recording of diastolic ﬂow reversals with expiration.

Case 3 A 60-year-old patient was transferred for treatment of his amyloid cardiomyopathy. His original workup started a little over one year ago. He went to his physician complaining of shortness of breath and weakness. Echocardiogram showed LV hypertrophy, and his LV ejection fraction was 40%. His coronary angiogram revealed no clinically signiﬁcant coronary artery disease, and right-heart catheterization showed elevated ﬁlling pressures with equalization. He was sent to surgery for pericardiectomy for a presumed diagnosis of CP, but at surgery there was no evidence for abnormal pericardium. There was, however, a nodule that was biopsied and showed deposits consistent with amyloid. He was then referred to our institution for subsequent management. This case is an example of the diﬃculty in distinguishing CP from RC. The right-heart catheterization results of the patient can be seen in both constriction and restriction but are classically associated with constriction, thus many may not pursue further workup for restriction. In this case, respiratory variation in ventricular systolic pressures as well as discordant pressure changes

in the left and right ventricles would have been helpful, along with evidence of interventricular dependence. Echocardiography may have revealed the appearance of cardiac amyloid. Appearance of LV hypertrophy was because of increased wall thickness. Myocardial tissue imaging of the mitral annulus would have shown marked reduction in E′ velocity. Endomyocardial biopsy may be performed in patients suspected of having RC. Biopsy is usually done to exclude speciﬁc heart muscle diseases such as cardiac amyloid, sarcoidosis, or eosinophilic myocarditis. In idiopathic RC, the myocardial biopsy demonstrates nonspeciﬁc ﬁbrosis with increased collagen deposition, myocellular hypertrophy without necrosis, or disarray. On the other hand, the myocardial biopsy is typically normal in CP unless the two conditions coexist.

Case 4 A 54-year-old man with a history of acute myocardial infarction (AMI) presented one month after AMI with pleuritic chest pain. He was treated with anti-inﬂammatory medications, and pain resolved but returned with shortness of breath, requiring admission. Echo ﬁndings were consistent with CP. CT of the chest revealed uniform thickening of the pericardium. He was placed on prednisone, with signiﬁcant improvement of symptoms. A repeat CT scan one week later showed resolution of pericardial thickness with normal-appearing pericardium (Fig. 24-13). The patient is diagnosed as having transient CP. CP may be transient because of inﬂammation of the pericardium. There is a subgroup of patients who, after a recent episode of acute pericarditis, present with constrictive physiologic features that resolve with medical treatment alone. In a review of 212 patients with echocardiographic ﬁndings of CP at our institution, 36 had echocardiographic resolution of constrictive hemodynamics without pericardiectomy.29 The most common cause of transient CP was again cardiac surgery. The average time for resolution was 8.3 weeks after initial diagnosis. The implication of this ﬁnding is that patients with symptoms and physiologic features consistent with CP who are hemodynamically stable with a recent onset can be managed with a trial of medical treatment up to 3 months prior to consideration of surgical pericardiectomy. Medical therapy is aimed at acute inﬂammation of the pericardium and can include NSAIDs,

Figure 24-13 Chest computed tomography (CT) image of 54-year-old man with constrictive pericarditis before (left) and after (right) treatment with prednisone. The pericardium is thick (arrows on left) at baseline. Repeat CT scan was done one week later and showed resolution of pericardial inflammation (arrows on right).

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion steroids, antibiotics, or chemotherapy, depending on the etiology of CP.

Case 5 A 66-year-old male has a history of aortic valve replacement for a bicuspid aortic valve, and mitral valve repair for mitral valve prolapse. His hospital course was uneventful. Two weeks after discharge, he complained of profound fatigue and was eventually readmitted for a syncopal event. Chest x-ray showed a large cardiac silhouette suggestive of pericardial eﬀusion. Echocardiogram not only conﬁrmed the eﬀusion, but showed evidence of tamponade physiology. Pericardiocentesis successfully removed 750 cc of ﬂuid. Repeat echocardiography after pericardiocentesis showed a tiny pericardial eﬀusion but persistent constrictive physiology, and the pericardium appeared inﬂamed. This is a typical presentation of eﬀusive-constrictive pericarditis, a rare syndrome in which constriction from the visceral surface of the heart is accompanied by a hemodynamically signiﬁcant eﬀusion in the pericardial space. The hallmark of this phenomenon is persistently elevated RA pressure after adequate pericardiocentesis. In one study, the prevalence of this disorder was 1.3% among patients with pericardial disease of any type and 6.9% among patients with clinical tamponade.30–31 The most common etiology was idiopathic and history of radiation therapy, but any cause of pericarditis can lead to eﬀusive-constrictive pericarditis. The diagnosis requires hemodynamic criteria from a right-heart catheterization or echocardiography soon after pericardiocentesis. One must recognize the hemodynamics of both tamponade and constriction to understand eﬀusive-constrictive pericarditis. Cardiac tamponade and CP are similar in that they both restrict ﬁlling of the ventricles. Tamponade can occur when the pericardial space is ﬁlled with ﬂuid. An echo free space persists throughout the cardiac cycle when the eﬀusion reaches 25 ml. As the pericardial eﬀusion increases, the movement of the parietal pericardium decreases. Even larger amounts of ﬂuid can cause the heart to actually swing in the pericardium. Echocardiographic features of tamponade include early diastolic collapse of the right ventricle, late diastolic inversion of the right atrium, abnormal ventricular septal motion, and respiratory variation in ventricular size. These features may not be present if the patient also has pulmonary hypertension and may not be speciﬁc since increased interventricular dependence, which is responsible for respiratory variation in ventricular ﬁlling, and abnormal ventricular septal motion can occur with increased respiratory eﬀorts and no pericardial eﬀusion. Therefore, hemodynamic evidence of cardiac tamponade needs to be identiﬁed to make a deﬁnitive diagnosis of tamponade as well as of CP. Doppler echocardiographic features of tamponade are due to respiratory variation in intrathoracic and intracardiac hemodynamics, just as in CP. Also as in CP, the ventricles are coupled because of the relatively ﬁxed cardiac volume. Tamponade has a blunted y descent secondary to lack of rapid ventricular ﬁlling at the start of diastole and a prominent x descent on the RA tracing. CP has a “W”shaped JVP tracing with a prominent y descent from rapid early ventricular ﬁlling. In contrast to Doppler echocardiographic ﬁndings of CP, the mitral inﬂow velocity pattern can show a relaxation abnormality pattern (E velocity is lower than A velocity with prolonged deceleration time) in cardiac tamponade since the left ventricle can be underﬁlled during an acute episode, and mitral annulus early diastolic velocity may not be increased. However, evidence of increased interventricular dependence is clearly

present in cardiac tamponade with respiratory variation in mitral and hepatic vein ﬂow velocities as seen in CP. Clinically, eﬀusive-constrictive pericarditis should be suspected if JVP remains elevated after successful pericardiocentesis. Hemodynamically, all intracardiac diastolic pressures remain elevated in this condition, even after intrapericardial pressure returns to normal with pericardiocentesis. A signiﬁcant subset of these patients do have inﬂammation of the pericardium, which can be demonstrated by delayed enhancement by gadolinium on MRI. Most eﬀusive-constrictive pericarditis belongs to transient constriction since it can be treated medically (with nonsteroidal or steroidal anti-inﬂammatory agents) in most patients.

SUMMARY AND FUTURE RESEARCH CP is the result of loss of elasticity of the pericardium surrounding the heart. This lack of distensibility of the pericardium causes diastolic dysfunction that is clinically evident as congestive heart failure with increased pulmonary and jugular venous pressures, including hepatomegaly, ascites, and peripheral edema. Systolic ventricular function may be well preserved, thus investigation of other organ systems is often pursued prior to pericardial disease. Once a cardiac abnormality is suspected, the diﬃculty is in distinguishing CP from RC, which have similar clinical and hemodynamic proﬁles. But because of their diﬀering causes and treatments, it is important to distinguish between the two. To understand the diﬀerence, one must remember the pathophysiologic mechanisms causing the diastolic dysfunction. In CP, the noncompliant pericardium causes the limitation of diastolic ﬁlling, but in RC, the pericardium is normal but the myocardium is stiﬀ and noncompliant. This diﬀerence in etiology allows us to observe unique hemodynamic features between the two entities. CP has distinct hemodynamic characteristics, which include dissociation between intrathoracic and intracardiac pressures and exaggerated ventricular interdependence in diastolic ﬁlling, which can be seen either invasively or noninvasively. Imaging modalities such as MRI and CT may be helpful in the diagnosis of constriction and restriction. Despite these tools, distinguishing between the two can be a clinical challenge, but it is important in deciding on treatment. CP is a treatable condition. Treatment depends on the form of the condition. Most patients will have chronic CP, with previous cardiac surgery being the most common cause. A small proportion, however, may have transient CP, which can be treated medically. The diagnostic approach and treatment must be individualized for each patient, and the most important diagnostic tool is clinical suspicion. REFERENCES 1. Spodick DH: The hairy hearts of hoary heroes and other tales: Medical history of the pericardium from antiquity through the twentieth century. In Fowler NO (ed): The Pericardium in Health and Disease. Mount Kisco, NY, Futura, 1985:1–17. 2. Bloomﬁeld RA, Lauson HD, Cournand A, et al: Recording of right heart pressures in normal subjects and in patients with chronic pulmonary disease and various types of cardiocirculatory disease. J Clin Invest 1946;25:639–664. 3. Meaney E, Shabetai R, Bhargava V: Cardiac amyloidosis, constrictive pericarditis, and restrictive cardiomyopathy. Am J Cardiol 1976;38:547– 556. 4. Ling LH, Oh JK, Breen JF, et al: Calciﬁc constrictive pericarditis: Is it still with us? Ann Intern Med 2000;132:444–450.

311

312

Chapter 24 • Pericardial Diseases: Constriction and Pericardial Effusion 5. Bongani MM, Burgess LJ, Doubell AF: Tuberculous pericarditis. Circulation. 2005;112:3608–3616. 6. Ammash NM, Seward JB, Bailey KR, et al: Clinical proﬁle and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490– 2496. 7. Vaitkus PT, Kussmaul WG: Constrictive pericarditis versus restrictive cardiomyopathy: A reappraisal and update of diagnostic criteria. Am Heart J 1991;122:1431–1441. 8. Hatle LK, Appleton CP, Popp RL: Diﬀerentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357–370. 9. Hurrell DG, Nishimura RA, Higano ST, et al: Value of dynamic respiratory changes in left and right ventricular pressures for the diagnosis of constrictive pericarditis. Circulation 1996;93:2007–2013. 10. Babuin L, Alegria JR, Oh JK, et al: Brain natriuretic peptide levels in constrictive pericarditis and restrictive cardiomyopathy. JACC 2006;47:1–2. 11. Leya FS, Arab D, Joyal D, et al: The eﬃcacy of brain natriuretic peptide levels in diﬀerentiating constrictive pericarditis from restrictive cardiomyopathy. J Am Coll Cardiol 2005;45:1900–1902. 12. Verny C, deGennes C, Sebastein P, et al: Heart conduction disorders in long-term treatment with chloroquine. Two new cases. Presse Med 1992;21:800–804. 13. Ling LH, Oh JK, Tei C, et al: Pericardial thickness measured with transesophageal echocardiography: Feasibility and potential clinical usefulness. J Am Coll Cardiol 1997;29:1317–1323. 14. Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 1994;23:154– 162. 15. Oh, JK, Tajik AJ, Appleton CP, et al: Preload reduction to unmask the characteristic Doppler features of constrictive pericarditis. A new observation. Circulation 1997;95:796–799. 16. Garcia MJ, Rodriguez L, Ares M, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue. J Am Coll Cardiol 1996;27:108–114. 17. Boonyaraterej S, Oh JK, Tajik AJ, et al: Comparison of mitral inﬂow and superior vena cava Doppler velocities in chronic obstructive pulmonary disease and constrictive pericarditis. J Am Coll Cardiol 1998;32:2047– 2048.

18. Abdalla IA, Murray RD, Lee JC, et al: Does rapid volume loading during transesophageal echocardiography diﬀerentiate constrictive pericarditis from restrictive cardiomyopathy? Echocardiography 2002;19:125–134. 19. Ha JW, Oh JK, Ommen SR, et al: Diagnostic value of mitral annular velocity for constrictive pericarditis in the absence of respiratory variation in mitral inﬂow velocity. J Am Soc Echocardiogr 2002;15:1468–1471. 20. Ha JW, Ommen SR, Tajik AJ, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy using mitral annular velocity by tissue Doppler echocardiography. Am J Cardiol 2004;94:316–319. 21. Ha JW, Oh JK, Ling LH, et al: Annulus paradoxus transmitral ﬂow velocity to mitral annular velocity ratio is inversely proportional to pulmonary capillary wedge pressure in patients with constrictive pericarditis. Circulation 2001;104:976–978. 22. Sohn FE, Kim YJ, Kim HS, et al: Unique features of early diastolic mitral annulus velocity in constrictive pericarditis. J Am Soc Echocardiogr 2004;17:222–226. 23. Casaclang-verosa G, Miyazaki C, Nishamura RA, et al: Strain Imaging can diﬀerentiate constriction from restriction. J Am Coll Card 2006; 47(Suppl A):90A. 24. Palka P, Lange A, Donnelly JE, et al: Diﬀerentiation between restrictive cardiomyopathy and constrictive pericarditis by early diastolic Doppler myocardial velocity gradient at the posterior wall. Circulation 2000;102:655–662. 25. Tabata T, Kabbani SS, Murray RD, et al: Diﬀerence in respiratory variation between pulmonary venous and mitral inﬂow Doppler velocities in patients with constrictive pericarditis with and without atrial ﬁbrillation. J Am Coll Cardiol 2001;37:1936–1942. 26. Breen JF: Imaging of the pericardium. J Thoracic Imaging 2001;16:47–54. 27. Masui T, Finck S, Higgins CB: Constrictive pericarditis and restrictive cardiomyopathy evaluation with MR imaging. Radiology 1992;182:369–373. 28. Ling L, Oh JK, Schaﬀ HV, et al: Constrictive pericarditis in the modern era: Evolving clinical spectrum and impact on outcome after pericardiectomy. Circulation 1999;1000:1380–1386. 29. Haley JH, Tajik AJ, Danielson GK, et al: Transient constrictive pericarditis: Causes and natural history. J Am Coll Cardiol 2004;43:271–275. 30. Sagristà-Sauleda J, Angel J, Sànchez A. Eﬀusive-constrictive pericarditis. N Engl J Med 2004;350:469–475. 31. Hancock EW: A clearer view of eﬀusive-constrictive pericarditis. N Engl J Med 2004;350:435–437.

BENJAMIN W. EIDEM, MD

25

Congenital Heart Disease INTRODUCTION PATHOPHYSIOLOGY OF DIASTOLIC DYSFUNCTION IN CHILDREN Normal Diastolic Function in Children CLINICAL RELEVANCE: CONGENITAL HEART DISEASE AND DIASTOLIC DYSFUNCTION Ventricular Volume Overload Ventricular Pressure Overload

Left Ventricular Hypertrophy Hypertrophic and Dilated Cardiomyopathies in Children Tetralogy of Fallot Single Ventricle Palliation Postoperative Congenital Heart Disease FUTURE DIRECTIONS

INTRODUCTION As invasive and noninvasive methods of assessment of ventricular performance evolve, the clinical importance of diastolic function in both children and adults with congenital heart disease has become better appreciated. Alterations in ventricular geometry and loading conditions are the hallmark of congenital heart disease and further complicate the quantitative evaluation of diastolic function. Additional intrinsic and extrinsic factors also may aﬀect diastolic performance, signiﬁcantly altering this phase of the cardiac cycle. Systolic ventricular function, atrial and ventricular compliance, ventricular ﬁlling pressure, pericardial constraint, and ventricular interaction may each have a signiﬁcant eﬀect on overall diastolic performance. This chapter will discuss current concepts in diastolic function in children and adults with congenital heart disease and detail ongoing clinical eﬀorts regarding the assessment of diastolic performance in this population.

PATHOPHYSIOLOGY OF DIASTOLIC DYSFUNCTION IN CHILDREN Diastole is a complex process involving both active and passive components. Abnormalities of relaxation and early rapid ﬁlling are often manifested by changes in the rate of relaxation and the amount of early rapid ﬁlling. Diastolic dysfunction also is manifested by changes in chamber stiﬀness or compliance. Adverse changes within the myocardial cytoskeleton are common in dia-

stolic disease processes, with increases in collagen content and altered extracellular matrix composition leading to altered chamber compliance. The rate of pressure decline within the ventricular chamber can be determined by invasive methods. Tau (τ), or pressure half-time, is the period of time for pressure to fall by 50% of its initial measured value. Impaired relaxation leads to a decreased rate of ventricular pressure decline. Lengthening of isovolumic relaxation time (IVRT) (deﬁned as the time interval between aortic valve closure and mitral valve opening) is also characteristic of abnormal diastolic ﬁlling and can be evaluated noninvasively by Mmode or pulsed-wave Doppler echocardiography. However, neither IVRT nor τ elucidates whether dysfunction occurs in active or passive relaxation, which act in concert to cause a fall in ventricular pressure and augment ﬁlling. As diastolic disease progresses, increased ventricular end diastolic pressure further increases τ and pressure halt time, while concomitant changes in atrial compliance and ﬁlling pressure act to shorten IVRT duration. Echocardiography, and in particular Doppler echocardiography, historically has been an essential noninvasive tool in the quantitative assessment of left ventricular (LV) diastolic function. Abnormalities of ventricular compliance and relaxation can be demonstrated by characteristic changes in mitral inﬂow and pulmonary venous Doppler patterns.1–4 The addition of newer methodologies including tissue Doppler echocardiography5–15 and ﬂow propagation velocities16–20 enhanced the ability of echocardiographers to deﬁne and quantitate these adverse changes in diastolic 313

314

Chapter 25 • Congenital Heart Disease performance. Because diastolic dysfunction often precedes systolic dysfunction, careful assessment of diastolic function is essential in the noninvasive characterization and evaluation of patients with congenital heart disease.

Normal Diastolic Function in Children Normal maturation of the neonatal myocardium occurs over the ﬁrst year of life, resulting in improved ventricular compliance with aging. Noninvasive evaluation of normal diastolic function in infants and children is inﬂuenced by several factors, including age, heart rate, and the respiratory cycle.21–26 Researchers have established reference values detailing both mitral and pulmonary venous Doppler velocities in a large cohort of children with unimpaired hearts (Tables 25-1, 25-2, and 25-3).27 Similar to many echocardiographic parameters, these Doppler velocities also are signiﬁcantly aﬀected by loading conditions, making determina-

tion of diastolic dysfunction using these parameters alone very challenging in patients with congenital heart disease.27

Mitral Inflow Doppler Mitral inﬂow Doppler represents the diastolic pressure gradient between the left atrium and the left ventricle (Fig. 25-1) (see Chapter 10). The early diastolic ﬁlling wave, or E wave, is the dominant diastolic wave in children and young adults and represents the peak left atrial (LA)-to-LV pressure gradient at the onset of diastole. The deceleration time (DT) of the mitral E wave reﬂects the period of time needed for equalization of LA and LV pressures. The late diastolic ﬁlling wave, or A wave, represents the peak pressure gradient between the left atrium and the left ventricle in late diastole at the onset of atrial contraction. Normal mitral inﬂow Doppler is characterized by a dominant E wave, a smaller A wave, and a ratio of E and A waves (E/A ratio) between

TABLE 25-1 NORMAL DOPPLER DATA (N = 233): MITRAL VALVE FLOW VARIABLES AND LEFT VENTRICULAR ISOVOLUMIC RELAXATION TIME (STRATIFIED BY AGE GROUP) 3–8 yrs (N = 75)

9–12 yrs (N = 72)

13–17 yrs (N = 76)

FACTOR

Mean

1 SD

Mean

1 SD

Mean

1 SD

E velocity (cm/sec) E TVI (cm) A velocity (cm/sec) A TVI (cm) A duration (msec) E at A velocity (cm/sec) E to A velocity ratio E to A TVI ratio Deceleration time (msec) End mitral A to R wave interval (msec) LV IVRT (msec)

92 12.0 42 3.7 136 16 2.4 3.7 145 34 62

14 2.6 11 1.1 22 7 0.7 2.0 18 16 10

86 12.3 41 3.7 142 14 2.2 3.7 157 29 67

15 2.9 9 1.0 21 5 0.6 1.5 19 15 10

88 14.0 39 3.7 141 12 2.3 4.2 172 27 74

14 2.9 8 1.1 22 4 0.6 1.7 22 19 13

A, atrial filling wave; E, early filling wave; IVRT, isovolumic relaxation time; LV, left ventricular; SD, standard deviation; TVI, time velocity integral. From O’Leary PW et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end diastolic pressure. Mayo Clin Proc 1998;73:616–628.

TABLE 25-2 NORMAL DOPPLER DATA (N = 223): PULMONARY VEIN FLOW VARIABLES 3–8 yrs (N = 75)

9–12 yrs (N = 72)

13–17 yrs (N = 76)

FACTOR

Mean

1 SD

Mean

1 SD

Mean

1 SD

Systolic velocity (cm/sec) Systolic TVI (cm) Diastolic velocity (cm/sec) Diastolic TVI (cm) Ratio of systolic to diastolic velocity Ratio of systolic to diastolic TVI Atrial reversal velocity (cm/sec) Atrial reversal duration (msec) Atrial reversal TVI (cm)

46 11.1 59 8.8 0.8 1.3 21 130 1.7

9 2.3 8 1.8 0.2 0.3 4 20 0.5

45 11.5 54 9.2 0.8 1.3 21 125 1.6

9 2.2 9 2.5 0.2 0.4 5 20 0.6

41 10.8 59 12.1 0.7 0.9 21 140 2.0

10 2.8 11 3.1 0.2 0.3 7 28 0.9

SD, standard deviation; TVI, time velocity integral. From O’Leary PW et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end diastolic pressure. Mayo Clin Proc 1998;73:616–628.

Chapter 25 • Congenital Heart Disease TABLE 25-3 INFLUENCES OF AGE AND HEART RATE ON DIASTOLIC DOPPLER VARIABLES IN CHILDREN BIVARIATE PARTIAL ASSOCIATIONS*

UNIVARIATE ASSOCIATIONS VARIABLE

Age

RR

Age

RR

Mitral E velocity Mitral A velocity End A to R interval Duration of A wave Mitral deceleration time Mitral E wave TVI Mitral A wave TVI Mitral E at A velocity Mitral E to A ratio (velocity) Mitral E to A ratio (TVI) LV IVRT PV systolic peak velocity PV diastolic peak velocity Peak PVAR velocity PVAR duration PV systolic TVI PV diastolic TVI PVAR TVI PV systolic to diastolic ratio (velocity) PV systolic to diastolic ratio (TVI) Ratio of PVAR to mitral A wave duration Ratio of PVAR to mitral A wave TVI

— ↓ ↑ — ↑↑↑ ↑↑ — ↓ — ↑ ↑↑ ↓ — — ↑ — ↑↑↑ ↑ ↓ ↓↓ — ↓

↑ ↓↓ — ↑ ↑↑↑ ↑↑↑ ↓ ↓↓ ↑↑↑ ↑↑↑ ↑↑ — ↑ — ↑↑ ↑ ↑↑↑ ↑ — ↓ — ↓↓

↓ ↑ ↑ — ↑ — ↑ — ↓ ↓ ↑ ↓ — — — — ↑ — — ↓ — —

↑ ↓↓ — — ↑ ↑↑↑ ↓ ↓↓ ↑↑↑ ↑↑↑ ↑ — ↑ — ↑↑ ↑ ↑ ↑ — ↓ — ↓↓

*Univariate associations column demonstrates the association between age or heart rate (RR interval) and each dependent variable without accounting for other influences. Bivariate partial associations column demonstrates the effect of age or heart rate on each dependent variable after controlling for the influence of the other independent variable (age or heart rate). Upward arrows indicate positive associations between age or RR interval and the measured variable; downward arrows indicate negative associations. The number of arrows shown increases as the degree of association increases. A, atrial; E, early; IVRT, isovolumic relaxation time; LV, left ventricular; PV, pulmonary vein; PVAR, pulmonary vein atrial reversal; RR, RR interval; TVI, time velocity integral; — = no effect; ↑ = weak association (R2 < 0.10); ↑↑ = moderate association (0.10 < R2 < 0.20); ↑↑↑ = strong association (R2 > 0.20). From O’Leary PW et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end diastolic pressure. Mayo Clin Proc 1998;73:616–628.

Impaired relaxation Normal Children

Venous flow

Figure 25-1 Spectrum of diastolic flow patterns in diastolic dysfunction in children. (From Olivier M et al: Serial Doppler assessment of diastolic function before and after the Fontan operation. J Am Soc Echocardiogr 2003;16:1136–1143.)

Decrease in compliance

Adults

Mild to moderate

E

AV valve

Velocity

Abnormal relaxation

Severe

A

S

D

VAR

I

II

III and IV

315

Chapter 25 • Congenital Heart Disease

ECG

E

MV

Velocity

A

DT

A-d

D

S

PV

1 and 3.1,27 Normal durations of mitral DT and IVRT vary with age and have been reported in both pediatric and adult populations.1–3,27–29 Mitral inﬂow Doppler velocities are aﬀected not only by changes in LV diastolic function but also by a variety of additional hemodynamic factors, including age, altered loading conditions, heart rate, and changes in atrial and ventricular compliance.1–3,28,30 Interpretation of characteristic patterns of mitral inﬂow must be carefully evaluated with particular attention paid to the potential impact of each of these hemodynamic factors on mitral inﬂow Doppler velocities. As in the adult population, the earliest stage of LV diastolic dysfunction demonstrated by mitral inﬂow Doppler in children is abnormal relaxation. This Doppler pattern is characteristic of normal aging in adults and represents a mild decrease in the rate of LV relaxation with continued normal LA pressure. It is characterized by a reduced E-wave velocity, increased A-wave velocity, decreased E/A ratio less than 1, and a prolonged mitral DT and IVRT. As diastolic dysfunction progresses, further changes in ventricular relaxation and compliance occur, leading to an increase in LA pressure. Increased LA pressure normalizes the initial transmitral gradient between the left atrium and the left ventricle, producing a “pseudonormalized” mitral inﬂow Doppler pattern with increased E-wave velocity and E/A ratio and normalized mitral DT and IVRT intervals. This pseudonormal Doppler pattern may be diﬃcult to distinguish from normal mitral inﬂow Doppler; however, maneuvers that decrease ventricular preload, like the Valsalva maneuver, as well as additional evaluation of pulmonary venous inﬂow Doppler can help unmask this advanced degree of LV diastolic dysfunction. Further deterioration of LV diastolic function results in restrictive ventricular ﬁlling with an additional increase in LA pressure and a concomitant decrease in ventricular compliance. The Doppler pattern of restrictive LV ﬁlling is characterized by additional increases in E-wave velocity, reduction in A-wave velocity, an increased E/A ratio greater than 3, and signiﬁcant shortening of both mitral DT and IVRT.

PVAR-d sTVI

dTVI

PVAR

A

Time

2.00 1.8 1.6 Ratio of PVAR and MV-A duration

316

1.4 1.2 1.0 0.8 0.6 0.4

Pulmonary Venous Doppler Pulmonary venous Doppler combined with mitral inﬂow Doppler provides a more comprehensive assessment of LA and LV ﬁlling pressures (see Fig. 25-1).27,31–34 Pulmonary venous inﬂow consists of three distinct Doppler waves: a systolic wave (S wave), a diastolic wave (D wave), and a reversal wave with atrial contraction (Ar wave). In adolescents and adults with normal hearts, the characteristic pattern of pulmonary venous inﬂow consists of a dominant S wave, a smaller D wave, and a small Ar wave of low velocity and brief duration. In neonates and younger children, a dominant D wave is often present with a similar brief lowvelocity, or even absent, Ar wave. With worsening LV diastolic dysfunction, LA pressure rises, leading to diminished systolic forward ﬂow into the left atrium from the pulmonary veins with relatively increased diastolic forward ﬂow, resulting in a diastolic dominance of pulmonary venous inﬂow. More importantly, both the velocity and the duration of the pulmonary venous Ar wave are increased. Pediatric and adult studies have demonstrated that an Ar-wave duration more than 30 msec longer than the corresponding mitral A-wave duration or a ratio of pulmonary venous Ar-wave duration to mitral A-wave duration greater than 1.2 is predictive of elevated LV ﬁlling pressure (Fig. 25-2).27,35–36

B

Normal EDP

High EDP

Figure 25-2 A, Diagram depicting mitral valve and pulmonary vein Doppler flow tracings. B, Detecting elevated end diastolic pressure >18 mmHg (EDP) with use of ratio of pulmonary vein atrial reversal (PVAR) to mitral valve (MV) atrial filling wave (A) duration. A, atrial filling wave; A-d, duration of atrial filling wave; D, pulmonary vein diastolic flow wave; DT, mitral deceleration time; dTVI, time velocity integral of pulmonary vein diastolic flow wave; E, early filling wave; ECG, electrocardiogram; PVAR, pulmonary vein atrial reversal wave; PVAR-d, duration of pulmonary vein atrial reversal flow; S, pulmonary vein systolic flow wave; sTVI, time velocity integral of pulmonary vein systolic flow wave. (From O’Leary PW et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular enddiastolic pressure. Mayo Clin Proc 1998;73:616–628.)

Tissue Doppler Imaging Tissue Doppler imaging is particularly well suited to the quantitative evaluation of LV diastolic function (Fig. 25-3) (see Chapter 12). Both early (Ea) and late (Aa) annular diastolic velocities can be readily obtained by tissue Doppler echocardiography. Similar to systolic tissue Doppler velocities, diﬀerences in diastolic velocities exist (1) between the subendocardium and the subepicardium, (2) from cardiac base to apex, and (3) among various

Chapter 25 • Congenital Heart Disease

S S

ICT

A

A

S

E

ICT

ICT IRT

IRT

IRT

A

B

A

C

E

E

Figure 25-3 Longitudinal tissue Doppler imaging velocities obtained at lateral mitral annulus (A), interventricular septum (B), and lateral tricuspid annulus (C). Tissue Doppler velocities include systolic (S), early diastolic (E), and late diastolic (A) myocardial velocities. Isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) are also demonstrated. (From Eidem BW et al: Impact of chronic left ventricular preload and afterload on Doppler tissue imaging velocities: A study in congenital heart disease. J Am Soc Echocardiogr 2005;18:830–838.)

myocardial wall segments.5,6,8,9,12,37–41 Previous studies have reported an excellent correlation between early annular diastolic mitral velocity and simultaneous invasive measures of diastolic function at cardiac catheterization.42 Early annular diastolic velocities also appear to be less sensitive to changes in ventricular preload compared with corresponding early transmitral Doppler inﬂow velocities.42–44 Signiﬁcant alterations in preload, however, have been shown to aﬀect these diastolic tissue Doppler velocities.45–47 The eﬀect of afterload on tissue Doppler velocities is less controversial, with many studies documenting signiﬁcant changes in systolic and diastolic annular velocities with changes in ventricular afterload.48–50 Therefore, the clinical use of tissue Doppler velocities in patients with valvular stenosis or other etiologies of altered ventricular afterload need to be interpreted carefully in light of this limitation. Tissue Doppler velocities are helpful in the discrimination between normal and pseudonormal transmitral Doppler ﬁlling patterns (Fig. 25-4).7,43,51–52 In addition to changes incurred by loading conditions, alterations in LA pressure and LV end diastolic pressure also aﬀect the early transmitral diastolic velocity. However, the corresponding tissue Doppler velocity is typically decreased in patients with pseudonormal ﬁlling, allowing diﬀerentiation of this abnormal ﬁlling pattern from one of normal transmitral Doppler inﬂow. Clinical reports have suggested a ratio of the early transmitral inﬂow Doppler signal to the lateral mitral annular early diastolic velocity (mitral E/Ea) as a noninvasive measure of LV ﬁlling pressure. Nagueh and colleagues demonstrated a signiﬁcant correlation of mitral E/Ea with invasively measured mean pulmonary capillary wedge pressure,43 while subsequent studies have further validated this ratio and reported its applicability in a variety of hemodynamic settings (Fig. 25-5).53–57 Additional novel indices of LV diastolic function using tissue Doppler echocardiography have recently been reported that may further expand the role of this modality in the clinical evaluation of LV ﬁlling pressures.52,58 Tissue Doppler also is of considerable clinical value in the differentiation of constrictive from restrictive LV ﬁlling (see Chapter 24).59–62 Evaluation of patients with constrictive pericarditis and restrictive cardiomyopathy with two-dimensional echocardiography and even invasive cardiac catheterization may fail to conﬁdently diﬀerentiate between these two disease states. Because the

NORMAL

IMPAIRED RELAXATION

Mitral inflow

Mitral inflow

E

PSEUDONORMAL Mitral inflow

E

A

A E

DTI

A

50 cm/sec

DTI

Sa

DTI

Sa

Sa

5 cm/sec

5 cm/sec

Ea Ea

Aa

Aa

Ea A a

Figure 25-4 Representative transmitral Doppler and tissue Doppler velocities in normal and diastolic dysfunction. Note significantly decreased tissue Doppler velocities with pseudonormal pattern. (From Nagueh SF et al: Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533.)

myocardium in patients with constrictive pericarditis is commonly normal, the corresponding tissue Doppler velocities are also normal. However, patients with restrictive cardiomyopathy have signiﬁcantly decreased early diastolic and systolic tissue Doppler velocities, allowing separation of these two distinct clinical entities. Tissue Doppler Studies in Children with Healthy Hearts To date, a number of studies have established baseline reference values of tissue Doppler velocities in children (Tables 25-4 and

317

Chapter 25 • Congenital Heart Disease 25-5).13–15,63–66 Similar to previously published adult reports, pediatric tissue Doppler velocities vary with age,15,63,66 heart rate,15,63 wall location,63 and myocardial layer (Fig. 25-6).67 In addition, pulsed-wave tissue Doppler velocities are highly correlated with parameters of cardiac growth, most notably LV end diastolic dimension and LV mass, with the most signiﬁcant changes in these velocities occurring during the ﬁrst year of life 45

y = 1.9 + 1.24x r = 0.87 n= 60

40 35 PCWP mmHg

318

30 25 20 15 10 5 0

5

10

15

20

25

30

35

(Fig. 25-7).63 In a recently published large study of infants and children, tissue Doppler velocities did not correlate signiﬁcantly with other more commonly utilized measures of systolic and diastolic ventricular performance, including LV shortening fraction, LV and RV myocardial performance indices, and transmitral inﬂow Doppler.63 This lack of correlation is likely due in part to pulsed-wave tissue Doppler assessments of longitudinal ventricular function, while other, more traditional, two-dimensional and Doppler methods assess radial and global measures of ventricular performance. Normative data for the E/Ea ratio, similar to those previously published for adults, have also been reported for children43–44,53–56 (Fig. 25-8).63 These values are signiﬁcantly altered by age, heart rate, ventricular wall location, and LV dimensions and mass.63 Values for E/Ea are highest in neonates and decrease with advancing age due primarily to increased Ea velocity. Simultaneous catheterization/echocardiographic measurements correlating the E/ Ea ratio in children with invasive measures of LV ﬁlling pressure are lacking to date. In a small cohort of children, invasive cardiac catheterization measures of LV function were compared with simultaneously obtained color M-mode and Doppler parameters of LV performance.68 The ratio of early diastolic mitral inﬂow Doppler velocity to ﬂow propagation velocity (E/Vp) correlated closely with invasive LV end diastolic pressure, while the septal Ea velocity correlated with the time constant of relaxation (τ). Additional studies using tissue Doppler have established normal atrioventricular electromechanical coupling intervals.65

E/Ea Figure 25-5 Relation of E/EA to pulmonary capillary wedge pressure. (From Nagueh SF et al: Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533.)

Color M-Mode Flow Propagation Velocity Flow propagation of early diastolic ﬁlling from the mitral annulus to the cardiac apex can be quantitated by color M-mode (see

TABLE 25-4 DEMOGRAPHICS AND ECHOCARDIOGRAPHIC DATA IN STUDY PATIENTS DEMOGRAPHICS

<1 yr

1–5 yrs

6–9 yrs

10–13 yrs

14–18 yrs

TOTAL

N Male Age (y) Weight (kg) BSA (m2) HR (bpm) Echocardiographic LV EDD (cm) LV ESD (cm) LV PWT (cm) LV SWT (cm) LV mass (g/m2) Mitral E velocity Mitral A velocity Mitral E/A ratio PV S-wave velocity PV D-wave velocity PV A-reversal velocity Tricuspid E velocity Tricuspid A velocity Tricuspid E/A ratio SF (%) LV MPI RV MPI

63 29 0.40 ± 0.30 6.6 ± 2.7 0.34 ± 0.08 124 ± 16

68 39 3.05 ± 1.51 15.1 ± 5.4 0.62 ± 0.14 105 ± 17

55 27 7.91 ± 1.12 33.8 ± 14.9 1.07 ± 0.27 80 ± 11

58 38 11.99 ± 1.11 47.2 ± 16.3 1.37 ± 0.29 75 ± 12

81 44 16.0 ± 1.40 66.1 ± 15.5 1.73 ± 0.25 69 ± 16

325 177 7.8 ± 6.0 33.3 ± 25.2 1.0 ± 0.6 90 ± 26

2.3 ± 0.3 1.4 ± 0.2 0.4 ± 0.1 0.5 ± 0.1 18.9 ± 6.5 79.7 ± 18.8 65.3 ± 13.3 12.4 ± 0.30 44.6 ± 10.3 46.0 ± 9.5 16.4 ± 6.3 53.3 ± 12.3 53.2 ± 13.0 1.01 ± 0.38 38.9 ± 4.1 0.33 ± 0.08 0.29 ± 0.09

3.1 ± 0.4 1.9 ± 0.3 0.6 ± 0.1 0.6 ± 0.1 43.6 ± 16.4 95.2 ± 19.5 61.3 ± 12.1 1.60 ± 0.46 48.0 ± 8.9 54.5 ± 11.0 20.6 ± 4.3 61.6 ± 12.5 48.3 ± 12.3 1.27 ± 0.31 38.0 ± 3.6 0.34 ± 0.07 0.28 ± 0.07

3.9 ± 0.4 2.4 ± 0.3 0.7 ± 0.1 0.8 ± 0.1 82.3 ± 28.3 94.4 ± 14.8 49.4 ± 12.5 1.99 ± 0.51 50.7 ± 11.3 53.3 ± 11.4 20.2 ± 3.8 60.5 ± 13.9 42.4 ± 10.8 1.49 ± 0.40 37.4 ± 3.8 0.32 ± 0.06 0.29 ± 0.08

4.3 ± 0.4 2.7 ± 0.3 0.8 ± 0.1 0.8 ± 0.2 110.1 ± 32.9 94.5 ± 16.0 49.5 ± 13.8 2.02 ± 0.58 49.0 ± 11.1 58.4 ± 12.1 21.2 ± 4.9 59.6 ± 11.4 39.2 ± 11.3 1.61 ± 0.47 37.4 ± 4.2 0.34 ± 0.06 0.28 ± 0.08

4.7 ± 0.4 3.0 ± 0.4 0.9 ± 0.2 1.0 ± 0.2 158.4 ± 48.5 90.3 ± 17.8 45.5 ± 13.2 2.13 ± 0.65 47.7 ± 7.3 57.9 ± 15.0 20.0 ± 5.2 60.4 ± 10.9 34.5 ± 11.2 1.88 ± 0.56 36.4 ± 4.3 0.34 ± 0.08 0.29 ± 0.08

3.6 ± 1.0 2.3 ± 0.6 0.7 ± 0.2 0.7 ± 0.2 81.8 ± 58.9 90.8 ± 18.5 54.4 ± 15.0 1.79 ± 0.61 48.7 ± 9.2 54.6 ± 12.9 20.5 ± 5.1 59.2 ± 12.4 43.3 ± 13.5 1.47 ± 0.53 37.6 ± 4.1 0.33 ± 0.08 0.28 ± 0.08

From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.

Chapter 25 • Congenital Heart Disease TABLE 25-5 PULSED-WAVE DOPPLER TISSUE VELOCITIES AND TIME INTERVALS IN HEALTHY CHILDREN BY AGE GROUP AGE GROUP

N

Mitral annular <1 yr

63

1–5 yrs

68

6–9 yrs

55

10–13 yrs

58

14–18 yrs

81

Total

325

Septal <1 yr

63

1–5 yrs

68

6–9 yrs

55

10–13 yrs

58

14–18 yrs

81

Total

325

Tricuspid annular <1 yr

63

1–5 yrs

68

6–9 yrs

55

10–13 yrs

58

14–18 yrs

81

Total

325

E*-WAVE VELOCITY

A*-WAVE VELOCITY

S*-WAVE VELOCITY

ICT

IRT

E/E* RATIO

9.7 ± 3.3 (8.8–10.5) 15.1 ± 3.4† (14.3–15.4) 17.2 ± 3.7† (16.2–18.3) 19.6 ± 3.4† (18.7–20.5) 20.6 ± 3.8 (19.7–21.4) 16.5 ± 5.3 (16.0–17.1)

5.7 ± 1.8 (5.3–6.2) 6.5 ± 1.9 (6.1–7.0) 6.7 ± 1.9 (6.2–7.3) 6.4 ± 1.8 (5.9–6.9) 6.7 ± 1.6 (6.3–7.1) 6.4 ± 1.9 (6.2–6.6)

5.7 ± 1.6 (5.3–6.1) 7.7 ± 2.1† (7.2–8.2) 9.5 ± 2.1† (8.9–10.1) 10.8 ± 2.9* (10.0–11.5) 12.3 ± 2.9† (11.6–12.9) 9.3 ± 3.4 (8.9–9.7)

77.4 ± 18.4 (72.7–82.0) 76.9 ± 15.9 (72.8–80.9) 77.9 ± 18.9 (72.4–83.4) 76.6 ± 16.2 (72.4–80.9) 78.9 ± 15.4 (75.4–82.3) 77.5 ± 16.7 (75.7–79.5)

57.0 ± 14.8 (53.1–60.8) 62.1 ± 13.2 (58.9–65.4) 62.9 ± 11.9 (59.5–66.3) 62.6 ± 12.4 (59.4–65.9) 69.5 ± 15.5* (66.1–73.0) 63.2 ± 14.4 (61.7–64.9)

8.8 ± 2.7 (8.1–9.5) 6.5 ± 2.0† (6.0–7.0) 5.8 ± 1.9 (5.3–6.4) 4.9 ± 1.3 (4.6–5.2) 4.7 ± 1.3 (4.4–5.0) 6.1 ± 2.4 (5.9–6.4)

8.1 ± 2.5 (7.5–8.7) 11.8 ± 2.0† (11.3–12.3) 13.4 ± 1.9† (12.8–13.9) 14.5 ± 2.6 (13.8–15.2) 14.9 ± 2.4 (14.3–15.4) 12.6 ± 3.4 (12.2–13.0)

6.1 ± 1.5 (5.7–6.4) 6.0 ± 1.3 (5.7–6.4) 5.9 ± 1.3 (5.5–6.3) 6.1 ± 2.3 (5.6–6.7) 6.2 ± 1.5 (5.9–6.6) 6.1 ± 1.6 (5.9–6.3)

5.4 ± 1.2 (5.1–5.7) 7.1 ± 1.5† (6.8–7.5) 8.0 ± 1.3 (7.6–8.4) 8.2 ± 1.3 (7.9–8.5) 9.0 ± 1.5 (8.7–9.3) 7.6 ± 1.9 (7.4–7.8)

77.5 ± 17.5 (73.0–82.0) 80.1 ± 15.5 (76.3–83.9) 82.8 ± 15.3 (78.4–87.2) 87.9 ± 16.4* (83.6–92.2) 88.4 ± 15.6 (84.9–91.9) 83.5 ± 16.5 (81.7–85.4)

53.0 ± 11.7 (50.0–56.0) 59.8 ± 12.0 (56.9–62.7) 65.6 ± 10.7 (62.5–68.7) 72.5 ± 12.3 (69.3–75.8) 77.5 ± 14.5 (74.3–80.8) 66.1 ± 15.3 (64.4–67.9)

10.3 ± 2.7 (9.7–11.0) 8.1 ± 1.8† (7.7–8.5) 7.2 ± 1.6 (6.8–7.7) 6.6 ± 1.4 (6.3–7.0) 6.4 ± 1.5 (6.1–6.8) 7.7 ± 2.3 (7.5–8.0)

13.8 ± 8.2 (11.7–15.9) 17.1 ± 4.0† (16.1–18.1) 16.5 ± 3.0 (15.7–17.4) 16.5 ± 3.1 (15.7–17.4) 16.7 ± 2.8 (16.0–17.3) 16.1 ± 4.7 (15.6–16.7)

9.8 ± 2.4 (9.1–10.5) 10.9 ± 2.7 (10.2–11.6) 9.8 ± 2.7 (9.0–10.6) 10.3 ± 3.4 (9.3–11.2) 10.1 ± 2.6 (9.5–10.7) 10.2 ± 2.8 (9.9–10.5)

10.2 ± 5.5 (8.8–11.7) 13.2 ± 2.0† (12.7–13.7) 13.4 ± 2.0 (12.8–14.0) 13.9 ± 2.4 (13.2–14.5) 14.2 ± 2.3 (13.7–14.7) 13.0 ± 3.4 (12.6–13.4)

68.7 ± 18.2 (63.9–73.5) 77.7 ± 15.0 (73.9–81.5) 91.8 ± 21.5† (85.5–98.0) 98.1 ± 21.7 (92.2–103.9) 101.9 ± 20.4 (97.2–106.6) 88.2 ± 23.1 (85.6–90.8)

52.0 ± 12.9 (48.5–55.4) 59.0 ± 13.9 (55.4–62.5) 58.5 ± 17.5 (53.4–63.6) 61.7 ± 19.9 (56.4–67.1) 62.9 ± 18.9 (58.5–67.3) 59.0 ± 17.2 (57.0–60.9)

4.4 ± 2.3 (3.8–5.0) 3.8 ± 1.1 (3.5–4.1) 3.6 ± 0.8 (3.4–3.9) 3.5 ± 1.4 (3.2–3.9) 3.7 ± 1.0 (3.5–3.9) 3.8 ± 1.4 (3.6–4.0)

*P < .05; †P < .01 compared with proceeding age group. Data expressed as mean ± SD (95% confidence interval). Doppler tissue imaging velocities are expressed in cm/sec. Time intervals are expressed in milliseconds. A, Late diastolic velocity; A*, late diastolic annular velocity; ICT, isovolumic contraction time; E, early diastolic inflow Doppler velocity; E*, early diastolic annular velocity; IRT, isovolumic relaxation time; S, systolic velocity; S*, systolic annular velocity. From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.

Chapter 11).52,54 As opposed to mitral inﬂow Doppler, the propagation velocity is signiﬁcantly less aﬀected by changes in heart rate, LA pressure, and loading conditions and may therefore more accurately reﬂect changes in myocardial relaxation. Numerous studies have demonstrated a signiﬁcant decrease in ﬂow propagation velocity in patients with diastolic dysfunction of varying etiology.53–56 In addition, the ratio of the mitral annular Doppler tissue E-wave velocity to ﬂow propagation velocity is a signiﬁcant predictor of congestive heart failure and outcome in patients after myocardial infarction.69–70 This ratio of ﬂow propagation and Doppler tissue imaging velocity also may be helpful in distinguishing a normal mitral inﬂow pattern from one of pseudonormalized mitral inﬂow. In a small cohort of children undergoing simultaneous cardiac catheterization and transthoracic echocardiography, Border et al.68 showed a signiﬁcant correlation between invasively measured LV end diastolic pressure and the ratio of

peak early transmitral Doppler ﬂow velocity to ﬂow propagation velocity (E/Vp) (Fig. 25-9).

CLINICAL RELEVANCE: CONGENITAL HEART DISEASE AND DIASTOLIC DYSFUNCTION Ventricular Volume Overload Altered ventricular geometry and loading conditions are the hallmarks of congenital heart disease. However, the majority of noninvasive measures of systolic and diastolic ventricular performance are signiﬁcantly aﬀected by changes in loading conditions. Traditional echocardiographic measures of systolic function, including LV shortening and LV ejection fraction (LVEF), as well as Doppler measures of LV diastolic function, namely pulmonary venous and mitral inﬂow Doppler, are signiﬁcantly aﬀected by

319

y = 11.778 + 0.615x r2 = 0.487, p < 0.001 SEE = 3.8

30 25 20 15 10 5

20

y = 6.059 + 0.050x r2 = 0.025, p = 0.005 SEE = 1.9

15 10 5 0

0 4

8

12

16

5

Age (yrs) 30

15 Septal A-wave velocity (cm/sec)

20 15 10 5 0

10

15

8

12

16

4

8

12

5

20

10

5

4

Tricuspid annular A-wave velocity (cm/sec) 20

12

16

20

y = 6.037 + 0.204x r2 = 0.419, p < 0.001 SEE = 1.4

15 10 5

4

8

12

16

20

0

4

Age (yrs)

16

8

0 0

20

y = 15.363 + 0.102x r2 = 0.016, p = 0.02 SEE = 4.7

0

10

Age (yrs)

y = 5.949 + 0.021x r2 = 0.006, p = 0.18 SEE = 1.6

Age (yrs) 40 35 30 25 20 15 10 5 0

15

0

25

y = 10.303 – .013x r2 = 0.001, p = 0.65 SEE = 2.8

20 15 10 5 0 0

4

Age (yrs)

8

12

Age (yrs)

8

12

16

20

16

20

Age (yrs) Tricuspid annular S-wave velocity (cm/sec)

4

20

20

0 0

y = 6.186 + 0.405x r2 = 0.512, p < 0.001 SEE = 2.4

25

Age (yrs)

y = 9.629 + 0.380x r2 = 0.450, p < 0.001 SEE = 2.5

25

30

0 0

20

Septal S-wave velocity (cm/sec)

0

Septal E-wave velocity (cm/sec)

Mitral annular S-wave velocity (cm/sec)

35

Mitral annular A-wave velocity (cm/sec)

Mitral annular E-wave velocity (cm/sec)

Chapter 25 • Congenital Heart Disease

Tricuspid annular E-wave velocity (cm/sec)

320

16

20

y = 11.543 + 0.191x r2 = 0.112, p < 0.001 SEE = 3.2

30 25 20 15 10 5 0 0

4

8

12

Age (yrs)

Figure 25-6 Effect of age on tissue Doppler velocities in healthy children. Data are expressed as mean ± SD and 95% confidence interval. A, late diastolic velocity; E, early diastolic velocity; S, systolic velocity. (From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.)

altered LV preload and afterload.27,31,71–81 While the distortion in ventricular geometry and loading are signiﬁcant limitations in routine two-dimensional and Doppler echocardiography in patients with these congenital heart lesions, tissue Doppler echocardiography is ideally suited to this quantitative evaluation because of its relative independence from these geometric constraints. Tissue Doppler has been reported to be relatively independent of changes in ventricular loading in adults with and without associated heart disease. Sohn et al. reported the relative preload independence of mitral annular tissue Doppler velocities in adults with unimpaired hearts as well as those with abnormal LV relaxation.42 These ﬁndings were challenged by Firstenberg et al., who reported signiﬁcantly altered early diastolic myocardial velocities in dogs with decreased ventricular preload.45 Pulsedwave tissue Doppler, however, appears to be less inﬂuenced by similar alterations in ventricular preload compared with transmitral Doppler velocities. Studies in children with congenital heart disease and associated chronic increases in LV preload have documented minimal changes in tissue Doppler velocities compared with pediatric controls. Harada et al. evaluated 33 children with either ventricular

septal defects (VSDs) or patent ductus arteriosi (PDAs) with increased LV preload using both tissue Doppler and conventional Doppler methodologies compared with simultaneous cardiac catherization-derived hemodynamic data.82 In their cohort, routine transmitral early diastolic velocities (E) were signiﬁcantly increased and correlated directly with increases in LA pressure and pulmonary-to-systemic ﬂow ratios. However, the corresponding early (Ea) and late (Aa) tissue Doppler velocities were not diﬀerent compared with controls despite increased LV preload. The E/Ea ratio was signiﬁcantly elevated in children with both VSDs and PDAs and correlated well with invasive LA pressure measurement. Postrepair, in a small number of children, tissue Doppler velocities remained unchanged despite the removal of this chronic LV volume overload.82 We reported similar ﬁndings in 94 children with varying sizes of VSDs.83 In our series, tissue Doppler velocities at both the lateral mitral and tricuspid annuli were unaﬀected by signiﬁcantly increased ventricular preload (Table 25-6). Isolated small diﬀerences in systolic and early diastolic velocities were demonstrated at the septal annulus and were thought to be related more to altered cardiac translation secondary to ventricular dilatation than to changes attributable to increased ventricular preload. In children with VSDs, the E/Ea

y = 1.831 + 4.049x r2 = 0.538, p < 0.001 SEE = 3.6

30 25 20 15 10 5

20

y = 5.582 + 0.227x r2 = 0.014, p = 0.035 SEE = 1.8

15 10 5 0

0 2

3

4

5

2

LV EDD (cm) 15

y = 3.586 + 2.466x r2 = 0.483, p < 0.001 SEE = 2.5

20 15 10 5 0

3

5

4

3

4

5

2

3

4

5

20

10

5

2

Tricuspid annular A-wave velocity (cm/sec)

25

2

3

4

5

15

5

6

5

6

5

6

10 5

1

6

2

15 10 5 0 1

2

LV EDD (cm)

3

3

4

LV EDD (cm)

y = 10.508 – 0.090x r2 = 0.001, p = 0.61 SEE = 2.8

20

6

4

y = 2.776 + 1.325x r2 = 0.464, p < 0.001 SEE = 1.4

LV EDD (cm)

5

3

0 1

6

y = 13.180 + 0.809x r2 = 0.026, p = 0.004 SEE = 4.7

1

10

LV EDD (cm)

y = 5.748 + 0.091x r2 = 0.003, p = 0.34 SEE = 1.6

LV EDD (cm) 40 35 30 25 20 15 10 5 0

15

1

Tricuspid annular S-wave velocity (cm/sec)

2

20

6

0 1

y = 0.190 + 2.506x r2 = 0.505, p < 0.001 SEE = 2.4

LV EDD (cm)

Septal A-wave velocity (cm/sec)

Septal E-wave velocity (cm/sec)

25

25

0 1

6

Septal S-wave velocity (cm/sec)

1

Tricuspid annular E-wave velocity (cm/sec)

Mitral annular S-wave velocity (cm/sec)

35

Mitral annular A-wave velocity (cm/sec)

Mitral annular E-wave velocity (cm/sec)

Chapter 25 • Congenital Heart Disease

4

5

25

y = 7.945 + 1.385x r2 = 0.150, p < 0.001 SEE = 3.1

20 15 10 5 0 1

6

LV EDD (cm)

2

3

4

LV EDD (cm)

25

y = 7.899 – 0.230x r2 = 0.327, p < 0.001 SEE = 2.0

20

Mitral annular E/E′ ratio

Mitral annular E/E′ ratio

Figure 25-7 Effect of left ventricular end diastolic dimension (LV EDD) on tissue Doppler velocities in healthy children. Data are expressed as mean ± SD and 95% confidence interval. A, late diastolic velocity; E, early diastolic velocity; S, systolic velocity. (From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.)

15 10 5 0 0

4

8

12

16

25

y = 1.451 + 0.051x r2 = 0.294, p < 0.001 SEE = 2.0

20 15 10 5 0

40 60 80 100 120 140 160 180

20

Heart rate (BPM)

25

y = 11.458 – 1.467x r2 = 0.339, p < 0.001 SEE = 2.0

20

Mitral annular E/E′ ratio

Figure 25-8 Effect of age, heart rate, left ventricular end diastolic dimension (LV EDD) and LV mass on mitral inflow Doppler early diastolic velocity (E)/early mitral annular diastolic tissue Doppler imaging velocity (E′) ratio in healthy children. Data are expressed as mean ± SD and 95% confidence interval. (From Eidem BW et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221.)

Mitral annular E/E′ ratio

Age (years)

15 10 5 0 1

2

3

4

LV EDD (cm)

5

6

y = 7.733 – 0.020x r2 = 0.233, p < 0.001 SEE = 2.1

25 20 15 10 5 0 0

100

200

LV mass (gm/m2)

300

321

322

Chapter 25 • Congenital Heart Disease

LV end-diastolic pressure (mmHg)

20

y = 0.14 + 5.5x r = 0.71 p < 0.001

18 16 14 12 10 8 6 4 2 0 0.0

A

0.5

1.0

B

1.5

2.0

2.5

3.0

E/Vp ratio

Figure 25-9 A, Measurement of flow propagation velocity (Vp) from color M-mode Doppler: Vp is determined by the slope (white line) of the first clearly demarcated aliasing velocity (red-yellow interface) during early left ventricular filling. B, Relationship between dimensionless index ratio of peak early transmitral flow ventricular velocity to flow propagation velocity (E/Vp) to invasively determined left ventricular (LV) end diastolic pressure. (From Border WL et al: Color M-mode and Doppler tissue evaluation of diastolic function in children: Simultaneous correlation with invasive indices. J Am Soc Echocardiogr 2003;16:988–994.)

TABLE 25-6 EFFECT OF INCREASING PRELOAD ON DOPPLER TISSUE IMAGING VELOCITIES IN PATIENTS WITH VENTRICULAR SEPTAL DEFECTS

N Male Doppler tissue Mitral MV-E MV-A MV-S Septal IVS-E IVS-A IVS-S Tricuspid TV-E TV-A TV-S Mitral E/Ea ratio Septal E/Ea ratio Tricuspid E/Ea ratio Echocardiographic Qp : Qs LV SF (%) LV MPI

SMALL VSD

CONTROL SUBJECTS

P VALUE

MODERATE-LARGE VSD

CONTROL SUBJECTS

P VALUE

56 22

56 25

— —

38 18

38 21

— —

14.6 ± 5.7 6.6 ± 1.8 7.7 ± 2.9

14.0 ± 4.8 6.4 ± 1.9 7.6 ± 2.5

.55 .53 .87

11.8 ± 4.0 6.6 ± 2.1 6.9 ± 2.1

13.1 ± 4.7 6.2 ± 2.6 7.3 ± 3.1

.22 .45 .50

11.0 ± 3.8 6.3 ± 1.5 6.5 ± 1.6

11.4 ± 3.1 6.0 ± 1.3 7.0 ± 1.5

.49 .29 .10

9.7 ± 3.1 6.7 ± 1.9 6.2 ± 1.6

10.9 ± 2.9 5.8 ± 1.2 6.6 ± 1.4

.09 .015 .26

16.1 ± 4.6 10.2 ± 2.4 12.2 ± 3.0 7.0 ± 2.7 9.0 ± 2.7 3.7 ± 1.5

15.6 ± 4.8 10.4 ± 2.8 12.0 ± 2.7 6.8 ± 2.4 8.0 ± 2.3 3.8 ± 1.0

.70 .65 .74 .68 .04 .70

16.7 ± 4.4 10.5 ± 2.2 11.8 ± 2.6 8.9 ± 3.7 10.8 ± 4.4 3.7 ± 1.5

15.1 ± 4.9 9.9 ± 2.5 11.5 ± 3.0 8.1 ± 3.0 9.2 ± 2.5 4.0 ± 1.4

.15 .30 .63 .32 .07 .34

1.5 ± 0.4 38.0 ± 4.6 0.35 ± 0.08

— 37.6 ± 3.9 0.33 ± 0.07

— .56 .12

2.4 ± 0.6 38.7 ± 4.7 0.34 ± 0.08

— 38.7 ± 3.9 0.29 ± 0.08

— .95 0.07

Doppler tissue imaging velocities are expressed in cm/s. Values expressed as mean ± SD. A, Late diastolic velocity; E, early diastolic velocity; IVS, septal annulus; LV, left ventricular; MPI, myocardial performance index; MV, lateral mitral annulus; Qp, total pulmonary blood flow; Qs, total systemic blood flow; S, systolic velocity; SF, shortening fraction; TV, lateral tricuspid annulus; VSD, ventricular sepatal defect. From Eidem BW et al: Impact of chronic left ventricular preload and afterload on Doppler tissue imaging velocities: A study in congenital heart disease. J Am Soc Echocardiogr 2005;18:830–838.

ratio at both the lateral mitral and septal annuli were minimally increased compared with controls; however, when divided into subgroups based on VSD size, no signiﬁcant change in this ratio was demonstrated with increasing LV preload. These data were consistent with previously published invasive hemodynamic data demonstrating normal LV ﬁlling pressures in patients with

VSDs with otherwise normal LV systolic and diastolic function.84 Congenital heart lesions involving the right ventricle frequently have concomitant changes in ventricular loading conditions. Quantitative noninvasive assessment of right ventricular (RV) function has been challenging because of the geometric shape of

Chapter 25 • Congenital Heart Disease the right ventricle. Tissue Doppler imaging allows quantitative nongeometric evaluation of longitudinal RV function along its primary axis of contraction and relaxation. The validity of tissue Doppler velocities in this setting is the topic of many recent reports. Pauliks et al. evaluated 39 children with atrial septal defects (ASDs) before and after interventional device closure.85 At baseline, children with ASDs had increased tricuspid and mitral annular velocities compared with controls, while RV isovolumic acceleration (IVA) was similar between the two groups. Following ASD closure, a transient immediate decrease in tissue Doppler velocities in all myocardial segments was demonstrated, while no change was evident in IVA. Tissue Doppler velocities normalized at 24 hours postprocedure, while IVA remained unchanged, demonstrating the probable load dependence of tissue Doppler velocities and the relative load independence of IVA in children undergoing ASD device closure. Other studies have suggested that the load dependence of tissue Doppler velocities in children with ASD depends upon RV size and relative compliance.86 Cheung et al. evaluated RV function with tissue Doppler imaging and showed improved global and regional indices of RV function after interventional device closure of ASDs but not with surgical closure of these defects.87 Other tissue Doppler studies have demonstrated improvement in LV diastolic function after ASD closure likely related to improved ventricular interaction with decreased RV dilatation and volume overload.88

Ventricular Pressure Overload Children with congenital heart disease commonly have myocardial hypertrophy due to increased afterload. Previous studies in both adults and children with ventricular hypertrophy caused by chronic elevation of afterload have shown variable eﬀects on LV systolic function.89–97 In children, studies utilizing endocardial indices such as EF and velocity of circumferential ﬁber shortening have shown increased LV function, while those corrected for afterload tend to show normal contractility.95–96 Patients with ventricular hypertrophy may present with an abnormality of diastolic function prior to overt changes in systolic performance. In adults with chronic pressure overload, conﬂicting data exist regarding the eﬀect of increasing wall thickness on active and passive properties of diastolic function,98–102 with increased ﬁbrosis noted in some studies.103–104 Children with chronic hypertrophy secondary to aortic stenosis105 or hypertension106 have distinct abnormalities of LV diastolic function, especially impaired LV ﬁlling when evaluated noninvasively. Invasive evaluation of diastolic performance, utilizing the time constant of relaxation (τ) or myocardial stiﬀness constant, is rarely performed in these patients, but these parameters have also been shown to be abnormal.107 Banerjee et al. evaluated ten patients with congenital obstruction of the left ventricular outﬂow tract (LVOT) (valvular aortic stenosis in seven children, coarctation of the aorta in two patients, and supravalvular aortic stenosis in one).108 Both noninvasive and invasive parameters of LV function were evaluated in these children and compared with normal controls. While systolic parameters, including fractional shortening and end systolic ﬁber elastance, were normal, children with LVOT obstruction had prolonged IVRT and time constants of relaxation. While active relaxation was impaired, passive diastolic properties, including both chamber stiﬀness and myocardial stiﬀness, were normal in this small cohort. These studies suggest that early detrimental changes secondary to hypertrophy lead to abnormal relaxation, while prolonged chronic elevation of after-

load may lead to more deﬁnitive changes in myocardial architecture, resulting in decreased ventricular compliance or even a restrictive ﬁlling pattern.109 Pacileo et al. reported the eﬀect of increased afterload on LV geometry and function in 22 children with moderate aortic valve stenosis.110 In their study, routine measures of LV systolic and diastolic function were normal despite increased intensity of integrated backscatter, suggesting altered myocardial architecture with concomitant ﬁbrosis. The clinical eﬀect of these potential anatomic changes on long-term ventricular pump function and relaxation suggests that more sensitive methods of regional functional assessment, such as tissue Doppler echocardiography, may help identify early subclinical changes in ventricular performance. Kiraly et al. have published data on 24 children with aortic valve stenosis and demonstrated decreased systolic and diastolic tissue velocities and strain rate velocities in the lateral and posterior LV walls, with longitudinal velocities more signiﬁcantly aﬀected than radial velocities.111 We have recently detailed a study of 96 children with varying severities of aortic valve stenosis.83 In this pediatric cohort, children with aortic stenosis had signiﬁcantly decreased systolic and early diastolic annular velocities at both the septal and lateral mitral annuli despite normal outcomes of traditional measures of systolic and diastolic ventricular performance (Table 25-7). Patients with the highest aortic valve gradients had the most signiﬁcant decreases in tissue Doppler velocities, suggesting that afterload plays a key role in these myocardial velocities. In addition, both lateral mitral and septal E/Ea ratios were elevated in children with aortic stenosis and correlated with disease severity consistent with previously published invasive studies suggesting increased LV ﬁlling pressures in these patients.101,112–114

Left Ventricular Hypertrophy The presence of ventricular hypertrophy in children may be due to a primary myopathy such as hypertrophic cardiomyopathy (HCM) secondary to altered hemodynamics and ventricular loading conditions, or to a compensatory response to intense athletic training. Pathologic hypertrophy leads to diastolic dysfunction with characteristic changes in mitral inﬂow Doppler of abnormal relaxation or pseudonormal ﬁlling. Tissue Doppler can be quite helpful in characterizing abnormal diastolic function in the hypertrophied left ventricle, including decreased early diastolic velocity and increased E/E′ ratio in the aﬀected myocardial segments. Numerous additional applications of tissue Doppler in adults with heart disease continue to become evident. Systolic and diastolic abnormalities of myocardial function have been characterized extensively in patients with HCM.115–121 Mutation carriers of HCM that lack the hallmark phenotypic expression of ventricular hypertrophy also have been identiﬁed utilizing this modality.115–118 Diﬀerentiation of pathologic etiologies of secondary ventricular hypertrophy (such as hypertension or inﬁltrative diseases), as well as physiologic adaptations of myocardial hypertrophy, in highly trained athletes from those with deﬁnitive HCM also has been reported.121–124 The eﬀect of medical and surgical interventions upon myocardial performance and cardiovascular hemodynamics in adults with HCM also has been detailed using tissue Doppler echocardiography.69–70,125 The role of cardiac resynchronization in patients with heart failure, as well as its applications in patients with cardiomyopathies, has broadened the appeal of tissue Doppler modalities in heart failure management strategies.126–132

323

324

Chapter 25 • Congenital Heart Disease TABLE 25-7 EFFECT OF INCREASING AFTERLOAD ON DOPPLER TISSUE IMAGING VELOCITIES IN PATIENTS WITH AORTIC VALVE STENOSIS

N Male Doppler tissue Mitral MV-E MV-A MV-S Septal IVS-E IVS-A IVS-S Tricuspid TV-E TV-A TV-S Mitral E/Ea ratio Septal E/Ea ratio Tricuspid E/Ea ratio Echocardiographic Mean gradient (mmHg) LV SF (%) LV MPI

MILD AS

CONTROL SUBJECTS

P VALUE

MODERATE TO SEVERE AS

CONTROL SUBJECTS

P VALUE

59 39

59 36

— —

37 23

37 25

— —

17.4 ± 4.3 6.7 ± 1.9 9.6 ± 2.6

18.7 ± 4.7 6.8 ± 2.0 10.4 ± 3.3

.12 .67 .12

15.3 ± 5.1 6.0 ± 2.5 8.5 ± 2.7

17.4 ± 4.8 6.6 ± 2.2 10.5 ± 3.5

.03 .27 .006

12.7 ± 2.8 6.4 ± 1.7 7.9 ± 1.6

13.8 ± 2.6 6.0 ± 1.50 8.3 ± 1.8

.025 .17 .19

11.0 ± 3.0 6.5 ± 1.3 7.2 ± 1.4

13.4 ± 8.2 6.5 ± 1.7 8.4 ± 1.9

.001 .83 .003

16.5 ± 4.1 10.2 ± 2.8 13.3 ± 2.4 6.7 ± 2.9 8.6 ± 2.1 4.0 ± 1.2

16.6 ± 3.4 10.1 ± 2.8 16.9 ± 2.4 5.5 ± 1.7 7.2 ± 1.8 3.7 ± 0.9

.88 .81 .34 .02 .001 .12

15.3 ± 4.0 10.3 ± 2.8 12.7 ± 2.5 7.5 ± 2.5 9.8 ± 2.9 4.2 ± 1.5

16.4 ± 4.5 10.2 ± 2.3 13.2 ± 2.5 5.7 ± 2.1 7.2 ± 2.0 4.0 ± 1.1

.28 .92 .34 .004 .0001 .54

11.6 ± 4.0 39.3 ± 3.5 0.34 ± 0.06

— 37.7 ± 3.5 0.33 ± 0.07

— .01 .38

31.7 ± 3.9 43.6 ± 5.8 0.33 ± 0.10

— 38.0 ± 4.9 0.33 ± 0.07

— .0002 .96

Values expressed as mean ± SD. Doppler tissue imaging velocities are expressed in cm/s. A, Late diastolic velocity; AS, aortic valve stenosis; E, early diastolic velocity; IVS, septal annulus; LV, left ventricular; MPI, myocardial performance index; MV, lateral mitral annulus; S, systolic velocity; SF, shortening fraction; TV, lateral tricuspid annulus. From Eidem BW et al: Impact of chronic left ventricular preload and afterload on Doppler tissue imaging velocities: A study in congenital heart disease. J Am Soc Echocardiogr 2005;18:830–838.

Hypertrophic and Dilated Cardiomyopathies in Children The use of tissue Doppler to predict clinical outcomes has emerged as a potentially important clinical application in children with cardiomyopathies. McMahon et al.133 prospectively evaluated 54 children with dilated cardiomyopathy (DCM) with both conventional echocardiographic indices and tissue Doppler velocities to determine predictors of adverse clinical outcomes (deﬁned as death, cardiac transplantation, or hospitalization). While tissue Doppler velocities, LV and RV Tei indices, RV fractional area change, and LVEF were all abnormal in DCM patients, only tricuspid Ea velocity less than 8.5 cm/sec and LVEF less than 30% were multivariate predictors of poor clinical outcome. Similarly, McMahon et al.134 evaluated LV diastolic function in children with HCM using tissue Doppler echocardiography compared with traditional echocardiographic parameters, exercise stress testing, and ambulatory Holter monitoring to determine their clinical utility in predicting adverse outcome (death or ventricular tachycardia), and signiﬁcant cardiac symptoms. In all, 80 children were prospectively evaluated, with the ratio of transmitral E to septal Ea found to be signiﬁcantly predictive of adverse clinical outcomes. In addition, this ratio correlated inversely with peak oxygen consumption obtained during exercise stress testing (Fig. 25-10). While LVEF, Tei index, maximal LV wall thickness, and LA volume were all signiﬁcantly diﬀerent compared with controls, none were predictive of the primary clinical endpoint.

Tetralogy of Fallot There is considerable evidence that altered RV compliance occurs in the immediate postoperative period as well as in the long-term in patients following repair of tetralogy of Fallot.135 These changes in RV compliance are not secondary to residual RVOT obstruction or elevated pulmonary arterial pressures but are thought to be more likely related to myocardial injury at the time of cardiopulmonary bypass. Norgard et al. evaluated 34 children after repair of tetralogy of Fallot. In their series, almost half of their patients had Doppler evidence of restrictive physiology in the immediate postoperative period, with restrictive changes resolving prior to hospital discharge in most children. Children who had a transannular patch as part of their repair were most likely to have restrictive RV physiology postoperatively and to manifest this abnormality again at midterm follow-up. Only those children who had restrictive physiology in the immediate postoperative period had similar ﬁndings present at midterm serial follow-up. Findings from previous studies showing decreased QRS duration on surface electrocardiography (ECG) or decreased incidence of ventricular arrhythmias in patients with tetralogy who also had restrictive physiology were not duplicated in Norgard’s series.136 Restrictive RV physiology at midterm follow-up, in contrast to the acute postoperative setting, may be beneﬁcial, limiting RV dilatation secondary to long-standing pulmonary regurgitation, and has been associated with improved exercise performance in these patients. The hallmark Doppler echocardiographic ﬁnding is antegrade diastolic ﬂow in the pulmonary artery with atrial

Chapter 25 • Congenital Heart Disease

Sa

0 –10

y = 54 – 2x r = 0.74 p < 0.001

60 Ea

Aa

A

20 Sa cm/sec

70

VO2 Max (ml/min/kg)

cm/sec

10

0

325

50 40 30 20

Aa Ea

–20

10 0

B

4

8

12

16

20

24

Septal E/Ea

Figure 25-10 On the left is a tissue Doppler profile demonstrating significantly reduced mitral septal Ea velocities in (A) child with hypertrophic cardiomyopathy (HCM) and ventricular tachycardia and (B) asymptomatic child with HCM. On the right is a graph correlating maximum VO2 and transmitral E/Ea septal ratio. There is a strong inverse relationship between maximal VO2 and E/septal Ea ratio. Aa, late diastolic velocity; Ea, early diastolic velocity; Sa, systolic velocity. (From McMahon CJ et al: Characterization of left ventricular diastolic function by tissue Doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation 2004;109:1756–1762.)

contraction. This echocardiographic ﬁnding suggests that secondary to decreased RV compliance, the right ventricle acts like a passive conduit, directing blood from the right atrium to the pulmonary artery during atrial systole (Fig. 25-11). Long-term follow-up of patients with tetralogy can be particularly challenging because of the common presence of signiﬁcant pulmonary regurgitation and RV dilatation leading to late morbidity and mortality. Studies to date have been mixed in their results concerning the eﬀect of chronic pulmonary regurgitation and RV dilatation on RV systolic function.137–140 Geva et al. evaluated 100 patients after tetralogy repair with cardiac magnetic resonance imaging (MRI) with hopes of identifying independent factors associated with impaired clinical status.141 Interestingly, neither the degree of pulmonary regurgitation nor the indexed RV end diastolic volume were predictive of clinical status; however, the presence of either moderate to severe RV or LV systolic dysfunction and older age at repair were found to be independently associated with impaired clinical status. This study and others suggest that clinical outcomes in tetralogy of Fallot may be more complex, with the interaction between the right and left ventricles playing an important role in patient outcome.142 Quantitative assessment of RV performance with tissue Doppler echocardiography after repair of tetralogy of Fallot also has been the subject of considerable investigation.143–146 Tissue Doppler velocities are decreased in patients with tetralogy post-repair, and these velocities correlate with the degree of pulmonary regurgitation.143–144 RV contractile reserve has been shown to be decreased during submaximal exercise and correlates with decreased tricuspid annular velocities, degree of pulmonary regurgitation, and increased brain natriuretic peptide in these children.146 RV isovolumic myocardial acceleration shows promise in the evaluation of children with tetralogy of Fallot and has correlates with the degree of pulmonary regurgitation postrepair.145

Figure 25-11 Pulsed-wave Doppler from a parasternal short-axis scan in a patient postoperative of tetralogy of Fallot demonstrating antegrade pulmonary artery flow with atrial contraction (arrow).

Single Ventricle Palliation When assessed serially, patients with complex congenital heart disease who have undergone the Fontan operation are shown to have abnormalities of diastolic ventricular function. Preoperatively, these patients often have evidence of both systolic and diastolic ventricular dysfunction that is likely secondary to chronic volume overload and cyanosis. While the systolic abnormalities may improve postoperatively,147–148 diastolic ﬁlling abnormalities often persist and may worsen over time.149 In fact, in a large series of patients with a double inlet left ventricle from the Mayo Clinic, diastolic dysfunction (i.e., elevated LV end diastolic pressure) was

326

Chapter 25 • Congenital Heart Disease one of two independent risk factors for late death after the Fontan operation.150 Gewillig et al. have evaluated the eﬀect of altered loading conditions on LV size and function after the Fontan operation. In their study, normalization of LV end diastolic volume and of ventricular hypertrophy was demonstrated on serial follow-up of patients with tricuspid atresia after Fontan palliation.151 This normalization of mass-to-volume ratio was associated with improved LV contractility indices (stress-velocity index). Sluysmens et al. also have evaluated children with single ventricle morphology to assess the eﬀect of the Fontan circulation on ventricular geometry and function.152 In their study of 84 children with double inlet left ventricles or tricuspid atresia, ventricular volumes were twice to three times normal for the age group, with an associated shift in ventricular geometry from an ellipsoidal to a spherical shape. Ventricular afterload became abnormal after 2 years of age because of abnormally decreased wall thickness-to-dimension and massto-volume ratios. Indices of LV function and contractility, including fractional shortening, EF, and velocity of circumferential ﬁber shortening, all became abnormal with advancing age, likely because of a combination of altered afterload and decreased myocardial contractility. More severely impaired systolic performance also was correlated with higher oxygen saturation, indicating the detrimental eﬀect of prolonged ventricular volume load on LV function. Similar to previous studies, age at repair was also a signiﬁcant factor, with children who underwent Fontan palliation before 10 years of age achieving normalization of afterload and improved contractility at serial follow-up.151,153–157 A high LV mass-to-volume ratio in the immediate postoperative period in children following Fontan palliation may be an indicator of increased early morbidity with pericardial or pleural eﬀusions.158–160 Normalization of mass-to-volume ratio in Fontan patients may not lead to improved diastolic performance.147,161–162 Increased collagen deposition within the hypertrophied ventricular myocardium likely leads to decreased compliance, as demon-

Echo I E/A ratio: 1.3 DT: 167 msec

AV (cm/sec)

100

Echo II E/A ratio: 1.2 DT: 148 msec

E

E

A

strated in other cardiac anomalies with similar alterations in loading conditions.163 The most common abnormality of diastolic function in these patients is abnormal relaxation with decreased early diastolic ﬁlling and increased compensatory late ﬁlling with atrial contraction. The additional presence of wall motion abnormalities, which are common in these patients, likely contributes to this altered diastology. Characteristic Doppler ﬁndings in patients after the Fontan operation are consistent with decreased ventricular compliance and include systolic dominance of pulmonary venous inﬂow, prolonged IVRT,161,164 and decreased peak early ﬁlling velocities161,164,165 and mitral DT. Additional ﬁndings of middiastolic mitral inﬂow149 and intracavitary ﬂow during IVRT in Fontan patients also suggest abnormal diastolic function.149,164 The presence of abnormalities of ventricular relaxation and compliance, if signiﬁcant, are poorly tolerated in the long term in patients with Fontan physiology. Conversely, in a younger cohort of patients evaluated both before and at intervals following the Fontan operation, Olivier et al. demonstrated only very mild abnormalities of Doppler diastolic dysfunction, which were present both before and after surgical palliation.166 In their group of 55 children and young adults with normal invasive measurement of LV end diastolic pressure, Doppler inﬂow from the mitral valve and pulmonary veins demonstrated a transitional pattern between that of children with normal relaxation and those with abnormal relaxation (Fig. 25-12). Lack of improvement in these Doppler parameters after a successful Fontan palliation was thought to be due to reduced ventricular preload after the Fontan operation and not to progressive impairment of diastolic relaxation or compliance.

Postoperative Congenital Heart Disease Measurement of systolic and diastolic function in children undergoing surgical repair can be quite challenging due to altered ventricular geometry and preoperative loading conditions. Children

Echo III E/A ratio: 1.2 DT: 183 msec

E

A

A

50

msec PV (cm/sec)

D

D

80 S

D

S

S

40

FFxdias: 0.6

FFxdias: 0.5

FFxdias: 0.6 PVAR

PVAR PVAR msec

Figure 25-12 Ventricular filling patterns before and after Fontan operation. Echo I, preoperative echo; Echo II, immediate postoperative echo; Echo III, long-term (>6 months) follow–up. (From Olivier M et al: Serial Doppler assessment of diastolic function before and after the Fontan operation. J Am Soc Echocardiogr 2003;16: 1136–1143.)

Chapter 25 • Congenital Heart Disease

FUTURE DIRECTIONS

Figure 25-13 Mitral valve Doppler inflow from transesophageal 4chamber view showing middiastolic flow reversal (arrow). (From Li JS et al: Abnormal left ventricular filling after neonatal repair of congenital heart disease: Association with increased mortality and morbidity. Am Heart J 1998;136:1075–1080.)

Medical and surgical management techniques for diagnosis and treatment of congenital heart disease in children and adults continue to evolve. A limited number of studies evaluating diastolic dysfunction in these populations have been performed to date; however, newer noninvasive modalities such as tissue Doppler echocardiography and strain rate imaging169 continue to broaden the ability of the clinician to identify ventricular dysfunction at an early stage and will likely provide opportunities to institute more eﬀective therapies in these patients. Exciting new modalities such as cardiac resynchronization therapy show promising results in adults with heart failure and may oﬀer similar beneﬁts to patients with congenital cardiac anomalies with abnormal ventricular performance. As our tools to identify hemodynamic and functional myocardial abnormalities continue to improve, researchers must critically evaluate the eﬀectiveness of novel medical and surgical treatment strategies on diastolic ventricular performance with the result being improved long-term clinical outcome in children and adults with congenital heart disease. REFERENCES

undergoing cardiopulmonary bypass for repair of congenital heart lesions have altered LV function postrepair.167 Chaturvedi et al. demonstrated that even during simple surgical procedures, including repair of ASDs (n = 11), supravalvular aortic stenosis (n = 1), and double chambered right ventricle (n = 1), children had abnormal systolic ventricular function postoperatively when studied with conductance catheters. A load-independent measure of contractility—end systolic elastance—decreased by 40% in these patients, possibly because of incomplete myocardial protection at the time of surgical repair. Similar detrimental changes in diastolic function were not demonstrated in this study likely because the measurements were made with an open chest wall prior to surgical closure. Evidence of abnormal diastolic function has been reported in neonates after repair of congenital heart disease.168 The presence of middiastolic ﬂow reversal (MDFR) on mitral inﬂow Doppler has been described in patients with severe aortic or mitral insufﬁciency, hypertrophic or restrictive cardiomyopathy, and atrioventricular block and is consistent with abnormal LV ﬁlling. Li et al. evaluated 40 infants with congenital heart disease (17 with D-transposition of the great arteries, 14 with coarctation of the aorta, 8 with interrupted aortic arch, and 1 with aortic valve stenosis). While MDFR was present in 5 of 40 neonates preoperatively, over half (21/40) manifested this Doppler abnormality postoperatively (Fig. 25-13). Those neonates with MDFR had higher mortality rates, prolonged duration of mechanical ventilation, increased incidence of pleural eﬀusions and pulmonary edema, and prolonged stays in intensive care units and hospitals compared with neonates without MDFR. Several factors, including the underlying cardiac anatomy, altered loading conditions, hypertrophy, and ﬂuid accumulation within the ventricular myocardium, leading to decreased ventricular compliance and altered ﬁlling pressures, may have contributed to the presence of MDFR. This Doppler pattern resolved in all surviving neonates by the fourth postoperative week. Just as RV compliance is a signiﬁcant predictor of outcome in tetralogy of Fallot, MDFR suggesting decreased LV compliance also appears to be a signiﬁcant predictor of morbidity and mortality in neonates.

1. Nishimura RA, Abel MB, Hatle LK, et al: Assessment of diastolic function of the heart: Background and current applications of Doppler echocardiography. Part II. Clinical studies. Mayo Clin Proc 1989;64:181–204. 2. Myreng V, Smiseth OA: Assessment of left ventricular relaxation by Doppler echocardiography. Circulation 1990;81:260–266. 3. Appleton CP, Hatle LK, Popp RL: Relation of transmitral ﬂow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426–440. 4. Thomas JD, Weyman AE: Echo Doppler evaluation of left ventricular diastolic function: Physics and physiology. Circulation 1991;84:977–90. 5. Isaaz K, Thompson A, Ethevenot G, et al: Doppler echocardiographic measurement of low velocity motion of the left ventricular posterior wall. Am J Cardiol 1989;64:66–75. 6. Isaaz K, Munoz del Romeral L, Lee E, Schiller NB: Quantitation of the motion of the cardiac base in normal subjects by Doppler echocardiography. J Am Soc Echocardiogr 1993;6:166–76. 7. Farias CA, Rodriquez L, Garcia MJ, et al: Assessment of diastolic function by tissue Doppler echocardiography: Comparison with standard transmitral and pulmonary venous ﬂow. J Am Soc Echocardiogr 1999;12: 609–617. 8. Galiuto L, Ignone G, DeMaria AN: Contraction and relaxation velocities of the normal left ventricle using pulsed-wave tissue Doppler echocardiography. Am J Cardiol 1998;81:609–614. 9. Donovan CL, Armstrong WF, Bach DS: Quantitative Doppler tissue imaging of the left ventricular myocardium: Validation in normal subjects. Am Heart J 1995;130:100–104. 10. Gulati VK, Katz WE, Follansbee WP, et al: Mitral annular descent velocity by tissue Doppler echocardiography as an index of global left ventricular function. J Cardiol 1996;77:979–984. 11. Garcia MJ, Rodriquez L, Ares M, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–114. 12. Garcia MJ, Rodriquez L, Ares M, et al: Myocardial wall velocity assessment by pulsed Doppler tissue imaging: Characteristic ﬁndings in normal subjects. Am Heart J 1996;132:648–656. 13. Rychik J, Tian ZY: Quantitative assessment of myocardial tissue velocities in normal children with Doppler tissue imaging. Am J Cardiol 1996;77: 1254–1257. 14. Frommelt PC, Ballweg JA, Whitstone BN, et al: Usefulness of Doppler tissue imaging analysis of tricuspid annular motion for determination of right ventricular function in normal infants and children. Am J Cardiol 2002;89:610–613. 15. Mori K, Hayabuchi Y, Kuroda Y, et al: Left ventricular wall motion velocities in healthy children measured by pulsed wave Doppler tissue echocardiography: Normal values and relation to age and heart rate. J Am Soc Echocardiogr 2000;13:1002–11.

327

328

Chapter 25 • Congenital Heart Disease 16. Brun P, Tribouilloy C, Duval AM, et al: Left ventricular ﬂow propagation during early ﬁlling is related to wall relaxation: A color M-mode Doppler analysis. J Am Coll Cardiol 1992;20:420–432. 17. Garcia MJ, Ares MA, Asher C, et al: Color M-mode ﬂow velocity propagation: An index of early left ventricular ﬁlling that combined with pulse Doppler peak E velocity may predict capillary wedge pressure. J Am Coll Cardiol 1997;29:448–454. 18. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular ﬁlling ﬂow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 1996;27:365–371. 19. Gonzales-Vilchez F, Ares M, Ayuela J, et al: Combined use of pulsed and color M-mode Doppler echocardiography for the estimation of pulmonary capillary wedge pressure: An empirical approach based on an analytical relation. J Am Coll Cardiol 1999;34:515–523. 20. Stugaard M, Brodahl U, Torp H, et al: Abnormalities of left ventricular ﬁlling in patients with coronary artery disease: Assessment by colour Doppler technique. Eur Heart J 1994;15:318–327. 21. Johnson GL, Moﬀett CB, Noonan JA: Doppler echocardiographic studies of diastolic ventricular ﬁlling patterns in premature infants. Am Heart J 1988;116:1568–1574. 22. Harada K, Takahashi Y, Shiota T, et al: Changes in transmitral and pulmonary venous ﬂow patterns in the ﬁrst day of life. J Clin Ultrasound 1995;23:399–405. 23. Harada K, Suzuki T, Tamura M, et al: Role of age on transmitral ﬂow velocity patterns in assessing left ventricular diastolic function in normal infants and children. Am J Cardiol 1995;76:530–532. 24. Harada K, Suzuki T, Tamura M, et al: Eﬀect of aging from infancy to childhood on ﬂow velocity patterns of pulmonary vein by Doppler echocardiography. Am J Cardiol 1996;77:221–224. 25. Riggs TW, Snider AR: Respiratory inﬂuence on right and left ventricular diastolic function in normal children. Am J Cardiol 1989;63:858– 861. 26. Riggs TW, Rodriquez R, Snider AR, Batton D: Doppler echocardiographic evaluation of right and left ventricular diastolic function in normal neonates. J Am Coll Cardiol 1989;13:700–705. 27. O’Leary PW, Durongpisitkul K, Cordes TM, et al: Diastolic ventricular function in children: A Doppler echocardiographic study establishing normal values and predictors of increased ventricular end-diastolic pressure. Mayo Clin Proc 1998;73:616–628. 28. Bryg RJ, Williams GA, Labvitz AJ: Eﬀect of aging on left ventricular diastolic ﬁlling in normal subjects. Am J Cardiol 1987;59:971– 974. 29. Bessen M, Gardin JM: Evaluation of left ventricular diastolic function. Cardiol Clin 1990;8:315–332. 30. Stoddard MF, Pearson AC, Kern MJ, et al: Inﬂuence of alteration in preload on the pattern of left ventricular diastolic ﬁlling assessed by Doppler echocardiography in humans. Circulation 1989;79:1226–1236. 31. Klein AL, Takik AJ: Doppler assessment of pulmonary venous ﬂow in healthy subjects and in patients with heart disease. J Am Soc Echocardiogr 1991;4:379–392. 32. Nishimura RA, Abel MD, Hatle LK, et al: Relation of pulmonary vein to mitral ﬂow velocities by transesophageal Doppler echocardiography: Eﬀect of diﬀerent loading conditions. Circulation 1990;81:1488– 1497. 33. Basnight MA, Gonzalez MS, Kershenovich SC, et al: Pulmonary venous ﬂow velocity: Relation to hemodynamics, mitral ﬂow velocity and left atrial volume, and ejection fraction. J Am Soc Echocardiogr 1991;4: 547–548. 34. Appleton CP, Gonzalez MS, Basnight MA, et al: Relationship of left atrial pressure and pulmonary venous ﬂow velocities: Importance of baseline mitral and pulmonary venous ﬂow velocity parameters studied in lightly sedated dogs. J Am Soc Echocardiogr 1994;7:264–275. 35. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular ﬁlling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. J Am Coll Cardiol 1993;22: 1972–1982. 36. Yamamoto K, Nishimura RA, Chaliki HP, et al: Determination of left ventricular ﬁlling pressure by Doppler echocardiography in patients with coronary artery disease: Critical role of left ventricular systolic function. J Am Coll Cardiol 1997;30:1819–1826. 37. Pai RG, Kanwaljit SG: Amplitudes, durations, and timings of apically directed left ventricular myocardial velocities, I: Their normal pattern and coupling to ventricular ﬁlling and ejection. J Am Soc Echocardiogr 1998;11: 105–111.

38. Rodriguez L, Garcia MJ, Ares M, et al: Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral inﬂow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 1996;131:982–987. 39. Alam M, Wardell J, Andersson E, et al: Characteristics of mitral and tricuspid annular velocities determined by pulsed Doppler tissue imaging in healthy subjects. J Am Soc Echocardiogr 1999;12:618–628. 40. Fleming AD, Xia X, McDicken WN, et al: Myocardial velocity gradients detected by Doppler imaging. Br J Radiol 1994;67:679–688. 41. Uematsu M, Miyatake K, Tabaka N, et al: Myocardial velocity gradient as a new indicator of regional left ventricular contraction: Detection by twodimensional tissue Doppler imaging technique. J Am Coll Cardiol 1995;26:217–223. 42. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–480. 43. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of ﬁlling pressures. J Am Coll Cardiol 1997;30:1527– 1533. 44. Aranda JM, Weston MW, Puleo JA, Fontanet HL: Eﬀect of loading conditions on myocardial relaxation velocities determined by tissue Doppler imaging in heart transplant recipients. J Heart Lung Transpl 1998;17: 693–697. 45. Firstenberg MS, Greenberg NL, Main ML, et al: Determinants of diastolic myocardial tissue Doppler velocities: Inﬂuences of relaxation and preload. J Appl Physiol 2001;90:299–307. 46. Nagueh SF, Sun H, Kopelen HA, et al: Hemodynamic determinants of the mitral annular diastolic velocities by tissue Doppler. J Am Coll Cardiol 2001;37:278–285. 47. Hung KC, Huang HL, Chu CM, et al: Evaluating preload dependence of a novel Doppler application in assessment of left ventricular diastolic function during hemodialysis. Am J Kidney Dis 2004;43:1040–1046. 48. Oki T, Fukada K, Tabata T, et al: Eﬀect of an acute increase in afterload on left ventricular regional wall motion velocity in healthy subjects. J Am Soc Echocardiogr 1999;12:476–483. 49. Muller S, Bartel T, Koopman J, et al: Tissue Doppler analysis is hindered in abnormal wall motion and changes in afterload. Int J Cardiol 2003;90:81–90. 50. Jacques DC, Pinsky MR, Severyn D, Gorcsan J: Inﬂuence of alterations in loading on mitral annular velocity by tissue Doppler echocardiography and its associated ability to predict ﬁlling pressures. Chest 2004;126: 1910–1918. 51. Garcia MJ, Thomas JD: Tissue Doppler to assess diastolic left ventricular function. Echocardiogr 1999;16:501–508. 52. Rivas-Gotz C, Khoury DS, Manolis M, et al: Time interval between onset of mitral inﬂow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation. Experimental studies and clinical application. J Am Coll Cardiol 2003;42:1463–1470. 53. Nagueh SF, Kopelen HA, Quinones MA: Assessment of left ventricular ﬁlling pressures by Doppler in the presence of atrial ﬁbrillation. Circulation 1996;94:2138–2145. 54. Sundereswaran L, Nagueh SF, Vardan S, et al: Estimation of left and right ventricular ﬁlling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 1998;82:352–357. 55. Nagueh SF, Mikati I, Kopelen HA, et al: Doppler estimation of left ventricular ﬁlling pressure in sinus tachycardia: A new application of tissue Doppler imaging. Circulation 1998;98:1644–1650. 56. Nagueh SF, Lakkis NM, Middleton KJ, et al: Doppler estimation of left ventricular ﬁlling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99:254–261. 57. Diwan A, McCulloch M, Lawrie GM, et al: Doppler estimation of left ventricular ﬁlling pressures in patients with mitral valve disease. Circulation 2005;111:3281–3289. 58. Ruan Q, Rao L, Middleton KJ, et al: Assessment of left ventricular diastolic function by early diastolic mitral annulus peak acceleration rate: Experimental studies and clinical application. J Appl Physiol 2006;100:679–684. 59. Garcia MJ, Rodriguez L, Ares M, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108–114. 60. Oki T, Tabata T, Yamada H, et al: Right and left ventricular wall motion velocities as diagnostic indicators of constrictive pericarditis. Am J Cardiol 1998;81:465–470.

Chapter 25 • Congenital Heart Disease 61. Ha JW, Oh JK, Ommen SR, et al: Diagnostic value of mitral annular velocity for constrictive pericarditis in the absence of respiratory variation in mitral inﬂow velocity. J Am Soc Echocardiogr 2002;15:1468– 1471. 62. Ha JW, Ommen SR, Tajik AJ, et al: Diﬀerentiation of constrictive pericarditis from restrictive cardiomyopathy using mitral annular velocity by tissue Doppler echocardiography. Am J Cardiol 2004;94:316–319. 63. Eidem BW, McMahon CJ, Cohen RR, et al: Impact of cardiac growth on Doppler tissue imaging velocities: A study in healthy children. J Am Soc Echocardiogr 2004;17:212–221. 64. Kapusta L, Thijssen JM, Cuypers MH, et al: Assessment of myocardial velocities in healthy children using tissue Doppler imaging. Ultrasound Med Biol 2000;26:229–237. 65. Swaminathan S, Ferrer PL, Wolﬀ GS, et al: Usefulness of tissue Doppler echocardiography for evaluating ventricular function in children without heart disease. Am J Cardiol 2003;91:570–574. 66. Harada K, Orino T, Yasuoka K, et al: Tissue Doppler imaging of the left and right ventricles in normal children. Tohoku J Exp Med 2000;191: 21–29. 67. Nii M, Mori K, Kuroda Y: Quantiﬁcation of the myocardial velocity gradient and myocardial wall thickening velocity in healthy children: A new indicator of regional myocardial wall motion. J Am Soc Echocardiogr 2002;15:624–632. 68. Border WL, Michelfelder EC, Glascock BJ, et al: Color M-mode and Doppler tissue evaluation of diastolic function in children: Simultaneous correlation with invasive indices. J Am Soc Echocardiogr 2003;16: 988–994. 69. Patel R, Nagueh SF, Tsybouleva N, et al: Simvastatin induces regression of cardiac hypertrophy and ﬁbrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2001;104:317–324. 70. Nagueh SF, Lakkis NM, Middleton KJ, et al: Changes in left ventricular diastolic function 6 months after nonsurgical septal reduction therapy for hypertrophic cardiomyopathy. Circulation 1999;99:344–347. 71. Rees AH, Rao PS, Rigby JJ, et al: Echocardiographic estimation of a leftto-right shunt in isolated ventricular septal defects. Eur J Cardiol 1978;7:25–33. 72. Baylen B, Meyer RA, Korfhagen J, et al: Left ventricular performance in the critically ill premature infant with patent ductus arteriosus and pulmonary disease. Circulation 1977;55:182–188. 73. McDonald IG: Echocardiographic assessment of left ventricular function in aortic valve disease. Circulation 1976;53:860–864. 74. Silverman NH, Ports TA, Snider AR, et al: Determination of left ventricular volume in children: Echocardiographic and angiographic comparisons. Circulation 1980;62:548–557. 75. Mercier JC, DiSessa TG, Jarmakani JM, et al: Two-dimensional echocardiographic assessment of left ventricular volumes and ejection fraction in children. Circulation 1982;65:962–969. 76. Dong SJ, Hees PS, Huang WM, et al: Independent eﬀects of preload, afterload, and contractility on left ventricular torsion. Am J Physiol 1999;277: H1053–H1060. 77. Rowland DG, Gutgesell HP: Noninvasive assessment of myocardial contractility, preload, and afterload in healthy newborn infants. Am J Cardiol 1995;75;818–821. 78. Hansen DE, Daughters GT II, Alderman EL, et al: Eﬀect of volume loading, pressure loading, and inotropic stimulation on left ventricular torsion in humans. Circulation 1991;83:1315–1326. 79. Ross J Jr: Afterload mismatch and preload reserve: A conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis 1976;18:255–264. 80. Rankin LS, Moos S, Grossman W: Alterations in preload and ejection phase indices of left ventricular performance. Circulation 1975;51:910–915. 81. Choong CY, Herrmann HC, Weyman AE, et al: Preload dependency of Doppler-derived indices of left ventricular diastolic function in humans. J Am Coll Cardiol 1987;10:800–808. 82. Harada K, Tamura M, Yasuoka K, Toyono M: A comparison of tissue Doppler imaging and velocities of transmitral ﬂow in children with elevated left ventricular preload. Cardiol Young 2001;11:261–268. 83. Eidem BW, McMahon CJ, Ayres NA, et al: Impact of chronic left ventricular preload and afterload on Doppler tissue imaging velocities: A study in congenital heart disease. J Am Soc Echocardiogr 2005;18:830– 838. 84. Kidd L, Driscoll DJ, Gersony WM, et al: Second natural history study of congenital heart defects: Results of treatment of patients with ventricular septal defects. Circulation 1993;87:I38–I55.

85. Pauliks LB, Chan KC, Chang D, et al: Regional myocardial velocities and isovolumic acceleration before and after device closure of atrial septal defects: A color tissue Doppler study. Am Heart J 2005;150:294–301. 86. Pascotto M, Caso P, Santoro G, et al: Analysis of right ventricular Doppler tissue imaging and load dependence in patients undergoing percutaneous closure of atrial septal defect. Am J Cardiol 2004;94:1202–1205. 87. Cheung YF, Lun KS, Chau AK: Doppler tissue imaging analysis of ventricular function after surgical and transcatheter closure of atrial septal defect. Am J Cardiol 2004;93:375–378. 88. Giardini A, Moore P, Brook M, et al: Eﬀect of transcatheter atrial septal defect closure in children on left ventricular diastolic function. Am J Cardiol 2005;95:1255–1257. 89. Sasayama S, Franklin D, Ross J Jr: Hyperperfusion with normal inotropic state of the hypertrophied left ventricle. Am J Physiol 1977;232: H418–H425. 90. Gunther S, Grossman W: Determinants of ventricular function in pressureoverload hypertrophy in man. Circulation 1979;59:679–688. 91. Wisenbaugh T, Allen P, Cooper G, et al: Contractile function, myosin ATPase activity and isoenzymes in the hypertrophied pig left ventricle after chronic pressure overload. Circ Res 1983;53:332–413. 92. Spann JF, Bove AA, Natrajan G, Kreulen T: Ventricular performance, pump function and compensatory mechanisms in patients with aortic stenosis. Circulation 1980;62:576–582. 93. Nakamura T, Kimura T, Arai S, et al: Left ventricular function of concentric hypertrophied heart after chronic pressure overload as studied in the isolated canine heart preparation. Jpn J Physiol 1984;34:613–628. 94. Broughton A, Korner PI: Left ventricular pump function in renal hypertensive dogs with cardiac hypertrophy. Am J Physiol 1986;251: H1260–H1266. 95. Leman RB, Spinale FG, Dorn GW, et al: Supernormal ejection performance is isolated to the ipsilateral congenitally pressure-overloaded ventricle. J Am Coll Cardiol 1989;13:1314–1319. 96. Donner R, Carabello BA, Black I, Spann JF: Left ventricular wall stress in compensated aortic stenosis in children. Am Heart J 1983;51:946– 951. 97. Dorn GW, Donner R, Assey ME, et al: Alterations in left ventricular geometry, wall stress, and ejection performance after correction of congenital aortic stenosis. Circulation 1988;78:1358–1364. 98. Grossman W, McLaurin LP, Stefadouros MA: Left ventricular stiﬀness associated with chronic pressure and volume overloads in man. Circ Res 1974;35:793–800. 99. Crawford MH, Walsh RA, Cragg D, et al: Echocardiographic left ventricular mass and function in the hypertensive baboon. Hypertension 1987;10:339–1345. 100. Peterson KL, Tsuji J, Johnson A, et al: Diastolic left ventricular pressurevolume and stress-strain relations in patients with valvular aortic stenosis and left ventricular hypertrophy. Circulation 1978;58:77–89. 101. Villari B, Hess OM, Kauﬀman P, et al: Eﬀects of aortic valve stenosis (pressure overload) on left ventricular systolic and diastolic function. Am J Cardiol 1992;69:927–934. 102. Pasipoularides A, Mirsky I, Hess OM, et al: Myocardial relaxation and passive diastolic properties in man. Circulation 1986;74:991–1001. 103. Hess OM, Schneider J, Koch R, et al: Diastolic function and myocardial structure in patients with myocardial hypertrophy: Special reference to normalized viscoelastic data. Circulation 1981;63:360–371. 104. Jones M, Ferrans VJ: Myocardial degeneration in congenital heart disease. Comparison of morphologic ﬁndings in young and old patients with congenital heart disease associated with muscular obstruction to right ventricular outﬂow. Am J Cardiol 1977;39:1051–1063. 105. Fifer MA, Borow KM, Colan SD, Lorell BH: Early diastolic left ventricular function in children and adults with aortic stenosis. J Am Coll Cardiol 1985;5:1147–1154. 106. Snider RA, Gidding SS, Rocchini AP, et al: Doppler evaluation of left ventricular diastolic ﬁlling in children with systemic hypertension. Am J Cardiol 1985;56:921–926. 107. Sandor GGS, Olley PM: Determination of left ventricular diastolic chamber stiﬀness and myocardial stiﬀness in patients with congenital heart disease. Am J Cardiol 1982;49:771–779. 108. Banerjee A, Mendelsohn AM, Knilans TK, et al: Eﬀect of myocardial hypertrophy on systolic and diastolic function in children: Insights from the force-frequency and relaxation-frequency relationships. J Am Coll Cardiol 1998;32:1088–1095. 109. Chan KY, Redington AN, Rigby ML, Gibson DG: Cardiac function after surgery for subaortic stenosis: Noninvasive assessment of left ventricular performance. Br Heart J 1991;66:161–165.

329

330

Chapter 25 • Congenital Heart Disease 110. Pacileo G, Calabro P, Limongelli G, et al: Left ventricular remodeling, mechanics, and tissue characterization in congenital aortic stenosis. J Am Soc Echocardiogr 2003;16:214–220. 111. Kiraly P, Kapusta L, Thijssen JM, et al: Left ventricular myocardial function in congenital valvar aortic stenosis assessed by ultrasound tissue-velocity and strain-rate techniques. Ultrasound Med Biol 2003;29:615–620. 112. Villari B, Vassalli G, Schneider J, et al: Age dependency of left ventricular diastolic function in pressure overload hypertrophy. J Am Coll Cardiol 1997;29:181–186. 113. Faggiano P, Sabatini T, Rusconi C, et al: Abnormalities of left ventricular ﬁlling in valvular aortic stenosis: Usefulness of combined evaluation of pulmonary veins and mitral inﬂow by means of transthoracic Doppler echocardiography. Int J Cardiol 1995;49:77–85. 114. Otto CM, Pearlman AS, Amsler LC: Doppler echocardiographic evaluation of left ventricular diastolic ﬁlling in isolated valvular aortic stenosis. Am J Cardiol 1989;63:313–316. 115. Nagueh SF, Bachinski LL, Meyer D, et al: Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 2001;104:128–130. 116. Nagueh SF, Kopelen HA, Lim DS, et al: Tissue Doppler imaging consistently detects myocardial contraction and relaxation abnormalities, irrespective of cardiac hypertrophy, in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2000;102:1346–1350. 117. Nagueh SF, McFalls J, Meyer D, et al: Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 2003;108:395–398. 118. Ho CY, Sweitzer NK, McDonough B, et al: Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–2997. 119. Severino S, Caso P, Galderisi M, et al: Use of pulsed Doppler tissue imaging to assess regional left ventricular diastolic function in hypertrophic cardiomyopathy. Am J Cardiol 1998;82:1394–1398. 120. Tabata T, Oki T, Yamada H, et al: Subendocardial motion in hypertrophic cardiomyopathy: Assessment from long- and short-axis views by pulsed tissue Doppler imaging. J Am Soc Echocardiogr 2000;13:108–115. 121. Vinereanu D, Florescu N, Sculthorpe N, et al: Diﬀerentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001;88:53–58. 122. Cardim N, Oliveira AG, Longo S, et al: Doppler tissue imaging: Regional myocardial function in hypertrophic cardiomyopathy and in athlete’s heart. J Am Soc Echocardiogr 2003;16:223–232. 123. Nunez J, Zamorano JL, Perez De Isla L, et al: Diﬀerences in regional systolic and diastolic function by Doppler tissue imaging in patients with hypertrophic cardiomyopathy and hypertrophy caused by hypertension. J Am Soc Echocardiogr 2004;17:717–722. 124. Oki T, Tanaka H, Yamada H, et al: Diagnosis of cardiac amyloidosis based on the myocardial velocity proﬁle in the hypertrophied left ventricular wall. Am J Cardiol 2004;93:864–869. 125. Araujo AQ, Arteaga E, Ianni BM, et al: Eﬀect of losartan on left ventricular diastolic function in patients with nonobstructive hypertrophic cardiomyopathy. Am J Cardiol 2005;96:1563–1567. 126. Sogaard P, Egeblad H, Kim WY, et al: Tissue Doppler imaging predicts improved systolic performance and reversed left ventricular remodeling during long-term cardiac resynchronization therapy. J Am Coll Cardiol 2002;40:723–730. 127. Sogaard P, Egeblad H, Pedersen AK, et al: Sequential versus simultaneous biventricular resynchronization for severe heart failure: Evaluation by tissue Doppler imaging. Circulation 2002;106:2078–2084. 128. Yu CM, Fung WH, Lin H, et al: Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol 2003;91:684–688. 129. Penicka M, Bartunek J, De Bruyne B, et al: Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. Circulation 2004;109:978–983. 130. Yu CM, Fung JW, Zhang Q, et al: Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation 2004;110:66–73. 131. Yu CM, Zhang Q, Fung JW, et al: A novel tool to assess systolic asynchrony and identify responders of cardiac resynchronization therapy by tissue synchronization imaging. J Am Coll Cardiol 2005;45:677–684.

132. Vannan MA, Pedrizzetti G, Li P, et al: Eﬀect of cardiac resynchronization therapy on longitudinal and circumferential left ventricular mechanics by velocity vector imaging: Description and initial clinical application of a novel method using high-frame-rate B-mode echocardiographic images. Echocardiography 2005;22:826–830. 133. McMahon CJ, Nagueh SF, Eapen RS, et al: Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: A prospective clinical study. Heart 2004;90:908–915. 134. McMahon CJ, Nagueh SF, Pignatelli RH, et al: Characterization of left ventricular diastolic function by tissue Doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation 2004;109: 1756–1762. 135. Norgard G, Gatzoulis MA, Josen M, et al: Does restrictive right ventricular physiology in the early postoperative period predict subsequent right ventricular restriction after repair of tetralogy of Fallot? Heart 1998;79: 481–484. 136. Gadzoulis MA, Till JA, Somerville J, et al: Mechanoelectrical interaction in tetralogy of Fallot. QRS prolongation relates to right ventricular size and predicts malignant ventricular arrhythmias and sudden death. Circulation 1995;92:231–237. 137. Rebergen SA, Chin JG, Ottenkamp J, et al: Pulmonary regurgitation in the late postoperative follow-up of tetralogy of Fallot. Volumetric quantitation by nuclear magnetic resonance velocity mapping. Circulation 1993;88: 2257–2266. 138. Niezen RA, Helbing WA, van Der Wall EE, et al: Biventricular systolic function and mass studied with MR imaging in children with pulmonary regurgitation after repair for tetralogy of Fallot. Radiology 1996;201: 135–140. 139. Helbing WA, Niezen RA, LeCessie S, et al: Right ventricular diastolic function in children with pulmonary regurgitation after repair of tetralogy of Fallot: Volumetric evaluation by magnetic resonance velocity mapping. J Am Coll Cardiol 1996;28:1827–1235. 140. Helbing WA, de Roos A: Clinical applications of magnetic resonance imaging after repair of tetralogy of Fallot. Pediatr Cardiol 2000;21: 70–90. 141. Geva T, Sandweiss BM, Gauvreau K, et al: Factors associated with impaired clinical status in long-term survivors of tetralogy of Fallot repair evaluated by magnetic resonance imaging. J Am Coll Cardiol 2004;43:1068– 1074. 142. Davlouros PA, Kilner PJ, Hornung TS, et al: Right ventricular function in adults with repaired tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging: Detrimental role of right ventricular outﬂow aneurysms or akinesia and adverse right-to-left ventricular interaction. J Am Coll Cardiol 2002;40:2044–2052. 143. Harada K, Toyono M, Yamamoto F: Assessment of right ventricular function during exercise with quantitative Doppler tissue imaging in children late after repair of tetralogy of Fallot. J Am Soc Echocardiogr 2004;17:863–869. 144. Yasuoka K, Harada K, Toyono M, et al: Tei index determined by tissue Doppler imaging in patients with pulmonary regurgitation after repair of tetralogy of Fallot. Pediatr Cardiol 2004;25:131–136. 145. Toyono M, Harada K, Tamura M, et al: Myocardial acceleration during isovolumic contraction as a new index of right ventricular contractile function and its relation to pulmonary regurgitation in patients after repair of tetralogy of Fallot. J Am Soc Echocardiogr 2004;17:332–337. 146. Ishii H, Harada K, Toyono M, et al: Usefulness of exercise-induced changes in plasma levels of brain natriuretic peptide in predicting right ventricular contractile reserve after repair of tetralogy of Fallot. Am J Cardiol 2005;95:1338–1343. 147. Gewillig MH, Lundstrom UR, Deanﬁeld JE, et al: Impact of Fontan operation on left ventricular size and contractility in tricuspid atresia. Circulation 1990;81:118–127. 148. Hagler DJ, Seward JB, Tajik AJ, et al: Functional assessment of the Fontan operation: Combined two-dimensional and Doppler echocardiographic studies. J Am Coll Cardiol 1984;4:745–764. 149. Cheung YF, Penny DJ, Redington AN: Serial assessment of left ventricular diastolic function after Fontan procedure. Heart 2000;83:420–424. 150. Earing MG, Cetta F, Driscoll DJ, et al: Long-term results of the Fontan operation for double inlet left ventricle. Am J Cardiol 2005;96:291–298. 151. Gewillig MH, Lundstrom UR, Deanﬁeld JE, et al: Impact of Fontan operation on left ventricular size and contractility in tricuspid atresia. Circulation 1990;81:118–127. 152. Sluysmans T, Sanders SP, van der Velde M, et al: Natural history and patterns of recovery of contractile function in single left ventricle after Fontan operation. Circulation 1992;86:1753–1761.

Chapter 25 • Congenital Heart Disease 153. Graham TP Jr, Franklin RCG, Wyse RKH, et al: Left ventricular wall stress and contractile function in childhood: Normal values and comparison of Fontan repair versus palliation only in patients with tricuspid atresia. Circulation 1986;74(Suppl I):I-61–I-69. 154. Fontan F, Baudet E: Surgical repair of tricuspid atresia. Thorax 1971;26:240–248. 155. Puga FJ, Chiavarelli M, Hagler DJ: Modiﬁcations of the Fontan operation applicable to patients with left atrioventricular valve atresia or single atrioventricular valve. Circulation 1987;76(Suppl III):III-53–III-60. 156. De Leval MR, Kilner P, Gewillig M, et al: Total cavopulmonary connection: A logical alternative to atriopulmonary connection for complex Fontan operations: Experimental studies and early clinical experience. J Thorac Cardiovasc Surg 1988;96:682–695. 157. Glenn WWL: Circulatory bypass of the right side of the heart: IV. Shunt between superior vena cava and distal right pulmonary artery: Report of a clinical application. New Engl J Med 1958;259:117–120. 158. Seliem M, Muster AJ, Paul MH, Benson DW Jr: Relation between preoperative left ventricular muscle mass and outcome of the Fontan operation in patients with tricuspid atresia. J Am Coll Cardiol 1989;14:750–755. 159. Kirklin JK, Blackstone EH, Kirklin JW, et al: The Fontan operation: Ventricular hypertrophy, age, and date of operation as risk factors. J Thorac Cardiovasc Surg 1986;92:1049–1064. 160. Mayer JE Jr, Helgason H, Jonas RA, et al: Extending the limits of the modiﬁed Fontan procedures. J Thorac Cardiovasc Surg 1986;92:1021–1028. 161. Frommelt PC, Snider AR, Meliones JN, et al: Doppler assessment of pulmonary artery ﬂow patterns and ventricular function after the Fontan operation. Am J Cardiol 1991;68:1211–1215.

162. Fogel MA, Weinberg PM, Chin AJ, et al: Late ventricular geometry and performance changes of functional single ventricle throughout stages of Fontan reconstruction assessed by magnetic resonance imaging. J Am Coll Cardiol 1996;28:212–221. 163. Iimoto DS, Covell JW, Harper E: Increase in cross-linking of type I and type III collagens associated with volume-loaded hypertrophy. Circ Res 1988;63:399–408. 164. Penny DJ, Rigby ML, Redington AN: Abnormal patterns of interventricular ﬂow and diastolic ﬁlling after the Fontan operation: Evidence for incoordinate ventricular wall motion. Br Heart J 1991;66:375–378. 165. Akagi T, Benson LN, Gilday DL, et al: Inﬂuence of ventricular morphology on diastolic ﬁlling performance in double inlet left ventricle after the Fontan procedure. J Am Coll Cardiol 1993;22:1948–1952. 166. Olivier M, O’Leary PW, Pankranz S, et al: Serial Doppler assessment of diastolic function before and after the Fontan operation. J Am Soc Echocardiogr 2003;16:1136–1143. 167. Chaturvedi RR, Lincoln C, Gothard JW, et al: Left ventricular dysfunction after open repair of simple congenital heart defects in infants and children: Quantitation with the use of a conductance catheter immediately after bypass. J Thorac Cardiovasc Surg 1998;115:77–83. 168. Li JS, Bengur AR, Ungerleider RM, et al: Abnormal left ventricular ﬁlling after neonatal repair of congenital heart disease: Association with increased mortality and morbidity. Am Heart J 1998;136:1075–1080. 169. Weideman F, Eyskens B, Jamal F, et al: Quantiﬁcation of regional left and right ventricular radial and longitudinal function in healthy children using ultrasound based strain rate and strain imaging. J Am Soc Echocardiogr 2002;15:20–28.

331

LIVIU KLEIN, MD, MS ROBERT O. BONOW, MD

26 Diabetes Mellitus INTRODUCTION PATHOPHYSIOLOGY Metabolic Disturbances Myocardial Fibrosis Small Vessel Disease Cardiac Autonomic Dysfunction Insulin Resistance

Interaction with Other Major Comorbidities CLINICAL RELEVANCE FUTURE RESEARCH

INTRODUCTION Diabetes mellitus has reached epidemic proportions, aﬀecting more than 170 million individuals worldwide. Global estimates for the year 2025 predict a further increase of almost 50%, with the greatest increases in the developing countries of Africa, Asia, and South America.1 This trend is particularly ominous, as those in developing nations tend to develop diabetes earlier in life (ages 40–64 years) than their counterparts in the developed world (≥65 years), implying a longer duration of exposure during the most productive years and therefore a potentially greater risk of diabetes-associated morbidity and mortality.2 Of the estimated 20 million persons in the United States who have diabetes mellitus, 90% to 95% have type II diabetes. Among those, 6 million are unaware of their condition.3 An additional 40 million show signs of insulin resistance and are at high risk of developing type II diabetes.3,4 Even more alarmingly, among obese white adolescents, 4% have type II diabetes and 25% have abnormal glucose tolerance,5 markedly increasing their likelihood of developing future premature cardiovascular complications. Cardiovascular disease is the leading cause of death among patients with diabetes, accounting for over 60% of mortalities.3 While diabetes is uniformly recognized as an important risk factor for the development of atherosclerosis and its complications, it is perhaps less well acknowledged that diabetes is a powerful and independent risk factor for the development of heart failure.

The Framingham Heart Study was the ﬁrst to demonstrate an increased risk for heart failure in patients with diabetes. The incidence of heart failure in these men and women was increased two- and ﬁvefold, respectively, compared with men and women without diabetes.6 The association was even stronger in patients younger than 65 years of age, being fourfold higher in diabetic men and eightfold higher in diabetic women than in nondiabetic subjects.6 Since then, additional studies, including the Studies of Left Ventricular Dysfunction (SOLVD),7 the Heart Outcomes Prevention Evaluation (HOPE) study,8 and the Cardiovascular Health Study (CHS),9 have identiﬁed diabetes as a major risk factor for the development of heart failure. In a large registry of almost 50,000 diabetic individuals, poor glycemic control was associated with an increased risk of developing heart failure: each 1% increase in the level of glycosylated hemoglobin (HbA1c) was associated with an 8% increase in the risk of heart failure.10 Conversely, the presence of heart failure was identiﬁed as a possible risk factor for diabetes. During a three-year follow-up of nondiabetic heart failure Italian patients, diabetes developed in 29% compared with 18% of matched controls; multivariate analysis showed heart failure to be an independent risk factor for the development of diabetes.11 Moreover, diabetic patients make up to 25% to 30% of all patients enrolled in large-scale heart failure clinical trials.12–14 The dire prognosis of diabetic heart failure patients is well established. In SOLVD,7 diabetes was a major risk factor for cardiovascular and all-cause mortality, and in the Diabetes Insulin Glucose in Acute Myocardial Infarction (DIGAMI) study, heart 333

334

Chapter 26 • Diabetes Mellitus failure was the most frequent cause of mortality in diabetics, accounting for 66% of deaths in the year following the ﬁrst myocardial infarction.15

bolic control, these pathological mechanisms are potentially reversible in the early phases, with normalization of the cardiac function.

PATHOPHYSIOLOGY

Free Fatty Acid Metabolism

The term diabetic cardiomyopathy was ﬁrst coined in 1972 by Rubler et al., who described four diabetic patients presenting with heart failure without evidence of coronary artery disease, hypertension, or valvular or congenital heart disease.16 Although initially controversial, the existence of diabetic cardiomyopathy has been conﬁrmed in the past three decades by epidemiological, clinical, and laboratory studies, which have shed light on the biochemical and pathological mechanisms involved (Fig. 26-1). The development of diabetic cardiomyopathy is likely multifactorial, with putative mechanisms including metabolic disturbances, myocardial ﬁbrosis, small vessel disease, autonomic dysfunction, and insulin resistance (Fig. 26-2).

Metabolic Disturbances Isolated diabetic cardiomyocytes17 in diabetic patients18 exhibit a signiﬁcant decrease in myocardial glucose supply and utilization, with the net eﬀect of reduced adenosine triphosphatase (ATP) availability. The slow rate of glucose transport across the sarcolemmal membrane is probably due to the cellular depletion of glucose transporters 1 and 4,19,20 which can be corrected by insulin therapy.20,21 The reduced glucose oxidation in turn is caused by the inhibitory eﬀect of fatty acid oxidation on pyruvate dehydrogenase complex, due to high levels of circulating free fatty acids.22 Experimental models have demonstrated that these metabolic abnormalities are associated with contractile dysfunction manifested by increased left ventricular (LV) end diastolic pressure and reduced cardiac output.23 Importantly, with improved meta-

Type I Diabetes mellitus

Abnormalities in free fatty acid metabolism caused by insulin resistance may be important contributors to the abnormal myocardial function in diabetes. High levels of free fatty acids lead to an inhibition of glucose oxidation, resulting in reduced myocardial ATP availability.22 In addition, abnormally high oxygen requirements associated with increased fatty acid metabolism cause an intracellular accumulation of potentially toxic intermediates, leading to impaired myocardial performance and severe morphological changes.24 These metabolic changes are coupled with a relative carnitine deﬁciency that is common in diabetes25 and are potentially reversible once glycemic control is improved.

Abnormalities in Regulation of Calcium Homeostasis The abnormal myocardial metabolism in diabetes leads to an accumulation of toxic molecules (e.g., long-chain acylcarnitines, free radicals), which in turn results in alterations in the function of regulatory and contractile proteins and decreased calcium sensitivity.26 The diminished calcium sensitivity along with shifts in cardiac myosin heavy chains (V1 to V3),27 reduction of sarcoplasmic reticulum calcium-ATPase (SERCA2a), and decreased SERCA2a pump gene expression28 may all contribute to impaired ventricular function.29 Finally, alterations in the expression of myosin isoenzymes and regulatory proteins and myosin phosphorylation have been demonstrated to contribute to the development of myoﬁbrillar remodeling in the diabetic heart30 and are closely associated with abnormalities in diastolic function.31

Type II Diabetes mellitus ↑ NEFA

↑ Acyl CoA ↑ TNFα /Ceramide

↓ Ca++ ↑ Apoptosis

↑ LV mass ↑ Fibrosis

LVH

Cellular insulin resistance

Hyper-insulinemia

Diastolic dysfunction

β-cell failure

LV systolic dysfunction Hypo-insulinemia

Hyperglycemia

↓ SERCA 2a ↓ RyR2 ↓ Na+/K+ ATPase ↓ Myofibrillar ATPase ↓ Microvascular flow reserve

Figure 26-1 Proposed hypothesis for the pathophysiology of diabetic cardiomyopathy. ATP, adenosine triphosphate; CoA, fatty acyl coenzyme A; LV, left ventricle; LVH, left ventricular hypertrophy; NEFA, nonesterified fatty acids; RyR2, ryanodine receptor 2; SERCA2a; sarco(endo)plasmic reticulum calcium ATPase 2a; TNFa, tumor necrosis factor α. (From Poornima IG et al: Diabetic cardiomyopathy: The search for a unifying hypothesis. Circ Res 2006;98:596–605.)

Chapter 26 • Diabetes Mellitus TRIGGERS

NEFA Figure 26-2 Cellular mechanisms involved in the pathophysiology of diabetic cardiomyopathy. AGE, advanced glycation end products; ATP, adenosine triphosphate; CoA, fatty acid coenzyme A; GADPH, glyceraldehyde-3-phosphate dehydrogenase; GSK-3b, glycogen synthase kinase-3b; MAP, mitogen-activated protein; mTOR, mammalian target of rapamycin; NEFA, nonesterified fatty acids; PARP, poly (ADP-ribose) polymerase; PI 3K, phosphatidylinositol 3kinase; PKC, protein kinase C; PTEN, phosphatase and tensin homolog deleted on chromosome 10; ROS, reactive oxygen species; TNFa, tumor necrosis factor α. (From Poornima IG et al: Diabetic cardiomyopathy: The search for a unifying hypothesis. Circ Res 2006;98:596–605.)

MEDIATORS

EFFECTORS

TARGETS

↑ Acyl CoA

↑ K+ATP channel

↓ Activator Ca++

↑ Atypical PKC ↑ PTEN

↓ Akt-1 activation

Insulin resistance

↑ TNFα

↑ Ceramide

Myocyte apoptosis

PI 3K/Akt-1

↓ GSK-3β ↑ mTOR

Myocyte hypertrophy

↑ MAP kinase

↑ Ras/↑ Rho

↑ Protein synthesis

↑ PKC

Calcium homeostasis

Hyperinsulinemia

Hyperglycemia

A magnetic resonance imaging (MRI) study of asymptomatic, normotensive, nonobese, well-controlled diabetic patients (mean HbA1c, 6.1 g/dL) showed ventricular diastolic dysfunction compared with control subjects who were matched for age, gender, body mass index (BMI), and blood pressure.32 These ﬁndings were associated with a signiﬁcantly lower ratio of myocardial phosphocreatine to ATP in diabetic patients compared with controls.32 Previous studies suggested that the lower phosphocreatine content and the switch in substrate preference from glucose to fatty acids may lead to lower levels of ATP in the sarcomeres, for which increased mitochondrial ATP production does not compensate.33 Lower cytosolic ATP concentration is associated with impaired calcium sequestration by the sarcoplasmic reticulum and impaired relaxation of cardiomyocytes.32

Myocardial Fibrosis Myocardial ﬁbrosis and myocyte hypertrophy are among the most frequently proposed mechanisms to explain cardiac changes in diabetic cardiomyopathy. Collagen accumulation in the diabetic myocardium may be due in part to impaired collagen degradation resulting from glycosylation of the lysine residues on collagen.34 Hyperglycemia also results in the production of reactive oxygen and nitrogen species, which increases oxidative stress and causes abnormal gene expression, altered signal transduction, and activation of the pathways leading to programmed myocardial cell death or apoptosis.35 This process is associated with the glycosylation of p53, resulting in an increment in angiotensin II synthesis36 that has dose-dependent eﬀects on collagen secretion and production in cardiac ﬁbroblasts.37 In addition, chronic metabolic abnormalities present in diabetes (postprandial hyperglycemia, hyperinsulinemia, insulin resistance) lead to alterations in endothelin-1 and its receptors,38 decreased levels of insulin-like growth factor-I,39 and increased production of transforming growth factor-β140 that result in promotion of angiotensin II activity with an increase in myocardial collagen content. The functional abnormalities in diabetic myocardium are associated with myocardial structural changes. Several studies using endomyocardial biopsies have shown a correlation between histological and clinical features in diabetes, with myocardial changes

↑ ROS → ↑ PARP ↓ ↓ GAPDH

↑ Hexosamine ↑ Polyol flux

Contractile proteins

↑ Age

Matrix proteins

more pronounced in symptomatic patients and in those with cardiomegaly.41,42 The role of ﬁbrosis in myocardial dysfunction is also supported by studies showing reversal of cardiac ﬁbrosis by short-term pirfenidone and spironolactone treatment, with improvement in diastolic stiﬀness in diabetic rats.43 Alterations in myocardial structure are usually minimal in the early stages of diabetes and may be reversible or partially reversible. As diabetes progresses, accumulation of collagen becomes obvious and may play a major role in the development of diastolic dysfunction.

Small Vessel Disease Structural Abnormalities of Vessels Although the contribution of small vessel disease to diabetic cardiomyopathy is controversial, there are several structural abnormalities of small vessels that are evident in the diabetic myocardium. The capillary basement membrane is thicker in patients with diabetes, and its thickness seems to be greater compared with patients with glucose intolerance and those without diabetics.44 In addition, diabetes patients exhibit capillary microaneurysms with reduced capillary density, focal subendothelial proliferation, and interstitial ﬁbrosis with myocyte atrophy.45–47

Functional Abnormalities of Vessels It has been proposed that diabetic cardiomyopathy is a consequence of repeated episodes of myocardial ischemia resulting from both structural and functional abnormalities in small vessels or from microvascular spasm during periods of increased myocardial demand.48,49 Such processes would lead to focal cell loss due to microvascular spasm and reperfusion injury, with the subsequent development of focal ﬁbrosis and reactive hypertrophy in response to myocardial necrosis. The myocardial blood ﬂow is not only reduced in diabetic patients but also correlates signiﬁcantly with fasting glucose concentration and average levels of HbA1c.50,51 Endothelium-dependent responses of both small and large vessels are impaired in diabetic patients, including those with an otherwise low likelihood of atherosclerosis.52,53 The half-life of nitric oxide is reduced due to increased oxidative stress,54–57 and

335

336

Chapter 26 • Diabetes Mellitus its activity is attenuated by accumulated glycosylation end products.58 In addition, diabetic endothelium manifests increased production of vasoconstrictor prostanoids59 and increased expression of protein kinase C activity.60 Protein kinase C activation is associated with abnormal retinal and renal hemodynamics in diabetic animals, and overexpression of the myocardial β-isoform is associated with cardiac hypertrophy and failure,61 implying that this may play a role in the development of diabetic cardiomyopathy by aﬀecting the small vasculature.

Cardiac Autonomic Dysfunction Studies in which sympathetic innervation was assessed quantitatively using 123 I-metaiodobenzylguanidine or 11 Chydroxyephedrine have shown a decreased myocardial uptake in 40% to 50% of diabetes patients, indicating the presence of cardiac autonomic dysfunction.62,63 It appears that this is a regional process, with the posterior myocardium being predominantly aﬀected64–66 and with areas of proximal hyperinnervation complicating distal denervation.67 Myocardial autonomic dysfunction is associated with altered myocardial blood ﬂow, with the regions of persistent sympathetic innervation exhibiting the greatest deﬁcits of vasodilator reserve.68 Decreased myocardial perfusion reserve may be in part responsible for the abnormal response to exercise in the early phases of diabetic cardiomyopathy69,70 and may explain its association with impairments of diastolic function.71–74

Insulin Resistance Cellular insulin resistance may precede frank diabetes by a decade or more and is associated with requisite compensatory increases in plasma insulin levels to maintain glucose homeostasis in the face of impaired cellular insulin action, principally in skeletal muscle and liver.75 The nature and extent of the insulin resistance may be selective to certain organ systems and may vary in terms of their metabolic, mitogenic, pro-survival, and vascular actions. Insulin may act as a growth factor in the myocardium, a concept that is supported by the experimental observation that sustained hyperinsulinemia leads to increased myocardial mass and decreased cardiac output in rats.76 Hyperinsulinemia leads to sodium retention, which may contribute to decompensation in persons with otherwise subclinical myocardial dysfunction due to volume expansion.77 Hyperinsulinemia also leads to sympathetic nervous system activation,78 which is related to an increased response to angiotensin II79 and increases the stimulating eﬀects of angiotensin II on cellular hypertrophy and collagen production,80 leading to myocardial hypertrophy and ﬁbrosis and likely subsequent heart failure. A very elegant recent study has shown that in a communitybased sample of men free of heart failure and valvular disease at baseline, insulin resistance predicted heart failure incidence independently of diabetes and other established risk factors for heart failure.81 Furthermore, this study indicated that the previously described association between obesity and subsequent heart failure may be mediated, at least in part, by insulin resistance.

Interaction with Other Major Comorbidities With the addition of untreated hypertension, myocardial ischemia, or both, the mild subclinical cardiomyopathy of diabetes may rapidly advance to clinical diastolic and systolic dysfunction. In clinical practice, it is diﬃcult to distinguish the concurrent roles of hypertension and ischemia in the development of diabetic

cardiomyopathy. Furthermore, the presence of silent ischemia in diabetic patients makes the diagnosis of diabetic cardiomyopathy more complicated.

Interaction with Hypertension The prevalence of hypertension is approximately doubled in diabetic patients compared with nondiabetic controls,82 and the clinical and morphological features of heart disease in hypertensive diabetic patients are more severe than those of hypertensive patients or diabetic patients alone. Myocardial ﬁbrosis and interstitial collagen deposition are greater when hypertension is associated with diabetes than when either entity exists in isolation,83 and these synergistic eﬀects on neurohormonal activation and oxidative stress may promote apoptotic myocyte loss, initiating a transition from a subclinical, compensated/hypertrophied state to overt cardiomyopathy.84 At least one study has documented an association between diabetes, hypertension, and the development of dilated cardiomyopathy.85 In addition, patients with diabetes and hypertension in combination have more severe abnormalities of ventricular relaxation than those with either condition alone.86

Interaction with Coronary Artery Disease Although lipid metabolism abnormalities associated with diabetes do not have direct inﬂuence on the development of diabetic cardiomyopathy, they are at least partly responsible for enhanced coronary atherosclerosis in these patients. Enhanced coronary atherosclerosis is directly related to myocardial ischemia, increased oxidative stress, and vascular endothelial dysfunction. Compared with nondiabetic patients, those patients with diabetes demonstrate impaired recruitment of contractile reserve in noninfarct segments and greater reduction in global systolic function immediately following myocardial infarction,87,88 changes that may be related to diminished coronary ﬂow reserve and microvascular dysfunction.89 Over the long term, these acute changes do not appear to be associated with a greater propensity for ventricular cavity dilation or progressive systolic dysfunction,90 and the increased incidence of heart failure in diabetic patients appears to be related to primary abnormalities of diastolic function. The progression of diabetic cardiomyopathy is a dynamic process and takes several years to develop (Table 26-1). In the initial phase, there is a short-term physiological adaptation to metabolic alterations that is potentially reversible once glycemic control has been restored. Thus, therapies during the early stages of diabetes can potentially prevent or delay the progression to more permanent sequelae. The late stage represents degenerative changes for which the myocardium has only limited capacity for repair. However, many factors, such as treatments, metabolic characteristics, lipid proﬁle, blood pressure, and other individual diﬀerences, may aﬀect the process of development of diabetic cardiomyopathy, and not all diabetic patients are aﬀected by the same factors or to the same degree, which may result in marked variability in the clinical manifestations of diabetic cardiomyopathy.

CLINICAL RELEVANCE LV diastolic dysfunction may be the ﬁrst stage of diabetic cardiomyopathy.91,92 In the Olmsted County study, close to 50% of participants with diabetes had echocardiographic evidence of diastolic dysfunction, compared with 27% of nondiabetic subjects.93 Almost none of these participants had a prior diagnosis of heart

Chapter 26 • Diabetes Mellitus TABLE 26-1 STAGES OF DIABETIC CARDIOMYOPATHY STAGES

CHARACTERISTICS

FUNCTIONAL FEATURES

STRUCTURAL FEATURES

DIAGNOSIS

Early

Depletion of glucose transporter 4 Increased free fatty acids Carnitine deficiency Calcium homeostasis changes Insulin resistance

No overt functional abnormalities or possible overt diastolic dysfunction but normal ejection fraction

Normal ventricular size, wall thickness, and mass

Sensitive methods such as strain, strain rate, and myocardial tissue velocity

Intermediate

Apoptosis and necrosis Increased angiotensin II Reduced insulin-like growth factor-I Increased production of transforming growth factor-β1 Mild cardiac autonomic dysfunction

Abnormal diastolic function and normal or slightly decreased ejection fraction

Slightly increased ventricular mass, wall thickness, or size

Conventional echocardiography or sensitive methods such as strain, strain rate, and myocardial tissue velocity

Late

Microvascular changes Hypertension Coronary artery disease Severe cardiac autonomic dysfunction

Abnormal diastolic function and ejection fraction

Significantly increased ventricular size, wall thickness, and mass

Conventional echocardiography

From Fang ZY et al: Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications. Endocr Rev 2004;25:543–567.

failure. Remarkably, this observational study showed that even mild impairment in diastolic function is associated with an eightfold risk of all-cause mortality compared with normal diastolic function.93 In the same study, 14% of diabetic patients also had an LV ejection fraction (LVEF) below 0.50 compared with only 5% of nondiabetic patients, providing evidence that diabetes can aﬀect both systolic and diastolic function. In a study of 86 patients with diabetes (43% of whom were women), more than 40% had diastolic dysfunction: 26% had impaired relaxation and 17% had pseudonormalization on Doppler echocardiogram.94 These ﬁndings are noteworthy, as these subjects were young (mean age, 43 years), normotensive (mean blood pressure, 125/80 mmHg), and under excellent diabetic control (mean HbA1c, 6.5 g/dL). In the Strong Heart Study, enrolling 2411 Native Americans, diabetic participants had evidence of impaired LV relaxation on Doppler echocardiography. The association between diabetes and abnormal LV relaxation was independent of age, blood pressure, LV mass, and systolic function.86 These abnormalities were more severe in the group with both diabetes and hypertension, showing the additive deleterious eﬀects on active LV relaxation when both these conditions are present.86 In the Multi-Ethnic Study of Atherosclerosis, 6800 men and women from four ethnic groups (Americans of African, Chinese, European, and Hispanic descent) underwent cardiac MRI at enrollment. Diabetic patients manifested increased LV mass and lower end diastolic and stroke volumes compared with participants with impaired fasting glucose and with nondiabetic patients.95 These ﬁndings were independent of traditional risk factors and other measures of subclinical atherosclerosis (such as coronary artery calcium or carotid artery intima-media thickness) and were especially signiﬁcant in African Americans and Hispanics. Although LVEF was not diﬀerent among diabetic and nondiabetic women, diabetic men had a signiﬁcantly lower LVEF compared with nondiabetic men, albeit within the normal range.95 These results strengthen the evidence in favor of a diabetic cardiomyopathy and suggest that this condition may start even

before clinical diabetes is diagnosed and may have distinct characteristics among diﬀerent gender and ethnic groups. Several studies have shown that the ﬁrst clinical manifestation of diastolic dysfunction is limited exercise tolerance. Poirier et al. reported that patients with well controlled diabetes and without overt coronary artery disease, hypertension, or heart failure had lower exercise performance on maximal treadmill testing than age-matched controls. The exercise limitation correlated with the severity of diastolic dysfunction as assessed by Doppler echocardiography.96 Microalbuminuria appears to be an independent risk factor for the development of diastolic dysfunction, perhaps being a marker for intramyocardial microangiopathy. In the Strong Heart Study, after adjusting for age, gender, BMI, systolic blood pressure, duration of diabetes, coronary artery disease, and LV mass, the prevalence of LV diastolic dysfunction increased as a function of increasing urinary albumin excretion.97 Further studies should address whether routine testing for microalbuminuria is indicated to identify diabetic patients with impaired LV relaxation.97 The inﬂuence of diabetic complications on diastolic function has been investigated in several other studies. Most of these studies showed that patients with diabetic retinopathy,98–101 nephropathy,102–104 or neuropathy105–107 had signiﬁcantly more abnormalities in diastolic function compared with diabetic patients without microvascular disease or with nondiabetic patients. In addition, the severity of diastolic dysfunction was related to the number of microvascular complications,100,108 glycemic control,86,109,110 or duration of diabetes.111–113 Despite growing awareness of the burden of diastolic heart failure (DHF), there have been few randomized clinical trials of drug therapies for these patients (see Chapters 32 and 34), and no trial that speciﬁcally assessed the unique role of diabetes. The Digitalis Investigation Group ancillary study randomized 988 patients with chronic heart failure who were in sinus rhythm and had an LVEF greater than 45% to digoxin or placebo, in addition to standard therapy.114 Although there were no diﬀerences in all-cause mortality (23.4% in both groups after a mean

337

338

Chapter 26 • Diabetes Mellitus follow-up of 37 months) or in the endpoint of death or hospitalization for worsening heart failure (24% and 21% in the placebo and digoxin groups, respectively; p = 0.136), there was a trend toward beneﬁt in the digoxin group for heart failure hospitalizations (22% and 18% in the placebo and digoxin groups, respectively; p = 0.094).114 This study is the basis for the level C recommendation for the use of digoxin to reduce symptoms of heart failure in patients with DHF.115 The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)–Preserved arm is the ﬁrst of several trials designed to study patients with DHF initiated in the last 5 years to have published its full results. The design of the study, in the context of the entire CHARM program, dictated the selection of patients with LVEF greater than 40%, allowing the inclusion of some patients with at least mild systolic dysfunction. The primary endpoint of cardiovascular death or heart failure hospitalization occurred in 22% of patients in the candesartan arm and 24% of those in the placebo arm (hazard ratio [HR], 0.89; 95% CI, 0.77–1.03).12 Cardiovascular deaths were identical in number in the two groups, but fewer patients in the candesartan group than the placebo group experienced heart failure hospitalizations (15.2% vs. 18.5%, p = 0.017).12 Although candesartan was associated with a reduction in the incidence of new-onset diabetes when compared with placebo,116 the authors did not present a separate analysis of its eﬀect on mortality or heart failure hospitalizations in the diabetic patients in the study. The Perindopril for Elderly Persons with Chronic Heart Failure (PEP-CHF) trial was a study of heart failure in elderly patients rather than a study of DHF.117 All 852 patients were older than 70 years and had evidence of chronic heart failure conﬁrmed by clinical and echocardiographic criteria (LVEF greater than 40%). At the end of the 26 months of follow-up, there was no diﬀerence in the primary outcome of all-cause mortality or heart failure hospitalizations between the placebo and the perindopril groups (25.1% vs. 23.6%, p = 0.545). Perindopril decreased heart failure hospitalizations during the ﬁrst year (HR, 0.63; 95% CI, 0.41–0.97) but not at the end of the follow-up (HR, 0.86; 95% CI, 0.6–1.20).117 In the authors’ opinion, the main reasons for the negative results were the enrollment of fewer patients (N = 1000) than anticipated, a lower event rate than predicted, and the use of open-label angiotensin-convertingenzyme (ACE) inhibitors in these patients after the ﬁrst year of follow-up.117 The Study of Eﬀects of Nebivolol Intervention on Outcomes and Rehospitalizations in Seniors with Heart Failure (SENIORS)

evaluated the eﬀect of a selective beta blocker with additional vasodilating properties in 2128 patients 70 years of age or older.14 Twenty percent of the study population had LVEFs above 45%. As with CHARM-Preserved, the characteristics of the overall population were quite diﬀerent from those of populations with DHF in epidemiology studies, in that 63% were men and 76% had ischemic heart disease as the etiology of heart failure. Nebivolol produced a signiﬁcant reduction in the primary endpoint of death or cardiovascular hospitalization, with 31.1% of patients in the nebivolol and 35.3% in the placebo group experiencing an event (HR, 0.86; 95% CI, 0.73–0.99).14 There was a modest trend toward an improvement in mortality (HR, 0.88; 95% CI, 0.71–1.08). The results in the group with LVEFs of 45% or greater were not presented separately. Patients without diabetes showed a signiﬁcant beneﬁt with nebivolol for the primary composite endpoint, while those with diabetes did not.14 With the exception of candesartan and perhaps digoxin, which have been shown to reduce the incidence of hospitalizations, the management of DHF is based largely on clinical experience, with the goal of controlling the deleterious processes that are known to exert important eﬀects on ventricular relaxation (i.e., hypertension, diabetes, ischemia, tachycardia, and atrial ﬁbrillation) (see Chapter 32).118 The ﬁrst treatment goal is to provide symptomatic relief by decreasing pulmonary congestion at rest and during exercise. This can be achieved by a reduction in LV diastolic volume (with the goal of reducing LV diastolic pressure), maintaining synchronous atrial contraction (by maintaining sinus rhythm), and increasing the duration of diastole (by reducing heart rate).118 Reduction in LV diastolic volume can be done by reducing total blood volume (through sodium and water restrictions and use of diuretics), decreasing central blood volume (through preload reduction with nitrates), and inhibiting the activation of the renin-angiotensin-aldosterone system (through ACE inhibitors, angiotensin-receptor blockers, and aldosterone antagonists, or a combination thereof ) (Table 26-2).118 LV ﬁlling in DHF occurs primarily in late diastole and is more dependent on atrial contraction than is ﬁlling in unimpaired hearts. Restoration and maintenance of sinus rhythm is preferred when atrial ﬁbrillation occurs in the setting of DHF. If this cannot be achieved, rate control is paramount.118 Tachycardia can cause an exacerbation of diastolic dysfunction by increasing myocardial oxygen demand (leading to ischemia) and by causing incomplete relaxation.118 Maintaining a resting heart rate around 60–70 bpm and blunting exercise-induced

TABLE 26-2 EFFECTS OF ANGIOTENSIN-CONVERTING-ENZYME INHIBITORS ON MORTALITY FROM SYSTOLIC HEART FAILURE IN DIABETIC AND NONDIABETIC PATIENTS Study Name CONSENSUS SAVE SMILE SOLVD-Prevention SOLVD-Treatment TRACE Random effects pooled estimate

TOTAL N

NONDIABETIC N

DIABETIC N

RR, NONDIABETIC (95% CI)

RR, DIABETIC (95% CI)

253 2231 1556 4228 2569 1749

197 1739 1253 3581 1906 1512 10188

56 492 303 647 663 237 2398

0.64 (0.46–0.88) 0.82 (0.68–0.99) 0.79 (0.54–1.15) 0.97 (0.83–1.15) 0.84 (0.74–0.95) 0.85 (0.74–0.97) 0.85 (0.78–0.92)

1.06 (0.65–1.74) 0.89 (0.68–1.16) 0.44 (0.22–0.87) 0.75 (0.55–1.02) 1.01 (0.85–1.21) 0.73 (0.57–0.94) 0.84 (0.70–1.00)

RR, risk reduction; CI, confidence interval; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; SAVE, Survival and Ventricular Enlargement; SMILE, Survival of Myocardial Infarction Long-Term Evaluation; SOLVD, Studies of Left Ventricular Dysfunction; TRACE, Trandolapril Cardiac Evaluation. From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment. Circulation. 2002;105:1503–1508.

Chapter 26 • Diabetes Mellitus TABLE 26-3 EFFECTS OF BETA BLOCKERS ON MORTALITY FROM SYSTOLIC HEART FAILURE IN DIABETIC AND NONDIABETIC PATIENTS Study Name CIBIS II COPERNICUS MERIT-HF Random effects pooled estimate

TOTAL N

NONDIABETIC N

DIABETIC N

RR, NONDIABETIC (95% CI)

RR, DIABETIC (95% CI)

2647 2287 3991

2335 1701 3006 7042

312 586 985 1883

0.66 (0.54–0.81) 0.67 (0.52–0.85) 0.62 (0.48–0.79) 0.65 (0.57–0.74)

0.81 (0.52–1.27) 0.68 (0.47–1.00) 0.81 (0.57–1.15) 0.77 (0.61–0.96)

RR, risk reduction; CI, confidence interval; CIBIS, Cardiac Insufficiency Bisoprolol Study; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure. From Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment. Circulation 2002;105:1503–1508.

tachycardia by using beta blockers and calcium channel antagonists may have beneﬁcial eﬀects and prevent elevated LV pressures and pulmonary congestion (Table 26-3).118 After symptom control, treatment should target the underlying disorders that caused DHF. Blood pressure should be maintained below 130/80, in keeping with current guidelines, and all patients with suspected ischemic etiology should undergo evaluation and revascularization.115 Regression of LV hypertrophy with beta blockers, calcium channel antagonists, and renin-angiotensinaldosterone system blockers can improve diastolic function.119 Although tight glycemic control decreases the risk of heart failure in persons with diabetes,10 the eﬀects of diﬀerent diabetic treatment regimens on DHF in this population are unknown. While diabetes is an important contributor to diastolic dysfunction and DHF, a signiﬁcant proportion of patients with heart failure and impaired systolic function also have diabetes. A recent meta-analysis has shown that the traditional therapies for systolic dysfunction with angiotensin-receptor inhibitors and beta blockers have the same beneﬁcial eﬀect in the diabetic population.120 In addition, eplerenone, a selective aldosterone blocker, is as eﬀective in preventing all-cause or cardiovascular mortality and cardiovascular events in diabetic patients as it does in nondiabetic subjects who have suﬀered a myocardial infarction and have decreased LVEF.121

FUTURE RESEARCH DHF is a major contributor to mortality, hospitalization, and medical costs in the United States. Two recent studies have shown that the percentage of patients hospitalized for decompensated heart failure with preserved systolic function (LVEF >50%) has increased over time and that their prognosis is as grim as that of those with impaired systolic function.122,123 The one-year mortality rates are in the 20% range, and the readmission rate for heart failure in the ﬁrst year after discharge is around 13%.123 DHF is usually associated with hypertension, atherosclerosis (involving the coronary arteries and aorta), and atrial ﬁbrillation, conditions that are common in the elderly. Thirty percent of patients with DHF have diabetes, and the proportion of diabetic patients with preserved EF has increased signiﬁcantly over time.122 Recent studies in experimental animal models and in humans suggest that diabetes results in functional, biochemical, and morphological myocardial abnormalities independent of coronary atherosclerosis and hypertension. These abnormalities lead to a speciﬁc diabetic cardiomyopathy that manifests mainly by impaired diastolic function.

Several trials evaluating established and novel treatment options in patients with DHF have been completed (e.g., PEPCHF and CHARM-preserved) and two trials are ongoing (Irbesartan in Heart Failure with Preserved Ejection Fraction [I-PRESERVE]124 and the Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure [TOPCAT]). The I-PRESERVE trial is a large trial designed speciﬁcally to examine patients with DHF. To more closely approximate the population of patients with DHF, only those 60 years or older and with LVEF 45% or greater are being entered. Furthermore, patients who have had prior documented moderate or severe systolic dysfunction, as evidenced by LVEF less than 40%, are excluded. Enrollment of 4128 patients has been completed. The mean age is older than 70 years, approximately 60% are women, and hypertension is the primary etiology of heart failure, with only approximately one quarter having known coronary disease. The primary endpoint of I-PRESERVE reﬂects the critical outcomes that aﬀect this population, including death from all causes, nonfatal myocardial infarction and stroke, and hospitalizations for worsening heart failure, unstable angina, and arrhythmias. Follow-up will be completed in early 2008 when the target of 1440 primary endpoint events will have occurred. The National Heart, Lung, and Blood Institute sponsored the TOPCAT study, which is enrolling 4500 patients 50 years of age and older with symptoms of heart failure and LVEF greater than 45%. Patients will be randomized to spironolactone or placebo and followed up for at least 3 years. Enrollment started in summer 2006 and the trial is expected to complete in 2011. The Japanese Diastolic Heart Failure Study ( J-DHF) is a multicenter, prospective, randomized trial designed to assess eﬀects of beta blockers in patients with DHF. A total of 800 patients will be enrolled and followed for at least 2 years. The primary outcome is a composite of cardiovascular death and unplanned admission to hospital for congestive heart failure. Other outcomes include all-cause mortality, worsening of the symptoms of heart failure, and a need for modiﬁcation of the treatment for heart failure.125 Glucose cross-link breakers (e.g., alagebrium chloride) are novel therapies for DHF. A small open-label study in patients older than 65 years of age showed that administration of alagebrium chloride for 16 weeks led to regression of LV mass and improvements in echocardiographic diastolic parameters and quality-of-life questionnaires (see Chapter 34).126 These encouraging results are likely to be followed by a larger, placebocontrolled trial. As of yet, no trials have addressed the unique contribution of diabetes to diastolic dysfunction and heart failure. Small studies

339

340

Chapter 26 • Diabetes Mellitus have suggested that metabolic modulators such as partial fatty acid oxidation inhibitors (ranolazine and trimetazidine) may improve myocardial glucose uptake, cardiac function, and exercise capacity in those with diabetes.127 In addition, a plethora of preclinical studies have shown that peroxisome proliferator activator receptors–gamma (e.g., thiazolidinediones) improve diastolic function and myocardial metabolism in diabetic animals, opening the avenue for clinical trials.128 When the results of these trials become available and with new trials under development, the management of this increasingly common condition will be more completely deﬁned. Although tight glycemic control decreases the risk of heart failure in persons with diabetes, the eﬀects of diﬀerent diabetic treatment regimens on DHF in this population are unknown and remain subject to future investigations. REFERENCES 1. Zimmet P, Alberti KG, Shaw J: Global and societal implications of the diabetes epidemic. Nature 2001;414:782–787. 2. King H, Aubert RE, Herman WH: Global burden of diabetes, 1995–2025: Prevalence, numerical estimates, and projections. Diabetes Care 1998;21: 1414–1431. 3. American Heart Association: Heart disease and stroke statistics 2007 update. Dallas: American Heart Association, 2007. 4. Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: Findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356–359. 5. Sinha R, Fisch G, Teague B, et al: Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002;346:802–810. 6. Kannel WB, Hjortland M, Castelli WP: Role of diabetes in congestive heart failure: The Framingham study. Am J Cardiol 1974;34:29–34. 7. Shindler DM, Kostis JB, Yusuf S, et al: Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) trials and registry. Am J Cardiol 1996;77:1017–1020. 8. Arnold JM, Yusuf S, Young J, et al: Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation 2003;107:1284–1290. 9. Gottdiener JS, Arnold AM, Aurigemma GP, et al: Predictors of congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cadiol 2000;35:1628–1637. 10. Iribarren C, Karter AJ, Go AS, et al: Glycemic control and heart failure among adult patients with diabetes. Circulation 2001;103:2668– 2673. 11. Amato L, Paolisso G, Cacciatore F, et al: Congestive heart failure predicts the development of non-insulin-dependent diabetes mellitus in the elderly: The Osservatorio Geriatrico Regione Campania Group. Diabetes Metab 1997;23:213–218. 12. Yusuf S, Pfeﬀer MA, Swedberg K, et al, for CHARM Investigators and Committees: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781. 13. Bardy GH, Lee KL, Mark DB, et al: Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators: Amiodarone or an implantable cardioverter-deﬁbrillator for congestive heart failure. N Engl J Med 2005;352:225–237. 14. Flather MD, Shibata MC, Coats AJ, et al, for SENIORS Investigators: Randomized trial to determine the eﬀect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–225. 15. Malmberg K, Ryden L, Efendic S, et al: Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): Eﬀects on mortality at 1 year. J Am Coll Cardiol 1995;26:57–65. 16. Rubler S, Dlugash J, Yuceoglu YZ, et al: New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30: 595–602. 17. Chen V, Ianuzzo CD, Fong BC, et al: The eﬀects of acute and chronic diabetes on myocardial metabolism in rats. Diabetes 1984;33:1078– 1084.

18. Ohtake T, Yokoyama I, Watanabe T, et al: Myocardial glucose metabolism in noninsulin–dependent diabetes mellitus patients evaluated by FDGPET. J Nucl Med 1995;36:456–463. 19. Eckel J, Reinauer H. Insulin action on glucose transport in isolated cardiac myocytes: Signalling pathways and diabetes induced alterations. Biochem Soc Trans 1990;18:1125–1127. 20. Garvey WT, Hardin D, Juhaszova M, et al: Eﬀects of diabetes on myocardial glucose transport system in rats: Implications for diabetic cardiomyopathy. Am J Physiol 1993;264:H837–H844. 21. Russell III RR, Yin R, Caplan MJ, et al: Additive eﬀects of hyperinsulinemia and ischemia on myocardial GLUT1 and GLUT4 translocation in vivo. Circulation 1998;98:2180–2186. 22. Liedtke AJ, DeMaison L, Eggleston AM, et al: Changes in substrate metabolism and eﬀects of excess fatty acids in reperfused myocardium. Circ Res 1988;62:535–542. 23. Lopaschuk GD, Russell JC: Myocardial function and energy substrate metabolism in the insulin-resistant JCR: LA corpulent rat. J Appl Physiol 1991;71:1302–1308. 24. Nakayama H, Morozumi T, Nanto S, et al: Abnormal myocardial free fatty acid utilization deteriorates with morphological changes in the hypertensive heart. Jpn Circ J 2001;65:783–787. 25. Malone JI, Schocken DD, Morrison AD, et al: Diabetic cardiomyopathy and carnitine deﬁciency. J Diabetes Complications 1999;13:86–90. 26. Malhotra A, Sanghi V: Regulation of contractile proteins in diabetic heart. Cardiovasc Res 1997;34:34–40. 27. Takeda N, Nakamura I, Hatanaka T, et al: Myocardial mechanical and myosin isoenzyme alterations in streptozotocin-diabetic rats. Jpn Heart J 1988;29:455–463. 28. Golfman L, Dixon IM, Takeda N, et al: Diﬀerential changes in cardiac myoﬁbrillar and sarcoplasmic reticular gene expression in alloxan-induced diabetes. Mol Cell Biochem 1999;200:15–25. 29. Abe T, Ohga Y, Tabayashi N, et al: Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Physiol Heart Circ Physiol 2002;282:H138–H148. 30. Dhalla NS, Liu X, Panagia V, et al: Subcellular remodeling and heart dysfunction in chronic diabetes. Cardiovasc Res 1998;40:239–247. 31. Bristow MR: Etomoxir: A new approach to treatment of chronic heart failure. Lancet 2000;356:1621–1622. 32. Diamant M, Lamb HJ, Groeneveld Y, et al: Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol 2003;42:328–335. 33. Lamb HJ, Beyerbacht HP, van der Laarse A, et al: Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 1999;99:2261–2267. 34. Regan TJ, Wu CF, Yeh CK, et al: Myocardial composition and function in diabetes. The eﬀects of chronic insulin use. Circ Res 1981;49:1268– 1277. 35. Frustaci A, Kajstura J, Chimenti C, et al: Myocardial cell death in human diabetes. Circ Res 2000;87:1123–1132. 36. Fiordaliso F, Leri A, Cesselli D, et al: Hyperglycemia activates p53 and p53regulated genes leading to myocyte cell death. Diabetes 2001;50: 2363–2375. 37. Lijnen PJ, Petrov VV, Fagard RH: Induction of cardiac ﬁbrosis by angiotensin II. Methods. Find Exp Clin Pharmacol 2000;22:709– 723. 38. Chen S, Evans T, Mukherjee K, et al: Diabetes-induced myocardial structural changes: Role of endothelin-1 and its receptors. J Mol Cell Cardiol 2000;32:1621–1629. 39. Kajstura J, Fiordaliso F, Andreoli AM, et al: IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II–mediated oxidative stress. Diabetes 2001;50:1414–1424. 40. Lee AA, Dillmann WH, McCulloch AD, et al: Angiotensin II stimulates the autocrine production of transforming growth factor-β1 in adult rat cardiac ﬁbroblasts. J Mol Cell Cardiol 1995;27:2347–2357. 41. Das AK, Das JP, Chandrasekar S: Speciﬁc heart muscle disease in diabetes mellitus—functional structural correlation. Int J Cardiol 1997;17: 299–302. 42. Zoneraich S: Small-vessel disease, coronary artery vasodilator reserve, and diabetic cardiomyopathy. Chest 1988;94:5–7. 43. Miric G, Dallemagne C, Endre Z, et al: Reversal of cardiac and renal ﬁbrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol 2001;133:687–694. 44. Fischer VW, Barner HB, Leskiw ML: Capillary basal laminar thickness in diabetic human myocardium. Diabetes 1979;28:713–719.

Chapter 26 • Diabetes Mellitus 45. Warley A, Powell JM, Skepper JN: Capillary surface area is reduced and tissue thickness from capillaries to myocytes is increased in the left ventricle of streptozotocin-diabetic rats. Diabetologia 1995;38:413–421. 46. Kawaguchi M, Techigawara M, Ishihata T, et al: A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels 1997;12:267–274. 47. Blumenthal HT, Alex M, Goldenberg S: A study of lesions of the intramural coronary branches in diabetes mellitus. Arch Pathol 1960;70:27–42. 48. Strauer BE, Motz W, Vogt M, et al: Impaired coronary ﬂow reserve in NIDDM: A possible role for diabetic cardiopathy in humans. Diabetes 1997;46(Suppl 2):S119–S124. 49. Durante W, Sunahara FA, Sen AK: Eﬀect of diabetes on metabolic coronary dilatation in the rat. Cardiovasc Res 1989;23:40–45. 50. Yokoyama I, Ohtake T, Momomura S, et al: Hyperglycemia rather than insulin resistance is related to reduced coronary ﬂow reserve in NIDDM. Diabetes 1998;47:119–124. 51. Meyer C, Schwaiger M: Myocardial blood ﬂow and glucose metabolism in diabetes mellitus. Am J Cardiol 1997;80:94A–101A 52. Nitenberg A, Valensi P, Sachs R, et al: Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes 1993;42:1017–1025. 53. Johnstone MT, Creager SJ, Scales KM, et al: Impaired endotheliumdependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510–2516. 54. Joﬀe II, Travers KE, Perreault-Micale CL, et al: Abnormal cardiac function in the streptozotocin-induced non-insulin-dependent diabetic rat: Noninvasive assessment with Doppler echocardiography and contribution of the nitric oxide pathway. J Am Coll Cardiol 1999;34:2111–2119. 55. Pieper GM, Langenstroer P, Gross GJ: Hydroxyl radicals mediate injury to endothelium-dependent relaxation in diabetic rat. Mol Cell Biochem 1993;122:139–145. 56. Hattori Y, Kawasaki H, Abe K, et al: Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol 1991;261:H1086–H1094. 57. Rosen P, Ballhausen T, Bloch W, et al: Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: Inﬂuence of tocopherol as antioxidant. Diabetologia 1995;38:1157–1168. 58. Bucala R, Tracey KJ, Cerami A: Advanced glycosylation products quench nitric oxide and mediate defective endothelium dependent vasodilatation in experimental diabetes. J Clin Invest 1991;87:432–438. 59. Tesfamariam B, Jakubowski JA, Cohen RA: Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2. Am J Physiol 1989;257: H1327–H1333. 60. Tesfamariam B, Brown ML, Cohen RA: Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest 1991;87:1643–1648. 61. Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 1988;47:859–866. 62. Miyanaga H, Yoneyama S, Kamitani T: Clinical usefulness of 123Imetaiodobenzylguanidine myocardial scintigraphy in diabetic patients with cardiac sympathetic nerve dysfunction. Jpn Circ J 1995;59:599– 607. 63. Allman KC, Stevens MJ, Wieland DM, et al: Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol 1993;22:1425–1432. 64. Schnell O, Muhr D, Weiss M, et al: Reduced myocardial 123Imetaiodobenzylguanidine uptake in newly diagnosed IDDM patients. Diabetes 1996;45:801–805. 65. Schnell O, Kirsch CM, Stemplinger J, et al: Scintigraphic evidence for cardiac sympathetic dysinnervation in long-term IDDM patients with and without ECG-based autonomic neuropathy. Diabetologia 1995;38: 1345–1352. 66. Turpeinen AK, Vanninen E, Kuikka JT, et al: Demonstration of regional sympathetic denervation of the heart in diabetes. Comparison between patients with NIDDM and IDDM. Diabetes Care 1996;19:1083– 1090. 67. Stevens MJ, Raﬀel DM, Allman KC, et al: Cardiac sympathetic dysinnervation in diabetes: Implications for enhanced cardiovascular risk. Circulation 1998;98:961–968. 68. Stevens MJ, Dayanikli F, Raﬀel DM, et al: Scintigraphic assessment of regionalized defects in myocardial sympathetic innervation and blood ﬂow regulation in diabetic patients with autonomic neuropathy. J Am Coll Cardiol 1998;31:1575–1584.

69. Taskiran M, Fritz-Hansen T, Rasmussen V, et al: Decreased myocardial perfusion reserve in diabetic autonomic neuropathy. Diabetes 2002;51: 3306–3310. 70. Scognamiglio R, Avogaro A, Casara D, et al: Myocardial dysfunction and adrenergic cardiac innervation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 1998;31:404–412. 71. Rajan SK, Gokhale SM: Cardiovascular function in patients with insulindependent diabetes mellitus: A study using noninvasive methods. Ann NY Acad Sci. 2002;958:425–430. 72. Erbas T, Erbas B, Kabakci G, et al: Plasma big-endothelin levels, cardiac autonomic neuropathy, and cardiac functions in patients with insulindependent diabetes mellitus. Clin Cardiol 2002;23:259–263. 73. Kahn JK, Zola B, Juni JE, et al: Radionuclide assessment of left ventricular diastolic ﬁlling in diabetes mellitus with and without cardiac autonomic neuropathy. J Am Coll Cardiol 1986;7:1303–1309. 74. Kreiner G, Wolzt M, Fasching P, et al: Myocardial m-[123I] iodobenzylguanidine scintigraphy for the assessment of adrenergic cardiac innervation in patients with IDDM: Comparison with cardiovascular reﬂex tests and relationship to left ventricular function. Diabetes 1995;44:543–549. 75. Shulman GI: Cellular mechanisms of insulin resistance. J Clin Invest 2000;106:171–176. 76. Holmäng A, Yoshida N, Jennische E, et al: The eﬀects of hyperinsulinaemia on myocardial mass, blood pressure regulation and central haemodynamics in rats. Eur J Clin Invest 1996;26:973–978. 77. DeFronzo RA, Cooke CR, Andres R, et al: The eﬀect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest 1975;55:845–855. 78. Anderson EA, Hoﬀman RP, Balon TW, et al: Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991;87:2246–2252. 79. Gaboury CL, Simonson DC, Seely EW, et al: Relation of pressor responsiveness to angiotensin II and insulin resistance in hypertension. J Clin Invest 1994;94:2295–2300. 80. Sartori M, Ceolotto G, Papparella I, et al: Eﬀects of angiotensin II and insulin on ERK1/2 activation in ﬁbroblasts from hypertensive patients. Am J Hypertens 2004;17:604–610. 81. Ingelsson E, Sundstrom J, Arnlov J, et al: Insulin resistance and risk of congestive heart failure. JAMA 2005;294:334–341. 82. Chobanian AV, Bakris GL, Black HR, et al: National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003;289:2560–2572. 83. van Hoeven KH, Factor SM: A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation 1990;82:848–855. 84. Taegtmeyer H, McNulty P, Young ME: Adaptation and maladaptation of the heart in diabetes: Part I: General concepts. Circulation 2002;105: 1727–1733. 85. Coughlin SS, Pearle DL, Baughman KL, et al: Diabetes mellitus and the risk of idiopathic dilated cardiomyopathy. The Washington DC Dilated Cardiomyopathy Study. Ann Epidemiol 1994;4:67–74. 86. Liu JE, Palmieri V, Roman MJ, et al: The impact of diabetes on left ventricular ﬁlling pattern in normotensive and hypertensive adults: The Strong Heart Study. J Am Coll Cardiol 2001;37:1943–1949. 87. Takahashi N, Iwasaka T, Suigura T, et al: Left ventricular regional function after acute myocardial infarction in diabetic patients. Diabetes Care 1989;12:630–635. 88. Iwasaka T, Takahashi N, Nakamura S, et al: Residual left ventricular pump function after acute myocardial infarction in diabetic patients. Diabetes Care 1992;15:1522–1526. 89. Nahser PJ Jr, Brown RE, Oskarsson H, et al: Maximal coronary ﬂow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 1995;91:635–640. 90. Solomon SD, St John Sutton M, Lamas GA, et al: Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction. Circulation 2002;106:1251–1255. 91. Piccini JP, Klein L, Gheorghiade M, Bonow RO. New insights into diastolic heart failure: Role of diabetes mellitus. Am J Med 2004;116 Suppl 5A:64S–75S 92. Raev DC: Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care 1994;17:633–639.

341

342

Chapter 26 • Diabetes Mellitus 93. Redﬁeld MM, Jacobsen SJ, Burnett JC Jr, et al: Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 94. Zabalgoitia M, Ismaeil MF, Anderson L, et al: Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus. Am J Cardiol 2001;87:320–323. 95. Bertoni AG, Goﬀ DC Jr, D’Agostino RB Jr, et al: Diabetic cardiomyopathy and subclinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 2006;29:588–594. 96. Poirier P, Bogaty P, Garneau C, et al: Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: Importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 2001;24:5–10. 97. Liu JE, Robbins DC, Palmieri V, et al: Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes. The Strong Heart Study. J Am Coll Cardiol 2003;41:2022–2028. 98. Albanna II, Eichelberger SM, Khoury PR, et al: Diastolic dysfunction in young patients with insulin-dependent diabetes mellitus as determined by automated border detection. J Am Soc Echocardiogr 1998;11:349– 355. 99. Asbun J, Villarreal FJ: The pathogenesis of myocardial ﬁbrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 2006;47:693–700. 100. Perez JE, McGill JB, Santiago JV, et al: Abnormal myocardial acoustic properties in diabetic patients and their correlation with the severity of disease. J Am Coll Cardiol 1992;19:1154–1162. 101. Annonu AK, Fattah AA, Mokhtar MS, et al: Left ventricular systolic and diastolic functional abnormalities in asymptomatic patients with noninsulin-dependent diabetes mellitus. J Am Soc Echocardiogr 2001;14: 885–891. 102. Watschinger B, Brunner C, Wagner A, et al: Left ventricular diastolic impairment in type 1 diabetic patients with microalbuminuria. Nephron 1993;63:145–151. 103. Guglielmi MD, Pierdomenico SD, Salvatore L, et al: Impaired left ventricular diastolic function and vascular post-ischemic vasodilation associated with microalbuminuria in IDDM patients. Diabetes Care 1995;18: 353–360. 104. Sato A, Tarnow L, Parving HH: Increased left ventricular mass in normotensive type 1 diabetic patients with diabetic nephropathy. Diabetes Care 1998;21:1534–1539. 105. Monteagudo PT, Moises VA, Kohlmann O Jr, et al: Inﬂuence of autonomic neuropathy upon left ventricular dysfunction in insulin-dependent diabetic patients. Clin Cardiol 2000;23:371–375. 106. Willenheimer RB, Erhardt LR, Nilsson H, et al: Parasympathetic neuropathy associated with left ventricular diastolic dysfunction in patients with insulin-dependent diabetes mellitus. Scand Cardiovasc J 1998;32: 17–22. 107. Irace L, Iarussi D, Guadagno I, et al: Left ventricular performance and autonomic dysfunction in patients with long-term insulin-dependent diabetes mellitus. Acta Diabetol 1996;33:269–273. 108. Raev DC: Left ventricular function and speciﬁc diabetic complications in other target organs in young insulin-dependent diabetics: An echocardiographic study. Heart Vessels 1994:9:121–128. 109. Uusitupa M, Siitonen O, Aro A, et al: Eﬀect of correction of hyperglycemia on left ventricular function in non-insulin-dependent (type 2) diabetics. Acta Med Scand 1983;213:363–368. 110. Fiorina P, La Rocca E, Astorri E, et al: Reversal of left ventricular diastolic dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic patients. Diabetes Care 2000;23:1804–1810. 111. Vanninen E, Mustonen J, Vainio P, et al: Left ventricular function and dimensions in newly diagnosed non-insulin-dependent diabetes mellitus. Am J Cardiol 1992;70:371–378. 112. Celentano A, Vaccaro O, Tammaro P, et al: Early abnormalities of cardiac function in non-insulin-dependent diabetes mellitus and impaired glucose tolerance. Am J Cardiol 1995;76:1173–1176.

113. Holzmann M, Olsson A, Johansson J, et al: Left ventricular diastolic function is related to glucose in a middle-aged population. J Intern Med 2002;251:415–420. 114. Ahmed A, Rich MW, Fleg JL, et al: Eﬀects of digoxin on morbidity and mortality in diastolic heart failure. The Ancillary Digitalis Investigation Group Trial. Circulation 2006;114:397–403. 115. Hunt SA, Abraham WT, Chin MH, et al: American College of Cardiology, American Heart Association Task Force on Practice Guidelines, American College of Chest Physicians, International Society for Heart and Lung Transplantation, Heart Rhythm Society ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;112: e154–e235. 116. Yusuf S, Ostergren JB, Gerstein HC, et al: Candesartan in Heart Failure– Assessment of Reduction in Mortality and Morbidity Program Investigators: Eﬀects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation 2005;112: 48–53. 117. Cleland JGF, Tendera M, Adamus J, et al: The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study. Eur Heart J 2006;27: 2338–2345. 118. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment. Circulation 2002;105:1503–1508. 119. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular ﬁlling after one year of antihypertensive treatment: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071–1076. 120. Shekelle PG, Rich MW, Morton SC, et al: Eﬃcacy of angiotensinconverting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: A meta-analysis of major clinical trials. J Am Coll Cardiol 2003;41: 1529–1538. 121. Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Eﬃcacy and Survival Study Investigators: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309– 1321. 122. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355: 251–259. 123. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355:260– 269. 124. Carson P, Massie BM, McKelvie R, et al, for the I-PRESERVE investigators: The Irbesartan in Heart Failure with Preserved Systolic Function trial: Rationale and design. J Cardiac Fail 2005;11:576–585. 125. Hori M, Kitabatake A, Tsutsui H, et al: The J-DHF Program Committee rationale and design of a randomized trial to assess the eﬀects of betablocker in diastolic heart failure: Japanese Diastolic Heart Failure Study ( J-DHF). J Card Fail 2005;11:542–547. 126. Little WC, Zile MR, Kitzman DW, et al: The eﬀect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191–195. 127. Essop MF, Opie LH: Metabolic therapy for heart failure. Eur Heart J 2004;25:1765–1768. 128. Nikolaidis LA, Levine TB: Peroxisome proliferator activator receptors (PPAR), insulin resistance, and cardiomyopathy: Friends or foes for the diabetic patient with heart failure? Cardiol Rev 2004;12:158–170.

RICHARD W. TROUGHTON, MB, ChB, PhD JAY RITZEMA-CARTER, BM M. GARY NICHOLLS, MB, ChB

27

Role of Neurohormones INTRODUCTION PATHOPHYSIOLOGY Neurohormonal Regulation of the Circulation: Normal Versus Heart Failure Neurohormones and the Transition from Hypertrophy to Heart Failure Neurohormonal Factors Contributing to Heart Failure Pathophysiology Pattern of Neurohormonal Activation in Heart Failure with Normal Left Ventricular Ejection Fraction CLINICAL RELEVANCE Neurohormones as Treatment Targets for Hypertension and Diastolic Heart Failure Natriuretic Peptides and Screening for Cardiac Dysfunction Diagnosis of Acute Heart Failure

Assessment of Prognosis Prediction of Heart Failure Events after Myocardial Infarction Monitoring Heart Failure and Optimizing Therapy Exogenous Administration of B-Type Natriuretic Peptide Differentiation of Constrictive Pericarditis from Restrictive Cardiomyopathy Cardiac Amyloid Chronic Renal Failure Valvular Heart Disease Hypertrophic Cardiomyopathy Hypertensive Subjects SUMMARY FUTURE RESEARCH

INTRODUCTION The critical role of neurohormonal factors in regulating circulation and volume status has been known for over a century. The importance of neurohormonal activation in heart failure pathophysiology was identiﬁed in the middle and latter part of the 20th century and formed the basis for the neurohormonal model of heart failure.1,2 Major contributions to this understanding came from observational data in large, well-characterized populations, often participating in studies of systolic heart failure treatments.2,3 In these studies, plasma levels of vasoactive hormones involved in regulation of circulation and renal function—such as vasopressin, renin, angiotensin II (A-II), aldosterone, the cardiac natriuretic peptides, and norepinephrine (NE)—were not only shown to be signiﬁcantly elevated compared with normal controls, but also clearly provided prognostic information.2–5 These seminal observations have since been conﬁrmed by multiple studies in a variety of settings.6–8 Early attention was focused on the pathophysiological roles of the sympathetic nervous system (SNS), the reninangiotensin system (RAS), and aldosterone.2,3,9 A large body of evidence, much of it emanating from studies using targeted blockade of neurohormones, attests to the pivotal role of these systems in established heart failure.2,3,9–15 The role of more recently discovered systems such as those involving cardiac natriuretic pep-

tides, endothelin (ET), and adrenomedullin (AM) has now become a major focus of study.16–18 The discovery of these and additional neurohormonal systems and clariﬁcation of their roles in heart failure has opened up exciting new opportunities to better deﬁne the pathophysiology of heart failure and to develop new therapies.19–23 The importance of the neurohormonal model of heart failure cannot be understated when considering the recent advances in heart failure treatment. Awareness that activation of the RAS, aldosterone, and the SNS leads to vasoconstriction, sodium retention, and adverse eﬀects on cardiac and vascular remodeling, thereby contributing to morbidity and mortality in systolic heart failure, has led to the development of successful therapies through blockade of these systems.10–15,24 Whether blockade of additional neurohormonal systems can be tolerated and oﬀers additional beneﬁt is unclear but remains the focus of several current studies.25–28 Likewise, it remains to be seen whether administration of vasodilator hormones such as the natriuretic peptides, urocortin, and AM or synthetic compounds acting as agonists on their speciﬁc receptors produce beneﬁcial eﬀects on cardiovascular and renal functions.20,29,30 In the case of B-type natriuretic peptide (BNP), this has led to a potential therapeutic application,31 an option that might also be possible for other peptides. 345

346

Chapter 27 • Role of Neurohormones Recent interest has focused on the potential role of neurohormones as markers of cardiac dysfunction and heart failure. In particular, BNP has been validated as a diagnostic marker for heart failure,32–35 and its role in monitoring and guiding therapy is being studied actively.36–38 A signiﬁcant limitation of the current understanding of neurohormonal factors in heart failure is that there is relatively scant data describing the pattern and role of neurohormonal activation for patients in whom left ventricular ejection fraction (LVEF) is preserved.39,40 The available neurohormonal model of heart failure is based largely on observations from patients with systolic heart failure or in whom left ventricular (LV) function was not well described. Based on the known diﬀerences in the epidemiology of heart failure with preserved versus impaired systolic function,41–44 it is likely that neurohormonal proﬁles will also diﬀer. Available data suggest that this is indeed the case.39,40 A greater understanding of neurohormonal proﬁles can potentially lead to new and more eﬀective therapy for heart failure in the setting of preserved LVEF.

PATHOPHYSIOLOGY Neurohormonal Regulation of the Circulation: Normal Versus Heart Failure Under normal conditions, tightly counterbalanced neurohormonal systems provide dynamic regulation of the circulation and of volume status.45 These ﬁnely tuned systems respond with various time frames to perturbations in body posture and volume status— for example, to maintain optimal perfusion of vital organs. On the one hand, arginine vasopressin (AVP), the SNS, and the RAS respond rapidly to stimuli such as falls in arterial pressure, reduced delivery of chloride and sodium to the macular densa, and altered plasma osmolality to maintain homeostasis by increasing vascular tone and inducing renal retention of sodium and water.45 In contrast, increased cardiac or vascular wall stress stimulates secretion of natriuretic peptides, AM, urocortin, and other endotheliumderived peptides that produce vasodilatation and promote diuresis.17,20,46 Within this complex counterpoised system, there are multiple levels of feedback and control. Vasoconstrictor systems can respond rapidly through near instantaneous changes in sympathetic outﬂow or rather more gradually through the reninangiotensin pathway and aldosterone.47 Equally, release of stored atrial natriuretic peptide (ANP) from granules in the atria allows rapid vasodilator and natriuretic responses,48 whereas more gradual eﬀects occur through changes in constitutive BNP synthesis.49 Multiple feedback interactions between vasodilator and vasoconstrictor systems at several levels modulate the overall balance. For example, A-II attenuates the natriuretic eﬀect of BNP while simultaneously contributing to activation of ANP and BNP synthesis through increased wall stress in cardiac myocytes.50 In contrast, the natriuretic peptides inhibit renin release and the aldosterone-stimulating actions of A-II.51,52 In established heart failure, the normal balance of neurohormonal regulation is disturbed (Fig. 27-1). Marked activation of both vasodilator and vasoconstrictor systems is seen.47 A key mechanism in this activation appears to be perceived end-organ hypoperfusion and a reduced ability of the heart to maintain adequate arterial ﬁlling and cardiac output.8,45,53 Such activation can be detected as an increase in circulating plasma neurohormone levels, but it occurs ﬁrst at the tissue level through upregu-

NYHA

Cardiac Natriruetic Peptides Adrenomedullin Prostaglandins Nitric oxide Bradykinin IV

Increasing severity of heart failure (NYHA I-IV)

NYHA I

NYHA I Vasodilator Natriuretic/diuretic Anti-mitotic Anti-hypertrophic

NYHA IV

Sympathetic system RA system Vasoconstrictor Aldosterone Anti-natriuretic Endothelin Mitotic TNF Hypertrophic

Figure 27-1 Heart failure is characterized by an imbalance in the neurohormonal factors that regulate the circulation and volume status. Vasoconstrictor systems overpower vasodilator systems, leading to sodium retention and cardiovascular remodeling.

lated gene expression in response to various stimuli, including cardiac injury, reduced organ or tissue perfusion, and ﬂuid overload.21,50,54,55 Neurohormonal activation may precede the onset of frank clinical heart failure and is a feature of asymptomatic LV dysfunction.56,57 A deﬁning characteristic of the neurohormonal response to cardiac injury or heart failure is the predominance of vasoconstrictor over vasodilator systems. This loss of counterpoise leads to attenuation of the beneﬁcial eﬀects of vasodilator systems and contributes to or mediates many of the major adverse pathophysiological changes in heart failure, including progressive renal dysfunction and LV remodeling.58–64

Neurohormones and the Transition from Hypertrophy to Heart Failure Adverse cardiac remodeling characterized by myocyte hypertrophy and interstitial or perimysial ﬁbrosis are hallmarks of heart failure with preserved ejection fraction (EF).65–67 While hemodynamic loading such as in hypertension or valvular disease is a critical stimulus for adverse remodeling, neurohormonal factors appear to be key mediators of cardiac and vascular remodeling processes that lead to heart failure.68–70 Increased myocardial levels of A-II, ET, and aldosterone have been demonstrated in models of hypertensive heart disease.55,71 Each has been linked to the development of ﬁbrosis, cardiomyocyte hypertrophy, ventricular remodeling, and progression to the heart failure phenotype.55,69,72–74 Increased levels of these and other hormones, including NE, can be directly toxic to the myocardium.75 Experimentally, blockade of these hormones attenuates the development of hypertrophy and ﬁbrosis while delaying the onset of heart failure.76–78 In contrast, other hormones, such as AM and the cardiac natriuretic peptides, are also activated in hypertension and heart failure but appear to attenuate adverse remodeling.79–81

Neurohormonal Factors Contributing to Heart Failure Pathophysiology Sympathetic Nervous System The SNS is a crucial regulator of arterial pressure and vital organ perfusion during the myriad of daily activities such as exercise, eating, and changing body posture.47 In heart failure, the SNS is

Chapter 27 • Role of Neurohormones activated at an early stage82 in response to reduced carotid and aortic baroreceptor sensitivity and altered arterial compliance.83 Changes in SNS activity in heart failure produce a dramatic reduction in regional blood ﬂow to the skin, gut, and kidney while maintaining vital ﬂow to coronary, cerebral, and skeletal muscle circulations.47 The SNS also contributes to the pathophysiology of heart failure through its stimulation of renin release.84 Increased sympathetic activation in heart failure can be documented by elevated plasma or urinary catecholamines; by increased NE spillover from the heart, kidney, brain, and skeletal muscle; or by increased common peroneal nerve sympathetic nerve traﬃc from microneurographic recordings. However it is documented, this activation correlates with the severity of LV dysfunction and predicts survival.2,82,85 While increased SNS activity in established systolic heart failure acts to maintain blood ﬂow to vital organs, long-term and intense overactivation can have harmful eﬀects through direct toxicity to myocardium, an adverse increase in LV afterloading (as a consequence of peripheral vasoconstriction), and LV hypertrophy (LVH) and subsequent dilatation.75 The pathophysiological importance of SNS activation and the beneﬁt of β-adrenergic receptor blockade in systolic heart failure is clearly established.14,15,86 SNS activation is generally considered to be also important in primary (essential) hypertension87–90 and reﬂects increased sympathetic neuronal ﬁring and decreased NE uptake.88 SNS activation is further augmented in hypertensive patients with heart failure, possibly through impaired baroreceptor function.91 There are, however, limited data regarding the degree of SNS activation in heart failure with preserved LVEF. Nevertheless, plasma NE levels do appear to rise in diastolic heart failure, but not to the extent seen in systolic heart failure.39,40 In animal models, the SNS appears to have a signiﬁcant role in the development of LVH, LV remodeling, and heart failure due to pressure overload. Dopamine beta-hydroxylase knockout mice do not develop LVH during aortic banding, suggesting an important requirement for the SNS in activation of signaling pathways and the development of hypertrophy and heart failure, at least in this model.92 Modulation of sympathetic activity may be one important mechanism of eﬀective antihypertensive therapy and prevention of heart failure. Therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers, both of which reverse LVH and reduce heart failure events in high-risk or hypertensive subjects, also suppresses cardiac eﬀerent sympathetic activity.93.94 The role of β-adrenergic receptor blockade as ﬁrst-line therapy for hypertension has, however, been questioned recently.95 First-line treatment with the alpha-adrenergic blocker doxazosin was reportedly associated with increased heart failure events compared with treatment with chlorthalidone, lisinopril, or amlodipine,96 although the accuracy of the diagnosis of heart failure has been questioned. Whereas the therapeutic eﬃcacy of selected β-adrenergic receptor blockers in patients with all grades of systolic heart failure is not in question, the place of these drugs in the treatment of established diastolic heart failure remains unclear. Treatment with carvedilol has been shown to have beneﬁcial eﬀects on LV diastolic function in the setting of heart failure with preserved EF,97,98 but the eﬀect on clinical outcomes is also uncertain.

Renin-Angiotensin System Secretion of renin from renal juxtaglomerular cells increases in response to many stimuli, including increased SNS activity, low

systemic and renal arterial perfusion pressure (renal baroreceptor mechanism), and reduced delivery of chloride and sodium to the distal renal tubule (macula densa mechanism).47 Vasopressin, prostaglandins, nitric oxide levels, the natriuretic peptides, AM, and A-II—by negative feedback—all modulate renin secretion.47 Circulating renin acts on angiotensinogen to produce angiotensin I, which is converted to A-II by ACE. A-II generated through non-ACE pathways, including tissue and serum proteases (chymases), may contribute to increased tissue and circulating A-II and return of plasma aldosterone to baseline, pre-ACE inhibitor treatment levels.99 The major pathophysiological actions of A-II are mediated via A-II type 1 receptors (AT1R).99 A potent vasoconstrictor, A-II also stimulates aldosterone secretion and AVP release and thirst, augments SNS activity, and antagonizes the actions of the natriuretic peptides.47 A-II has critical eﬀects on renal function and, experimentally, stimulates hypertrophy of vascular smooth muscle cells (VSMCs) and cardiomyocytes, thereby contributing to vascular as well as cardiac remodeling.99 The pivotal role of the RAS in systolic heart failure and the beneﬁcial eﬀect of either ACE inhibition or AT1R blockade is well established.100–102 A large body of basic science and clinical research implicates the RAS in the pathophysiology of heart failure with normal systolic function.69,72–74,103,104 In animal models and cell culture studies, A-II has been shown to stimulate stretch-induced cardiomyocyte hypertrophy105 and promote ﬁbrosis through increased collagen deposition and impaired metalloproteinase function. AII also augments diastolic wall stress during volume overload, leading to increased expression of fetal genes associated with remodeling.50 Furthermore, A-II stimulates increases in intracellular calcium levels, which may contribute to abnormal diastolic function and wall stress. A-II also increases activity of nicotinamide adenine dinucleotide phosphate oxidase (NADPH), causing superoxide production that may trigger vascular nitric oxide synthase uncoupling, leading to impaired nitric oxide signaling, endothelial dysfunction, and vascular remodeling.106,107 Evidence from animal models points to a contributory role for A-II in hypertensive heart failure. Dahl salt-sensitive rats fed a high salt diet developed hypertension and subsequent hypertensive cardiomyopathy and heart failure by age 19 weeks.72 In this model, expression of A-II mRNA increases more than fourfold at the onset of heart failure. Administration of low-dose AT1R blocker at subvasodepressor levels prevents the onset of heart failure in this model, suggesting an important eﬀect of A-II that is independent of arterial pressure.72 In the same model, AT1R blockade expression was upregulated despite increased A-II expression, suggesting abnormal receptor/agonist balance.108 Further evidence for A-II causing hypertrophy and subsequent heart failure comes from a transgenic mouse model of localized excess angiotensinogen production.74,103 In this model, excess localized cardiomyocyte A-II levels are associated with myocyte and ventricular hypertrophy even in the absence of increased arterial pressure. Hypertrophy is reversed with eﬀective blockade of A-II production by ACE inhibition or by AT1R blockade at hemodynamically neutral doses.74,103 Studies of hypertension in humans indicate a pivotal role for the RAS. In particular, treatment of hypertension with ACE inhibitors or AT1R blockers is associated with greater reductions in LVH than are seen with beta blockers and calcium channel blockers, achieving similar blood pressure lowering.109 In LVH secondary to aortic stenosis, intracoronary administration of the ACE inhibitor enalaprilat, at a level that did not

347

348

Chapter 27 • Role of Neurohormones alter measured ACE activity or plasma levels of renin and ANP, produced decreases in LV end diastolic pressure accompanied by improvements in diastolic distensibility and isovolumic relaxation, suggesting that the actions of intracardiac A-II contribute to abnormal diastolic wall stress and ﬁlling patterns in LVH.110 Treatment with AT1R blockade or ACE inhibition has been shown to reduce ﬁbrosis and indices of cardiac stiﬀness and diastolic dysfunction in subjects with hypertension.111–113 Importantly, ACE inhibition or AT1R blockade in high-risk subjects or after myocardial infarction has been shown to reduce cardiovascular events, including heart failure.114,115 The largest randomized treatment study in heart failure with preserved systolic function demonstrated that AT1R blockade with candesartan reduced heart failure hospitalization.24

Aldosterone Aldosterone secretion from the zona glomerulosa of the adrenal cortex is stimulated by a range of secretagogues, of which A-II is the most potent, although potassium and adrenocorticotropic hormone (ACTH) (which augment aldosterone production) and the cardiac natriuretic peptides (which are inhibitory) may be important in heart failure.116 ACE inhibitors may initially reduce aldosterone formation, but levels often rise later,117 possibly reﬂecting incomplete ACE inhibition, non-ACE-generated A-II, and the action of other aldosterone secretagogues.118 Aldosterone has an important role in established systolic heart failure.116 Early studies in patients with heart failure demonstrated that aldosterone levels were often (though not invariably) elevated; but perhaps more importantly, the kidney failed to “escape” from the antinatriuretic actions of aldosterone.119 Furthermore, the kidney in heart failure is more sensitive than normal to the sodium-retaining action of aldosterone.119,120 There is evidence for an equally important role for aldosterone in mediating the cardiac and vascular remodeling that occurs as hypertension progresses to heart failure.73,121 Local synthesis of aldosterone and expression of mineralocorticoid receptors (MCRs) have been demonstrated within the cardiac interstitium and cardiomyocytes, although there is dispute regarding the capability of the heart to secrete aldosterone.122 Whether of adrenal origin or secreted within the heart, aldosterone appears to increase collagen deposition and ﬁbrosis and cause hypertrophy of cardiomyocytes.121 Recent cohort studies demonstrate correlations between plasma aldosterone levels and the degree of concentric LVH,123,124 particularly in women.124 The relationship of aldosterone to LVH may be independent of hemodynamic loading, indicating speciﬁc eﬀects on cardiomyocyte hypertrophy and interstitial ﬁbrosis.73 Aldosterone may also impair arterial compliance, an index of vascular remodeling in hypertensive heart failure.125,126 Speciﬁc aldosterone blockade appears to reduce collagen formation and ﬁbrosis.76,78,127 More recently, aldosterone blockade was shown to improve myocardial function in hypertensive patients with heart failure symptoms and echocardiographic evidence of LVH with diastolic dysfunction.128 Compared with placebo, 6 months of treatment with spironolactone resulted in signiﬁcant improvements in longitudinal systolic LV strain and strain rate, a decrease in left atrial (LA) area, and improvements in conventional Doppler estimates of LV stiﬀness and end diastolic pressure. There was also a signiﬁcant improvement in arterial compliance with spironolactone. These eﬀects support the hypothesis that aldosterone contributes to adverse myocardial and vascular remodeling in hypertensive heart disease.

Arginine Vasopressin AVP secretion is mediated by multiple stimuli, including high plasma osmolality, low intracardiac and arterial pressure, circulating A-II, ANP, and adrenergic and other neurohormonal factors.45 AVP increases water uptake in the collecting ducts via vasopressin (V)2 receptors and produces vasoconstriction and impaired cardiac contractility via V1 receptors.129 Elevated plasma AVP levels are often seen in heart failure even when cardiac ﬁlling pressures are high, suggesting that carotid baroreceptor activation may outweigh inhibitory cardiac stretch reﬂexes.45 Experimentally, AVP receptor antagonists partially correct hyponatremia in this setting, suggesting that AVP along with the RAS and other systems play a mechanistic role in the hyponatremia of heart failure.47 AVP levels are often elevated in asymptomatic LV dysfunction.57 In addition, levels are elevated in heart failure when LVEF is preserved, suggesting an important pathophysiological role in this context.39 AVP has recently become a therapeutic target in heart failure.130 V2 blockade increases free water excretion without altering renal hemodynamics or function131 and appeared beneﬁcial in initial studies: Larger morbidity and mortality studies are under way.25,26 Given the elevation of AVP levels in heart failure with preserved LVEF, V2 blockade could potentially be a target for therapy in this context, but this possibility remains to be tested in this setting.

Endothelin-1 ET-1 is a potent vasoconstrictor peptide secreted mainly from vascular endothelial cells in response to falls in vascular shear stress and stimulation by neurohormones (NE, A-II, and AVP), tissue growth factor–β, and cytokines (such as tumor necrosis factor [TNF]–α).18,132 Nitric oxide, the natriuretic peptides, and prostacyclin inhibit ET-1 synthesis. ET-1 is synthesized also in cardiac myocytes, VSMCs, and renal tubular and glomerular mesangial cells.133 Pre-pro-ET is cleaved to form “big endothelin” (Big ET), which in turn is converted to vasoactive ET-1 by endothelin-converting enzyme.133 ET-1 acts via ET-A and ET-B receptors.134,135 Binding with ET-A increases mobilization of intracellular calcium to produce vasoconstriction and positive inotropy. ET-A receptors also mediate the hypertrophic action of ET-1 in VSMCs, cardiomyocytes, and glomerular mesangial cells via protein kinase C and mitogen-activated protein kinase.133 Plasma ET-1 levels are higher in venous than arterial blood, reﬂecting vascular secretion.133 Under normal conditions, ET-1 contributes to basal vascular tone and cardiac function through paracrine and autocrine actions. In heart failure, plasma ET levels rise in proportion to the severity of cardiac dysfunction136–139 and are powerful independent predictors of outcome.140,141 Myocardial ET-1 levels and ET-A receptor density also increase in heart failure,55,142,143 in which ET-1 initially increases cardiac contractility at the cost of impaired myocardial energy balance.133 Under experimental conditions, ET-1 induces vasoconstriction, hypertrophy of cardiac myocytes, and cellular injury through direct toxic eﬀects.133,142 Chronic activation of tissue and plasma ET-1 in experimental models is associated with cardiac and vascular remodeling and a decline in LV function.136 In contrast, myocardial ET-1 expression falls with unloading of the left ventricle.144 A number of studies implicate a synergistic interaction of ET-1 with A-II in the development of LVH and diastolic heart

Chapter 27 • Role of Neurohormones failure.55,71,72,145,146 Myocardial expression of A-II occurs prior to ET-1 in models of hypertensive heart failure and appears to stimulate myocardial ET-1 expression.55,72,145 ET-A receptor blockade attenuates the development of LVH and heart failure in hypertension models71,146 but is associated with augmented RAS activity.147 Unsurprisingly then, combined ET receptor blockade and ACE inhibition appears more eﬀective than either agent alone at reversing LVH in heart failure models.145 While a short-term ET-A or a combined ET-A/ET-B receptor blockade in systolic heart failure demonstrated beneﬁcial eﬀects on endothelial function and hemodynamics,148–150 results of mortality and morbidity studies with dual receptor blockade have been disappointing.151 The relative merit of selective ET-A blockade and whether earlier blockade of ET in hypertension can prevent LVH and diastolic heart failure is the focus of current research.

Tissue Necrosis Factor–Alpha TNF-α is a 76–amino-acid peptide secreted in response to a range of stimuli.152 TNF-α circulates in the blood (and is also present as a transmembrane form) and acts via speciﬁc receptors to induce pleomorphic eﬀects in many cells. TNF-α promotes the inﬂammatory response, stimulates growth factors, and is directly cytotoxic to endothelial cells. Plasma TNF-α levels are elevated and may have a pathophysiological role in malignancy, septic shock, rheumatoid arthritis, and transplant rejection.152 TNF-α appears to have a role in the pathophysiology of endstage heart failure, where plasma levels are elevated and correlate with symptomatic status.152 It has a direct eﬀect on cardiac muscle, including negative inotropism (through inhibition of calcium regulation in the cytoplasmic reticulum and inactivation of βadrenergic receptors), activation of matrix metalloproteases, and promotion of cardiomyocyte hypertrophy.152 Overexpression of TNF-α produces a dilated cardiomyopathy phenotype with heart failure and premature death.152 TNF-α may mediate these eﬀects through expression of fetal gene programs in cardiac myocytes, activation of pro-apoptotic pathways, and stimulation of other cytokines. Despite promising indications that expression of the cardiomyopathic phenotype could be attenuated by anticytokine strategies, subsequent studies in advanced heart failure have not demonstrated a clinical beneﬁt from TNF-α blockade.153–155

Cardiotrophin-1 Cardiotrophin (CT)-1 is a 201–amino-acid peptide from the interleukin (IL)-6 family of cytokines. It appears to have a key role in mediating myocyte hypertrophy.156 Absence of CT-1 leads to hypoplastic development of the heart, whereas increased CT-1 is associated with myocyte hypertrophy that can lead to eccentric LVH and chamber dilatation.156 CT-1 expression is induced by mechanical stretch and is augmented by sympathetic stimulation.157 Increased expression is also seen in hypoxia, indicating a potential protective and reparative role in myocardial ischemia.158 CT-1 expression increases in experimental heart failure and may precede BNP activation.21,22 Circulating CT-1 levels appear to rise in human heart failure in relation to the severity of LV dysfunction.159 Increased myocardial CT-1 expression is associated with downregulation of its major receptor, glycoprotein 130,160 but whether or not this contributes to impaired contractility is unclear.156 The role of CT-1 in diastolic heart failure is less clear. However in experimental models, transplantation of CT-1–expressing myoblasts into hyper-

tensive rat hearts attenuated the progression to heart failure, indicating a potential protective role.161

Adrenomedullin AM is a 52–amino-acid peptide from the calcitonin gene related peptide (CGRP) family that acts via calcitonin receptorlike receptors (CRLRs) modiﬁed by receptor activator modifying proteins (RAMPs) 2 and 3, with cAMP as second messenger.17,79,162,163 Secreted mainly from vascular endothelial and smooth muscle cells, mRNA and peptide immunoreactivity for AM and its receptors have been demonstrated in cardiac myocytes and ﬁbroblasts with increased expression in models of cardiac hypertrophy and heart failure.79 Recent data suggest that AM may have protective actions during development of hypertensive heart failure. Exogenous AM appears to reduce ﬁbrosis in vivo and in cultured cardiac ﬁbroblasts.17 AM also appears to speciﬁcally inhibit AII–stimulated hypertrophic responses and upregulation of ANP and BNP in cardiac myocytes.164 During development of hypertrophy in the salt-sensitive hypertensive rat model, myocardial expression and peptide levels of AM increased early, congruent with natriuretic peptide levels and before RAS activation occurred.79 Chronic administration of low-dose AM in this model signiﬁcantly lowered LV diastolic pressure, increased cardiac output, and lowered end systolic elastance. These eﬀects were accompanied by a signiﬁcant attenuation of RAS activation and prolongation of the time to onset of heart failure or death.163 In human subjects, plasma levels of AM increase in relation to the severity of heart failure.162,165 Short-term infusion in human hypertensive or heart failure subjects to achieve AM levels within the pathophysiological range signiﬁcantly lowered blood pressure and increased cardiac output and diuresis, while attenuating aldosterone secretion.30,166 These ﬁndings suggest that AM may have an important protective role in attenuating the progression to hypertrophy and heart failure. Whether augmentation of endogenous levels or exogenous treatment could be used therapeutically has not been evaluated.

Urocortin The urocortin (UCN) peptides 1, 2, and 3 belong to the corticotrophin-releasing factor (CRF) family that acts via CRF receptor subtypes with cAMP as second messenger.167,168 These peptides have multiple actions, including stress and inﬂammatory responses. Plasma levels are increased in human heart failure but have not been carefully examined in hypertension. Infusion studies in animal models and human subjects demonstrate that UCN-1 and UCN-2 have diﬀerential cardiovascular actions, with the latter causing more profound lowering of blood pressure and increased cardiac output associated with attenuation of RAS activation and maintenance of renal function.20,29,169 The role of UCN-1 and -2 in the development of cardiac hypertrophy and progression to heart failure has not been clearly elucidated.20,170

Cardiac Natriuretic Peptides The cardiac natriuretic peptides are a group of related hormones with structural homology and similar bioactivity.81,171 These peptides share a highly conserved ring structure that is responsible for bioactivity (Fig. 27-2).172 Each is secreted in a 1 : 1 ratio with the amino-terminal portion of its pro-hormone.49 Normally secreted in small amounts—giving picomolar levels in the

349

350

Chapter 27 • Role of Neurohormones ANP

BNP

CNP

H2N

H2N

Ser Pro Lys Ser Met Leu H2N Gly Val Arg Gln Leu Arg Lys Met Gly Arg Met Leu Lys Leu Arg Gly Ser Gly Gly Gly Asp Asp Asp Ser Lys Ser Phe Phe Phe Arg Arg Arg Ser Gly Gly Cys Cys Cys Ile Ile Ile

HOOC

Cys Gly Asn Gly Ala Ser Leu Gln Phe Gly Ser Arg Tyr HOOC

Cys Ser Lys Gly Ser Val Leu Ser Leu Gly Ser Arg Arg His

HOOC

Cys

Gly

Gly Leu Gly Ser

Ser Met

Figure 27-2 The natriuretic peptide family: atrial natriuretic peptide (ANP); B-type, or brain, natriuretic peptide (BNP); and C-type natriuretic peptide (CNP) share the same ring structure, which forms the basis for many of their shared physiological actions. Dark (filled) circles indicate amino acids common to all three human hormones. (Modified from Ruskoaho R: Endocrine Reviews 2003;24:341–356.)

circulation—synthesis increases with pressure and volume overload as fetal gene expression is reactivated.49 The ANP and BNP peptides are synthesized primarily by cardiac myocytes in response to mechanical stretch.16,48 Synthesis is regulated by multiple factors, including activity of other vasoactive hormones, such as A-II. Their major actions are mediated through natriuretic peptide receptor (NPR)–A, which is widespread, including in the vasculature and renal tubules.173 These peptides produce vasodilatation and natriuresis and also suppress thirst and inhibit RAS and aldosterone secretion, ﬁbrosis, and proliferative responses to cardiac or vascular injury.46 ANP and BNP are actively cleared by competitive uptake at NPR-C receptors or by cleavage of the ring structure by neutral endopeptidase, which is found in high density within the renal tubules.174 Plasma levels of atrial and B-type peptides are higher in women, increase with age and renal dysfunction, and fall with increasing body mass index (BMI).175 In contrast, C-type natriuretic peptide (CNP) is secreted primarily from vascular endothelial cells and acts predominantly as a vasodilator.176 Its metabolism and clearance are less well characterized.23 Although circulating levels of all the natriuretic peptides show relationships with indices of systolic and diastolic LV function and to LVH, the strongest correlations are seen in general for BNP.177 Atrial Natriuretic Peptide (ANP/NT-proANP) This peptide is secreted mainly from the cardiac atria and to a lesser extent from the ventricles. Increased wall stretch stimulates its release from storage granules while also augmenting its transcription and synthesis.178 ANP contributes to control of basal vascular tone and blood pressure. In ANP gene knockout mice, absence of ANP was associated with mildly elevated basal blood pressure compared with wild-type littermates.171 NPR-A receptor knockout mice also developed hypertension by a mechanism independent of salt intake.171 In healthy human volunteers, low-dose ANP and BNP infusions that produce plasma levels within the normal range induced vasodilatation, natriuresis, and inhibition of renin and aldosterone.179 Falls in blood pressure reﬂect a reduction in cardiac

preload and direct arterial vasodilatation.81 Long-term (4–5 day) infusions of low-dose ANP induce sustained falls in arterial pressure, peripheral vascular resistance, plasma volume, and central ﬁlling pressure, without activating the RAS, aldosterone, or SNS.179 Similar eﬀects have been seen during BNP infusion, although fewer studies have been performed.180 The cardiac peptides produce natriuresis and diuresis via renal glomerular and tubular actions.52 The natriuretic action of ANP and BNP is highly dependent on renal perfusion pressure.179 ANP increases glomerular ﬁltration rate by simultaneously dilating glomerular aﬀerent arterioles, constricting eﬀerent arterioles, and relaxing glomerular mesangial cells.181,182 It also blocks sodium reabsorption in the distal collecting ducts, antagonizes AVPmediated water uptake in collecting ducts, and inhibits A-II– mediated sodium and water uptake in proximal tubules.52 Administration of a competitive antagonist for the NPR-A receptor blocks the natriuretic action of the natriuretic peptides in normal and heart-failed animals.183 Under most circumstances, ANP and BNP inhibit the RAS, aldosterone, and SNS. Experimental administration of the NPR blocker HS142 produces an elevation in plasma levels of renin activity, aldosterone, and catecholamines.179 Conversely, low-dose infusion of ANP to produce physiological or mildly elevated plasma levels results in suppression of aldosterone secretion and reduced renin and SNS activity.179 ANP (and BNP) inhibits renin release from the juxtaglomerular apparatus and reduces peripheral sympathetic tone through eﬀects on baroreceptors, suppression of catecholamine release from autonomic nerve endings, and inhibition of central sympathetic outﬂow.179 C-type Natriuretic Peptide (CNP/NT-CNP) Produced mainly from vascular endothelial cells,176 CNP is synthesized as a precursor and cleaved into a biologically active carboxy-terminal peptide, CNP, and an apparently inactive amino-terminal peptide, NT-proCNP. In normal humans, circulating levels of CNP are very low and at the limits of detection measurement by immunoassays. The greater size and presumed longer plasma half-life of NT-proCNP may allow more accurate measurement and a more reliable indication of CNP production.

Chapter 27 • Role of Neurohormones Contradictory reports have suggested the presence or absence of elevated plasma CNP concentrations in congestive heart failure.184 In one large cohort, NT-proCNP levels were clearly shown to be elevated in heart failure.23 Levels of NT-proCNP are independently related to gender, age, and LV systolic function. Levels rise with age, are higher in men than women, and are inversely related to creatinine clearance. Plasma NT-proCNP also appears to identify heart failure with modest incremental diagnostic value over NT-proBNP and independent of age, gender, and renal function.23 Although CNP is reportedly a potent venodilator,171 it has little eﬀect on arterial pressure when infused intravenously into healthy volunteers.176 Its actions in heart failure and hypertension are not yet clearly deﬁned.

2200 2000 1800 1600 1400 1200 1000 800 600 400 200 0 –200

r 2 = 0.325, P < 0.001 BNP (pg/ml)

BNP (pg/ml)

B-Type Natriuretic Peptides BNPs/NT-proBNPs are synthesized and secreted mainly from LV cardiomyocytes. The primary stimulus is mechanical stretch due to increased wall stress. Diastolic wall stress appears to be the most important stimulus (Fig. 27-3),185 which in part explains higher levels in systolic dysfunction where end diastolic volumes are larger.16,54,185,186 Signiﬁcant atrial and right ventricular (RV) contributions to total BNP/NT-proBNP secretion are seen in advanced heart failure.187,188 Cleavage of the precursor peptide (proBNP, amino acids 1–108) produces the 32–amino-acid BNP (77–108) and its corresponding aminoterminal component, NT-proBNP (1–76), which are secreted in 1 : 1 ratio.16,189 Plasma levels of these peptides correlate strongly with each other.34,190 BNP is bioactive and has a shorter half-life due to active clearance, hence levels are lower than for the more stable NT-proBNP by a factor of 5–10-fold.34 Levels of both peptides increase in parallel with LV pressure or volume loading16,191 and reﬂect the severity of LV dysfunction, correlating inversely with LVEF and positively with increasing LV mass,

0

0

r 2 = 0.277, P < 0.001

BNP (pg/ml)

BNP (pg/ml)

2200 2000 1800 1600 1400 1200 1000 800 600 400 200 0 –200 100

200

300

r 2 = 0.328, P < 0.001

B

EF (%)

0

C

2200 2000 1800 1600 1400 1200 1000 800 600 400 200 0 –200

10 20 30 40 50 60 70 80

A Figure 27-3 Correlation between Btype natriuretic peptide (BNP) and left ventricular functional parameters in 160 patients with systolic or diastolic heart failure. A, Left ventricular ejection fraction (EF) (%). B, End diastolic pressure (EDP) (mmHg). C, End systolic wall stress (SWS) (kdynes/cm2). D, End diastolic wall stress (EDWS) (kdynes/ cm2). Plasma BNP levels are most closely related to EDWS. (Modified from Iwanaga et al: B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: Comparison between systolic and diastolic heart failure. JACC 2006;47:742–748.)

indices of LV ﬁlling pressure, LV stiﬀness,192 and measures of LA size.193 Wide interindividual variation in BNP and NT-proBNP levels in stable symptomatic heart failure reﬂects many factors.187,194,195 In addition to age and gender, key determinants include renal dysfunction and atrial ﬁbrillation, both of which cause higher levels.175,195–199 Higher levels in renal dysfunction appear to reﬂect reduced clearance, as the transcardiac gradient, reﬂecting cardiac secretion, appears unaltered in this setting.195 Nevertheless, increased cardiac production is probable in many patients with end-stage renal failure, since heart failure, LVH, and coronary artery disease are common and leading causes of death in this setting. Body mass is an important determinant of BNP levels, possibly through increased NPR-C receptors in adipose tissue. NT-proBNP levels are less aﬀected by body mass, possibly owing to a diﬀerent clearance mechanism.200 RV systolic function and mitral regurgitation are key determinants in more advanced heart failure, reﬂecting LA and RV production. Most of the interindividual variation in peptide levels is explained by LV systolic and diastolic functions, RV dysfunction, renal function, gender, age, and mitral regurgitation.187 Hereditary factors or molecular heterogeneity may be responsible for much of the residual variation in BNP levels.201,202 BNP levels therefore act as a global marker of cardiac as well as end-organ dysfunction rather than as an index of a single cardiac index, such as LA pressure.203 Levels should be understood within the context of these multiple determining factors. In severe heart failure, BNP levels and gene expression are strongly related to changes in multiple genes that play a part in LV remodeling, such as matrix metalloproteinases.204 Mehra et al. looked at gene expression in myocardium from donor hearts at the time of transplantation and demonstrated that upregulation of BNP was associated with upregulation of more than 25 speciﬁc

400

SWS (kydnes/cm2)

500

600

10

15

20 25 30

35 40

EDP (mm/Hg) 2200 2000 1800 1600 1400 1200 1000 800 600 400 200 0 –200

r 2 = 0.887, P < 0.001

0

D

5

20 40 60 80 100 120 140 160 EDWS (kdynes/cm2)

351

352

Chapter 27 • Role of Neurohormones genes associated with cellular remodeling, vascular injury and repair, and alloimmune inﬂammatory interactions. Additional genes involved in stem cell mobilization pathways and apoptosis were also identiﬁed. These ﬁndings suggest that BNP may be a marker of active remodeling.204 A variety of immunoassays are available for the measurement of BNP and NT-proBNP.34,205,206 Each has diﬀerent assay characteristics with speciﬁc detection limits and analytical coeﬃcients of variation. There are signiﬁcant correlations between diﬀerent assay measurements taken from the same samples.34 However, assays with lower analytical variation are more likely to detect clinically important changes in serial samples.205,207 There has been recent interest in the biological variation in serial samples from clinically stable patients. Coeﬃcients of biological variability in circulating levels of BNP or NT-proBNP vary between 30% and 55%.208–210 In healthy subjects in whom peptide levels are very low, a doubling in levels—for example, from 8 to 16 pg/ml— would be necessary for a change to conﬁdently exceed usual biological variation.208–210 In unstable heart failure patients, a change of 30% is likely to exceed background variation. The clinical importance of the usual variation seen in peptide levels requires some clariﬁcation. These changes almost certainly reﬂect subclinical changes in hemodynamic indices,209 dynamic myocardial ischemia,211 and the complex neurohormonal milieu that regulates BNP secretion.208–210 Serial BNP or NT-proBNP levels have greater prognostic value than a single value, suggesting that there may be a role for repeated measurements to identify response to therapy and to stratify risk.211–215 Activation of the cardiac natriuretic peptide system is a feature of hypertension. Plasma levels increase in relation to hemodynamic load and to the degree of LVH.177 In animal models such as the spontaneously hypertensive rat, BNP gene expression has been demonstrated before the development of LVH. In human hypertensive subjects, plasma BNP levels are elevated compared with age-matched controls and reﬂect LV wall thickness, the severity of LVH, and LA dilatation. Levels of BNP are higher again in subjects with symptomatic heart failure due to diastolic dysfunction when compared with matched controls with hypertension and LVH.216 It seems unlikely that BNP levels can be used to accurately determine invasively measured LV pressures, particularly in the setting of a normal LVEF.217 While cross-sectional observational studies demonstrate statistically signiﬁcant positive correlations for BNP with LV end diastolic pressure and pre-atrial contraction (pre-A) pressure, the associations are relatively weak.217 In patients with more advanced heart failure during hemodynamically guided treatment with pulmonary artery catheter monitoring of LV ﬁlling pressures, there are concordant changes in simultaneously measured BNP levels and pulmonary capillary wedge pressures, but the changes do not correlate strongly.218,219 Maximal changes in BNP levels lag hemodynamic changes by up to 24 hours, presumably reﬂecting relatively sluggish changes in constitutive synthesis and secretion of these peptides. Patients in whom BNP levels do not fall, despite an improvement in LA pressure estimates, are, however, at highest risk for adverse events.218,219 Data from patients with implantable hemodynamic monitoring devices indicate that while absolute levels of BNP or NT-proBNP reﬂect multiple factors speciﬁc to that individual patient, changes in BNP from baseline for that patient are highly correlated with changes in estimated LV ﬁlling pressures.209 Whether this is true in the setting of a normal EF is still the subject of ongoing study.

Prostaglandins Hormones in the prostaglandin family are derived from arachidonic acid and are synthesized throughout the body.220 Prostaglandin I2 and E2 are potent vasodilators.220 Their levels increase in heart failure in plasma and at tissue level, particularly in the kidneys.45,47,220 The prostaglandins modulate the secretion and eﬀects of ANP, renin, and A-II, and prostaglandin release is in turn increased by A-II, NE, and AVP.45,47,49 Prostaglandins play an important role in renal homeostasis during heart failure.47,53,220 The adverse renal glomerular and tubular eﬀects of nonsteroidal anti-inﬂammatory drugs in heart failure reﬂect their inhibition of prostaglandins.47,220

Pattern of Neurohormonal Activation in Heart Failure with Normal Left Ventricular Ejection Fraction The pattern of neurohormonal activation in systolic heart failure has been well characterized.2,3 In contrast there are fewer data in the context of heart failure when LVEF is preserved.221 While the clinical presentation may be similar, the demographic features of heart failure with preserved EF diﬀer from those of systolic heart failure.41 Patients with preserved EF are generally older, more likely to be female, more likely to have antecedent hypertension and diabetes, and less likely to have had prior myocardial infarction than counterparts with systolic heart failure.41 There may be diﬀerences in ethnic or racial proﬁles as well. Each of these differences is likely to aﬀect the neurohormonal proﬁle seen in heart failure with preserved EF.221 Intuitively, it seems likely that there may be a lesser degree of hemodynamic impairment in the context of heart failure with preserved EF, particularly with regard to arterial underﬁlling, a key stimulus for neurohormonal activation.45 Hence it seems likely that the degree of neurohormonal activity detected in plasma may be less than that seen in systolic heart failure. In one sense, the diﬀerentiation of systolic from diastolic heart failure on the basis of arbitrary cutpoints in EF could be regarded as artiﬁcial and an oversimpliﬁcation of the underlying pathophysiology. This is particularly so as the degree of neurohormonal activation reﬂects indices of cardiac function such as LVEF, wall stress, and end diastolic pressure in a relatively continuous manner. Data from the Vasodilator in Heart Failure Trials (V-HeFT) study indicate that lesser degrees of systolic impairment are associated with less neurohormonal activation. The V-HeFT study group assessed patients with milder versus more severe (LVEF <35%) systolic dysfunction. Patients with a higher LVEF (>35%) had less activation of NE and fewer adverse clinical outcomes.222 A number of studies have attempted to deﬁne the neurohormonal proﬁle of heart failure with preserved systolic function.39,40 Cohort sizes are relatively small, but the study groups were well characterized and aﬀord some insight. In general, these studies demonstrate that there is neurohormonal activation in heart failure where LV ejection is preserved but that this activation is mild and signiﬁcantly less than that seen in systolic heart failure.221 A group of patients from the Studies of Left Ventricular Dysfunction (SOLVD) registry with radiological pulmonary congestion and either preserved LVEF (>45%, n = 41) or systolic impairment (LVEF <45%, n = 89) were compared with matched controls.39 Plasma levels of NE, vasopressin, ANP, and renin activity were signiﬁcantly elevated in systolic heart failure subjects compared

Chapter 27 • Role of Neurohormones plasma NE, ANP, and BNP levels were signiﬁcantly higher than controls in both diastolic and systolic heart failure groups.40 Whereas NE levels were similar in the two heart failure groups, both ANP and BNP were signiﬁcantly higher in patients with systolic versus diastolic heart failure.40 In a prospective study of 556 patients presenting with heart failure in the Olmsted County community, Bursi et al. found that plasma BNP levels (median, 257; interquartile range [IQR], 115–211 pg/ml) were signiﬁcantly higher than those of asymptomatic subjects in the same community (17–58 pg/ml).175,223 BNP levels in the 248 subjects with an LVEF below 50% (388 [164–251] pg/l) were signiﬁcantly higher than levels in the 308 subjects with preserved EF (183 [88–351] pg/ml; p < 0.001). BNP levels also increased signiﬁcantly with more severe diastolic dysfunction in the group of patients with reduced systolic function and in the group with preserved systolic function. BNP levels were independently associated with age, LVEF, and severity of diastolic dysfunction. These ﬁndings indicate that both systolic and diastolic dysfunctions are important determinants of BNP levels. The pattern of neurohormonal activation in acute heart failure with preserved systolic function is less clear. In one small study, 14 of 30 patients presenting with acute heart failure had an LVEF greater than 50%.224 Plasma NE and BNP levels were measured within 48 hours of presentation and at follow-up. NE levels were signiﬁcantly elevated in both diastolic and systolic heart failure groups to a similar degree both at admission with acute heart failure and at follow-up. In contrast, BNP levels were elevated above normal controls in the diastolic heart failure group but on average were less than half the level seen in systolic heart failure.224

with controls and, with the exception of vasopressin, were higher than in heart failure patients with a normal EF. These diﬀerences remained signiﬁcant when adjusted for clinical and treatment variables. Subjects with preserved EF had small but signiﬁcant increases in plasma renin activity and vasopressin levels compared with controls (Fig. 27-4). The impact of drug treatment, including diuretics and ACE inhibitors, may have contributed to diﬀerences in hormones between the groups. In a second, more recent study, Kitzman et al. studied 147 clinically stable subjects aged at least 60 years.40 Fifty-nine subjects had stable heart failure with an LVEF of at least 50% and no evidence of valvular disease, ischemic heart disease, or pulmonary disease. A further 60 subjects had systolic heart failure with LVEF under 35%. These two groups were compared with 28 age-matched control subjects.40 All subjects underwent comprehensive echocardiography, symptom-limited exercise testing, and blood sampling for neurohormones. Compared with both control and systolic heart failure groups, the diastolic heart failure group diﬀered signiﬁcantly, with more women, greater mean BMI, a higher frequency of hypertension, higher recorded blood pressures, and less frequent treatment with diuretics, ACE inhibitors, nitrates, and beta blockers. There were also trends to more frequent diabetes history and greater use of calcium channel blockers. Diastolic heart failure subjects had similar LV volumes and EFs to controls, but greater LV mass. Systolic heart failure subjects had substantially larger LV volumes, lower EFs, and greater LV mass than both diastolic heart failure and control subjects. Diastolic indices were similar in all heart failure subjects. LA size was not reported. Exercise performance was impaired to a similar degree in both systolic and diastolic heart failure groups. Mean

PLASMA NOREPINEPHRINE P < 0.002

5 Median PRA (ng/ml/hr)

600 Median PNE (ng/ml)

PLASMA RENIN ACTIVITY

500 400 300 200 100 0

4 P < 0.02 3 P < 0.02 2 1 0

(246–446)

(282–449)

(350–698)

(0.3–0.8)

Median ANP (pg/ml)

Median AVP (pg/ml)

Figure 27-4 Neurohormonal activation in patients with heart failure and preserved (green bars) and reduced (purple bars) left ventricular systolic function in the Studies of Left Ventricular Dysfunction (SOLVD) registry. Healthy controls are shown by the blue bars. CHF, congestive heart failure; EF, ejection fraction. (Modified from Hogg et al: Neurohumoral pathways in heart failure with preserved systolic function. Prog Cardiovasc Dis 2005;47:357–366.)

P < 0.0007

5

5

P < 0.005 3 2 1

(0.5–8.7)

ATRIAL NATRIURETIC PEPTIDE

VASOPRESSIN

4

(0.4–2.1)

4 3 2 1 0

0 (1.4–2.4) N = 56 Control

(1.7–3.1) n = 41 CHF with EF > 45%

(1.9–3.5) n = 89 CHF with EF < 45%

(31–64) N = 56 Control

(32–116) n = 41 CHF with EF > 45%

(54–225) n = 89 CHF with EF < 45%

353

354

Chapter 27 • Role of Neurohormones

1000 900 800 700 600 500 400 300 200 100 0

CLINICAL RELEVANCE Neurohormones as Treatment Targets for Hypertension and Diastolic Heart Failure Neurohormonal systems are the target for a number of the eﬀective antihypertensive therapies.14,15,227 Treatment of hypertension with ACE inhibitors, AT1R antagonists, or aldosterone receptor blockade is associated with regression of LVH and improved diastolic function.104,228,229 More importantly, these agents reduce the incidence of new heart failure.228,230–232 Furthermore, in combination with β-adrenergic receptor blockers, they are the cornerstone therapy for systolic heart failure,13–15,101,116,233 but only AT1R antagonists have been tested in a large randomized study in the context of heart failure with preserved systolic function.24 Smaller studies suggest beneﬁcial eﬀects on diastolic function and neurohormonal activation from aldosterone, β-adrenergic receptors, and ACE inhibitors. However, adequate mortality studies have not been performed in the setting of heart failure with preserved systolic function.97,128,234–237

Natriuretic Peptides and Screening for Cardiac Dysfunction Because plasma BNP and NT-proBNP levels reﬂect LV structural and functional abnormalities, potentially they could be used to screen for cardiac dysfunction. This approach could identify subclinical abnormalities or facilitate more appropriate referral for echocardiography. Several studies have demonstrated potential utility for screening with BNP or NT-proBNP

ENP (mmHg)

25 P <0.001

P = n.s.

20 15 10 5 0

SHF

SWS (kdynes/cm2)

and nonrestrictive ﬁlling (38 ± 7) or preserved systolic function (34 ± 6).

30

450 400 350 300 250 200 150 100 50

P <0.001

0 SHF

SHF

DHF

DHF

EDWS (kydnes/cm2)

BNP (pg/ml)

These ﬁndings suggest a similar level of compensatory sympathetic activation whether heart failure is due to systolic or primarily diastolic abnormality. Higher BNP levels in systolic heart failure most likely reﬂect the eﬀect of LV geometry on wall stress, the primary stimulus for BNP secretion.185 Iwanaga et al. assessed 62 subjects with diastolic heart failure and 98 with systolic heart failure and found a strong correlation in both groups between plasma BNP levels and end diastolic wall stress, both of which were higher in the systolic heart failure group, reﬂecting in part larger LV volumes (Fig. 27-5).185 The relative levels of BNP in acute heart failure with reduced versus preserved EF have been conﬁrmed in larger studies. In the Breathing Not Properly (“BNP”) multinational study, of 1582 patients presenting with acute dyspnea, a subgroup of 452 patients with conﬁrmed heart failure subsequently underwent echocardiography within 30 days of admission.225 One hundred and sixty ﬁve of these (35%) had preserved LV systolic function with LVEF greater than 45%. Within this group, median BNP levels of 413 pg/ml at presentation were higher than for non–heart failure patients (34 pg/ml) but signiﬁcantly lower than for the 283 subjects with systolic heart failure (821 pg/ml). There were, however, signiﬁcant diﬀerences in demographic and clinical factors between the two heart failure groups, rendering interpretation diﬃcult. BNP levels for the systolic heart failure group may have been underestimated due to an upper limit of only 1300 pg/ml for the assay.225,226 No other neurohormones were reported from this series. Plasma AM levels were assessed by Yu et al. in a study of 77 patients with heart failure and either normal or impaired LVEF.162 AM levels were higher in subjects with heart failure (47.5 ± 6.5 pmol/L) than those without (6.9 ± 1.2; p < 0.01). There was a gradient in AM levels, which were signiﬁcantly higher in those with both systolic heart failure and a restrictive ﬁlling pattern (92 ± 21) than in those with either systolic impairment

100 90 80 70 60 50 40 30 20 10 0

DHF

P <0.001

SHF

DHF

Figure 27-5 Differences in B-type natriuretic peptide (BNP) and left ventricular (LV) functional parameters between subjects with systolic heart failure (SHF) (n = 98) and diastolic heart failure (DHF) (n = 62). The box defines the interquartile range with the median indicated by the crossbar. The error bars indicate the 10th and 90th percentiles. LVEDP is similar in subjects with heart failure due to either cause, but SWS, EDWS, and plasma levels of BNP are all higher in SHF. EDP, end diastolic pressure (mmHg); EDVI, end diastolic volume index (ml/m2); EDWS, end diastolic wall stress (kdynes/cm2); SWS, end systolic wall stress (kdynes/cm2). (Modified from Iwanaga et al: B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: Comparison between systolic and diastolic heart failure. JACC 2006;47:742–748.)

Chapter 27 • Role of Neurohormones (Table 27-1).238–243 Accuracy of these peptides for detecting cardiac dysfunction appears to depend on the clinical context, the abnormality in question, and its prevalence within that population.241 In patients referred for echocardiography, several studies with moderate-sized cohorts have demonstrated that BNP has excellent sensitivity and speciﬁcity for detecting systolic (LVEF <40%–50%) or diastolic dysfunction. Greater negative predictive, or “rule out,” values are seen when prevalence is lower, while speciﬁcity and positive predictive values are higher with higher prevalence.242,243 Krishnaswamy et al. studied 400 patients referred for echocardiography and demonstrated excellent detection of any ventricular dysfunction by BNP, with a level of at least 75 pg/ml having an accuracy of 90% for detecting either systolic (LVEF <50%, n = 225) or diastolic dysfunction (impaired relaxation or worse on transmitral ﬁlling; n = 98).244 Among patients with

isolated diastolic abnormality, BNP levels were higher in those with restrictive ﬁlling patterns than those with impaired relaxation. Highest levels were seen with systolic impairment and restrictive diastolic ﬁlling. Because of overlap between groups, BNP levels did not diﬀerentiate systolic from primary diastolic dysfunction with preserved EF.244 Lubien et al. assessed the utility of BNP in detecting diastolic dysfunction in the setting of normal systolic function (LVEF >50%; LV internal diastolic diameter <5.5 cm) in 294 patients referred for echocardiography.242 Clinical heart failure was present in 5% of the cohort. Diastolic function was deﬁned as normal, impaired relaxation, pseudonormal, or restrictive based on transmitral ﬁlling patterns without reference to tissue Doppler or other diastolic indices. BNP levels (Biosite® assay) increased with greater severity of diastolic dysfunction and were higher still if

TABLE 27-1 SENSITIVITY AND SPECIFICITY OF BNP AND NT-PROBNP LEVELS IN SCREENING FOR LEFT VENTRICULAR DYSFUNCTION. Adapted with Permission From Rodeheffer, JACC 2004; 44: 740–9 [240]. B-TYPE NATRIURETIC PEPTIDE AS A MEASURE OF VENTRICULAR FUNCTION IN SUBJECTS REFERRED FOR ECHOCARDIOGRAPHY Study

Cohort Type

End Point

Prevalence

AUC

SENS*

SPEC*

PPV*

NPV*

Yamamoto et al177

Echocardiography referrals; n = 466 Echocardiography referrals; n = 200

EF < 45%

11%

0.79

79%

64%

21%

96%

EF < 50% or diastolic dysfunction Diastolic dysfunction

47%

0.96

86%

98%

98%

89%

40%

0.92

74%

98%

96%

85%

AUC

SENS*

SPEC*

PPV*

NPV*

Maisel et al243

Lubien et al242

Echocardiography referrals; n = 294

B-TYPE NATRIURETIC PEPTIDE FOR SCREENING COMMUNITY AND CLINIC POPULATIONS Study

Cohort Type

End Point

Vasan et al246

Community volunteers, n = 3,177; age 55 ± 10 yrs

Redfield et al245

Community population based, n = 1,997; age 62 ± 11 yrs

EF ≤ 50% EF ≤ 40% LV mass ↑ EF ≤ 50% EF ≤ 40% Moderate-severe DD %

5.6% 2.2% 4.8% 6.0% 1.1% 6.9%

M 0.72; W 0.56 M 0.79; W 0.85 M 0.72; W 0.57 M 0.69; W 0.70 M 0.90; W 0.92 M 0.79; W 0.77

42% 55% 41% 64% 90% 75%

90% 89% 90% 68% 76% 69%

30% 18% 32% NA 4% 15%

94% 98% 93% NA 99% 97%

CostelloBoerrigter200

Community population based, n = 1,869; Age < 65 yrs Age > 65 yrs Community population based; n = 1,252; age 51 ± 14 yrs Community volunteers, n = 1,098; age 56 yrs

EF < 40 EF < 40 EF ≤ 30%

1% 3.5% 3.2%

M 0.97; W 0.97 M 0.93; W 0.91 0.88

90.9% 88.5% 76%

90.9% 88.4% 87%

NA NA 16%

NA NA 98%

“Heart disease” (atrial fibrillationflutter, MI, valvular or hypertensive, cardiomyopathy, ASD, cor pulmonale) “Heart disease”

3.6%

0.97

90%

96%

44%

99%

2.7%

0.94

85%

92%

NA

NA

McDonagh et al56

Nakamura et al238

Niinuma et al240

Health screening clinic; n = 481

Prevalence

*Calculated at the B-type natriuretic peptide discriminatory value that provides best overall test accuracy; i.e., provides the highest combination of sensitivity and specificity. ASD, atrial septal defect; DD, diastolic dysfunction; LV, left ventricular; M, men; MI, myocardial infarction; NA, not available; W, women; AUC, area under the receiver operating curve; EF, ejection fraction; NPV, negative predictive value; PPV, positive value; SENS, sensitivity; SPEC, specificity.

355

356

Chapter 27 • Role of Neurohormones 500

800 700

400

No clinical CHF Clinical CHF

P = 0.003

600 500

300

400 200

300 200

100

100 0

0 Normal

A

Impaired relaxation

Pseudo- Restrictivenormal like

Impaired relaxation

B

clinical heart failure was present (Fig. 27-6). A BNP level of 65 pg/ml had a sensitivity of 85%, a speciﬁcity of 83%, and an overall accuracy of 84% for detecting any diastolic abnormality when systolic function was normal. Accuracy was higher when only restrictive ﬁlling was considered, with an area under the receiver operating characteristic (ROC) curve of 0.98. BNP levels also diﬀerentiated the presence of an LA abnormality and increased LV mass.242 Findings from these studies suggest that BNP levels reﬂect the severity of diastolic dysfunction and may accurately predict abnormal diastolic function, particularly restrictive ﬁlling, in the majority of patients referred for echocardiography. In particular, low levels appear to rule out signiﬁcant diastolic or systolic abnormality. In community settings, up to half of all cases with LV dysfunction may be clinically undetected.56 A reliable and inexpensive screening test for asymptomatic LV dysfunction could potentially improve detection in the community. Several large studies have assessed screening of the general population with BNP or NTproBNP to detect systolic dysfunction (LVEF <50%), increased LV mass, or diastolic dysfunction graded primarily on the basis of transmitral ﬁlling as at least moderate (pseudonormal) or severe (restrictive).7,245–247 The prevalence of these abnormalities in each study was low (≤6%). The consistent ﬁnding was a high negative predictive value (93%–99%) for low BNP levels, but lower overall speciﬁcity and accuracy.245,248 The Framingham study group found that BNP did not signiﬁcantly improve detection of LV systolic dysfunction or LVH over standard clinical and electrocardiographic parameters.248 In the study from Olmsted County, diﬀerences in BNP and NT-proBNP test performance were noted for men and women. Although very low levels of BNP excluded signiﬁcant LV dysfunction, unadjusted levels appeared suboptimal for routine use in screening the general population, with conﬁrmatory echo still required in up to 40% of the study population and up to 60% of cases missed when a single unadjusted BNP value was used.241 The same group subsequently tested NTproBNP, compared it with BNP in 1869 community subjects, and found that NT-proBNP was at least as eﬀective as BNP (measured by the Biosite assay) in detecting an LVEF of less than 40%, and in older men it was superior to BNP.200 Because the dominant eﬀect on BNP and NT-proBNP levels was from age and gender, use of cutpoints that adjusted for these variables provided more accurate detection of LV systolic or diastolic dysfunction.200 Sen-

Pseudonormal

Restrictivelike

Figure 27-6 A, Mean ± SEM for normal values of brain natriuretic peptide (BNP) versus impaired relaxation, pseudonormal, and restrictive-like filling patterns. Each abnormal group was different from the normal group (p <0.001). B, Comparison of three diastolic filling patterns subdivided by whether patients had symptoms. Values are mean ± SEM. Subgroups of diastolic dysfunction patients with clinical congestive heart failure (CHF) overall had higher BNP levels than those without symptoms. (Modified from Lubien et al: Utility of B-natriuretic peptide in detecting diastolic dysfunction: Comparison with Doppler velocity recordings. Circulation 2002;105:595–601.)

sitivity and speciﬁcity of between 90% and 100% could be achieved for NT-proBNP in detecting an LVEF less than 40%. Use of ageand gender-adjusted cutpoints for NT-proBNP reduced the number of conﬁrmatory echocardiograms required to at most 9.5% of the population and reduced “missed cases” to no more than 12.5% of the population.200 Both NT-proBNP and BNP were less robust when screening for diastolic dysfunction, either alone or in combination with systolic dysfunction. These ﬁndings suggest that NT-proBNP may be a useful screening test for systolic dysfunction—especially if appropriate age and gender cutpoints are applied—but not for diastolic dysfunction. Lack of speciﬁcity in this context is likely to reﬂect increased peptide levels due to other cardiac abnormalities, such as RV dysfunction, valvular disease, and concomitant conditions, like azotemia, atrial ﬁbrillation, and thyroid disease.249,250 A major potential confounder could also be inducible myocardial ischemia, which has been shown to increase BNP and NT-proBNP levels.251,252

Diagnosis of Acute Heart Failure The accurate diagnosis of acute heart failure can be a diﬃcult challenge. The diagnosis may be incorrect in up to half of cases in primary care and more frequently in the setting of preserved LVEF.253,254 BNP and NT-proBNP are now validated as diagnostic markers for acute heart failure based on consistent ﬁndings from multiple observational studies performed in diﬀerent countries and using multiple assays.32,33,35,255 Plasma levels of BNP and NT-proBNP are elevated in acute heart failure. Distinct cutpoints with high negative predictive value can be deﬁned that rule out acute heart failure. Levels of 100 pg/ml for BNP and 400 pg/ml for NTproBNP have become established as rule-out values.32,33,35,255 In contrast, because of the eﬀect of age, gender, and other factors on peptide levels, a single level with high positive predictive value for conﬁrming heart failure is diﬃcult to deﬁne. A greater understanding of the factors inﬂuencing BNP and NT-proBNP levels has led to a more sophisticated approach to choosing cutpoint levels for accurate heart failure diagnosis, depending on age, gender, renal function, and other factors.35,256 In general, very high levels, such as greater than 1600 pg/ml for NT-proBNP, have high positive predictive value for a diagnosis of acute heart failure. Values between the rule-out and rule-in cutpoints could indicate heart failure, but diagnoses such as atrial ﬁbrillation, pulmonary

Chapter 27 • Role of Neurohormones embolism, and even LV dysfunction without acute decompensation could also explain these levels. The studies that validated BNP and NT-proBNP for diagnosis were performed in mixed populations in whom acute heart failure occurred in the context of either normal or impaired LVEF. The “BNP” study investigators assessed the utility of BNP in diﬀerentiating acute heart failure associated with normal or impaired LVEF in a cohort of 452 patients who subsequently underwent echocardiography within 30 days of admission.257 BNP levels were higher in all patients with heart failure than for non–heart failure subjects. BNP levels were also signiﬁcantly higher in subjects with systolic heart failure than those with heart failure but preserved EF.257 Despite this, BNP levels did not accurately diﬀerentiate between heart failure with preserved or impaired EF. A combination of higher BNP levels, lower oxygen saturation, previous history of myocardial infarction (MI) and higher heart rate suggested systolic heart failure. While BNP or NT-proBNP can therefore be used to accurately diagnose acute heart failure, the etiology of heart failure needs to be characterized with additional tests such as echocardiography. More importantly, two recent randomized studies have demonstrated that routine use of BNP improves the accuracy of diagnosis and initial management of heart failure while also proving to be cost eﬀective.254,258 Both studies included unselected patients with acute dyspnea that was due to heart failure in 50% of cases. Heart failure could be due to impaired or preserved EF. In the ﬁrst study, 305 patients who presented with unexplained dyspnea in primary care were randomized to routine care with or without access to NT-proBNP levels.254 In the group for whom physicians had NT-proBNP levels available, accuracy of diagnosis improved from 50% to 70% (p < 0.01 compared with control).254 In the second study, a similar design was employed in the emergency department, where subjects presenting with acute dyspnea were randomized to treatment groups with or without NT-proBNP levels. Subjects in the NT-proBNP group were less likely to be admitted to the hospital or the intensive care unit and had shorter hospital stays and lower overall cost of care. No diﬀerences were seen in 30-day mortality or readmission rates.258

Assessment of Prognosis It was a seminal ﬁnding that neurohormonal activation in heart failure was associated with an adverse prognosis, particularly for NE, the RAS, aldosterone, AM, and AVP.2,3,47 A large number of studies have since demonstrated the consistent ﬁnding that BNP or NT-proBNP levels are among the most powerful prognostic markers in heart failure, independent of LVEF, symptomatic class, age, and other key determinants of survival.259–264 Levels of these peptides predict mortality, risk of hospitalization, and heart failure decompensation across all stages of heart failure, from asymptomatic subjects without heart failure to advanced stage D heart.86,264–266 Recently, additional studies have demonstrated that serial measurement of BNP or NT-proBNP provides independent prognostic information that is incremental to single baseline values.212–215 Because of their widespread use in the diagnosis of heart failure, BNP and NT-proBNP are the best candidates for routine clinical use as prognostic markers. Other neurohormones, such as ET-1, are also powerful predictors of prognosis, sometimes incremental to BNP; but as for the RAS, AM, and NE, their routine use in clinical management is not currently recommended.140

Prediction of Heart Failure Events after Myocardial Infarction Heart failure is an important complication of acute coronary syndromes (ACSs), including MI. Multiple studies have demonstrated that neurohormonal activation occurs after an ACS or MI.190,267–272 This activation reﬂects the severity of myocardial damage and hemodynamic compromise. Increased RAS, aldosterone, and SNS activation contribute to progressive cardiac remodeling and adverse clinical outcomes. Blockade of these systems attenuates LV remodeling and reduces mortality and heart failure events in subjects with systolic impairment after MI.228,273–276 Recently, the role of neurohormones as markers of prognosis after ACS or MI has been highlighted.190,267–271 BNP and NTproBNP levels are equally powerful independent predictors of mortality and heart failure events after an ACS.190,267–270 Prediction of mortality and heart failure events is both incremental and complementary to risk stratiﬁcation by LVEF.267 The highest mortality or heart failure rates are seen in subjects with LV systolic impairment (LVEF <40%) and higher NT-proBNP levels (>1200 pg/ml). Subjects without systolic impairment or NTproBNP elevation were at very low risk for heart failure (1%) or death (5%) over 3 years of follow-up. Either isolated systolic impairment or NT-proBNP elevation carries an intermediate risk (Fig. 27-7). The increased risk in subjects in the latter group with preserved systolic function but elevated NT-proBNP may be multifactorial, relating perhaps to age, abnormalities of LV mass and diastolic function, inducible ischemia, or greater renal impairment.252,267,277,278

Monitoring Heart Failure and Optimizing Therapy The best method for monitoring and optimizing the treatment of heart failure remains unclear.279 This is particularly true in the setting of a preserved LVEF, where there is a limited evidence base for eﬀective medications and where some therapeutic windows, like for diuretics, are narrow. Recent attention has focused on whether neurohormonal markers that reﬂect symptomatic status and the severity of cardiac dysfunction can also be used to monitor heart failure status and guide optimal drug dosing. The most likely candidates for monitoring and guiding therapy are the BNPs. Recent studies in patients with systolic heart failure suggest a potential beneﬁt for drug treatment guided by BNP or NTproBNP levels.38,280 Given that natriuretic peptide levels fall with eﬀective loop diuretics, ACE inhibitors, AT1R blockers, aldosterone receptor antagonists, and, after an initial rise, beta blockers in subjects with preserved systolic function,97,128,236,281 it is possible that treatment guided by BNP or NT-proBNP may be eﬀective in this setting. This hypothesis is currently being tested in several studies that include patients with heart failure and preserved EF.36,37

Exogenous Administration of B-Type Natriuretic Peptide Infusion of BNP has beneﬁcial eﬀects in systolic heart failure, producing vasodilatation, reduced ﬁlling pressures, and increased diuresis.31,282,283 This has led to its use as a therapy for decompensated heart failure, although concerns have been expressed regarding possible adverse eﬀects of BNP infusion on renal function. The majority of studies have assessed BNP infusion in the setting of impaired LV systolic dysfunction.282,283 Whether BNP infusion

357

Chapter 27 • Role of Neurohormones myocardial wall stress is not elevated. The value of BNP when pericardial and myocardial dysfunctions are both present is unclear, but levels may not be as discriminating in this context.

Event free survival %

100 90

ns

†

80 † 70

†

†

60 Death

50 0

400

800

1200

1600

138 70 18 46

53 34 6 22

Days Group 1 2 3 4

296 193 36 141

248 154 31 103

198 125 26 73

Events (14) (27) (2) (52)

% 5 14 6 37

Cardiac Amyloid In one large consecutive series of patients with light chain amyloidosis, NT-proBNP levels were highly sensitive and speciﬁc in detecting cardiac involvement.286 Levels were much higher in subjects with cardiac involvement (508 pmol/L) than in those without (22 pmol/L) and were strongly related to the severity of diastolic abnormality. NT-proBNP levels were the strongest predictor of clinical outcome, and serial levels were more sensitive than conventional echocardiographic indices at detecting a clinical improvement or worsening during follow-up. These ﬁndings suggest that NT-proBNP may be a useful marker for detection and monitoring of cardiac amyloid.

100 Event free survival %

358

90

Chronic Renal Failure

†

† ns

† ns

80

†

Heart failure admission

70 0

400

800

1200

1600

137 63 15 34

53 29 3 13

Days Group 1 2 3 4

296 193 36 141

245 144 30 87

196 116 23 58

Events (3) (15) (4) (26)

% 1 8 11 18

Figure 27-7 Event-free survival in 666 patients with acute myocardial infarction for death (top) or admission with heart failure (bottom) according to combinations of plasma N-terminal brain natriuretic peptide (N-BNP) above or below median levels and left ventricular ejection fraction (LVEF) <40% or ≥40%. Group 1 (yellow line), N-BNP less than median; LVEF ≥40%. Group 2 (blue line), N-BNP greater than median; LVEF ≥40%. Group 3 (green line), N-BNP less than median; LVEF ≥40%. Group 4 (red line), N-BNP greater than median; LVEF <40%. *p < 0.05; **p < 0.01; †p < 0.001. (Modified from Richards AM et al: B-type natriuretic petides and ejection fraction for prognosis after myocardial infarction. Circulation 2003;107:2786–2792.)

is eﬀective in the setting of preserved EF is less clear; however, beneﬁcial hemodynamic and neurohormonal actions of BNP have been demonstrated in this setting.284

Differentiation of Constrictive Pericarditis from Restrictive Cardiomyopathy Constrictive pericarditis and restrictive cardiomyopathy can be diﬃcult to diﬀerentiate either clinically or with imaging. One recent small study demonstrated that BNP levels could accurately diﬀerentiate pericardial constriction from restrictive cardiomyopathy.285 In this study, BNP levels were higher in restrictive cardiomyopathy compared with the constriction group (828 ± 172 pg/ml vs. 128 ± 53 pg/ml), reﬂecting increased myocardial diastolic wall stress. In contrast, lower levels in pericardial constriction reﬂect the underlying pathophysiology, with abnormal diastolic ﬁlling resulting from pericardial constraint, while

Plasma BNP and NT-proBNP levels are elevated in chronic renal failure in relation to the severity of renal dysfunction.287–289 Peptide levels also reﬂect the presence of LVH, underlying coronary artery disease, and heart failure but lack speciﬁcity as markers of systolic versus diastolic dysfunction.287–289 In subjects with renal dysfunction, these peptides retain their value as diagnostic and prognostic markers for heart failure and risk of all-cause and cardiovascular mortality,290 but discriminating cutpoints are higher.197,291 For example, in the “BNP” study, optimal values for diagnosing acute heart failure based on ROC curves were 70, 104, 201, and 225 pg/ml for patients with estimated glomerular ﬁltration rates of greater than 90, 60–89, 30–59, and less than 30 ml/ min/1.73 m2, respectively.197 Levels of BNP and NT-proBNP reﬂect volume status, and hence these peptides have been proposed as a guide to hemodialysis; however, their role in this regard is untested.292

Valvular Heart Disease Levels of BNP and NT-proBNP reﬂect severity of LVH and diastolic wall stress in aortic stenosis.293,294 Levels of both peptides are strongly related to symptom onset with aortic stenosis and increase according to New York Heart Association class.250 Plasma BNP levels also correlate with symptom severity in patients, even when LV systolic function is normal.295 Serial monitoring could potentially identify subjects with valvular disease progressing to a more symptomatic stage and could therefore guide timing of surgical intervention.

Hypertrophic Cardiomyopathy Levels of the natriuretic peptides are elevated in subjects with hypertrophic cardiomyopathy (HCM) in relation to the severity of LVH.296–298 Levels are higher in patients with more advanced heart failure symptoms and greater abnormalities of diastolic function.296,297,299 The transcardiac gradient in BNP levels also correlates with the degree of LV outﬂow obstruction.300 BNP levels may also reﬂect subclinical myocardial ischemia in HCM.301 Plasma NT-proANP levels are elevated in children with genes associated with HCM before signiﬁcant phenotypic changes or hypertrophy develops, suggesting that there may be a role

Chapter 27 • Role of Neurohormones for screening of potential carriers with natriuretic peptide levels.302

Hypertensive Subjects A series of studies indicate that BNP and NT-proBNP levels identify LVH, signiﬁcant diastolic dysfunction, and heart failure in hypertensive subjects.177,216,303,304 Peptide levels correlate with the severity of LVH and with indices of diastolic dysfunction177,303 and are also higher in hypertensive patients with LVH and diastolic heart failure than in matched subjects with a similar degree of LVH and diastolic dysfunction but no heart failure.216 BNP levels also may identify hypertensive subjects with LV systolic dysfunction.304 In community screening, higher BNP levels are associated with a higher risk of subsequently developing hypertension.305 These ﬁndings suggest that BNP levels could potentially help identify risk of hypertension and subsequent onset of heart failure or development of LV systolic dysfunction in hypertensive patients.

SUMMARY Neurohormonal factors play an important role in volume, blood pressure, and electrolyte homeostasis under physiological circumstances and in the pathophysiology of “essential” hypertension and heart failure with preserved LV systolic function. These neurohormonal factors contribute to many of the adverse cardiac remodeling processes that are pivotal in the transition from hypertension to heart failure. For example, the SNS, the RAS, aldosterone, and ET stimulate cardiomyocyte hypertrophy and interstitial ﬁbrosis while also creating adverse eﬀects on blood vessels and some aspects of renal function. The counterbalancing eﬀects of the natriuretic peptides, AM, and other vasodilating compounds attenuate the actions of the vasoconstrictor, growthpromoting, sodium-retaining systems and also inhibit adverse cardiac remodeling. Circulating levels of some neurohormones, including renin, the natriuretic peptides, NE, and vasopressin, are increased in heart failure with preserved systolic function, but not to the same extent as is seen in systolic heart failure. Whether or not this observation has therapeutic implications remains to be seen. Blockade of neurohormonal systems that contribute to the pathophysiology of hypertension and heart failure is now a key pharmacotherapeutic strategy. In particular, the ACE inhibitors, angiotensin receptor blockers, and beta blockers all reduce or attenuate LVH and reduce morbidity and mortality. Whereas use of these drugs in heart failure due to LV systolic dysfunction is soundly based, their eﬀects on morbidity and mortality in patients with preserved systolic function remain to be deﬁned. Likewise, the eﬀects of treatments aimed at augmenting the actions of natriuretic peptides, AM, and other vasodilator and growth inhibitory peptides in heart failure with preserved systolic function require formal study. Plasma levels of the BNPs are elevated in relation to LV wall stress and can be used to accurately rule out heart failure in acutely dyspneic patients. They may also have a role in screening for asymptomatic LV dysfunction and in guiding pharmacotherapy. Research is required to deﬁne the degree and patterns of activation of newer neurohormonal systems in heart failure with preserved systolic function, together with clinical eﬀects of blocking

“adverse” and enhancing “protective” neurohormonal systems in these patients.

FUTURE RESEARCH A greater understanding is needed of the pattern and severity of neurohormonal activation in heart failure where systolic function is preserved. This can be obtained only from larger observational studies with accurate characterization of cardiac function. Further studies are needed that carefully document the pattern of neurohormonal activation in relation to clinical, hemodynamic, and echocardiographic indices in patients with heart failure and preserved LVEF. In addition to deﬁning the pattern of plasma hormone levels, there is a need for greater characterization of the pattern of gene expression and neurohormonal synthesis in myocardium and other tissue beds across the spectrum from asymptomatic stage A to symptomatic stages B to D heart failure.265 A greater understanding of patterns of plasma and tissue neurohormonal activation and of the major stimuli and regulators of this activation can lead to new therapeutic interventions that attenuate or prevent the progression to heart failure. Further studies are needed to clarify the role that neurohormones may have as biomarkers in identifying subjects at risk for progressing to heart failure. Early identiﬁcation of high-risk individuals can lead to earlier intervention and prevention of heart failure. The use of neurohormones such as BNP and NT-proBNP to guide the optimal drug treatment of heart failure is currently being tested. In at least two studies, patients with heart failure and preserved systolic function are included in the sample populations.36,37 Recently published European guidelines on diastolic heart failure suggest that cardiac natriuretic peptides are recommended for exclusion of diastolic heart failure because of their high negative predictive value and are not recommended for diagnosis. However, when they are used for diagnosis of diastolic heart failure (NT-proBNP > 220 pg/ml, Roche Diagnostics or BNP > 220 pg/ml, Triage Biosite), there must be additional noninvasive studies showing diastolic dysfunction including tissue Doppler imaging, echo blood ﬂow Doppler parameters, left ventricular volume mass index, or presence of atrial ﬁbrillation (see Chapter 6).306 Neurohormonal systems are currently the targets of new therapies being evaluated for the treatment of severe hypertension and of systolic heart failure. ET receptor blockade may be of value in the treatment of severe hypertension. V2 receptor antagonism and adenosine receptor blockade are currently being tested for the treatment of systolic heart failure. Whether these agents are eﬀective in treating acute heart failure in patients with preserved LVEF is uncertain. REFERENCES 1. Packer M: The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992; 20:248–54. 2. Cohn JN, Levine TB, Olivari MT, et al: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819–823. 3. Francis GS, Cohn JN, Johnson G, et al: Plasma norepinephrine plasma renin activity and congestive heart failure. Relations to survival and the eﬀects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87(6 Suppl):VI40–VI48. 4. Loeb HS, Johnson G, Henrick A, et al: Eﬀect of enalapril hydralazine plus isosorbide dinitrate and prazosin on hospitalization in patients with chronic

359

360

Chapter 27 • Role of Neurohormones

5.

6.

7. 8. 9.

10. 11. 12. 13. 14. 15. 16.

17. 18. 19. 20. 21. 22. 23. 24.

25. 26.

congestive heart failure. The V-HeFT VA Cooperative Studies Group Circulation 1993;87(6 Suppl):VI78–VI87. Johnson G, Carson P, Francis GS, et al: Inﬂuence of prerandomization (baseline) variables on mortality and on the reduction of mortality by enalapril Veterans Aﬀairs Cooperative Study. on Vasodilator Therapy of Heart Failure (V-HeFT II). V-HeFT VA Cooperative Studies Group. Circulation 1993;87(6 Suppl):VI32–VI39. Richards AM, Doughty R, Nicholls MG, et al: Plasma N-terminal pro– brain natriuretic peptide and adrenomedullin: Prognostic utility and prediction of beneﬁt from carvedilol in chronic ischemic left ventricular dysfunction Australia–New Zealand Heart Failure. Group J Am Coll Cardiol 2001;37:1781–1787. McDonagh TA, Cunningham AD, Morrison CE, et al: Left ventricular dysfunction natriuretic peptides and mortality in an urban population. Heart 2001;86:21–26. Packer M, Lee WH, Kessler D, et al: Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. Circulation 1987;75(5 Pt 2):IV80–IV92. Swedberg K, Eneroth P, Kjekshus J, et al: Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality CONSENSUS Trial Study Group. Circulation 1990;82:1730–1736. Cohn JN, Archibald DG, Ziesche S, et al: Eﬀect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314:1547–1552. Packer M, Bristow MR, Cohn JN, et al: The eﬀect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349–1355. The SOLVD Investigators: Eﬀect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302. The SOLVD Investigators: Eﬀect of enalapril on mortality and the development of heart failure. in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–691. The Cardiac Insuﬃciency Bisoprolol Study. II (CIBIS-II): A randomised trial. Lancet 1999;353(9146):9–13. Eﬀect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT–HF). Lancet 1999;353(9169):2001–2007. Mukoyama M, Nakao K, Hosoda K, et al: Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 1991;87:1402–1412. Nishikimi T, Matsuoka H: Cardiac adrenomedullin: Its role in cardiac hypertrophy and heart failure. Curr Med Chem Cardiovasc Hematol Agents 2005;3:231–242. Yanagisawa M, Kurihara H, Kimura S, et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332(6163):411–415. Nakamura R, Kato J, Kitamura K, et al: Adrenomedullin administration immediately after myocardial infarction ameliorates progression of heart failure. in rats Circulation 2004;110:426–431. Rademaker MT, Cameron VA, Charles CJ, et al: Integrated hemodynamic hormonal and renal actions of urocortin 2 in normal and paced sheep: beneﬁcial eﬀects in heart failure. Circulation 2005;112:3624–3632. Jougasaki M, Tachibana I, Luchner A, et al: Augmented cardiac cardiotrophin-1 in experimental congestive heart failure. Circulation 2000;101:14–17. Jougasaki M, Leskinen H, Larsen AM, et al: Ventricular cardiotrophin-1 activation precedes BNP in experimental heart failure. Peptides 2003;24: 889–892. Wright S, Prickett TC, Doughty RN, et al: Amino-terminal pro– C-type natriuretic peptide in heart failure. Hypertension 2004;43: 94–100. Yusuf S, Pfeﬀer MA, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362(9386): 777–781. Gheorghiade M, Gattis WA, O’Connor CM, et al: Eﬀects of tolvaptan a vasopressin antagonist in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA 2004;291:1963–1971. Gheorghiade M, Orlandi C, Burnett JC, et al: Rationale and design of the multicenter randomized double-blind placebo-controlled study to evaluate the Eﬃcacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST). J Card Fail 2005;11:260–269.

27. Mehra MR, Uber A, Francis GS: Heart failure therapy at a crossroad: Are there limits to the neurohormonal model? J Am Coll Cardiol 2003;41:1606–1610. 28. Modlinger S, Welch WJ: Adenosine A1 receptor antagonists and the kidney. Curr Opin Nephrol Hypertens 2003;12:497–502. 29. Davis ME, Pemberton CJ, Yandle TG, et al: Eﬀect of urocortin 1 infusion in humans with stable congestive cardiac failure. Clin Sci (Lond) 2005;109:381–388. 30. Lainchbury JG, Nicholls MG, Espiner EA, et al: Bioactivity and interactions of adrenomedullin and brain natriuretic peptide in patients with heart failure. Hypertension 1999;34:70–75. 31. Colucci WS, Elkayam U, Horton D, et al: Intravenous nesiritide a natriuretic peptide in the treatment of decompensated congestive heart failure Nesiritide Study Group N Engl J Med 2000;343:246–253. 32. Davis M, Espiner E, Richards G, et al: Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet 1994;343(8895):440–444. 33. Maisel AS, Krishnaswamy P, Nowak RM, et al: Rapid measurement of Btype natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–167. 34. Lainchbury JG, Campbell E, Frampton CM, et al: Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath Journal of the American College of Cardiology 2003;42:728–735. 35. Januzzi JL, van Kimmenade R, Lainchbury J, et al: NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: An international pooled analysis of 1256 patients: The International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330–337. 36. Brunner-La Rocca H, Buser T, Schindler R, et al: Management of elderly patients with congestive heart failure—-design of the Trial of Intensiﬁed versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME–CHF). Am Heart J 2006;151:949–955. 37. Lainchbury JG, Troughton RW, Frampton CM, et al: NTproBNP-guided drug treatment for chronic heart failure: Design and methods in the “BATTLESCARRED” trial. Eur J Heart Fail 2006;8:532–538. 38. Troughton RW, Frampton CM, Yandle TG, et al: Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355(9210):1126–1130. 39. Benedict CR, Weiner DH, Johnstone DE, et al: Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: Results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry The SOLVD Investigators. J Am Coll Cardiol 1993;22 (4 Suppl A):146A–153A. 40. Kitzman DW, Little WC, Brubaker H, et al: Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–2150. 41. Hogg K, Swedberg K, McMurray J: Heart failure with preserved left ventricular systolic function: Epidemiology clinical characteristics and prognosis. J Am Coll Cardiol 2004;43:317–327. 42. Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al: Diﬀerences between patients with a preserved and a depressed left ventricular function: A report from the EuroHeart Failure Survey Eur Heart J 2004;25:1214–1220. 43. Berry C, Hogg K, Norrie J, et al: Heart failure with preserved left ventricular systolic function: A hospital cohort study. Heart 2005;91:907–913. 44. Varela-Roman A, Grigorian L, Barge E, et al: Heart failure in patients with preserved and deteriorated left ventricular ejection fraction. Heart 2005;91:489–494. 45. Schrier RW, Abraham WT: Hormones and hemodynamics in heart failure. N Engl J Med 1999;341:577–585. 46. Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med 1998;339:321–8. 47. Francis GS: Vasoactive hormone systems. In Poole-Wilson, et al (eds): Heart failure. Oxford, Churchill Livingstone, 1997:215–234. 48. Rodeheﬀer RJ, Tanaka I, Imada T, et al: Atrial pressure and secretion of atrial natriuretic factor into the human central circulation. J Am Coll Cardiol 1986; 8:18–26. 49. Thibault G, Amiri F, Garcia R: Regulation of natriuretic peptide secretion by the heart. Annu Rev Physiol 1999;61:193–217. 50. Yamakawa H, Imamura T, Matsuo T, et al: Diastolic wall stress and ANG II in cardiac hypertrophy and gene expression induced by volume overload. Am J Physiol Heart Circ Physiol 2000;279:H2939–H2946. 51. Hunt J, Espiner EA, Nicholls MG, et al: Diﬀering biological eﬀects of equimolar atrial and brain natriuretic peptide infusions in normal man. J Clin Endocrinol Metab 1996;81:3871–3876. 52. Maack T: Role of atrial natriuretic factor in volume control. Kidney Int 1996;49:1732–1737.

Chapter 27 • Role of Neurohormones 53. Packer M: Neurohormonal interactions and adaptations in congestive heart failure. Circulation 1988;77:721–730. 54. Hama N, Itoh H, Shirakami G, et al: Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation 1995;92:1558–1564. 55. Zolk O, Quattek J, Seeland U, et al: Activation of the cardiac endothelin system in left ventricular hypertrophy before onset of heart failure in TG(mREN2)27 rats. Cardiovasc Res 2002;53:363–371. 56. McDonagh TA, Morrison CE, Lawrence A, et al: Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 1997;350(9081):829–833. 57. Francis GS, Benedict C, Johnstone DE, et al: Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724–1729. 58. Cohn JN, Ferrari R, Sharpe N: Cardiac remodeling—concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 2000;35:569–582. 59. Greenberg B, Quinones MA, Koilpillai C, et al: Eﬀects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation 1995;91:2573–2581. 60. Sutton MG, Sharpe N: Left ventricular remodeling after myocardial infarction: Pathophysiology and therapy. Circulation 2000;101:2981– 2988. 61. Dzau VJ: Renal eﬀects of angiotensin-converting enzyme inhibition in cardiac failure. Am J Kidney Dis 1987;10(1 Suppl 1):74–80. 62. Ichikawa I, Pfeﬀer JM, Pfeﬀer MA, et al: Role of angiotensin II in the altered renal function of congestive heart failure. Circ Res 1984;55:669–675. 63. Packer M: Interaction of prostaglandins and angiotensin II in the modulation of renal function in congestive heart failure. Circulation 1988; 77(6 Pt 2):I64–I73. 64. Charloux A, Piquard F, Doutreleau S, et al: Mechanisms of renal hyporesponsiveness to ANP in heart failure. Eur J Clin Invest 2003;33:769– 778. 65. van Heerebeek L, Borbely A, Niessen HW, et al: Myocardial structure and function diﬀer in systolic and diastolic heart failure. Circulation 2006;113:1966–1973. 66. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure. Circulation 2006;113:1922–1925. 67. Weber KT, Brilla CG: Structural basis for pathologic left ventricular hypertrophy. Clin Cardiol 1993;16(5 Suppl 2):II10–I14. 68. Lisy O, Redﬁeld MM, Jovanovic S, et al: Mechanical unloading versus neurohumoral stimulation on myocardial structure and endocrine function in vivo. Circulation 2000;102:338–343. 69. Chinnaiyan KM, Alexander D, and McCullough A Role of angiotensin II in the evolution of diastolic heart failure. J Clin Hypertens (Greenwich) 2005;7:740–747. 70. Malhotra R, Sadoshima J, Brosius FC 3rd, et al: Mechanical stretch and angiotensin II diﬀerentially upregulate the renin-angiotensin system in cardiac myocytes in vitro. Circ Res 1999;85:137–146. 71. Iwanaga Y, Kihara Y, Inagaki K, et al: Diﬀerential eﬀects of angiotensin II versus endothelin-1 inhibitions in hypertrophic left ventricular myocardium during transition to heart failure. Circulation 2001;104:606–612. 72. Yamamoto K, Masuyama T, Sakata Y, et al: Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts. Cardiovasc Res 2000;47:274–283. 73. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium ﬁbrosis and renin-angiotensin-aldosterone system Circulation 1991;83: 1849–1865. 74. Mazzolai L, Nussberger J, Aubert JF, et al: Blood pressure–independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension 1998;31:1324–1330. 75. Bristow MR: Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558–569. 76. Brilla CG, Matsubara LS, Weber KT: Antiﬁbrotic eﬀects of spironolactone in preventing myocardial ﬁbrosis in systemic arterial hypertension. Am J Cardiol 1993;71:12A–16A. 77. Emoto N, Raharjo SB, Isaka D, et al: Dual ECE/NEP inhibition on cardiac and neurohumoral function during the transition from hypertrophy to heart failure in rats. Hypertension 2005;45:1145–1152. 78. Brilla CG, Matsubara LS, Weber KT: Anti-aldosterone treatment and the prevention of myocardial ﬁbrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 1993;25:563–575.

79. Nishikimi T, Tadokoro K, Mori Y, et al: Ventricular adrenomedullin system in the transition from LVH to heart failure in rats. Hypertension 2003;41:512–518. 80. Wiese S, Breyer T, Dragu A, et al: Gene expression of brain natriuretic peptide in isolated atrial. and ventricular human myocardium: Inﬂuence of angiotensin II and diastolic ﬁber length. Circulation 2000;102: 3074–3079. 81. Espiner EA, Richards AM, Yandle TG, et al: Natriuretic hormones. Endocrinol Metab Clin North Am 1995;24:481–509. 82. Grassi G, Cattaneo BM, Mancia G: Sympathetic nervous system. In PooleWilson, et al (eds): Heart failure. Oxford, Churchill Livingstone, 1997: 199–214. 83. Ferguson DW, Berg WJ, Sanders JS: Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: Evidence from direct microneurographic recordings. J Am Coll Cardiol 1990;16:1125–1134. 84. Witty RT, Davis JO, Shade RE, et al: Mechanisms regulating renin release in dogs with thoracic caval constriction. Circ Res 1972 31:339 347. 85. Mancia G, Grassi G, Parati G, et al: Evaluating sympathetic activity in human hypertension. J Hypertens Suppl 1993;11(Suppl 5):S13–S19. 86. Hartmann F, Packer M, Coats AJ, et al: Prognostic impact of plasma Nterminal pro–brain natriuretic peptide in severe chronic congestive heart failure: A substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation 2004;110:1780–1786. 87. Petersson MJ, Rundqvist B, Johansson M, et al: Increased cardiac sympathetic drive in renovascular hypertension. J Hypertens 2002;20: 1181–1187. 88. Schlaich M, Lambert E, Kaye DM, et al: Sympathetic augmentation in hypertension: Role of nerve ﬁring norepinephrine reuptake and angiotensin neuromodulation. Hypertension 2004;43:169–175. 89. Rahn KH, Barenbrock M, Hausberg M: The sympathetic nervous system in the pathogenesis of hypertension. J Hypertens Suppl 1999;17: S11–S14. 90. Esler M: The sympathetic system and hypertension. Am J Hypertens 2000;13(6 Pt 2):99S–105S. 91. Grassi G, Seravalle G, Quarti-Trevano F, et al: Eﬀects of hypertension and obesity on the sympathetic activation of heart failure patients. Hypertension 2003;42:873–877. 92. Rapacciuolo A, Esposito G, Caron K, et al: Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressureoverload cardiac hypertrophy. J Am Coll Cardiol 2001;38:876–882. 93. Kasama S, Toyama T, Kumakura H, et al: Eﬀects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction. J Am Coll Cardiol 2005;45: 661–667. 94. Sakata K, Shirotani M, Yoshida H, et al: Comparison of eﬀects of enalapril and nitrendipine on cardiac sympathetic nervous system in essential hypertension. J Am Coll Cardiol 1998;32:438–443. 95. Lindholm LH, Carlberg B, Samuelsson O: Should beta blockers remain ﬁrst choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366(9496):1545–1553. 96. Group TACR: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967–1975. 97. Bergstrom A, Andersson B, Edner M, et al: Eﬀect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail 2004;6:453–461. 98. Nodari S, Metra M, Dei Cas L: Beta-blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective randomized comparison of the long-term eﬀects of atenolol vs nebivolol. Eur J Heart Fail 2003;5:621–627. 99. Burnier M, Brunner HR: Angiotensin II receptor antagonists. Lancet 2000;355(9204):637–645. 100. Cohn JN, Johnson G, Ziesche S, et al: A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–310. 101. Granger CB, McMurray JJ, Yusuf S, et al: Eﬀects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARMAlternative trial. Lancet 2003;362(9386):772–776. 102. McMurray JJ, Ostergren J, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic func-

361

362

Chapter 27 • Role of Neurohormones

103. 104.

105. 106. 107. 108.

109.

110.

111. 112. 113.

114. 115.

116.

117. 118. 119. 120. 121. 122. 123. 124. 125.

tion taking angiotensin-converting-enzyme inhibitors: The CHARMAdded trial. Lancet 2003;362(9386):767–771. Mazzolai L, Pedrazzini T, Nicoud F, et al: Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice. Hypertension 2000;35:985–991. Friedrich S Lorell BH Rousseau MF, et al: Intracardiac angiotensin– converting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation 1994;90: 2761–2771. Yamazaki T, Komuro I, Kudoh S, et al: Angiotensin II partly mediates mechanical stress–induced cardiac hypertrophy. Circ Res 1995;77: 258–265. Mollnau H, Wendt M, Szocs K, et al: Eﬀects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 2002;90:E58–E65. Hare JM: Nitroso-redox balance in the cardiovascular system. N Engl J Med 2004;351:2112–2114. Yamamoto K, Masuyama T, Sakata Y, et al: Local neurohumoral regulation in the transition to isolated diastolic heart failure in hypertensive heart disease: Absence of AT1 receptor downregulation and ‘overdrive’ of the endothelin system. Cardiovasc Res 2000;46:421–32. Okin M, Devereux RB, Jern S, et al: Regression of electrocardiographic left ventricular hypertrophy by losartan versus atenolol: The Losartan Intervention for Endpoint reduction in Hypertension (LIFE) Study. Circulation 2003;108:684–690. Friedrich S, Lorell BH, Rousseau MF, et al: Intracardiac angiotensinconverting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation 1994; 90:2761–2771. Diez J, Querejeta R, Lopez B, et al: Losartan-dependent regression of myocardial ﬁbrosis is associated with reduction of left ventricular chamber stiﬀness in hypertensive patients. Circulation 2002;105:2512–2517. Brilla CG, Funck RC, Rupp H: Lisinopril-mediated regression of myocardial ﬁbrosis in patients with hypertensive heart disease. Circulation 2000;102:1388–1393. Ciulla MM, Paliotti R, Esposito A, et al: Diﬀerent eﬀects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial ﬁbrosis: Results of a randomized trial. Circulation 2004;110:552–557. Pfeﬀer MA, McMurray JJ, Velazquez EJ, et al: Valsartan captopril or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893–1906. Yusuf S, Sleight P, Pogue J, et al: Eﬀects of an angiotensin-convertingenzyme inhibitor ramipril on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–153. Pitt B, Zannad F, Remme WJ, et al: The eﬀect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–717. Lang CC, McAlpine HM, Kennedy N, et al: Eﬀects of lisinopril on congestive heart failure in normotensive patients with diastolic dysfunction but intact systolic function. Eur J Clin Pharmacol 1995;49(1–2):15–19. Pitt B: “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: Implications for therapy. Cardiovasc Drugs Ther 1995;9:145–149. Nelson DH, August JT: Abnormal response of oedematous patients to aldosterone or deoxycortone. Lancet 1959;2:883–885. Barger AC, Muldowney F, Liebowitz MR: Role of the kidney in the pathogenesis of congestive heart failure. Circulation 1959;20:273–285. Zannad F, Dousset B, Alla F: Treatment of congestive heart failure: Interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension 2001;38:1227–1232. Funder JW: Cardiac synthesis of aldosterone: Going, going, gone? Endocrinology 2004;145:4793–4795. Fagard RH, Lijnen J, Petrov VV: Opposite associations of circulating aldosterone and atrial natriuretic peptide with left ventricular diastolic function in essential hypertension. J Hum Hypertens 1998;12:195–202. Vasan RS, Evans JC, Benjamin EJ, et al: Relations of serum aldosterone to cardiac structure: Gender-related diﬀerences in the Framingham Heart Study. Hypertension 2004;43:957–962. Blacher J, Amah G, Girerd X, et al: Association between increased plasma levels of aldosterone and decreased systemic arterial compliance in subjects with essential hypertension. Am J Hypertens 1997;10(12 Pt 1):1326– 1334.

126. Duprez DA, De Buyzere ML, Rietzschel ER, et al: Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J 1998;19:1371–1376. 127. Izawa H, Murohara T, Nagata K, et al: Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial ﬁbrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: A pilot study. Circulation 2005;112:2940–2945. 128. Mottram M, Haluska B, Leano R, et al: Eﬀect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558–565. 129. Goldsmith SR, Gheorghiade M: Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005;46:1785–1791. 130. Lee CR, Watkins ML, Patterson JH, et al: Vasopressin: A new target for the treatment of heart failure. Am Heart J 2003;146:9–18. 131. Costello-Boerrigter LC, Smith WB, Boerrigter G, et al: Vasopressin-2– receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol 2006;290:F273–F278. 132. Sutsch G, Barton M: Endothelin in heart failure. Curr Hypertens Rep 1999;1:62–68. 133. Miyauchi T, Masaki T: Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol 1999;61:391–415. 134. Huggins J, Pelton JT, Miller RC: The structure and speciﬁcity of endothelin receptors: Their importance in physiology and medicine. Pharmacol Ther 1993;59:55–123. 135. Luscher TF: Endothelin, endothelin receptors and endothelin antagonists. Curr Opin Nephrol Hypertens 1994;3:92–98. 136. Yamauchi-Kohno R, Miyauchi T, Hoshino T, et al: Role of endothelin in deterioration of heart failure. due to cardiomyopathy in hamsters: increase in endothelin-1 production in the heart and beneﬁcial eﬀect of endothelin-A receptor antagonist on survival and cardiac function. Circulation 1999;99:2171–2176. 137. Wei CM, Lerman A, Rodeheﬀer RJ, et al: Endothelin in human congestive heart failure. Circulation 1994;89:1580–1586. 138. McMurray JJ, Ray SG, Abdullah I, et al: Plasma endothelin in chronic heart failure. Circulation 1992;85:1374–1379. 139. Parker JD, Thiessen JJ: Increased endothelin-1 production in patients with chronic heart failure. Am J Physiol Heart Circ Physiol 2004;286: H1141–H1145. 140. Masson S, Latini R, Anand IS, et al: The prognostic value of big endothelin1 in more than 2300 patients with heart failure enrolled in the Valsartan Heart Failure Trial (Val-HeFT). J Card Fail 2006;12:375–380. 141. Boerrigter G, Burnett JC: Endothelin in neurohormonal activation in heart failure. Coron Artery Dis 2003;14:495–500. 142. Pieske B, Beyermann B, Breu V, et al: Functional eﬀects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium. Circulation 1999;99:1802–1809. 143. Motte S, van Beneden R, Mottet J, et al: Early activation of cardiac and renal endothelin systems in experimental heart failure. Am J Physiol Heart Circ Physiol 2003;285:H2482–H2491. 144. Morawietz H, Szibor M, Goettsch W, et al: Deloading of the left ventricle by ventricular assist device normalizes increased expression of endothelin ET(A) receptors but not endothelin-converting enzyme-1 in patients with end-stage heart failure. Circulation 2000;102(19 Suppl 3):III188– III193. 145. New RB, Sampson AC, King MK, et al: Eﬀects of combined angiotensin II and endothelin receptor blockade with developing heart failure: Eﬀects on left ventricular performance. Circulation 2000;102:1447–1453. 146. Yamamoto K, Masuyama T, Sakata Y, et al: Prevention of diastolic heart failure. by endothelin type A receptor antagonist through inhibition of ventricular structural remodeling in hypertensive heart. J Hypertens 2002;20:753–761. 147. Schirger JA, Chen HH, Jougasaki M, et al: Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention. Circulation 2004;109:249–254. 148. Torre-Amione G, Young JB, Durand J, et al: Hemodynamic eﬀects of tezosentan an intravenous dual endothelin receptor antagonist in patients with class III to IV congestive heart failure. Circulation 2001;103: 973–980. 149. Berger R, Stanek B, Hulsmann M, et al: Eﬀects of endothelin a receptor blockade on endothelial function in patients with chronic heart failure. Circulation 2001;103:981–986. 150. Spieker LE, Mitrovic V, Noll G, et al: Acute hemodynamic and neurohumoral eﬀects of selective ET(A) receptor blockade in patients with conges-

Chapter 27 • Role of Neurohormones

151.

152. 153.

154. 155. 156. 157. 158. 159. 160. 161.

162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174.

tive heart failure. ET 003 Investigators. J Am Coll Cardiol 2000;35: 1745–1752. Teerlink JR, McMurray JJ, Bourge RC, et al: Tezosentan in patients with acute heart failure: Design of the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Study (VERITAS). Am Heart J 2005;150:46–53. Feldman AM, Combes A, Wagner D, et al: The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol 2000;35: 537–544. Chung ES, Packer M, Lo KH, et al: Randomized double-blind placebocontrolled pilot trial of inﬂiximab a chimeric monoclonal antibody to tumor necrosis factor–alpha in patients with moderate-to-severe heart failure: Results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–3140. Bozkurt B, Torre-Amione G, Warren MS, et al: Results of targeted anti– tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 2001;103:1044–1047. Mann DL, McMurray JJ, Packer M, et al: Targeted anticytokine therapy in patients with chronic heart failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594–1602. Bristow MR, Long CS: Cardiotrophin-1 in heart failure. Circulation 2002;106:1430–1432. Lowes BD, Gilbert EM, Abraham WT, et al: Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med 2002;346:1357–1365. Freed DH, Cunnington RH, Dangerﬁeld AL, et al: Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infarcted heart. Cardiovasc Res 2005;65:782–792. Talwar S Squire IB Downie F, et al: Elevated circulating cardiotrophin-1 in heart failure: Relationship with parameters of left ventricular systolic dysfunction. Clin Sci (Lond) 2000;99:83–88. Zolk O, Ng LL, O’Brien RJ, et al: Augmented expression of cardiotrophin-1 in failing human hearts is accompanied by diminished glycoprotein 130 receptor protein abundance. Circulation 2002;106:1442–1446. Toh R, Kawashima S, Kawai M, et al: Transplantation of cardiotrophin1–expressing myoblasts to the left ventricular wall alleviates the transition from compensatory hypertrophy to congestive heart failure in Dahl saltsensitive hypertensive rats. J Am Coll Cardiol 2004;43:2337–2347. Yu CM, Cheung BM, Leung R, et al: Increase in plasma adrenomedullin in patients with heart failure characterized by diastolic dysfunction. Heart 2001;86:155–160. Nishikimi T, Yoshihara F, Horinaka S, et al: Chronic administration of adrenomedullin attenuates transition from left ventricular hypertrophy to heart failure in rats. Hypertension 2003;42:1034–1041. Luodonpaa M, Vuolteenaho O, Eskelinen S, et al: Eﬀects of adrenomedullin on hypertrophic responses induced by angiotensin II endothelin-1 and phenylephrine. Peptides 2001;22:1859–1866. Pousset F, Masson F, Chavirovskaia O, et al: Plasma adrenomedullin a new independent predictor of prognosis in patients with chronic heart failure. Eur Heart J 2000;21:1009–1014. Troughton RW, Lewis LK, Yandle TG, et al: Hemodynamic hormone and urinary eﬀects of adrenomedullin infusion in essential hypertension. Hypertension 2000;36:588–593. Vaughan J, Donaldson C, Bittencourt J, et al: Urocortin a mammalian neuropeptide related to ﬁsh urotensin I and to corticotropin-releasing factor. Nature 1995;378(6554):287–292. Kimura Y, Takahashi K, Totsune K, et al: Expression of urocortin and corticotropin-releasing factor receptor subtypes in the human heart. J Clin Endocrinol Metab 2002;87:340–346. Rademaker MT, Charles CJ, Espiner EA, et al: Beneﬁcial hemodynamic endocrine and renal eﬀects of urocortin in experimental heart failure: Comparison with normal sheep. J Am Coll Cardiol 2002;40:1495–1505. Rademaker MT, Charles CJ, Espiner EA, et al: Four-day urocortin-I administration has sustained beneﬁcial haemodynamic hormonal and renal eﬀects in experimental heart failure. Eur Heart J 2005;26:2055–2062. Wilkins MR, Redondo J, Brown LA: The natriuretic-peptide family. Lancet 1997;349(9061):1307–1310. Ruskoaho H: Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 2003;24:341–356. Maack T, Nikonova, LN Friedman O, et al: Functional properties and dynamics of natriuretic peptide receptors. Proc Soc Exp Biol Med 1996;213:109–116. Rademaker MT, Charles CJ, Kosoglou T, et al: Clearance receptors and endopeptidase: Equal role in natriuretic peptide metabolism in heart failure. Am J Physiol 1997;273(5 Pt 2):H2372–H2379.

175. Redﬁeld MM, Rodeheﬀer RJ, Jacobsen SJ, et al: Plasma brain natriuretic peptide concentration: Impact of age and gender. J Am Coll Cardiol 2002;40:976–982. 176. Hunt J, Richards AM, Espiner EA, et al: Bioactivity and metabolism of C-type natriuretic peptide in normal man. J Clin Endocrinol Metab 1994;78:1428–1435. 177. Yamamoto K, Burnett JC Jr, Jougasaki M, et al: Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988–994. 178. Edwards BS, Zimmerman RS, Schwab TR, et al: Atrial stretch not pressure is the principal determinant controlling the acute release of atrial natriuretic factor. Circ Res 1988;62:191–195. 179. Espiner E, Richards A, Nicholls M: Physiology of natriuretic peptides. In Levin ER, Nadler JL (eds): Endocrinology of cardiovascular function. Boston, Kluwer Academic, 1998:121–135. 180. Holmes SJ, Espiner EA, Richards AM, et al: Renal endocrine and hemodynamic eﬀects of human brain natriuretic peptide in normal man. J Clin Endocrinol Metab 1993;76:91–96. 181. Dunn BR, Ichikawa I, Pfeﬀer JM, et al: Renal and systemic hemodynamic eﬀects of synthetic atrial natriuretic peptide in the anesthetized rat. Circ Res 1986;59:237–246. 182. Marin-Grez M, Fleming JT, Steinhausen M: Atrial natriuretic peptide causes pre-glomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature 1986;324(6096):473–476. 183. Brandt RR, Burnett Jr JC: Humoral control of the kidney during congestive heart failure: Role of the cardiac natriuretic peptides and angiotensin II. In Poole-Wilson A, et al (eds): Heart failure. Oxford, Churchill Livingstone, 1997:143–154. 184. Wei CM, Heublein DM, Perrella MA, et al: Natriuretic peptide system in human heart failure. Circulation 1993;88:1004–1009. 185. Iwanaga Y, Nishi I, Furuichi S, et al: B-type natriuretic peptide strongly reﬂects diastolic wall stress in patients with chronic heart failure: Comparison between systolic and diastolic heart failure. J Am Coll Cardiol 2006;47:742–748. 186. Sumida H, Yasue H, Yoshimura M, et al: Comparison of secretion pattern between A-type and B-type natriuretic peptides in patients with old myocardial infarction. J Am Coll Cardiol 1995;25:1105–1110. 187. Troughton RW, Prior DL, Pereira JJ, et al: Plasma B-type natriuretic peptide levels in systolic heart failure: Importance of left ventricular diastolic function and right ventricular systolic function. J Am Coll Cardiol 2004;43: 416–422. 188. Mariano-Goulart D, Eberle MC, Boudousq V, et al: Major increase in brain natriuretic peptide indicates right ventricular systolic dysfunction in patients with heart failure. Eur J Heart Fail 2003;5:481–488. 189. Hunt J, Yandle TG, Nicholls MG, et al: The amino-terminal portion of pro–brain natriuretic peptide (Pro-BNP) circulates in human plasma. Biochem Biophys Res Commun 1995;214:1175–1183. 190. Richards M, Nicholls MG, Espiner EA, et al: Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease. J Am Coll Cardiol 2006;47:52–60. 191. Yoshimura M, Yasue H, Okumura K, et al: Diﬀerent secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993;87:464–469. 192. Watanabe S, Shite J, Takaoka H, et al: Myocardial stiﬀness is an important determinant of the plasma brain natriuretic peptide concentration in patients with both diastolic and systolic heart failure. Eur Heart J 2006;27: 832–838. 193. Nishikimi T, Yoshihara F, Morimoto A, et al: Relationship between left ventricular geometry and natriuretic peptide levels in essential hypertension. Hypertension 1996;28:22–30. 194. Tang WH, Girod J, Lee MJ, et al: Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure. Circulation 2003;108:2964–2966. 195. Tsutamoto T, Wada A, Sakai H, et al: Relationship between renal function and plasma brain natriuretic peptide in patients with heart failure. J Am Coll Cardiol 2006;47:582–586. 196. Wang TJ, Larson MG, Levy D, et al: Impact of obesity on plasma natriuretic peptide levels. Circulation 2004;109:594–600. 197. McCullough A, Duc P, Omland T, et al: B-type natriuretic peptide and renal function in the diagnosis of heart failure: An analysis from the Breathing Not Properly Multinational Study. Am J Kidney Dis 2003;41:571– 579. 198. Lukowicz TV, Fischer M, Hense HW, et al: BNP as a marker of diastolic dysfunction in the general population: Importance of left ventricular hypertrophy. Eur J Heart Fail. 2005;7:525–531.

363

364

Chapter 27 • Role of Neurohormones 199. Knudsen CW, Omland T, Clopton P, et al: Impact of atrial ﬁbrillation on the diagnostic performance of B-type natriuretic peptide concentration in dyspneic patients: An analysis from the breathing not properly multinational study. J Am Coll Cardiol 2005;46:838–844. 200. Costello-Boerrigter LC, Boerrigter G, Redﬁeld MM, et al: Amino-terminal pro–B-type natriuretic peptide and B-type natriuretic peptide in the general community: Determinants and detection of left ventricular dysfunction. J Am Coll Cardiol 2006;47:345–353. 201. Tsuyuki RT, Yusuf S, Rouleau JL, et al: Combination neurohormonal blockade with ACE inhibitors angiotensin II antagonists and beta-blockers in patients with congestive heart failure: Design of the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study. Can J Cardiol 1997;13:1166–1174. 202. Ala-Kopsala M, Magga J, Peuhkurinen K, et al: Molecular heterogeneity has a major impact on the measurement of circulating N-terminal fragments of A- and B-type natriuretic peptides. Clin Chem 2004;50:1576– 1588. 203. Nishikimi T, Matsuoka H: Routine measurement of natriuretic peptide to guide the diagnosis and management of chronic heart failure. Circulation 2004;109:e325–326; author reply e325–326. 204. Mehra MR, Uber A, Walther D, et al: Gene expression proﬁles and B-type natriuretic peptide elevation in heart transplantation: More than a hemodynamic marker. Circulation 2006;114(1 Suppl):I21–I26. 205. Clerico A, Prontera C, Emdin M, et al: Analytical performance and diagnostic accuracy of immunometric assays for the measurement of plasma Btype natriuretic peptide (BNP) and N-terminal proBNP. Clin Chem 2005;51:445–447. 206. Hammerer-Lercher A, Ludwig W, Falkensammer G, et al: Natriuretic peptides as markers of mild forms of left ventricular dysfunction: Eﬀects of assays on diagnostic performance of markers. Clin Chem 2004;50:1174–1183. 207. Clerico A, Zucchelli GC, Pilo A, et al: Clinical relevance of biological variation of B-type natriuretic peptide. Clin Chem 2005;51:925–926. 208. Wu AH, Smith A, Wieczorek S, et al: Biological variation for N-terminal pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure. American Journal of Cardiology 2003;92:628–631. 209. Braunschweig F, Fahrleitner-Pammer A, Mangiavacchi M, et al: Correlation between serial measurements of N-terminal pro brain natriuretic peptide and ambulatory cardiac ﬁlling pressures in outpatients with chronic heart failure. Eur J Heart Fail 2006;8:797–803. 210. Bruins S, Fokkema MR, Romer JW, et al: High intraindividual variation of B-type natriuretic peptide (BNP) and amino-terminal proBNP in patients with stable chronic heart failure. Clin Chem 2004;50:2052–2058. 211. Morrow DA, de Lemos JA, Blazing MA, et al: Prognostic value of serial Btype natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. JAMA 2005;294:2866–2871. 212. Cheng V, Kazanagra R, Garcia A, et al: A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: A pilot study. J Am Coll Cardiol 2001;37:386–391. 213. Dias P, Rodrigues RA, Queiros MC, et al: Prognosis in patients with heart failure and preserved left ventricular systolic function. Rev Port Cardiol 2001;20:1223–1232. 214. Bettencourt P, Ferreira S, Azevedo A, et al: Preliminary data on the potential usefulness of B-type natriuretic peptide levels in predicting outcome after hospital discharge in patients with heart failure. Am J Med 2002;113: 215–219. 215. Johnson W, Omland T, Hall C, et al: Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol 2002;39:1623–1629. 216. Yamaguchi H, Yoshida J, Yamamoto K, et al: Elevation of plasma brain natriuretic peptide is a hallmark of diastolic heart failure independent of ventricular hypertrophy. J Am Coll Cardiol 2004;43:55–60. 217. Joung B, Ha JW, Ko YG, et al: Can pro-brain natriuretic peptide be used as a noninvasive predictor of elevated left ventricular diastolic pressures in patients with normal systolic function? Am Heart J 2005;150:1213–1219. 218. Kazanegra R, Cheng V, Garcia A, et al: A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: A pilot study. J Card Fail 2001;7:21–29. 219. O’Neill JO, Bott-Silverman CE, McRae AT 3rd, et al: B-type natriuretic peptide levels are not a surrogate marker for invasive hemodynamics during management of patients with severe heart failure. Am Heart J 2005; 149:363–369. 220. Dzau VJ Vascular and renal prostaglandins as counter-regulatory systems in heart failure. Eur Heart J 1988;9(Suppl H):15–19.

221. Hogg K, McMurray J: Neurohumoral pathways in heart failure with preserved systolic function. Prog Cardiovasc Dis 2005;47:357–366. 222. Carson P, Johnson G, Fletcher R, et al: Mild systolic dysfunction in heart failure (left ventricular ejection fraction >35%): Baseline characteristics prognosis and response to therapy in the Vasodilator in Heart Failure Trial (V-HeFT). J Am Coll Cardiol 1996;27:642–649. 223. Bursi F, Weston SA, Redﬁeld MM, et al: Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–2216. 224. Vinch CS, Aurigemma G, Hill JC, et al: Usefulness of clinical variables echocardiography and levels of brain natriuretic peptide and norepinephrine to distinguish systolic and diastolic causes of acute heart failure. Am J Cardiol 2003;91:1140–1143. 225. Maisel AS, McCord J, Nowak RM, et al: Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure. with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study. J Am Coll Cardiol 2003;41:2010–2017. 226. Maisel AS, Krishnaswamy P, Nowak RM, et al: Rapid measurement of Btype natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–167. 227. Eﬀects of an angiotensin-converting-enzyme inhibitor ramipril on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145–153. 228. Pitt B, Reichek N, Willenbrock R, et al: Eﬀects of eplerenone enalapril and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: The 4E–left ventricular hypertrophy study. Circulation 2003;108:1831–1838. 229. Grandi AM, Imperiale D, Santillo R, et al: Aldosterone antagonist improves diastolic function in essential hypertension. Hypertension 2002;40: 647–652. 230. Fox KM Eﬃcacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised double-blind placebo-controlled multicentre trial. (the EUROPA study). Lancet 2003;362(9386):782–788. 231. Arnold JM, Yusuf S, Young J, et al: Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2003;107:1284–1290. 232. Davis BR, Piller LB, Cutler JA, et al: Role of diuretics in the prevention of heart failure: The antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2006;113:2201–2210. 233. Eﬀects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987; 316:1429–1435. 234. Flather MD, Shibata MC, Coats AJS, et al: Randomized trial to determine the eﬀect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–225. 235. Campbell DJ, Aggarwal A, Esler M, et al: Beta blockers angiotensin II and ACE inhibitors in patients with heart failure. Lancet 2001;358(9293): 1609–1610. 236. Fung JW, Yu CM, Yip G, et al: Eﬀect of beta blockade (carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure. Am J Cardiol 2003;92: 406–410. 237. Takeda Y, Fukutomi T, Suzuki S, et al: Eﬀects of carvedilol on plasma Btype natriuretic peptide concentration and symptoms in patients with heart failure and preserved ejection fraction. Am J Cardiol 2004;94:448– 453. 238. Nakamura M, Endo H, Nasu M, et al: Value of plasma B type natriuretic peptide measurement for heart disease screening in a Japanese population. Heart 2002;87:131–135. 239. Nakamura M, Tanaka F, Sato K, et al: B-type natriuretic peptide testing for structural heart disease screening: A general population-based study. J Card Fail 2005;11:705–712. 240. Niinuma H, Nakamura M, Hiramori K: Plasma B-type natriuretic peptide measurement in a multiphasic health screening program. Cardiology 1998;90:89–94. 241. Rodeheﬀer RJ: Measuring plasma B-type natriuretic peptide in heart failure: Good to go in 2004? J Am Coll Cardiol 2004;44:740–749. 242. Lubien E, DeMaria A, Krishnaswamy P, et al: Utility of B-natriuretic peptide in detecting diastolic dysfunction: Comparison with Doppler velocity recordings. Circulation 2002;105:595–601. 243. Maisel AS, Koon J, Krishnaswamy P, et al: Utility of B-natriuretic peptide as a rapid point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J 2001;141:367–374.

Chapter 27 • Role of Neurohormones 244. Krishnaswamy P, Lubien E, Clopton P, et al: Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction. Am J Med 2001;111:274–279. 245. Redﬁeld MM, Rodeheﬀer RJ, Jacobsen SJ, et al: Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: a community-based study. Circulation 2004;109:3176–3181. 246. Vasan RS, Benjamin EJ, Larson MG, et al: Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: The Framingham Heart Study. JAMA 2002;288:1252–1259. 247. Bibbins-Domingo K, Ansari M, Schiller NB, et al: Is B-type natriuretic peptide a useful screening test for systolic or diastolic dysfunction in patients with coronary disease? Data from the Heart and Soul Study. Am J Med 2004;116:509–516. 248. Vasan RS, Benjamin EJ, Larson MG, et al: Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: The Framingham heart study. JAMA 2002;288:1252–1259. 249. Gerber IL, Stewart RA, French JK, et al: Associations between plasma natriuretic peptide levels symptoms and left ventricular function in patients with chronic aortic regurgitation. Am J Cardiol 2003;92:755–758. 250. Gerber IL, Stewart RA, Legget ME, et al: Increased plasma natriuretic peptide levels reﬂect symptom onset in aortic stenosis. Circulation 2003;107:1884–1890. 251. Sabatine MS, Morrow DA, de Lemos JA, et al: Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia. J Am Coll Cardiol 2004;44:1988–1995. 252. Bibbins-Domingo K, Ansari M, Schiller NB, et al: B-type natriuretic peptide and ischemia in patients with stable coronary disease: Data from the Heart and Soul study. Circulation 2003;108:2987–2992. 253. Caruana L, Petrie MC, Davie A, et al: Do patients with suspected heart failure and preserved left ventricular systolic function suﬀer from “diastolic heart failure” or from misdiagnosis? A prospective descriptive study. BMJ 2000;321:215–218. 254. Wright S, Doughty RN, Pearl A, et al: Plasma amino-terminal pro–brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care: A randomized controlled trial. J Am Coll Cardiol 2003;42:1793–1800. 255. Lainchbury JG, Campbell E, Frampton CM, et al: Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. J Am Coll Cardiol 2003;42:728–735. 256. Maisel AS, Clopton P, Krishnaswamy P, et al: Impact of age race and sex on the ability of B-type natriuretic peptide to aid in the emergency diagnosis of heart failure: Results from the Breathing Not Properly (BNP) multinational study. Am Heart J 2004;147:1078–1084. 257. Maisel AS, McCord J, Nowak RM, et al: Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction: Results from the Breathing Not Properly Multinational Study. J Am Coll Cardiol 2003;41:2010–2017. 258. Mueller C, Scholer A, Laule-Kilian K, et al: Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350:647–654. 259. Latini R, Masson S, Anand I, et al: The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J 2004;25:292–299. 260. Logeart D, Thabut G, Jourdain P, et al: Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol 2004;43:635–641. 261. Latini R, Masson S, Wong M, et al: Incremental prognostic value of changes in B-type natriuretic peptide in heart failure. Am J Med 2006; 119:70.e23–70.e30. 262. Anand IS, Fisher LD, Chiang YT, et al: Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107:1278–1283. 263. Kirk V, Bay M, Parner J, et al: N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs reduced systolic function: Data from the prospective Copenhagen Hospital Heart Failure Study (CHHF). Eur J Heart Fail 2004;6:335–341. 264. Wang TJ, Larson MG, Levy D, et al: Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350: 655–663. 265. Hunt SA ACC/AHA 2005; guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001; Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46: e1–e82.

266. Blankenberg S, McQueen MJ, Smieja M, et al: Comparative impact of multiple biomarkers and N-Terminal pro–brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2006;114:201–208. 267. Richards AM, Nicholls MG, Espiner EA, et al: B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation 2003;107:2786–2792. 268. Richards AM, Nicholls MG, Yandle TG, et al: Plasma N-terminal pro– brain natriuretic peptide and adrenomedullin: New neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 1998;97:1921–1929. 269. De Lemos JA, Morrow DA, Bentley JH, et al: The prognostic value of Btype natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–1021. 270. Omland T, Aakvaag A, Bonarjee VV, et al: Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction: Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996;93:1963–1969. 271. Rouleau JL, de Champlain J, Klein M, et al: Activation of neurohumoral systems in postinfarction left ventricular dysfunction J Am Coll Cardiol 1993;22:390–398. 272. Gill D, Seidler T Troughton RW, et al: Vigorous response in plasma Nterminal pro–brain natriuretic peptide (NT–BNP) to acute myocardial infarction. Clin Sci (Lond) 2004;106:135–139. 273. Pfeﬀer MA, Braunwald E, Moye LA, et al: Eﬀect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669–677. 274. Doughty RN, Whalley GA, Walsh HA, et al: Eﬀects of carvedilol on left ventricular remodeling after acute myocardial infarction: The CAPRICORN Echo Substudy. Circulation 2004;109:201–206. 275. Dargie HJ Eﬀect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001;357(9266):1385–1390. 276. St John Sutton M, Pfeﬀer MA, Moye L, et al: Cardiovascular death and left ventricular remodeling two years after myocardial infarction: Baseline predictors and impact of long-term use of captopril: Information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation 1997;96:3294–3299. 277. Hillis GS, Moller JE, Pellikka A, et al: Noninvasive estimation of left ventricular ﬁlling pressure by E/e’ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360– 367. 278. Moller JE, Hillis GS, Oh JK, et al: Left atrial volume: A powerful predictor of survival after acute myocardial infarction. Circulation 2003;107: 2207–2212. 279. Tang WH, Francis GS: The diﬃcult task of evaluating how to monitor patients with heart failure. J Card Fail 2005;11:422–424. 280. Jourdain P, Funck F, Gueﬀet P, et al: Beneﬁts of BNP plasma levels for optimizing therapy: The systolic heart failure treatment supported by BNP multicenter randomized trial (STARS-BNP). J Am Coll Cardiol 2007;49:1733–1739. 281. Rousseau MF, Gurne O, van Eyll C, et al: Eﬀects of benazeprilat on left ventricular systolic and diastolic function and neurohumoral status in patients with ischemic heart disease. Circulation 1990;81(2 Suppl): III123–III129. 282. Yoshimura M, Yasue H, Morita E, et al: Hemodynamic renal and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 1991;84:1581–1588. 283. Lainchbury JG, Richards AM, Nicholls MG, et al: The eﬀects of pathophysiological increments in brain natriuretic peptide in left ventricular systolic dysfunction. Hypertension 1997;30(3 Pt 1):398–404. 284. Clarkson B, Wheeldon NM, MacFadyen RJ, et al: Eﬀects of brain natriuretic peptide on exercise hemodynamics and neurohormones in isolated diastolic heart failure. Circulation 1996;93:2037–2042. 285. Leya FS, Arab D, Joyal D, et al: The eﬃcacy of brain natriuretic peptide levels in diﬀerentiating constrictive pericarditis from restrictive cardiomyopathy. J Am Coll Cardiol 2005;45:1900–1902. 286. Palladini G, Campana C, Klersy C, et al: Serum N-terminal pro–brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation 2003;107:2440–2445. 287. DeFilippi CR, Fink JC, Nass CM, et al: N-terminal pro–B-type natriuretic peptide for predicting coronary disease and left ventricular hypertrophy in

365

366

Chapter 27 • Role of Neurohormones

288.

289.

290. 291.

292. 293. 294. 295. 296. 297.

asymptomatic CKD not requiring dialysis. Am J Kidney Dis 2005;46: 35–44. Luchner A, Hengstenberg C, Lowel H, et al: Eﬀect of compensated renal dysfunction on approved heart failure markers: Direct comparison of brain natriuretic peptide (BNP) and N-terminal pro-BNP. Hypertension 2005;46:118–123. Vickery S, Price C, John RI, et al: B-type natriuretic peptide (BNP) and amino-terminal proBNP in patients with CKD: Relationship to renal function and left ventricular hypertrophy. Am J Kidney Dis 2005;46:610– 620. Zoccali C, Mallamaci F, Benedetto FA, et al: Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients. J Am Soc Nephrol 2001;12:1508–1515. Anwaruddin S, Lloyd-Jones DM, Baggish A, et al: Renal function congestive heart failure and amino-terminal pro–brain natriuretic peptide measurement: Results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. J Am Coll Cardiol 2006;47:91–97. Dastoor H, Bernieh B, Boobes Y, et al: Plasma BNP in patients on maintenance haemodialysis: A guide to management? J Hypertens 2005;23:23–28. Vanderheyden M, Goethals M, Verstreken S, et al: Wall stress modulates brain natriuretic peptide production in pressure overload cardiomyopathy. J Am Coll Cardiol 2004;44:2349–2354. Ikeda T, Matsuda K, Itoh H, et al: Plasma levels of brain and atrial natriuretic peptides elevate in proportion to left ventricular end-systolic wall stress in patients with aortic stenosis. Am Heart J 1997;133:307–314. Sutton TM, Stewart RA, Gerber IL, et al: Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J Am Coll Cardiol 2003;41:2280–2287. Maron BJ, Tholakanahalli VN, Zenovich AG, et al: Usefulness of B-type natriuretic peptide assay in the assessment of symptomatic state in hypertrophic cardiomyopathy. Circulation 2004;109:984–989. Briguori C, Betocchi S, Manganelli F, et al: Determinants and clinical signiﬁcance of natriuretic peptides and hypertrophic cardiomyopathy. Eur Heart J 2001;22:1328–1336.

298. Kim SW, Park SW, Lim SH, et al: Amount of left ventricular hypertrophy determines the plasma N-terminal pro–brain natriuretic peptide level in patients with hypertrophic cardiomyopathy and normal left ventricular ejection fraction. Clin Cardiol 2006;29:155–160. 299. Arteaga E, Araujo AQ, Buck P, et al: Plasma amino-terminal pro–B-type natriuretic peptide quantiﬁcation in hypertrophic cardiomyopathy. Am Heart J 2005;150:1228–1232. 300. Ogino K, Ogura K, Kinugawa T, et al: Neurohumoral proﬁles in patients with hypertrophic cardiomyopathy: Diﬀerences to hypertensive left ventricular hypertrophy. Circ J 2004;68:444–450. 301. Nakamura T, Sakamoto K, Yamano T, et al: Increased plasma brain natriuretic peptide level as a guide for silent myocardial ischemia in patients with non-obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:1657–1663. 302. Poutanen T, Tikanoja T, Jaaskelainen, et al: Diastolic dysfunction without left ventricular hypertrophy is an early ﬁnding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain alpha-tropomyosin and myosin-binding protein C genes. Am Heart J 2006;151:725.e1–725.e9. 303. Furumoto T, Fujii S, Mikami T, et al: Increased plasma concentrations of N-terminal pro–brain natriuretic peptide reﬂect the presence of mildly reduced left ventricular diastolic function in hypertension. Coron Artery Dis 2006;17:45–50. 304. Luchner A, Burnett JC Jr, Jougasaki M, et al: Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens 2000;18:1121–1128. 305. Freitag MH, Larson MG, Levy D, et al: Plasma brain natriuretic peptide levels and blood pressure tracking in the Framingham Heart Study. Hypertension 2003;41:978–983. 306. Paulus WJ, Tschope C, Sanderson JE, et al: How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539–2550.

28

WILLIAM H. GAASCH, MD EDMUND A. BERMUDEZ, MD CATALIN F. BAICU, PhD

Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY Cardiac Structure and Diastolic Function Contractile Behavior Response to Exercise FUTURE RESEARCH

INTRODUCTION In diastolic heart failure, the left ventricular ejection fraction (LVEF) is normal and the dominant functional abnormality resides in diastole. Thus, there is increased passive stiﬀness with impaired relaxation of the ventricle, which results in a disturbed pattern of left ventricular (LV) ﬁlling and elevated end diastolic pressure.1,2 Global systolic performance, function, and contractility remain normal.3,4 However, several reports indicate that abnormalities in regional shortening are present in patients with diastolic heart failure.5–9 These ﬁndings have been interpreted as evidence supporting the notion that heart failure is somehow caused by these regional abnormalities in shortening.5 The signiﬁcance of these observations, particularly their relation to the syndrome of heart failure, remains uncertain. Accordingly, in this chapter we will review the published data on LV global and regional systolic function in diastolic heart failure and will attempt to reconcile what appear to be disparate conclusions about LV systolic function in patients with this condition.

PATHOPHYSIOLOGY The term diastolic dysfunction refers to an abnormality of LV diastolic distensibility, ﬁlling, or relaxation—regardless of whether the EF is normal or abnormal and whether the patient is asymptomatic or symptomatic with clinical evidence of heart failure. In the absence of symptoms, those with a normal EF and diastolic dysfunction are said to have preclinical heart disease or asymptomatic diastolic dysfunction.10,11 Patients with the signs and symptoms of heart failure, a normal LVEF, and LV diastolic dysfunction are said to have diastolic heart failure.2 If nonmyocardial causes of heart failure (e.g., mitral stenosis) are excluded, such patients meet published criteria for diastolic heart failure.12 Thus, diastolic heart failure refers to a syndrome of heart failure that is not caused by reduced systolic function, but rather is closely related to chronic structural remodeling and abnormalities in the diastolic properties of the left ventricle. These deﬁnitions of asymptomatic diastolic dysfunction and diastolic heart failure parallel those used in asymptomatic and symptomatic patients with LV systolic dysfunction and facilitate the use of a pathophysiologic, diagnostic, and therapeutic framework that includes all patients with LV dysfunction.11

Cardiac Structure and Diastolic Function The anatomic features of hearts from patients with diastolic heart failure diﬀer substantially from those with systolic heart failure (Table 28-1) (see Chapter 2). Patients with diastolic heart failure generally exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by a normal or nearnormal end diastolic volume and increased wall thickness with a 367

368

Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure arterial tone can cause a substantial increase in left atrial (LA) and pulmonary venous pressures (i.e., diastolic heart failure).

TABLE 28-1 CHARACTERISTICS OF DIASTOLIC VS. SYSTOLIC HEART FAILURE (HF)

Clinical Features Symptoms (e.g., dyspnea) Congestive state (e.g., edema) Exercise tolerance Neurohormonal activation (e.g., BNP) LV Structure and Geometry LV mass and geometry Relative wall thickness End diastolic volume Cardiomyocytes Extracellular matrix

Contractile Behavior

DIASTOLIC HF

SYSTOLIC HF

Yes Yes

Yes Yes

Decreased Yes

Decreased Yes

Global Contractile Behavior Concentric LVH Increased Normal Increased diameter Increased collagen

Eccentric LVH Decreased Increased Increased length Decreased collagen

BNP, brain natriuretic peptide; LV, left ventricular; LVH, left ventricular hypertrophy.

TABLE 28-2 LEFT VENTRICULAR (LV) VOLUME, MASS, GEOMETRY, AND SYSTOLIC LOAD IN NORMAL CONTROL SUBJECTS AND PATIENTS WITH DIASTOLIC HEART FAILURE (DHF)

LV end diastolic volume (ml) LV end systolic volume (ml) LV mass (g) Relative wall thickness Systolic blood pressure (mmHg) LV systolic wall stress (g/cm2)

A comprehensive description of the systolic or contractile behavior of the left ventricle requires measurement of LV performance, function, and contractility, as well as a consideration of ventricular remodeling and loading conditions and a distinction between global and regional properties.

NORMAL

DHF

p

115 ± 9 45 ± 12 164 ± 35 0.38 ± 0.06 128 ± 8

103 ± 22 45 ± 11 251 ± 101 0.53 ± 0.11 160 ± 40

<0.001 NS <0.001 <0.001 <0.001

201 ± 32

187 ± 44

NS

Data are mean ± SD. From Baicu CF et al: Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005;111:2306–2312.

high ratio of mass-to-volume and a high ratio of wall thicknessto-chamber radius (Table 28-2). At the microscopic level, the cardiomyocyte exhibits an increased diameter, and there is an increase in the amount of collagen surrounding the myocytes. These anatomic or structural features tend to parallel abnormalities in diastolic function.3,4 The passive elastic properties of the ventricle and the process of active relaxation determine the LV diastolic pressure-volume (P-V) relation and diastolic function.1 Abnormal passive elastic properties are caused largely by increased myocardial mass and alterations in the extramyocardial collagen network, but changes in intramyocardial components (e.g., titin) also contribute to an increase in passive stiﬀness.13,14 The eﬀects of abnormally prolonged or delayed myocardial relaxation can be superimposed on the passive diastolic P-V curve and cause a further increase in diastolic pressure relative to volume. Those changes in passive stiﬀness, relaxation, or both produce an upward displacement of the diastolic P-V relation, and as a result, chamber compliance is reduced, the time course of ﬁlling is altered, and LV diastolic pressure is elevated. Under these circumstances a relatively small increase in central blood volume or an increase in venous and

The functional capacity of the whole ventricle is most appropriately described by a composite of parameters reﬂecting LV performance, function, and contractility. Such parameters are determined using a combination of cardiac catheterization and imaging techniques.1,3 Performance The pumping ability or performance of the left ventricle is best described by the stroke work, which credits the ventricle for pressure and volume work in a single integrated index. This index of performance is determined as the product of developed pressure and total stroke volume. Thus it becomes obvious that it may be increased in hypertensive patients or decreased in patients with a small LV chamber and a low stroke volume. However, stroke work is normal in the vast majority of patients with diastolic heart failure (Fig. 28-1 and Table 28-3).3 It should be recognized that this performance index reﬂects a pumping property of the whole ventricle, not that of a unit of myocardium. Indeed, if the value for stroke work is expressed relative to LV mass, work may be subnormal. Thus, myocardial performance (work per gram of myocardium) may be abnormal in patients with LV hypertrophy (LVH), but the pump performance (stroke work) of the whole ventricle remains normal. Function A classic ventricular function curve can be constructed by plotting coordinates of LV performance (stroke work) against preload (end diastolic volume). When LV contractility is increased, this stroke work versus preload relation is shifted upward; when contractility is decreased, the relation is shifted downward. Such Frank-Starling ventricular function curves credit the ventricle for pressure development and shortening, and the analysis incorporates ventricular preload. This method provides a preloadrecruitable stroke work relation, which remains normal in patients with diastolic heart failure (see Fig. 28-1 and Table 28-3). The term ventricular function has been redeﬁned and expanded to include a variety of shortening parameters, the most common of which is LVEF. This dimensionless parameter reﬂects volume strain (change in volume divided by initial volume). It is by deﬁnition normalized and does not require consideration of absolute volume or body size. Decades ago, the prognostic value of the EF was conﬁrmed in patients with coronary and valvular heart disease.15 Since then, it has been applied in virtually all forms of heart disease, and with rare exception, if the EF is normal—all other indices of LV global performance, function, and contractility remain in the normal range. It should be recognized, however, that the EF, like all other shortening parameters, is inﬂuenced by acute or short-term alterations in LV preload, afterload, and contractility, as well as by chronic remodeling and hypertrophy, both of which contribute to long-term changes in load and contractility. Despite these limitations, EF remains the

10 8 6 4 2 0

80

150

p = 0.13

Ejection fraction (%)

p = 0.26

Preload recruitable stroke work (gram/cm2)

Stroke work (Kg.cm)

12

120

Normal Diastolic heart failure

90 60 30

p = 0.29

60 40 20 0

0 Normal Diastolic heart failure

Figure 28-1 Left ventricular stroke work and preload-recruitable stroke work in diastolic heart failure. Stroke work (left) is not significantly different from normal. Preload-recruitable stroke work (right) is not significantly different from normal. Thus, ventricular performance and function are normal in diastolic heart failure. Data are mean ± SE.

Peak (+)dP/dt (mmHg/sec)

Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure 2400

p = 0.54

1800 1200

Normal Diastolic heart failure

600 0 Normal Diastolic heart failure

Figure 28-2 Left ventricular ejection fraction and peak positive (+)dP/dt in diastolic heart failure. The ejection fraction, by definition, exceeds 50% and is not significantly different from normal. Peak (+)dP/dt (right) is not significantly different from normal in diastolic heart failure; this indicates normal ventricular contractility. Data are mean ± SE.

TABLE 28-3 LEFT VENTRICULAR (LV) SYSTOLIC PERFORMANCE, FUNCTION, AND CONTRACTILITY IN NORMAL CONTROL SUBJECTS AND PATIENTS WITH DIASTOLIC HEART FAILURE (DHF) NORMAL

DHF

p

LV Systolic Performance SW (kg-cm)

8.8 ± 2.5

8.4 ± 2.3

LV Systolic Function SW/EDV (g/cm2) PRSW (g/cm2) Fractional shortening (%) Ejection fraction (%) Vcf (circumferences/sec) PEP/LVET

74 ± 10 109 ± 18 33 ± 5 0.61 ± 0.07 1.8 ± 0.2 0.37 ± 0.19

81 ± 14 99 ± 22 27 ± 4 0.58 ± 0.06 1.8 ± 0.2 0.35 ± 0.13

<0.01 NS NS NS NS NS

LV Contractility Peak (+)dP/dt (mmHg/s) ESP/ESV (mmHg/ml) Ees (mmHg/ml) Ees′ (mmHg/g)

1664 ± 305 2.1 ± 0.8 1.6 ± 0.5 1.2 ± 0.4

1596 ± 362 2.6 ± 1.1 2.4 ± 0.9 1.1 ± 0.6

NS <0.05 <0.001 NS

NS

Data are mean ± SD. SW, stroke work, EDV, end diastolic volume, PRSW, preload recruitable stroke work, Vcf, circumferential fiber shortening velocity, PEP, pre-ejection period, LVET, left ventricular ejection time, ESP, end systolic pressure, ESV, end systolic volume, Ees, elastance at end systole, Ees′, normalized elastance. From Baicu CF et al: Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005;111:2306–2312.

most widely applied and clinically useful index of LV systolic function. By deﬁnition, EF is normal (or near normal) in diastolic heart failure. Likewise, circumferential shortening measured at the endocardial surface, expressed as a fractional change (%), is normal, as is the relation between fractional shortening (FS) and systolic wall stress. Contractility The inotropic or contractile state of the whole ventricle is referred to as ventricular contractility. The concept of LV contractility is analogous to that of myocardial contractility, which is a property of the myocardium that is independent of loading conditions. Indices of ventricular contractility have conventionally been classiﬁed as: 1. Isovolumic phase indices (e.g., (+)dP/dt) 2. Ejection phase indices (e.g., relation of systolic wall stress to ejection fraction) 3. End systolic indices (e.g., end systolic elastance)

Unfortunately none of these indices is truly independent of loading conditions or ventricular remodeling. For example, (+)dP/dt may be altered by an acute change in preload, whereas end systolic elastance (Ees) may be aﬀected by chronic changes in LV mass/volume ratio (m/v).16,17 When studied in a chronic steady state, patients with diastolic heart failure exhibit normal values for peak (+)dP/dt, normal values for systolic elastance, and normal stress-shortening relations (Figs. 28-2, 28-3, and 28-4, and see Table 28-3). These data indicate that ventricular contractility is normal in patients with diastolic heart failure. Summary Indices of LV systolic performance, function, and contractility are normal in patients with diastolic heart failure. These normal indices can be taken as evidence that the pumping ability of the whole ventricle (global systolic behavior) is normal. This conclusion does not exclude the possibility that abnormalities in regional function may exist in some patients.

Regional Contractile Behavior Measurements of the extent and velocity of regional myocardial length transients (both shortening and lengthening) can be made using a variety of techniques, including echocardiography and tissue Doppler imaging (TDI). For example, M-mode echocardiography can be used to describe mitral annular motion or displacement and to assess long-axis shortening. Echocardiography can also be used to deﬁne circumferential shortening at the LV endocardial surface or at the midwall. TDI technology has made it possible to assess length transients in multiple areas of interest along the long axis of the ventricle. To be interpreted appropriately, the measurements must be normalized to produce regional strain and strain rate; these parameters are dimensionless and are expressed as percent change and inverse seconds, respectively. Figure 28-5 illustrates the directions of LV longitudinal, circumferential, and radial strain (ε). Systolic strain or shortening may be expressed as the ratio of: (end diastolic length − end systolic length)/ end diastolic length

369

Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure εl

Midwall fractional shortening (%)

50 Normal Normal +/ – 95% Diastolic heart failure

40

εl : Longitudinal strain εr

30

εr : Radial strain

20

εc

εc : Circumferential strain

10 0

Endocardial fractional shortening (%)

0

75

50

150

225

300

Figure 28-5 Diagram indicating the direction of different myocardial strain vectors.

Normal Normal +/– 95% Diastolic heart failure

40

even some individuals with LV concentric remodeling in the absence of hypertension.18–20 These regional shortening abnormalities reﬂect regional myocardial function and may have prognostic value, but there is little relation between midwall shortening and the signs or symptoms of heart failure.

30 20 10 0 0

75

150

225

Mean systolic stress

300

(gram/cm2)

4 p < 0.001 3 2 1 0

End systolic elastance (mmHg/g)

Figure 28-3 Left ventricular stress-shortening relations in diastolic heart failure. At the endocardial surface in the circumferential plane, all stressshortening coordinates lie in the normal range (top). By contrast, approximately one third of the midwall stress-shortening coordinates lie below the range of normal (bottom). Thus, ventricular contractility remains normal in the presence of depressed regional (i.e., midwall) stress-shortening relations.

End systolic elastance (mmHg/ml)

370

1.6

p = 0.56

1.2 0.8 0.4

Longitudinal Shortening The published data on regional (long-axis) function in diastolic heart failure are limited, but there is general agreement that abnormal extent and velocity of shortening are abnormal in a minority of patients with diastolic heart failure.4 For example, Yip et al.5 and Petrie et al.7 found systolic mitral annular displacement to be abnormal in one third to one half of their patients. Yu et al.6 and Nikitin et al.8 found reduced velocity along the long axis in less than half of their patients. Critical review of these data suggests that the heart failure seen in their patients with a normal EF was not related to the abnormalities in long-axis shortening.4 Summary Based on the published data from patients with diastolic heart failure (and some with asymptomatic LVH and diastolic dysfunction), it appears that approximately one third to one half of the patients exhibit some abnormality of regional systolic function, but it has not been shown that such abnormalities are responsible for the clinical syndrome of heart failure. This area of clinical investigation requires additional studies using appropriate strain and strain rate calculations and modern imaging techniques.

0 Normal Diastolic heart failure

Normal Diastolic heart failure

Figure 28-4 Left ventricular end systolic elastance in diastolic heart failure. End systolic elastance is higher than normal in diastolic heart failure (left). When normalized for the mass/volume ratio, which corrects for the effects of chronic ventricular remodeling, the elastance value is not significantly different from normal (right). Data are mean ± SE.

Circumferential Shortening Stress-shortening relations at the midwall of the left ventricle are abnormal in approximately one third of patients with diastolic heart failure and normal shortening at the endocardial surface (see Fig. 28-3). A similar ﬁnding has been described in patients with hypertensive heart disease, patients with aortic stenosis, and

Response to Exercise The presence of normal LV performance, function, and contractility in a stable resting or basal state does not necessarily mean that the LV response to exercise is normal. Indeed, there is evidence that increased diastolic stiﬀness of the ventricle has at least two limiting eﬀects on the LV response to exercise. First, increased LV stiﬀness limits utilization of the Frank-Starling mechanism and thereby reduces the ability to augment stroke volume.21 Thus, LV diastolic dysfunction is responsible for an abnormality in systolic performance (during exercise). Second, increased LV stiﬀness is responsible for the dramatic increase in LV diastolic and pulmonary venous pressure that occurs as venous return increases during exercise.22 While other factors likely contribute to the impaired exercise tolerance that is seen in patients with diastolic

Chapter 28 • Global and Regional Systolic Function of the Left Ventricle in Diastolic Heart Failure dysfunction, with or without heart failure, these studies indicate that a primary causative mechanism resides in diastole.

FUTURE RESEARCH The diagnosis of heart failure is made clinically, requiring the presence of signs and symptoms (e.g., dyspnea, edema). Heart failure syndrome can be caused by LV systolic dysfunction, diastolic dysfunction, or both. In systolic heart failure, the dominant abnormalities reside in systole. In diastolic heart failure, the dominant functional abnormalities reside in diastole; LV global systolic performance, function, and contractility remain normal. Abnormal regional systolic function is present in one third to one half of all patients with diastolic heart failure, but more research is needed to determine whether such regional dysfunction contributes signiﬁcantly to the clinical syndrome of heart failure. REFERENCES 1. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure: Abnormalities in active relaxation and passive stiﬀness of the left ventricle. N Eng J Med 2004;350:1953–1959. 2. Aurigemma GP, Gaasch WH: Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 3. Baicu CF, Zile MR, Aurigemma GP, Gaasch WH: Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 2005;111:2306–2312. 4. Aurigemma GP, Zile MR, Gaasch WH: Contractile behavior of the left ventricle in diastolic heart failure: With emphasis on regional systolic function. Circulation 2006;113:296–304. 5. Yip G, Wang M, Zhang Y, et al: Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: Time for a redeﬁnition. Heart 2002;87:121–125. 6. Yu C, Lin H, Yang H, et al: Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation 2002;105:1195–1201. 7. Petrie MC, Caruana L, Berry C, McMurray JJV: Diastolic heart failure or heart failure caused by subtle left ventricular systolic dysfunction. Heart 2002;87:29–31.

8. Nikitin NP, Witte KK, Clark AL, Cleland JCF: Color tissue Dopplerderived long-axis left ventricular function in heart failure with preserved global systolic function. Am J Cardiol 2002;90:1174–1177. 9. Bruch C, Herrmann B, Schmermund A, et al: Impact of disease activity on left ventricular performance in patients with acromegaly. Am Heart J 2002;144:538–543. 10. Redﬁeld MM, Jacobsen SJ, Burnett JC, et al: Burden of systolic and diastolic ventricular dysfunction in the community. JAMA 2003;289:194–202. 11. Gaasch WH: Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. J Am Med Assoc 1994;271: 1276–1280. 12. Yturralde FR, Gaasch WH: Diagnostic criteria for diastolic heart failure. Progress in CV disease. Prog Cardiovacs Dis 2005;47:314–319. 13. LeWinter MM: Titin isoforms in heart failure. Circulation 2004;110; 109–111. 14. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure. Circulation 2006;113:1922–1925. 15. Cohn PF, Gorlin R, Cohn LH, Collins JJ: Left ventricular ejection fraction as a prognostic guide in surgical treatment of coronary and valvular heart disease. Am J Card 1974;34:136–140. 16. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and arterial stiﬀening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:656–658. 17. Pak PH, Maughan WL, Baughman KL, et al: Mechanism of acute mechanical beneﬁt from VDD pacing in hypertrophied heart: Similarity of responses in hypertrophic cardiomyopathy and hypertensive heart disease. Circulation 1998;98:242–248. 18. Aurigemma GP, Silver KH, Priest MA, Gaasch WH: Geometric changes allow for normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Coll Cardiol 1995;26: 195–202. 19. Aurigemma GP, Silver KH, McLaughlin M, et al: Impact of chamber geometry and gender on left ventricular systolic function in patients >60 years of age with aortic stenosis. Am J Cardiol 1994;74:794–798. 20. Aurigemma GP, Gaasch WH, McLaughlin M, et al: Reduced left ventricular systolic pump performance and depressed myocardial contractile function in patients >65 years of age with normal ejection fraction and a high relative wall thickness. Am J Cardiol 1995;76:702–705. 21. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic ﬁlling in essential hypertension: Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. 22. Kitzman DW, Higginbotham BM, Bobb FR, et al: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: Failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17: 1065–1072.

371

SANJAY KUMAR, MD RICHARD A. GRIMM, DO

29

Pacing and Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY Basics of Pacing and Cardiac Resynchronization Therapy Diastolic Dysfunction CLINICAL RELEVANCE Overall Effects of Pacing on Cardiac Function Pacing and Diastolic Function Effect of Cardiac Resynchronization Therapy on Diastolic Function Optimization of Atrioventricular Delay and Diastolic Function

Optimization of Interventricular Interval and Diastolic Function Adverse Effects of Pacing FUTURE RESEARCH Right Ventricular Outflow Tract Pacing Atrial-Based Managed Ventricular Pacing Mode in Dual-Chamber Implantable Cardioverter-Defibrillators The Best Modality of Cardiac Resynchronization Therapy Direct His Bundle Pacing Role of Cardiac Resynchronization Therapy for Diastolic Heart Failure

INTRODUCTION According to the American Heart Association, nearly 5 million Americans are living with heart failure, and approximately 550,000 new cases are diagnosed each year. Diastolic heart failure (DHF) contributes to approximately 40% to 50% of congestive heart failure (CHF) patients admitted to hospitals. DHF is characterized by clinical signs and symptoms of heart failure, normal ejection fraction (EF), and evidence of abnormal left ventricular (LV) relaxation, ﬁlling, diastolic distensibility, or diastolic stiﬀness.1,2 Zile et al. studied 63 patients with DHF with cardiac catheterization and echocardiography. Almost all had one or more abnormal indices of diastolic function.3 A recent population study showed that by comparison with systolic heart failure (SHF), DHF is more likely distinguished by older age, female sex, and a history of hypertension, as well as atrial ﬁbrillation. Although the adjusted 1-year mortality rate was higher for systolic than diastolic dysfunction, the heart failure readmission rate was similar at 30 days (4.5% vs. 4.7% p = 0.66) and 1 year (13.5% vs. 16.1% p = 0.09).4 More than 40% of heart failure patients have preserved systolic function, suggesting that diastolic dysfunction may be responsible

for the clinical manifestation of heart failure in these patients. Persson et al. studied 312 patients (mean age, 66; EF, 50%; female, 34%) over a median 569 days. Patients with normal diastolic function and mild diastolic dysfunction (abnormal relaxation) had a good prognosis, whereas moderate and severe diastolic dysfunctions (restrictive physiology) were associated with increased cardiovascular morbidity and mortality. Moderate and severe diastolic dysfunctions were the only predictors for cardiovascular death or heart failure hospitalization (p < 0.003).5 Apart from prognosis, the ventricular myocardium of DHF diﬀers from that of SHF. DHF is associated with myocyte hypertrophy, higher myoﬁbrillar density, elevated myocyte relative thickness, and increased myoﬁlamentary Ca2+ sensitivity.6 Since the beginning of pacing therapy in 1958, tremendous improvement in technology has produced more sophisticated, eﬃcient, and compact pacemakers. The pacing sites, pacing modes, and baseline heart function inﬂuence diastolic heart function, and various authors have reported the eﬀects of pacing on one or more diastolic function parameters. This chapter will discuss and explore this evolving understanding of the eﬀects of pacing therapy on diastolic function and DHF. 373

374

Chapter 29 • Pacing and Diastolic Heart Failure

PATHOPHYSIOLOGY Basics of Pacing and Cardiac Resynchronization Therapy Pacemakers generate an electrical charge through electrodes that produce action potentials in myocardial cells. These action potentials, if above threshold, stimulate surrounding myocardium (capture), and a wave of electrical discharge (depolarization) moves away from the electrode to energize cardiac chambers. Electromechanical coupling follows in the direction of depolarization. A unichamber lead is usually in the right ventricular apex (RVA), from which a wave of depolarization travels posteriorly and toward the cardiac base. Although it aﬀects ventricular contraction, this can be at the cost of ventricular dyssynergy. Dual-chamber pacemakers have an additional lead in the right atrium. Depending on the mode, the atrial lead will sense intrinsic atrial depolarization and be inhibited as well as activate the ventricular lead at a preset time interval (atrioventricular [AV] delay) if no intrinsic ventricular depolarization is sensed. This allows for AV synchrony and improved diastolic ﬁlling of the left ventricle. AV synchrony is achieved by single-chamber atrial rateresponsive (AAIR) or dual-chamber rate-responsive (DDDR) programming. Cardiac resynchronization therapy (CRT) requires placement of two ventricular leads: one positioned at the RVA (or RV outﬂow tract [RVOT]) and the other in the posterolateral ventricular wall (via the coronary sinus). CRT has been advocated for patients with New York Heart Association (NYHA) stage III/IV heart failure, left ventricular (LV) dysfunction (EF ≤35%) refractory to optimal drug therapy, and prolonged QRS interval (>120 ms). CRT has resulted in improvement in quality of life, 6-minute hall walk, EF, and reversal of LV remodeling and mortality.7 The principal mechanism underlying CRT is that LV dysfunction is often associated with QRS prolongation. Such conduction delay can cause dyssynchronous contraction of the ventricle, resulting in ineﬃcient function. Delay of diﬀerent myocardial segments of the ventricular wall can be seen on standard twodimensional echocardiographic imaging, but more sophisticated Doppler modalities have proven useful and predictive of a favorable response to CRT when measured prior to a planned implant. More speciﬁcally, tissue velocity imaging has proven useful, as longitudinal velocity timing can be sampled and compared between opposing basal segments of the left ventricle, resulting in a measure of intraventricular dyssynchrony. This provides a more precise parameter for identifying dyssynchronous contraction than QRS morphology or duration.

Diastolic Dysfunction Diastolic dysfunction is associated with functional abnormalities of diastolic relaxation, ﬁlling, or distensibility, while DHF is associated with signs and symptoms of heart failure, normal EF, and abnormalities of one or more parameters of diastolic function.3 It is important to understand that physiologically, diastole is considered to begin from the period of reduced ventricular ejection, encompassing isovolumic relaxation and ﬁlling phases of ventricles. It begins when calcium ions are taken up into the sarcoplasmic reticulum so that myocyte relaxation dominates over contraction, and LV pressure starts to fall. Performance of the ventricle as a pump is highly dependent on diastolic ﬁlling of the ventricle (preload). Frank-Starling’s law of the heart dictates that

stroke volume is related to end diastolic volume. The greater the initial LV volume, the greater the peak pressure reached and the faster the rate of relaxation (lusitropic eﬀect).8 There are two major disease processes of diastole that aﬀect ﬁlling or distensibility: abnormal relaxation and increase in myocardial stiﬀness. Abnormal relaxation is usually aﬀected early in the disease process and can be measured by cardiac catheterization or echocardiographic techniques. An increase in myocardial stiﬀness represents advanced diastolic dysfunction and is usually associated with an increase in LV end diastolic pressure. LV stiﬀness refers to a change in diastolic LV pressure relative to diastolic LV volume (dp/dv) and equals the slope of the diastolic pressurevolume relation (P-VR). It is also inversely proportional to deceleration time (DT). Thus, a rapid DT indicates elevated LV early diastolic chamber stiﬀness.9 Echocardiography has emerged as a simple and reliable noninvasive method of evaluating systolic and diastolic function. Detailed description of the role of echocardiography in the classiﬁcation of diastolic dysfunction is discussed in Chapters 6 and 10–12.

CLINICAL RELEVANCE Diastolic dysfunction is a feature representing abnormal diastole; however, DHF as an entity needs only one or more features of diastolic dysfunction. The currently accepted deﬁnition of DHF requires signs and symptoms of heart failure and normal EF (≥50%). Historically, EF has been regarded as a vital component of normal systolic function, but other markers (e.g., ventricular systolic synchrony, LV end systolic volume [LVESV], dp/dt) are also important. Interestingly, DHF has been shown to have many features typically regarded as markers of systolic dysfunction. Recent studies have dispelled the commonly held belief that patients with DHF have only abnormalities of relaxation. Synchronicity studies, especially based on tissue Doppler imaging (TDI), have shown that systolic asynchrony is a relatively common ﬁnding (33%–39%) in DHF.10,11 Yu et al. reported the prevalence of isolated diastolic asynchrony in 22%, isolated systolic asynchrony in 25%, and coexisting diastolic and systolic asynchrony in 14% of patients with DHF. The corresponding prevalence in the SHF group was 17%, 31%, and 26%, respectively (Figs. 29-1 and 29-2).11 Biventricular (biV) pacing produces improvement in LV function and symptomatic status by reducing systolic dyssynchrony in patients with SHF.12 Patients with CRT have consistently shown an improvement in many echocardiographic systolic as well as diastolic parameters. Though studies are brimming with reports of improvement in systolic parameters (e.g., EF, LVESV, time to peak systolic myocardial velocities) in CRT patients, a similar demonstration for diastolic parameters has been less consistent. A recent wave of articles has explored the subtle but signiﬁcant role of diastolic function in heart failure.13–15 This chapter attempts to uncover current evidence for the role and interaction of pacing, particularly CRT, in inﬂuencing diastolic dysfunction and DHF.

Overall Effects of Pacing on Cardiac Function Pacing has multiple eﬀects on ventricular function depending on pacing site, pacing conﬁguration, and disease status. The eﬀect may be positive, as seen with atrial pacing in patients with sinus node dysfunction, where it results in an increase in heart rate and

Chapter 29 • Pacing and Diastolic Heart Failure

Figure 29-1 Mechanical asynchrony in diastolic heart failure (DHF) observed by tissue Doppler imaging. An example of a patient with DHF (ejection fraction, 62%) who had evidence of diastolic asynchrony, as illustrated by the scattered time to peak early diastolic velocity (arrowheads). The systolic asynchrony is relatively mild (arrow). (From Yu et al: Diastolic and systolic asynchrony in patients with diastolic heart failure: A common but ignored condition. J Am Coll Cardiol 2007;49:97–105.)

Figure 29-2 Mechanical asynchrony in diastolic heart failure (DHF) observed by tissue Doppler imaging. Another patient with DHF (ejection fraction, 55%) had evidence of systolic asynchrony, as illustrated by the scattered time to peak systolic velocity (arrow). This patient had no evidence of diastolic asynchrony (arrowhead). (From Yu et al: Diastolic and systolic asynchrony in patients with diastolic heart failure: A common but ignored condition. J Am Coll Cardiol 2007;49:97–105.)

TABLE 29-1 EFFECT OF PACING ON DIASTOLIC PARAMETERS ATRIAL PACING

RIGHT VENTRICULAR PACING

BIVENTRICULAR PACING

LEFT VENTRICULAR PACING

Increase in LVEDP66 No significant change in LVEDD and LVESD67 Decrease in E-wave TVI and increase in pulmonary venous flow in CAD68

Minimal change in LVESV7 No change in LVEDV and LVESV69 Increased LVEDP Increased myocardial stiffness70 Decreased E-wave velocity69

Decreased LVEDV18,45 Decreased LVEDP17,18 Decreased LVESV21

Decrease in LV (−)dp/dt72 Increase in Tau72

Decreased LV (−)dp/dt17 Increased Tau70 No significant change in peak LV (−)dp/dt between RVOT and RVA pacing56

Decreased LVEDV and LVESV69,71,20 Increased diastolic filling time7,16 Decreased E-wave velocity69 Decrease in E/A ratio7,23 Decrease in E/Vp ratio Increase in pulmonary S/D flow ratio Decrease in pulmonary vein atrial reversal velocity Increase in DT23 Lower Tau but higher LV (−)dp/dt compared with RVA pacing16 Decreased LV (−)dp/dt17

cardiac output. However, the eﬀect may be negative, as seen with right ventricular (RV) apical pacing in patients with bradycardic indications and normal baseline LV function, which is thereby impaired. A detailed overview of the eﬀects of pacing on diastolic cardiac function (as it pertains to diastolic physiology) is given in Tables 29-1 and 29-2.

Pacing and Diastolic Function Hay et al.16 studied short-term eﬀects of RV pacing (RVA and RVOT), LV free wall pacing, and biV pacing in patients with heart failure (EF 14%–30%). Systolic function improved in all modes, but more so in the biV group. However, only the biV group showed improved diastolic function (isovolumic relaxation and diastolic ﬁlling times). The authors suggested that single-site LV pacing, in contrast to biV pacing, might induce some intraventricular dyssynchrony that could impact relaxation.

Decreased LV (−)dp/dt17 No significant change in LV(−)dp/dt18

Myocardial relaxation is inﬂuenced by chamber load and homogeneity of activation. Auricchio et al. studied 27 CHF patients with conduction disorders. RV, LV, and biV pacing were compared. BiV and LV pacing increased LV (+)dp/dt and aortic pulse pressure more than did RV pacing. LV diastolic performances also changed in all pacing conﬁgurations, but the changes were small and inconsistent (LV end diastolic pressure [LVEDP] decreased and absolute value of LV (−)dp/dt also decreased, indicating slower relaxation). The important variables predicting outcome were pacing site, appropriate AV delay, and prolonged QRS width.17 Simantirakis et al. studied 12 patients with AV node ablation (due to atrial ﬁbrillation) but with normal LV systolic function. LV-based pacing (LV free wall or biV) was compared with RV apical pacing. LV-based pacing improved indices of LV systolic function more than did RV pacing. Indices of LV diastolic ﬁlling (EDP, EDV) were better during LV-based pacing, whereas LV

375

376

Chapter 29 • Pacing and Diastolic Heart Failure TABLE 29-2 EFFECTS OF PACING SITE ON CARDIOVASCULAR SYSTEM

Cellular Level

Tissue Level

Organ Level

Body Level

DYSSNCHRONOUS PACING, RVA PACING

SYNCHRONOUS PACING, BIV PACING

Increased tissue norepinephrine level42 Asymmetric hypertrophy58 Increased stress kinase phosphorylation73 Shift in titin isoform74 Reduced Ca++-ATPase, phospholamban, and connexin43,75 Mismatch of tissue perfusion42 Reduction in LV shortening fraction54 Chronic LV remodeling58 Depressed fiber-sheet extension and wall thickening by epicardial pacing77 Prolonged QRS duration62 Increased LAE and LAP37,38 Rightward shift of LV ES PVR Decreased SV and EDV42 Upward and left shift of LV end diastolic P-VR70 Reduced cardiac output34,57,62 Increased atrial fibrillation82,83 Increased risk of heart failure and death34,52,82 Increased incidence of thromboembolism40

Increased septal glucose uptake24 Decreased interstitial remodeling, TNF-α expression, and apoptosis76

diastolic function indices such as (−)dp/dtmax, Tau [τ], and passive diastolic chamber stiﬀness did not change signiﬁcantly.18 This reﬂects a more complex inﬂuence of preactivation and atrial contraction on chamber load present during sinus rhythm.

Effect of Cardiac Resynchronization Therapy on Diastolic Function CRT has been shown to improve NYHA functional class, quality of life indicators, and EF. It is also associated with improved LV geometry (reduction in LV end diastolic and systolic diameter as well as volume) and reduction in mitral regurgitation. Patients who respond to CRT are often those with positive structural and functional LV remodeling.7,19 The mechanisms of beneﬁt of CRT are several, including synchronization of systolic function as well as enhancement of diastolic function.17,20–22 The literature is replete with studies supporting the beneﬁcial eﬀects of CRT on systolic function but is less proliﬁc with respect to diastolic function.13,14,16–18 Table 29-3 provides a list of eﬀects of CRT on diastolic parameters. CRT does appear to have a beneﬁcial eﬀect on diastolic properties of the failing heart. CRT enhances diastolic ﬁlling patterns in patients with systolic dysfunction. In a recent study, 23 patients were evaluated at 1 week prior as well as 1 and 6 months after implantation. Signiﬁcant clinical improvement was noted in all patients. Compared with baseline, the ratio of early to late peak velocities (E/A) decreased signiﬁcantly (1.5 to 0.8) at 6 months. The pulmonary systolic ﬂow to diastolic ﬂow ratio (PVs/PVd) increased from 0.9 to 1.3 at 6 months, and the ratio of early peak velocity to LV ﬂow propagation velocity (E/Vp) decreased from 2.7 to 2 at 1 month, then to 1.9 at 6 months. Patients who demonstrated improvement in EF of more than 25% were designated responders (N = 17, 74%). In these patients, the E wave and pulmonary venous (PV) atrial reversal velocity decreased, E-wave deceleration time increased, and the E/Vp ratio improved signiﬁcantly (all diastolic parameters), whereas in the nonresponder population, changes in LV diastolic parameters remained insigniﬁcant.23

Correction of LV contractile dysfunction Reverse remodeling7 Increased myocardial efficiency of O2 use78,79 Effect on myocardial perfusion (increase80,81; no change79) Increased SBP, SV, dp/dtmax, and EF but decreased EDV, ESV, Tei index, and MR7 Increased diastolic filling16,24 Shortening of IVMD Increased DT and E-A separation24 Increased EF and IVRT16 Improved NYHA class, quality of life, and 6 min walk7 Reduced heart failure, hospitalization, and mortality84,85

In the Multicenter Insync Randomized Clinical Evaluation (MIRACLE) study, 323 patients were randomized into two groups: control (n = 151) and CRT (n = 172). Echocardiographic parameters were measured at baseline, then 3 and 6 months after intervention. Signiﬁcant reduction in LVEDV and LVESV occurred at 3 months in the CRT group compared with the control group. The reduction in LVEDV and LVESV continued between 3 and 6 months. There were signiﬁcant increases in EF of 2.6% at 3 months and 3.6% at 6 months in the CRT group. There was also a signiﬁcant increase in deceleration slope and deceleration time of the E wave (during rapid ﬁlling) at 3 and 6 months in the CRT group. The maximum E-wave velocity and myocardial performance index decreased signiﬁcantly at followup, consistent with improved ventricular function. There was no signiﬁcant change in peak A-wave velocity, E/A wave velocity ratio, and isovolumic relaxation time (IVRT) in the CRT or the control group.7 Of note, optimization of the AV delay and synchronous biV pacing resulted in prolongation of the duration of LV ﬁlling (diastolic ﬁlling time), separation of the rapid ﬁlling phase from atrial systolic contraction, concomitant shortening of interventricular mechanical delay (IVMD), and simultaneous ventricular depolarization that coordinated contraction and relaxation. There was also a signiﬁcant improvement in the diastolic deceleration slope and deceleration time of the rapid ventricular ﬁlling wave velocity (E wave), leading to better diastolic ﬁlling.7,24 In CRT patients, there was a signiﬁcant improvement in the myocardial performance index (Tei index) at 3 months that continued between 6 and 12 months compared with the control group. The Tei index is a parameter representing both systolic and diastolic performance and is the summation of isovolumic contraction time and IVRT divided by the ejection time. CRT failed, however, to show signiﬁcant remodeling in patients with SHF and restrictive LV diastolic ﬁlling (characterized by a short deceleration time and peak E-wave velocity >1 m/sec).7,24 Reduction in ventricular systolic dyssynchrony is one of the major mechanisms by which CRT provides beneﬁt.12,25 Various methods of measuring synchrony are being investigated. TDI has

Chapter 29 • Pacing and Diastolic Heart Failure TABLE 29-3 EFFECTS OF CRT ON DIASTOLIC DYSFUNCTION PARAMETERS DIASTOLIC DYSFUNCTION PARAMETERS Velocities

Time

Ratios

Volume

MARKERS Mitral E velocity Mitral A velocity Flow propagation velocity Mean Em velocity (Global Em) Mean Am velocity Deceleration time Diastolic filling time Isovolumic relaxation time Tau, time constant of relaxation Negative dp/dt Q-Em time difference (SD in Te) Te-difference between 2 wall segments Interventricular mechanincal delay Mitral E/A ratio Mitral E/Em ratio Mitral E/Vp ratio PVs/Pvd ratio Deceleration slope Myocardial performance index LVEDV LVESV

INFLUENCE OF CRT Yes No No

REFERENCES 13,14,7

Yes No Yes

13,7

Yes

13,14,7

Yes

13,14

Yes

16

Yes Yes

17 13,14

No

provided an easy-to-use tool to quantify dyssynchrony both in systole and in diastole. Echocardiographic studies have concentrated on the basal and middle segments of the heart, ignoring the apex, because of limitations of TDI when applied to the apical segments. Dyssynchronous contraction and relaxation have been measured as standard deviations of the time to peak segmental myocardial velocity of 12 myocardial segments, the maximum time diﬀerence between opposing myocardial segments, or the average of peak myocardial velocities of myocardial segments. Waggoner et al. studied diastolic function in patients with severe SHF after CRT. Diastolic LV ﬁlling indices (mitral E/A, E/Em, E/ﬁlling pressure [FP] ratios), as well as diastolic synchrony (Q-Em velocity diﬀerence) changed favorably at 4 months, especially in the non-ischemic cardiomyopathy group. The cohort with ischemic cardiomyopathy had signiﬁcant improvement in only Em global velocity (a measure of diastolic asynchrony) at 4 months. Diastolic ﬁlling indices were also predictive of long-term event rates (heart failure hospitalization).13 In another study, by Yu et al., in which patients were divided between responders (45%) and nonresponders (55%) based on LV reverse remodeling (reduction of LVESV ≥15%) after CRT, responders had signiﬁcant reduction in E/Em ratio (a marker of LV FP; 30 to 22, p < 0.05). Responders also had signiﬁcant prolongation in LV ﬁlling time (381 to 441 msec, p < 0.05). Patients with baseline abnormal relaxation patterns had greater reduction of LV volumes than those exhibiting a pseudonormal pattern (29% vs. 11%, p < 0.05). Another interesting ﬁnding was that nonresponders diﬀered signiﬁcantly from responders with respect to baseline E/A ratio, IVRT, mean Em, and mean Am (Table 29-4). However, in this uncontrolled trial, systolic (but not diastolic) dyssynchrony was a predictor of favorable reduction in LVESV.14 As yet, there is no indisputable evidence that CRT improves either systolic or diastolic function in DHF. It is hoped that recognition of diastolic dyssynchrony and subsequent intervention may improve outcome in patients with heart failure.

Yes

7

Yes Yes Yes Yes Yes

13,23 13 13,23 23 7

Yes

7,14

Optimization of Atrioventricular Delay and Diastolic Function

Yes Yes

7 7,13,14

An optimal and appropriate AV delay should result in optimum ﬁlling of the left ventricle without interruption of the A wave, thereby allowing complete diastolic ﬁlling. A short AV delay may

TABLE 29-4 DIFFERENCE BETWEEN RESPONDERS AND NONRESPONDERS TO CRT WITH RESPECT TO BASELINE DIASTOLIC AND SYSTOLIC PARAMETERS PARAMETERS

BASELINE PARAMETERS

RESPONDERS (N = 42)

NONRESPONDERS (N = 34)

p VALUE

Diastolic Parameters

E/A ratio Isovolumic relaxation time (msec) Mean Em (cm/sec) Mean Am (cm/sec) SD in Ts, 12 segments (msec) Septal-to-lateral delay in Ts (msec)

0.89 ± 0.72 131 ± 33 3.17 ± 1.72 4.48 ± 1.54 44.9 ± 9.5 60.9 ± 35.9

1.29 ± 0.56 106 ± 37 4.33 ± 1.88 3.62 ± 1.38 26 ± 11 23 ± 30

<0.05 <0.05 ≤0.005 ≤0.005 <0.001 <0.001

Systolic Parameters

From Yu CM et al: Are left ventricular diastolic function and diastolic asynchrony important determinants of response to cardiac resynchronization therapy? Am J Cardiol 2006;98:1083–1087.

377

378

Chapter 29 • Pacing and Diastolic Heart Failure enable ventricular contraction before complete emptying of the left atrium has occurred. Approximately one third of CRT patients either do not improve or may in fact worsen following implantation of a biV pacing device. Optimization of AV timing is not only critical to achieve optimal resynchronization therapy, and in turn LV function, but it may enable some of these nonresponders to improve functionally and hemodynamically.17,26 Diastolic, rather than systolic, function has been the target and parameter of choice to optimize hemodynamics in many labs that routinely conduct AV optimization examinations. This is, in part, because of the relative ease by which diastolic function can be interrogated noninvasively with Doppler echocardiography. Rokey et al. studied patients with programmable AV sequential pacemakers with pulse Doppler interrogation of the mitral inﬂow. Doppler velocities were recorded for three settings of AV delay: 75, 150, and 250 msec. They found an inverse relation between the eﬀectiveness of atrial contraction and early diastolic ﬁlling (E wave). It was postulated that at a short AV delay, atrial contraction is aborted and the left atrium remains with a larger residual volume at end diastole. During systole, LA volume and pressure increase further, resulting in a higher AV pressure gradient after mitral opening and thus an increase in peak inﬂow rate. The opposite occurs with enhanced atrial emptying and an improved atrial ﬁlling fraction brought about by optimizing the AV delay.27 Dual-chamber pacing in patients with hypertrophic cardiomyopathy revealed that there was a decrease in cardiac output and peak dp/dt as well as an increase in mean LA pressure and time constant of isovolumic relaxation (τ) in patients when paced with a short AV delay (<60 msec). During pacing at optimal AV delay (the longest AV interval with pre-excitation), there was a similar trend, with deterioration in both systolic and diastolic function variables, but of less magnitude than those during pacing at the shortest AV interval.28 The eﬀects of AV delay optimization for patients with AV conduction disease requiring dual-chamber pacing are well described, but the inﬂuence on patients with heart failure who frequently have normal AV conduction is just becoming apparent. It has been shown that patients with CHF have higher LV (+)dp/ dt and aortic pulse pressure at patient-speciﬁc optimal AV delays. Response seems to diﬀer for patients with wide QRS compared with narrow QRS. Aurrichio et al. studied pacing in CHF and suggested that the maximum acute beneﬁt of CRT could be achieved by patient-speciﬁc AV delays.17 AV synchrony is frequently targeted in CRT patients as a means for optimization. Studies have shown that optimization of AV delay results in improved NYHA functional class as well as greater cardiac output.29 An optimum AV delay is programmed when the end of the Doppler A wave (corresponding to LA contraction) occurs just before the onset of aortic systolic Doppler ﬂow. Ritter et al. and others have reported simple and practical AV delay optimization algorithms. Ritter’s method includes setting the AV delay to an inappropriately short then long AV interval and measuring a surrogate of the atrial electrical mechanical delay (QA interval) at each setting. This is accomplished by measuring the interval between the onset of the Q wave and the termination of the mitral A wave.30 The iterative technique to AV delay optimization also requires recognition of A-wave truncation. Mitral inﬂow is recorded at programmed long sensed AV delay, such as 150 msec, then AV delay is decreased by intervals of 10–20 msec until the A-wave begins to truncate. Once A-wave truncation is seen, AV delay is

lengthened in 10 msec steps until there is no truncation. This generates an optimized AV delay when ventricular contraction occurs just at the end of the atrial contribution. Kedia et al. studied the eﬀects of AV optimization in a cohort of CRT patients. These patients had an AV optimization performed within 30 days post-implantation and were followed up for 23 months. At baseline, approximately 50% of the patients had stage 1 (abnormal relaxation) diastolic ﬁlling. Nearly 10% had improvement in diastolic stage (e.g., stage III to II, stage II to I). Approximately 40% had a ﬁnal AV delay setting greater than 140 msec. AV block, atrial enlargement, and a paced rhythm were signiﬁcantly associated with a ﬁnal AV delay setting of greater than 140 msec. Regardless of whether the AV delay was set at less than or greater than 140 msec, the mortality rate was similar between groups. The authors suggested that interrogation of the mitral inﬂow for diastolic function staging be performed in all patients following implant of a CRT device and that AV optimization be attempted primarily in patients with stage II or III diastolic dysfunction (Fig. 29-3).26 Moreover, patients who initially

A

B

C Figure 29-3 This patient with an ischemic cardiomyopathy presented to the echocardiography laboratory with a baseline, out-of-the-box atrioventricular (AV) delay setting of 110 msec, following implantation of a biventricular pacemaker. A, Mitral inflow interrogation revealed a large E wave and a very low amplitude A wave consistent with stage III diastolic dysfunction. B, Prolongation of the AV delay to 280 msec demonstrates significantly improved diastolic function (A-wave amplitude = 60 cm/sec); however, the A wave terminates prior to the onset of ventricular depolarization (prior to the QRS onset). C, Empiric adjustment of the AV delay setting back to 230 msec now reveals a satisfactory (physiologic) relationship of the A-wave and the QRS onset, optimizing diastolic filling.

Chapter 29 • Pacing and Diastolic Heart Failure 23%, p < 0.01) and increasing EF (from 22% to 29%, p < 0.01). However, optimum sequential CRT (preactivation of the left ventricle in 9 patients and of the right ventricle in 11) caused a further reduction in the extent of DLC from 33% to 23% (p < 0.01) and an increase in EF from 29% to 33% (p < 0.01). Without any further optimization of AV delay, the diastolic ﬁlling time increased from 430 ± 88 msec during simultaneous CRT to 460 ± 80 msec (p < 0.05) during optimum sequential CRT.33

present with stage I diastolic ﬁlling should be maintained at their present AV delay settings (Fig. 29-4). A recommended strategy for managing patients who have recently undergone CRT is illustrated in Figure 29-5.

Optimization of Interventricular Interval and Diastolic Function Current generations of CRT devices also allow for optimization of ventricle-to-ventricle (VV) timing. In patients with heart failure and LV dyssynchrony, proper timing of the interventricular pacing interval (VV interval) may further optimize LV function. Although the proper timing of the VV interval is clearly beneﬁcial in select patients, a deﬁnitive beneﬁt of this feature has not yet been proven. Van Gelder et al. studied LV dp/dt in patients with severe LV dysfunction. They were able to elicit additional increase in dp/dt after optimizing the VV interval (3%–8%). Maximum dp/dt was achieved with pacing “LV ﬁrst” in 44 patients; “simultaneous right and LV” pacing in 6 patients; and “RV pacing ﬁrst” in 3 patients. Such beneﬁt has been attributed to improved LV synchrony, resulting in a change in preload and reduction in mitral regurgitation.31 Speciﬁc measurements for ventricular dyssynchrony correlate with hemodynamic changes in patients with biV pacing. Bordachar et al. demonstrated that individually optimized sequential biV pacing compared with simultaneous biV pacing increases cardiac output and decreases mitral regurgitation in patients with heart failure.32 The deﬁnition of an optimum VV delay has not been characterized. However, it has been suggested to be an interventricular delay that reduces LV dyssynchrony and/or maximizes LV systolic function. Sogaard et al. evaluated the impact of sequential CRT with individualized interventricular delay programming. Simultaneous CRT was better than “no CRT” in reducing delayed longitudinal contraction (DLC) (from 48% to

Adverse Effects of Pacing Recently, there has been a surge in the discussion on the adverse eﬀects of pacing, which depend on the pacing mode, Mitral inflow pattern following CRT procedure Stage I

Stage II or III

Mitral E-A reversal, QA interval > 40 msec, pulmonary vein S>D

AV optimization (Ritter or iterative)

Maintain baseline AV delay setting

Target Stage I diastolic filling

Figure 29-5 Recommended approach for optimizing atrioventricular (AV) delay utilizing mitral inflow assessment of diastolic function in patients undergoing cardiac resynchronization therapy (CRT). In patients exhibiting an E/A reversal pattern (stage I diastolic dysfunction), no adjustment in AV delay is necessary, whereas in those manifesting stage II or III diastolic dysfunction, an attempt is made to achieve stage I diastolic dysfunction by adjusting the AV delay.

Baseline AV delay 120 msec

A

Mitral flow 40 msec

Figure 29-4 This 65-year-old female with a dilated cardiomyopathy systolic/pulmonary cardiac resynchronization therapy 24 hours earlier presented to the echocardiography laboratory for an atrioventricular (AV) delay optimization. The AV delay was empirically set at 120 msec at the time of the implant. A, Mitral inflow upon presentation to echo lab. B, Interrogation of mitral inflow revealed stage I diastolic dysfunction (E/A reversal), satisfactory E- and A-wave separation, termination of the A wave >40 msec after the onset of ventricular depolarization (QRS onset), and normal pulmonary vein systolic/diastolic (S/D) ratio, suggesting low/ normal atrial filling pressures. C, Based on these satisfactory hemodynamic findings, the AV delay was maintained at 120 msec.

B Final AV delay 120 msec

C

379

380

Chapter 29 • Pacing and Diastolic Heart Failure dyssynchrony, duration of pacing, and underlying cardiac disease.

Pacing Mode Rosenqvist et al. compared two pacing modes (single-lead ventricular [VVI] vs. single-lead atrial [AAI]) in sinus node disease and showed that the incidence of CHF and high-degree AV block was higher in the VVI group than in the AAI group.34 The Pacemaker Selection in Elderly (PASE) trial revealed that patients with sinus node dysfunction (no AV block) had a poorer quality of life and cardiovascular functional status with ventricular pacing than with dual-chamber pacing. Although there was an improved quality of life with dual-chamber pacing compared with ventricular pacing, superiority of preventing stroke or death was not seen in these larger trials.35,36

Dyssynchrony Ventricular dyssynchrony is associated with pacing modes as well as cardiac disease. Two areas of dyssynchrony are AV dyssynchrony and ventricular dyssynchrony. AV dyssynchrony occurs when the atria do not contract synchronously with the ventricle. It can result in incomplete ﬁlling of the ventricles and is associated with LA enlargement, elevated LA pressure, and dizziness (pacemaker syndrome).37,38 Ventricular pacing without atrial pacing (lack of AV synchrony) is associated with a higher incidence of AV block, atrial ﬁbrillation, CHF, and mortality.34,39,40 Ventricular dyssynchrony has been studied widely with respect to LV activation from the RVA. RVA pacing leads to abnormal activation of the ventricle, QRS prolongation, and dyssynchronous contraction. Studies have revealed that ventricular pacing depresses LV pumping function, causes mismatching of perfusion, and elevates tissue norepinephrine levels.41,42 RV apical pacing produces an LV activation sequence resembling left bundle branch block.43 This alteration in mechanical activation may cause impaired hemodynamic performance.44 Prolonged QRS duration (≥190 msec) is associated with an increase in morbidity of CHF.45 RVA pacing is also associated with increased LA pressure and giant PV ﬂow reversal.46 RV apical pacing can cause chronic changes in regional myocardial perfusion, cellular structure, and ventricular geometry that may impair ventricular performance.47–50 The adverse eﬀects of ventricular dyssynchrony and AV dyssynchrony may explain the association of RVA pacing with increased risk of heart failure hospitalization in clinical trials.51 The Dual Chamber and VVI Implantable Deﬁbrillator (DAVID) trial found an increase in the composite endpoint of death and ﬁrst heart failure hospitalization in the DDDR-70 group, who had more RV pacing than the VVI-40 group.52 Moss et al. also noted a higher incidence of heart failure in patients receiving a deﬁbrillator compared with the group on medical therapy for ventricular arrhythmias.53

Duration of Pacing The actual amount and duration of RVA pacing are also associated with adverse eﬀects, as demonstrated in the DAVID trial as well as the Mode Selection Trial (MOST). In the DAVID trial, the VVI group had a backup pacing rate of 40/minute, but the DDDR group had a rate-responsive pacing at 70/minute. The DDDR group paced the ventricle approximately 55% of the time

compared with 0.6%–3.0% in the VVI group. The authors attributed the increased incidence of adverse eﬀects to a higher frequency of ventricular pacing.52 In MOST, patients with sinus node dysfunction were divided into a rate-responsive VVI (VVIR) and a DDDR group. Cumulative percent ventricular pacing (Cum%VP) was obtained from stored pacemaker data. The VVIR group with Cum%VP greater than 80, as well as the combined group (the VVIR group with Cum%VP ≤80 plus the DDDR group with Cum%VP >40), had a higher incidence of heart failure hospitalization compared with the DDDR group with no greater than 40 Cum%VP.51

Underlying Cardiac Status Importantly, the underlying cardiac condition also aﬀects the incidence of adverse eﬀects. In MOST, the authors noted that risk of heart failure hospitalization was 42 times higher in patients with high-risk substrates (low EF, history of myocardial infarction, CHF, and spontaneous prolonged QRS duration).51 In pediatric patients, chronic RV pacing reduced LV shortening fraction only in those with structural heart disease.54 A recent trial, however, reported a reduction in LV function in patients with complete heart block irrespective of their baseline LV function. A clinically signiﬁcant decrease in LVEF was noted in 29% of all patients and 33% of those with normal baseline LVEF.55

Pacing Site Location Generally, pacing is believed to enhance pump function by increasing systolic contraction and improving diastolic ﬁlling; however, the performance is based on the clinical indication, clinical substrate, pacing mode, and pacing site. The search for the optimal pacing site is ongoing and potentially patient speciﬁc. Buckingham et al. compared the eﬀects of pacing at the RVOT to RVA in patients with low EF (<40%). EF, peak dp/dt, peak (−)dp/dt, and τ were measured. There was a subtle improvement in diastolic and systolic function with pacing in the RVOT compared with traditional RVA pacing.56 Pacing of the left ventricle at the site of greatest delay is also associated with increased stroke work and lower ESV in patients with dilated cardiomyopathy. RV pacing in such patients produces minimal changes in the pressure-volume analysis.20 Prinzen et al. noted that dyssynchronous activation of the ventricles in canine models reduced LV pump function. Pacing at the RVA (conventional pacing site) reduced LV function more than pacing at a high ventricular septum or at LV sites.57 RVOT pacing intuitively enables more natural electrical activation. Pacing at three diﬀerent sites (RVOT, LV apex, and right atrium) in dogs was also studied in detail by Prinzen et al. Maps of the sequence of electrical activation, ﬁber strain, and blood ﬂow in epicardial layers were obtained. Gradients of epicardial electrical activation time, ﬁber strain, and blood ﬂow pointed in the same direction during RVOT pacing, but in opposite directions compared with LV apical pacing. The result indicated that electrical activation is an important determinant for the distribution of ﬁber strain and blood ﬂow in the LV wall.58 The impact of RVOT, LV, and biV pacing on LV function was studied in humans by Lieberman et al. LV pressure-volume data were recorded for 13 patients (average age, 65; 10 with CHF and 4 without; mean QRS, 89 ms). Results showed that single-site LV pacing was similar to biV pacing. LV and biV pacing were superior to all RV sites for the most variables (EF, stroke volume, (+)dp/dt). The

Chapter 29 • Pacing and Diastolic Heart Failure optimal RV lead location varied among patients depending on underlying etiology.59

Modes of Pacing Evidence favors maintaining AV synchrony for better clinical outcomes. Patients with sick-sinus syndrome without AV block do well with AAIR pacing; however, if a patient has signiﬁcant AV block, a ventricular lead is needed. Whether all patients should have a dual-chamber pacemaker has been debated on two fronts: cost of the device and the recent suggestion of increased adverse events. Pacing modes that do not restore AV synchrony are associated with regurgitation of the mitral and tricuspid valves, incidence of atrial ﬁbrillation, and thromboembolism.37,60 For systolic heart failure, the Device Evaluation of Contak Renewal 2 and Easytrak 2 (DECREASE-HF) trial compared simultaneous biV (SimBiv), sequential biV (SeqBiv), and LV pacing in 306 patients (NYHA III or IV; mean EF ≤35%; QRS ≥150 msec). After 6 months, the SimBiv group had the greatest reduction in LVEDV and LVESV. All groups exhibited a reduction in LV volumes as well as improvement in systolic performances.61

FUTURE RESEARCH Right Ventricular Outflow Tract Pacing Major drawbacks of RVA pacing are asynchrony and the abnormal sequence of activation of the left ventricle. Adverse eﬀects like reduced pump function, heart failure, and death have been attributed to these mechanisms. It is surmised that RVOT pacing would preserve normal activation sequence and may provide beneﬁt. Skadsberg compared RVA with RVOT pacing in swine and found that RVOT pacing provided intrinsic like activation and preserved LV systolic and diastolic functions.62

Atrial-Based Managed Ventricular Pacing Mode in Dual-Chamber Implantable Cardioverter-Defibrillators Due to ventricular dyssynchronization caused by RV pacing and increased risk of CHF, atrial ﬁbrillation, and death, investigators are trying to devise a mode that reduces Cum%VP compared with DDDR. Managed ventricular pacing (MVP) would provide AAIR pacing with ventricular monitoring and backup DDDR during AV block. An early report shows an absolute and relative reduction in Cum%VP during MPV (from 99% to 85%).63

The Best Modality of Cardiac Resynchronization Therapy Investigation for the best modality of CRT is ongoing. All the modalities compared in the DECREASE-HF trial (SimBiv, SeqBiv, and LV pacing) were eﬀective in reducing LV volumes during follow-up, but the SimBiv pacing group had the greatest improvement.61 In CRT, improving LV dp/dt has been a major target. Multisite pacing including RV bifocal (RVA + RVOT), biV 1 (RVA + LV lateral), biV 2 (RVOT + LV lateral), and trisite pacing (RVA + RVOT + LV lateral) has been compared. RVA stimulation impaired LV function, whereas RVOT pacing preserved LV func-

tion. RV bifocal pacing provided a modest but favorable eﬀect. LV lateral, biV, and trisite pacing showed better performance in systolic phase. Trisite pacing demonstrated an additional eﬀect on diastolic function (increase in LV (−)dp/dt).64

Direct His Bundle Pacing Direct His bundle (DHB) pacing has been considered to prevent ventricular dyssynchrony that results from RVA pacing. Permanent DHB pacing was tested in 20 patients. Mechanical dyssynchrony was measured in terms of interventricular mechanical delay (IMD), and septal to left posterior wall motion delay (SPWD) was measured. There was signiﬁcant reduction in the index of dyssynchrony in DHB versus RVA pacing.65

Role of Cardiac Resynchronization Therapy for Diastolic Heart Failure Whether CRT could be used as therapy for DHF is unclear today, but recent articles have provided interesting data on DHF. Investigators have argued that the exact pathophysiologic mechanism of symptoms in DHF patients is still unclear. It seems that a mixture of systolic and diastolic abnormalities varying in patients depending on etiology and comorbidities may be responsible.15 CRT has established its role for patients with systolic dysfunction and seems linked to diastolic parameters. One may speculate that advanced pacing techniques would ﬁnd a role in treatment of DHF. An understanding of the positive and negative eﬀects of pacing is imperative in order to appropriately apply pacing modalities and appropriate conﬁgurations when treating patients with both SHF and DHF. Although in many instances a predictable result can be anticipated when applying pacing therapy to a given condition, it is important to recognize that interrogation of ventricular function (systolic and diastolic) is necessary to conﬁrm the anticipated result.

ABBREVIATIONS A wave: late left ventricular ﬁlling velocity wave Doppler tracing secondary to atrial contraction AAI: pacing conﬁguration where atrium is paced, atrium is sensed, and on sensing, atrium gets inhibited Am: peak myocardial velocity at late diastole, measured to assess diastolic function A rev: atrial reversal wave velocity detected by Doppler at right upper pulmonary vein AV: atrioventricular AVD: atrioventricular delay BiV: biventricular (involving both right and left ventricle) CAD: coronary artery disease CHF: congestive heart failure CRT: cardiac resynchronization therapy DCM: dilated cardiomyopathy DDD: pacing conﬁguration where both atrium and ventricle can be paced, both can sense, and on sensing, the atrium gets inhibited and paces ventricle at preset AV delay (if no intrinsic ventricular depolarization noted); on sensing, ventricular leads get inhibited. DDDR: R refers to rate responsiveness of pacer to physiological demand. A feature of newer pacemakers

381

382

Chapter 29 • Pacing and Diastolic Heart Failure DHF: diastolic heart failure, a measure of systolic dyssynchrony DLC: delayed longitudinal contraction dp/dt: pressure derivative of left ventricle showing ability to build pressure per unit change in time dp/dv: change in pressure per unit change in volume (stiﬀness) DT: deceleration time dv/dp: change in volume per unit change in pressure (compliance) −dp/dt: LV pressure-derivative minimum. Negative pressure derivative of left ventricle showing fall in pressure per unit change in time, an indicator of relaxation dp/dtmax: maximum rate of rise of ventricular pressure; is highly sensitive to acute changes in contractility. It is more useful in assessing directional changes in contractility during acute intervention when used in combination with a measure of left ventricular preload. dp/dtmin: peak rate of ventricular pressure fall during isovolumetric pressure decline. It is inﬂuenced by the pressure at the time of aortic valve closure and is not a good measure of the rate of isovolumetric relaxation. E-wave: early left ventricular ﬁlling velocity wave, an early part of diastolic phase detected as Doppler wave by echo E/A ratio: peak velocity of E wave divided by peak velocity of atrial Doppler wave EDP: end diastolic pressure EDV: end diastolic volume EF: ejection fraction Em: peak myocardial velocity at early diastole, measured in different segments for assessing diastolic function ESV: end systolic volume IVCT: isovolumic contraction time IVMD: interventricular mechanical delay IVRT: isovolumic relaxation time LAE: left atrial enlargement LAP: left atrial pressure LV: left ventricular LVA: left ventricular apex LVEDD: left ventricular end diastolic diameter LVEDV: left ventricular end diastolic volume LV ES PVR: left ventricular end systolic pressure-volume relation LVESV: left ventricular end systolic volume LVH: left ventricular hypertrophy MI: myocardial infarction MPI: myocardial performance index or index of myocardial performance or Tei index MR: mitral regurgitation NYHA: New York Heart Association; has four categories of functional class for patients with heart failure PVd: pulmonary venous peak diastolic velocity PVs: pulmonary venous peak systolic velocity P-VR: pressure-volume relation QRS: QRS wave on surface electrocardiogram RV: right ventricular RVA: right ventricular apex RVOT: right ventricular outﬂow tract SBP: systolic blood pressure SD: standard deviation SSS: sick-sinus syndrome SV: stroke volume Tau (τ): time constant of an exponential ﬁt of the time course of isovolumetric pressure decline; a parameter measuring

ventricular relaxation. The normal range is 37– 67 msec. Tei index: summation of isovolumic contraction time and isovolumic relaxation time divided by ejection time; a measure of systolic as well as diastolic function Te: time to peak myocardial early diastolic velocity with reference to QRS Te-diﬀ: maximal diﬀerence in myocardial time to peak early diastolic velocity between two left ventricular segments Ts: time to peak myocardial systolic velocity during the ejection phase with reference to QRS Ts-diﬀ: maximal diﬀerence in myocardial time to peak systolic velocity between two left ventricular segments TVI: time-velocity integral; measured by outline of spectral Doppler tracing. It represents the distance traveled by the column of blood in one beat. Vp: left ventricular ﬂow propagation velocity recorded at mitral valve level in diastole VV: interventricular (between right and left ventricle) VVI: pacing conﬁguration where ventricle is paced, ventricle is sensed, and gets inhibited after sensing an intrinsic depolarization (In VVIR, R stands for rate responsiveness.) REFERENCES 1. European Study Group on Diastolic Heart Failure: How to diagnose diastolic heart failure. Eur Heart J 1998;19:990–1003. 2. Zile MR, Gaasch WH, Carroll JD, et al: Heart failure with a normal ejection fraction: Is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation 2001;104: 779–782. 3. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiﬀness of the left ventricle. N Engl J Med 2004;350:1953–1959. 4. Bhatia SR, Lee, D, Haouzi A, et al: Diastolic heart failure: Comparison of outcomes to systolic heart failure in a population based study. Circulation 2005;112(Suppl II):2200. Abstract. 5. Persson H, Lonn E, Edner M, et al: Diastolic dysfunction in heart failure with preserved systolic function: Need for objective evidence: Results from the CHARM Echocardiographic Substudy–CHARMES. J Am Coll Cardiol 2007;49:687–694. 6. Van Heerebeek L, Borbely A, Niessen HW, et al: Myocardial structure and function diﬀer in systolic and diastolic heart failure. Circulation 2006;113:1966–1973. 7. St John Sutton MG, Plappert T, Abraham WT, et al: Eﬀect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985–1990. 8. Braunwald E: Normal and abnormal cardiac function. In Heart: A textbook of cardiovascular medicine, 6th ed, WB Saunders, 2001:464. 9. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiﬀness from the time for deceleration of early left ventricular ﬁlling. Circulation 1995;92:1933–1939. 10. Wang J, Kurrelmeyer KM, Torre-Amione G, et al: Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the eﬀect of medical therapy. J Am Coll Cardiol 2007;49:88–96. 11. Yu CM, Zhang Q, Yip GW, et al: Diastolic and systolic asynchrony in patients with diastolic heart failure: A common but ignored condition. J Am Coll Cardiol 2007;49:97–105. 12. Bax JJ, Abraham T, Barold SS, et al: Cardiac resynchronization therapy: Part 1. Issues before device implantation. J Am Coll Cardiol 2005;46: 2153–2167. 13. Waggoner AD, Rovner A, de las Fuentes L, et al: Clinical outcomes after cardiac resynchronization therapy: Importance of left ventricular diastolic function and origin of heart failure. J Am Soc Echocardiogr 2006;19:307–313. 14. Yu CM, Zhang Q, Yip GW, et al: Are left ventricular diastolic function and diastolic asynchrony important determinants of response to cardiac resynchronization therapy? Am J Cardiol 2006;98:1083–1087. 15. Sanderson JE: Systolic and diastolic ventricular dyssynchrony in systolic and diastolic heart failure. J Am Coll Cardiol 2007;49:106–108.

Chapter 29 • Pacing and Diastolic Heart Failure 16. Hay I, Melenovsky V, Fetics BJ, et al: Short-term eﬀects of right-left heart sequential cardiac resynchronization in patients with heart failure, chronic atrial ﬁbrillation, and atrioventricular nodal block. Circulation 2004;110: 3404–3410. 17. Auricchio A, Stellbrink C, Block M, et al: Eﬀect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999;99:2993–3001. 18. Simantirakis EN, Vardakis KE, Kochiadakis GE, et al: Left ventricular mechanics during right ventricular apical or left ventricular–based pacing in patients with chronic atrial ﬁbrillation after atrioventricular junction ablation. J Am Coll Cardiol 2004;43:1013–1018. 19. Yu CM, Bleeker GB, Fung JW, et al: Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580–1586. 20. Kass DA, Chen CH, Curry C, et al: Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567–1573. 21. Nelson GS, Berger RD, Fetics BJ, et al: Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation 2000;102:3053–3059. 22. Yu CM, Chau E, Sanderson JE, et al: Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438–445. 23. Agacdiken A, Vural A, Ural D, et al: Eﬀect of cardiac resynchronization therapy on left ventricular diastolic ﬁlling pattern in responder and nonresponder patients. Pacing Clin Electrophysiol 2005;28:654–660. 24. St John Sutton MG, Keane MG: Reverse remodelling in heart failure with cardiac resynchronisation therapy. Heart 2007;93:167–171. 25. Kass DA: Ventricular dyssynchrony and mechanisms of resynchronization therapy. Oxford Journals 2002;4:D23–D30. 26. Kedia N, Ng K, Apperson-Hansen C, et al: Usefulness of atrioventricular delay optimization using Doppler assessment of mitral inﬂow in patients undergoing cardiac resynchronization therapy. Am J Cardiol 2006;98: 780–785. 27. Rokey R, Quinones MA, Zoghbi WA, et al: Inﬂuence of left atrial systolic emptying on left ventricular early ﬁlling dynamics by Doppler in patients with sequential atrioventricular pacemakers. Am J Cardiol 1988;62: 968–971. 28. Nishimura RA, Hayes DL, Ilstrup DM, et al: Eﬀect of dual-chamber pacing on systolic and diastolic function in patients with hypertrophic cardiomyopathy. Acute Doppler echocardiographic and catheterization hemodynamic study. J Am Coll Cardiol 1996;27:421–430. 29. Kindermann M, Frohlig G, Doerr T, et al: Optimizing the AV delay in DDD pacemaker patients with high degree AV block: Mitral valve Doppler versus impedance cardiography. Pacing Clin Electrophysiol 1997;20(10 Pt 1):2453–2462. 30. Ritter P, Padeletti L, Gillio-Meina L, et al: Determination of the optimal atrioventricular delay in DDD pacing. Comparison between echo and peak endocardial acceleration measurements. Europace 1999;1:126–130. 31. van Gelder BM, Bracke FA, Meijer A, et al: Eﬀect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy. Am J Cardiol 2004;93:1500–1503. 32. Bordachar P, Laﬁtte S, Reuter S, et al: Echocardiographic parameters of ventricular dyssynchrony validation in patients with heart failure using sequential biventricular pacing. J Am Coll Cardiol 2004;44:2157–2165. 33. Sogaard P, Egeblad H, Pedersen AK, et al: Sequential versus simultaneous biventricular resynchronization for severe heart failure: Evaluation by tissue Doppler imaging. Circulation 2002;106:2078–2084. 34. Rosenqvist M, Brandt J, Schuller H: Long-term pacing in sinus node disease: Eﬀects of stimulation mode on cardiovascular morbidity and mortality. Am Heart J 1988;116(1 Pt 1):16–22. 35. Linde C, Leclercq C, Rex S, et al: Long-term beneﬁts of biventricular pacing in congestive heart failure: Results from the Multisite Stimulation in Cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111–118. 36. Kerr CR, Connolly SJ, Abdollah H, et al: Canadian Trial of Physiological Pacing: Eﬀects of physiological pacing during long-term follow-up. Circulation 2004;109:357–362. 37. Little RC: Eﬀect of atrial systole on ventricular pressure and closure of the A-V valves. Am J Physiol 1951;166:289–295. 38. Furman S, Cooper JA: Atrial ﬁbrillation during A-V sequential pacing. Pacing Clin Electrophysiol 1982;5:133–135.

39. Alpert MA, Curtis JJ, Sanfelippo JF, et al: Comparative survival after permanent ventricular and dual chamber pacing for patients with chronic high degree atrioventricular block with and without preexistent congestive heart failure. J Am Coll Cardiol 1986;7:925–932. 40. Andersen HR, Thuesen L, Bagger JP, et al: Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 1994;344:1523–1528. 41. Park RC, Little WC, O’Rourke RA: Eﬀect of alteration of left ventricular activation sequence on the left ventricular end-systolic pressure-volume relation in closed-chest dogs. Circ Res 1985;57:706–717. 42. Lee MA, Dae MW, Langberg JJ, et al: Eﬀects of long-term right ventricular apical pacing on left ventricular perfusion, innervation, function and histology. J Am Coll Cardiol 1994;24:225–232. 43. Vassallo JA, Cassidy DM, Miller JM, et al: Left ventricular endocardial activation during right ventricular pacing: Eﬀect of underlying heart disease. J Am Coll Cardiol 1986;7:1228–1233. 44. Rosenqvist M, Bergfeldt L, Haga Y, et al: The eﬀect of ventricular activation sequence on cardiac performance during pacing. Pacing Clin Electrophysiol 1996;19:1279–1286. 45. Miyoshi F, Kobayashi Y, Itou H, et al: Prolonged paced QRS duration as a predictor for congestive heart failure in patients with right ventricular apical pacing. Pacing Clin Electrophysiol 2005;28:1182–1188. 46. Tabata T, Grimm RA, Bauer FJ, et al: Giant ﬂow reversal in pulmonary venous ﬂow as a possible mechanism for asynchronous pacing-induced heart failure. J Am Soc Echocardiogr 2005;18:722–728. 47. Nielsen JC, Bottcher M, Nielsen TT, et al: Regional myocardial blood ﬂow in patients with sick sinus syndrome randomized to long-term single chamber atrial or dual chamber pacing—eﬀect of pacing mode and rate. J Am Coll Cardiol 2000;35:1453–1461. 48. Karpawich PP, Justice CD, Cavitt DL, et al: Developmental sequelae of ﬁxed-rate ventricular pacing in the immature canine heart: An electrophysiologic, hemodynamic, and histopathologic evaluation. Am Heart J 1990;119:1077–1083. 49. Adomian GE, Beazell J: Myoﬁbrillar disarray produced in normal hearts by chronic electrical pacing. Am Heart J 1986;112:79–83. 50. van Oosterhout MF, Prinzen FW, Arts T, et al: Asynchronous electrical activation induces asymmetrical hypertrophy of the left ventricular wall. Circulation 1998;98:588–595. 51. Sweeney MO, Hellkamp AS: Heart failure during cardiac pacing. Circulation 2006;113:2082–2088. 52. Wilkoﬀ BL, Cook JR, Epstein AE, et al: Dual-chamber pacing or ventricular backup pacing in patients with an implantable deﬁbrillator: The Dual Chamber and VVI Implantable Deﬁbrillator (DAVID) Trial. JAMA 2002;288:3115–3123. 53. Moss AJ, Zareba W, Hall WJ, et al: Prophylactic implantation of a deﬁbrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–883. 54. Shalganov TN, Paprika D: Evolution of left ventricular function with permanent right ventricular pacing in pediatric patients with and without structural heart disease. Circulation Supplement II 2005 2005;112:2812. 55. Iler MA, Tillan K: Incidence of left ventricular dysfunction after pacemaker implantation for complete heart block. J Am Coll Cardiol 2006 2006: 21A. 56. Buckingham TA, Candinas R, Attenhofer C, et al: Systolic and diastolic function with alternate and combined site pacing in the right ventricle. Pacing Clin Electrophysiol 1998;21:1077–1084. 57. Prinzen FW, Peschar M: Relation between the pacing induced sequence of activation and left ventricular pump function in animals. Pacing Clin Electrophysiol 2002;25(4 Pt 1):484–498. 58. Prinzen FW, Augustijn CH, Arts T, et al: Redistribution of myocardial ﬁber strain and blood ﬂow by asynchronous activation. Am J Physiol 1990;259(2 Pt 2):H300–308. 59. Lieberman RA: Pressure-volume plane analysis to determine optimal ventricular pacing lead position in patients with normal QRS duration. Circulation 2004;110 (Suppl III):606, 2815. 60. Baig MW, Perrins EJ: The hemodynamics of cardiac pacing: Clinical and physiological aspects. Prog Cardiovasc Dis 1991;33:283–298. 61. Rao RK, Viloria E: Reduced ventricular volumes and improved systolic performance with cardiac resynchronization therapy: A comparison of simultaneous biventricular pacing vs. sequential biventricular pacing vs. left univentricular pacing. J Am Coll Cardiol 2006 2006:21A, 818– 817. 62. Scadsberg DA: Right ventricular outﬂow tract pacing preserves left ventricular activation pattern and optimizes hemodynamic function. Circulation 2004;110 (Suppl III):568, 2642.

383

384

Chapter 29 • Pacing and Diastolic Heart Failure 63. Sweeney MO: Multicenter, prospective, randomized trial of a new atrialbased managed ventricular pacing mode (MVP) in dual chamber ICDs. Circulation 2004;110 (Suppl III):444, 2088. 64. Inoue K, Otsuki, Y: Evaluation of left ventricle pressure derivative enhanced by multi site pacing in patients with heart failure. J Am Coll Cardiol 2006 2006:22A, 969–132. 65. Catanzariti D, Massimilano M: Permanent His bundle pacing does not induce dyssynchrony. An intrapatient comparison. J Am Coll Cardiol 2006 2006:23A, 969–138. 66. Voelker W, Mauser M, Kimmig A, et al: Eﬀect of rapid atrial pacing on left ventricular ejection fraction in patients without organic heart disease. Z Kardiol 1987;76:223–230. 67. Nielsen JC, Kristensen L, Andersen HR, et al: A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: Echocardiographic and clinical outcome. J Am Coll Cardiol 2003;42:614–623. 68. Hoﬀmann R, Lambertz H, Thoennissen G, et al: Altered left ventricular diastolic function post–atrial pacing in coronary artery disease and left ventricular hypertrophy: Further insights by pulmonary venous ﬂow analysis. Eur Heart J 1994;15:1096–1105. 69. Yu CM, Lin H, Fung WH, et al: Comparison of acute changes in left ventricular volume, systolic and diastolic functions, and intraventricular synchronicity after biventricular and right ventricular pacing for heart failure. Am Heart J. 2003;145:E18. 70. Bourdillon PD, Lorell BH, Mirsky I, et al: Increased regional myocardial stiﬀness of the left ventricle during pacing-induced angina in man. Circulation 1983;67:316–323. 71. Lamp B, Faber L, Heintze J, et al: Long-term outcome of cardiac resynchronization therapy. Circulation 2004;110(Suppl III):480, 2263. Abstract. 72. Bedotto JB, Grayburn PA, Black WH, et al: Alterations in left ventricular relaxation during atrioventricular pacing in humans. J Am Coll Cardiol 1990;15:658–664. 73. Schulz R, Aker S, Belosjorow S, et al: Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits. Am J Physiol Heart Circ Physiol 2003;285:H2084–2090. 74. Bell SP, Nyland L, Tischler MD, et al: Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 2000;87:235–240.

75. Spragg DD, Leclercq C, Loghmani M, et al: Regional alterations in protein expression in the dyssynchronous failing heart. Circulation 2003;108: 929–932. 76. D’Ascia C, Cittadini A, Monti MG, et al: Eﬀects of biventricular pacing on interstitial remodelling, tumor necrosis factor–alpha expression, and apoptotic death in failing human myocardium. Eur Heart J 2006;27:201–206. 77. Ashikaga H, Omens JH, Ingels NB Jr, et al: Transmural mechanics at left ventricular epicardial pacing site. Am J Physiol Heart Circ Physiol 2004;286: H2401–2407. 78. Ukkonen H, Beanlands RS, Burwash IG, et al: Eﬀect of cardiac resynchronization on myocardial eﬃciency and regional oxidative metabolism. Circulation 2003;107:28–31. 79. Sundell J, Engblom E, Koistinen J, et al: The eﬀects of cardiac resynchronization therapy on left ventricular function, myocardial energetics, and metabolic reserve in patients with dilated cardiomyopathy and heart failure. J Am Coll Cardiol 2004;43:1027–1033. 80. Shukla G, Orlov MV: Does bi-ventricular pacing improve myocardial perfusion? Circulation 2005;112(Suppl II):2847. Abstract. 81. Knaapen P, van Campen LM, de Cock CC, et al: Eﬀects of cardiac resynchronization therapy on myocardial perfusion reserve. Circulation 2004;110:646–651. 82. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al: Adverse eﬀect of ventricular pacing on heart failure and atrial ﬁbrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932– 2937. 83. Nielsen JC, Andersen HR, Thomsen PE, et al: Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single-chamber atrial or ventricular pacing. Circulation 1998;97:987–995. 84. Bristow MR, Saxon LA, Boehmer J, et al: Cardiac-resynchronization therapy with or without an implantable deﬁbrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–2150. 85. Cleland JG, Daubert JC, Erdmann E, et al: The eﬀect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549.

ANAND PRASAD, MD BENJAMIN D. LEVINE, MD

30

Aging and Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY Clinical Presentation of Diastolic Heart Failure in the Senior Population Diagnosis of Diastolic Heart Failure in the Senior Population Prognosis of Diastolic Heart Failure in the Senior Population

Etiology of Diastolic Dysfunction and Diastolic Heart Failure in the Senior Population CLINICAL RELEVANCE Challenges in Designing Trials and Treatments for Diastolic Heart Failure Novel Therapies on the Horizon FUTURE RESEARCH APPENDIX

INTRODUCTION The number of seniors in the United States and throughout the developed world is rising. As of 2003, roughly 36 million, or 12%, of the U.S. population were older than 65 years of age. Improvements in nutrition, disease prevention, and treatment have all contributed to this rise, with life expectancy at birth increasing from 47.3 years in 1900 to 76.9 years in 2000.1 Despite declining death rates from cardiovascular disease, more seniors now are living with chronic heart conditions, including hypertension (HTN), coronary artery disease (CAD), and congestive heart failure (CHF). In fact, the primary index diagnosis for the majority of hospitalizations of seniors in the United States is now CHF. The morbidity, mortality, and ﬁnancial costs of this disease are substantial in this population, with approximately 43,600 deaths (94% of total deaths from CHF) and 700,000-plus hospitalizations costing more than $20 billion per year in the United States.2,3 This epidemic is likely to worsen in the near future, as the “baby boom” generation enters its seventh decade (Fig. 30-1). By 2050, the senior population is expected to top 86 million individuals, highlighting the importance of this issue.1 To eﬀectively manage this rising burden of CHF in the senior population, a better understanding of the speciﬁc cardiovascular changes that occur with senescence is necessary. Unlike younger CHF patients, who often present with depressed ventricular function and chamber dilatation due to ischemic heart disease, as many as half of the senior CHF population has no evidence of depressed ventricular function and actually has a normal ejection

fraction (EF), or so-called diastolic heart failure (DHF).4–6 This chapter will address the eﬀect of DHF in the senior population, explore the speciﬁc age-associated pathophysiological changes of the heart that may provide the substrate for the development of DHF, and ﬁnally examine the challenges involved in devising new therapies for this disorder.

PATHOPHYSIOLOGY Clinical Presentation of Diastolic Heart Failure in the Senior Population The clinical proﬁle of senior heart failure patients is markedly diﬀerent than that of younger patients. In 1995, Vasan et al. concluded, based on a cumulative analysis of available studies of CHF and normal left ventricular (LV) systolic function, that the prevalence of normal function in CHF patients under 65 years of age was signiﬁcantly lower than that in those older than 65.7 More recent data support this claim. Based on population and hospitalization registry data, such as the Olmsted County experience, the Enhanced Feedback for Eﬀective Cardiac Treatment (EFFECT) dataset from Ontario, Canada, and the Acute Decompensated Heart Failure National Registry (ADHERE), DHF is predominantly a disease of the elderly, and its prevalence is on the rise (Fig. 30-2).8–10 Data from these and several other studies have demonstrated that the prototypical patient presenting with this disorder is in the seventh or eighth decade of life, female, obese, hypertensive, more often diabetic, and often aﬄicted with atrial 385

Chapter 30 • Aging and Diastolic Heart Failure 100 Population of seniors (millions)

772,000 Projected new CHF cases in 2040

TABLE 30-1 VALUES USED TO DEFINE “NORMAL” LEFT VENTRICULAR EJECTION FRACTION (EF)8–14

77.2

80

348,000 New CHF cases in 2000 53.7

60 34.8

40 25.5 16.6

20

0 1940

9.2

11.3

12.7

1960

1980

2000

16.5

2020

20.5

2040

2060

Time (years, projected into the future) Persons (millions) % of population Figure 30-1 Incidence of congestive heart failure (CHF) in persons aged at least 65 years. The population of seniors is expected to rise over the next 40 years in the United States, as is the number of patients with new-onset CHF. (Modified from Owan TE, Redfield MM: Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 2005;47:320–332.)

70 Patients with preserved ejection fraction (%)

386

r = 0.92, P <0.001

60 50 40 30 20 0 1986

1990

1994

1998

2002

Figure 30-2 Based on a community sample of 4596 consecutive patients admitted with congestive heart failure (CHF) from Olmsted County, Minnesota, the prevalence of CHF with a preserved ejection fraction has increased over a 15-year period. (Modified from Owan TE et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. NEJM 2006;355:251–259.)

ﬁbrillation.11–14 These comorbid conditions are not simply innocent bystanders but, as will be described in this chapter, may actively contribute to the pathophysiology of DHF.

Diagnosis of Diastolic Heart Failure in the Senior Population The diagnostic criteria for DHF have been reviewed elsewhere in this book and are no diﬀerent in the senior population (see Chapter 6). It should be emphasized, however, that it is diﬃcult, if not impossible, to make a diagnosis of DHF, as opposed to systolic heart failure (SHF), by history or clinical presentation alone. Patients with DHF may have higher blood pressure and more often have atrial ﬁbrillation at the time of presentation, but these are by no means universal ﬁndings.7–9 The most recent Heart Failure Society 2006 guidelines recommend that a diagnosis of DHF “can be made by the combination of clinical signs and

STUDY

EF % USED AS “NORMAL” OR “PRESERVED”

Olmsted County study ADHERE Ancillary DIG study CHARM-Preserved study MISCHF registry PEP-CHF Yale–New Haven Experience

≥50 ≥40 ≥45 ≥40 ≥50 ≥45 ≥40

ADHERE, Acute Decompensated HEart Failure National REgistry; DIG, Digitalis Investigation Group; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; MISCHF, Management to Improve Survival in Congestive Heart Failure; PEP-CHF, Perindopril in Elderly People with Chronic Heart Failure.

symptoms of CHF coupled with a preserved or relatively preserved EF.”15 In contrast, the 2005 guidelines from the American Heart Association/American College of Cardiology for the diagnosis and management of chronic heart failure suggest that the addition of measures of LV relaxation and LV volume are needed for a deﬁnitive diagnosis.16 Unfortunately, the inclusion criteria for a diagnosis of DHF and the terms “preserved” and “normal” are open to interpretation, and this uncertainty has led to signiﬁcant debate and inconsistency among studies.17–19 The vague deﬁnition of DHF is a source of much controversy in its trials. The EF used in the clinical studies, registry analyses, and population surveys has varied (Table 30-1). For example, in the dataset from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial, of the 3023 patients with “preserved” systolic function randomized, 35% (1072 patients) had EFs of 41%–49%. These EF determinations are not absolute numbers and carry with them a margin of error. The EF measurement has a high degree of variability, depending on the speciﬁc technique used, and is subject to both intra- and interobserver variability.20,21 Using noncontrast echocardiography, for example, the variation for individual patients can be as high as 10% (EF units) compared with measurements on magnetic resonance imaging (MRI), and the intra- and interobserver variabilities can reach as high as 10%–15% (EF units).21 Therefore, an EF at the lower limits of what is considered normal in a clinical trial, such as 41% in the CHARM trial, could actually be signiﬁcantly lower and introduce error into the dataset. This issue may be of particular importance in women. The Dallas Heart Study examination of MRI-derived EF in a probability-based sample of Dallas County residents aged 30 to 65 years (1435 women and 1183 men) found that women tended to have higher EFs than men (Fig. 30-3).22 These ﬁndings persisted even when body size was taken into consideration. The authors concluded that a low EF (below the 2.5th percentile of the population sampled) was deﬁned as below 61% in women and below 55% in men. These data suggest that an EF of 50% in women may not be normal, and an EF of 40% is certainly abnormal. While the designation of a particular EF as “normal” is somewhat arbitrary, the use of a higher EF as the cutoﬀ for diﬀerentiating systole versus diastole may be more helpful in limiting inclusion of patients with SHF into clinical trials. This ambiguity surrounding EF also raises the point that the actual incidence of

Figure 30-3 Women have higher ejection fractions (EFs) than men. Histograms of EF from the Dallas Heart Study. (Modified from Chung AK et al: Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: The Dallas Heart Study. Circulation 2006;113:1597–1604.)

Percent of participants (%)

Chapter 30 • Aging and Diastolic Heart Failure 35

p <0.001

Men Women

30

387

25 20 15 10 5 0 <40

45

50

55

60

65

70

75

80

85

90

>95

Left ventricular ejection fraction (%)

200 LBNP

Baseline

Saline infusion

180 Sedentary Fit Young

Figure 30-4 Effect of aging and lifelong fitness on Doppler variables. Isovolumetric relaxation time (IVRT) derived from Doppler echocardiography in young subjects, sedentary seniors, and master athlete seniors. Normal healthy aging results in a prolongation of IVRT across all loading conditions: baseline, lower body negative pressure (LBNP), and saline loading (p < 0.001), while lifelong endurance training has no effect on relaxation (p = 0.546). PCWP, pulmonary capillary wedge pressure. (Modified from Prasad A et al: The effects of aging and physical activity on Doppler measures of diastolic function. Am J Cardiol 2007;99:1629–1636.)

IVRT (msec)

160

140

120

100

80

DHF in the community may not be as high as the rates that have been previously reported. Since the prototypical patient with DHF is more often female, the growing epidemic of DHF in women may reﬂect inclusion of patients with occult or misclassiﬁed systolic dysfunction. The use of more rigid EF criteria in population studies may also help clarify this issue as well. In addition to controversies regarding EF, there has been discussion in the literature as to whether Doppler velocity patterns are suﬃcient to diagnose DHF, or for that matter whether such measurements are even needed at all.18,19 DHF, like all forms of CHF, is a clinical diagnosis that should be supported by an objective assessment of LV systolic function. The use of Doppler echocardiography in the senior population, in particular, raises some important considerations. It is true that most, if not all, senior patients with DHF will have alterations in Doppler measures of diastolic function (diastolic dysfunction); however, these measurements should not be assumed to be speciﬁc or pathognomonic for DHF. Both completely healthy sedentary seniors and highly trained senior master athletes manifest profound changes in their Doppler patterns compared with young controls, suggesting that these alterations are a speciﬁc manifestation of normal aging (Figs. 30-4 and 30-5).23 The master athletes, who from a symptomatic and functional standpoint are at the extreme opposite spectrum from DHF patients, have marked Doppler abnormalities despite also having peak oxygen uptakes comparable to individuals 30 years younger.24 Given these data, one could make

0

2

4

6

8

10

12

14

16

18

20

22

PCWP (mmHg)

the argument that the terms diastolic dysfunction and abnormal ﬁlling pattern are inexact when used in this context and should perhaps be revised. The diastolic Doppler patterns seen in the senior population are best described as normal for age, much like gray hair or wrinkling of the skin (see Appendix).

Prognosis of Diastolic Heart Failure in the Senior Population While slightly better than that of SHF, the short-term prognosis of patients with DHF is not benign. The mortality rate during acute hospitalization was 2.8% in ADHERE (vs. 3.9% in the SHF group).9 Similar to patients with SHF, patients with DHF and concomitant hypotension, hyponatremia, advanced age (>73 years), and elevated blood urea nitrogen (BUN) were at increased odds for mortality based on multivariate analysis. Notably, elevation of resting heart rate (HR) (>78 bpm) was particularly detrimental to patients with preserved function, perhaps suggesting the importance of maintaining an adequate diastolic ﬁlling period in this population. The longer-term prognosis of patients with DHF versus SHF has been debated. These results have been conﬂicting, primarily because of diﬀerences in study design and inclusion of community versus clinical-trial patient populations.8,10,25,26 Two recent studies may help shed light on this issue. The long-term survival data from the Olmsted County study are detailed in Figure 30-6A. In

388

Chapter 30 • Aging and Diastolic Heart Failure

E

A E

E A

120 90 60

A

30 cm/sec

Fit senior Sedentary senior Young C B E/A = 1.1 E/A = 0.6 E/A = 2.8 Figure 30-5 Effects of aging and fitness on the E/A ratio. Transmitral Doppler velocity profiles taken at rest from A, a young subject, B, a sedentary senior, and C, a master athlete senior. Normal healthy sedentary aging results in a decrease in the ratio of the peak early (E) to late (A) transmitral Doppler velocities (E/A ratio) (A vs. B). Lifelong endurance training does not completely prevent the decline in the E/A ratio (A vs. C). (Modified from Prasad A et al: The effects of aging and physical activity on Doppler measures of diastolic function. Am J Cardiol 2007;99:1629–1636.)

A

this study, data from 4596 consecutive patients admitted with a diagnosis of CHF were examined and segregated by EF. The mortality rate in DHF patients admitted with CHF was only slightly lower than in patients with SHF (29% vs. 32% at one year and 65% vs. 68% at 5 years).8 Interrogation of the EFFECT dataset from Canada, which examined similar variables in 2802 patients with a discharge diagnosis of CHF, found no statistically signiﬁcant diﬀerence in adjusted mortality rates at one year (see Fig. 30-6B).10 These studies suggest that the late survival in the two forms of CHF is not radically diﬀerent from each other, despite very diﬀerent pathophysiological mechanisms.

Etiology of Diastolic Dysfunction and Diastolic Heart Failure in the Senior Population The cause or causes of DHF in seniors remain controversial. As the name “diastolic heart failure” implies, the long-accepted but poorly understood explanation for the etiology of this disorder has centered on impairments of lusitropic function in these patients. Recent studies have now conﬁrmed the presence of abnormalities in active ventricular relaxation and static chamber stiﬀness, mostly in male patients with heart failure and a normal EF.27 However, our laboratory has demonstrated that even healthy sedentary aging results in marked abnormalities of these very same diastolic properties, suggesting that additional factors inﬂuence the development of DHF in seniors.28 What then separates a patient with DHF from an otherwise healthy sedentary adult? To answer this question, we will ﬁrst examine the changes in diastolic function that occur with normal aging and then discuss

the comorbid conditions that might be additive and result in heart failure. Sedentary aging, even in the absence of comorbid conditions, results in marked changes of cardiovascular structure and function, including slowing of active myocardial relaxation and decreased static LV chamber compliance. While a detailed examination of the hemodynamic determinants of diastolic function has been reviewed in Chapters 2, 5, and 7, we will examine the eﬀects of aging on these processes in some detail.

Slowing of Myocardial Relaxation and Impairment of Ventricular Suction There have been few invasive studies directly examining LV relaxation of the aged human heart because of the obvious ethical concerns about cardiac catheterization in normal healthy subjects. Furthermore, the few available studies have included only small numbers of seniors, making it diﬃcult to draw deﬁnite conclusions. One of the ﬁrst invasive studies to suggest a relationship between age and slowing of active myocardial relaxation was done by Hirota in 1980.29 He examined the time constant of LV pressure decline using micromanometer-tipped high-ﬁdelity catheters in several groups of subjects with suﬃcient symptoms to warrant referral for diagnostic cardiac catheterization. His subjects included a group of 18 individuals (4 of whom were older than 60 years) whom he deemed “normal” because of an absence of LV dysfunction or CAD. In these subjects, he noted a weak but signiﬁcant correlation between age and prolongation of the time constant of LV relaxation (Fig. 30-7A). In contrast, Yamakado

Chapter 30 • Aging and Diastolic Heart Failure n = 18, r = 0.652

1.0

60

Preserved ejection fraction

0.6

Age (years)

Survival

0.8

0.4 Reduced ejection fraction

0.2

40

20

P = 0.03 0.0 0

1

2

3

4

5

Year No. at risk 2424 Reduced ejection fraction

1637

1350

10

1049

813

20

A

604

30

40

50

Time constant T (nsec)

100

r = 0.001, nsec

90 2166 Preserved ejection fraction

1539

1270

1001

758

574 Tb–1 (msec)

A 100 95 Survival (%)

80

90

60 50 40 30

Preserved ejection fraction

20

85

10 80

0 Reduced ejection fraction

75

10

20

30

40

50

60

70

80

60

70

80

Age (years)

70 0

80 50

100

150

200

250

300

350

400

Days

Figure 30-6 Slightly higher survival rates for patients with preserved versus reduced ejection fraction in the A, Olmsted County experience (unadjusted hazard ratio = 0.96; 95% CI, 0.93–1.00; p = 0.03) and similar adjusted mortality rates in B, the EFFECT dataset from Ontario, Canada (hazard ratio = 1.13; 95% CI, 0.94–1.36; p = 0.18). (A, Modified from Owan TE et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. NEJM 2006;355:251–259. B, Modified from Bhatia RS et al: Outcome of heart failure with preserved ejection fraction in a population-based study. NEJM 2006;355:260–269.)

r = 0.02, nsec

70 60 Tw–1 (msec)

0

B

70

50 40 30 20 10 0

et al. examined LV relaxation using similar methods and found no correlation with age and the time constants of relaxation (see Fig. 30-7B).30 Unfortunately, of the 55 patients who met inclusion criteria for this study, only 9 were older than 65 years of age. The most robust information examining the issue of aging and LV relaxation in humans comes from noninvasive data. Alterations in LV diastolic function with senescence were ﬁrst hinted at by Harrison et al., who in 1964 used carotid pulse contour analysis and precordial “kinetocardiograms” (measuring chest wall motion) to suggest a prolongation of isovolumetric relaxation time in older compared with younger individuals.31 Subsequently, M-mode echocardiograms were examined from the Baltimore Longitudinal Study on Aging and demonstrated a reduction in the rate of mitral valve closure (E-F slope) with increasing age, also consistent with slowed relaxation.32 Since then, similar observations have been made by many investigators, by assessing either peak ﬁlling rates by nuclear imaging or mitral inﬂow patterns by Doppler echocardiography, involving many thousands

10

B

20

30

40

50

Age (years)

Figure 30-7 Relationship between age and left ventricular (LV) relaxation: invasive studies. A, Correlation between age and the time constant of relaxation in normal subjects by Hirota (n = 18, r = 0.652). B, Example of lack of correlation between age and time constants (Tb-1 and Tw-1) of LV relaxation. (A, Modified from Hirota Y: A clinical study of left ventricular relaxation. Circulation 1980;62:756–763. B, Modified from Yamakado T et al: Effects of aging on left ventricular relaxation in humans. Analysis of left ventricular isovolumic pressure decay. Circulation 1997;95:917–923.)

of patients from diverse ethnic, geographic, and age distributions.33–52 One of the largest studies published to date, from the Cardiovascular Health Study examining more than 5000 men and women in a community-based population, conﬁrmed that regardless of gender or the presence of speciﬁc cardiovascular diseases such as HTN or CAD, there is a progressive reduction in early ﬁlling velocity (E wave) and increase in late ﬂow velocity

389

Chapter 30 • Aging and Diastolic Heart Failure (Tau, τ) with normal aging.57 There are a variety of well-described changes that occur within the aging cardiac myocyte, resulting in alterations of both the electrical and mechanical processes underlying contraction and relaxation. Some of these changes include altered myocyte Ca2+ handling, shifts in myosin heavy chain isoforms, and reductions of β-receptor activity.58–60 There is a large body of data, derived predominantly from rodent experiments, to support the role of changes in Ca2+ handling as the central etiology of this process.59,61–63 Since sequestration of Ca2+ occurs during the ﬁrst third of diastole, it is not surprising that the Doppler measures we have described, which examine early diastolic processes, would be altered with aging. Early diastole is very dependent on reuptake of Ca2+ from the cytosol back into the sarcoplasmic reticulum (Fig. 30-9) (see

(A wave) with increasing age, consistent with the pattern of impaired relaxation.53 With the introduction of newer Doppler techniques as discussed in Chapters 11 and 12, there have been additional insights into the alterations of speciﬁc components of myocardial relaxation processes with aging. Early diastolic tissue Doppler velocities, which represent longitudinal myocardial motion during active relaxation, are slower with aging.23,54 In addition, color Mmode–derived indices such as the propagation velocity of early mitral inﬂow (Vp) and the magnitude of early diastolic intraventricular pressure gradients (IVPGs) appear to be diminished by aging.23,55 The changes in these newer Doppler variables highlight an important characteristic of the senescent heart, namely the loss of vigorous diastolic suction. As discussed in a previous chapter of this book, diastolic suction is the result of restoring forces created during contraction to below the equilibrium volume during the prior ventricular systole (see Chapter 5). This stored potential energy is released during the subsequent diastolic period, actively drawing blood from the base of the heart to the apex. The magnitude of this force can be estimated by examining the pressure diﬀerences within the LV chamber itself.55,56 These IVPGs are markedly reduced during sedentary but healthy aging compared with healthy young adults (Fig. 30-8).55 In theory, decreased suction could impair ﬁlling of a stiﬀ noncompliant heart during conditions of rapid heart rate, orthostatic stress (as left atrial [LA] pressure is acutely lowered), or a volume challenge when the left ventricle must accommodate a large amount of blood in a relatively short time. The potential clinical eﬀect of this loss of suction and its hemodynamic consequences in the aged population has not yet been fully examined. Most of our knowledge of the mechanisms underlying the ageassociated changes in LV relaxation comes from animal- and cellbased experimental data. Concordant with human Doppler data, invasive studies in rodents have demonstrated a reduction in the rate of LV pressure decline during early diastole (−dP/dT) and therefore prolongation of the time constant of early relaxation

4 Elderly sedentary Young IVPG (mmHg)

3

2

1

0 0

5

10

15

20

PCWP (mmHg) Figure 30-8 Early diastolic intraventricular pressure gradients (IVPGs) in healthy sedentary seniors and young subjects. Normal aging results in a decrease in diastolic suction. PCWP, pulmonary capillary wedge pressure. (Modified from Popovic ZB et al: Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and fitness. Am J Physiol 2006;290:H1454–H1459.)

CELLULAR Ca FLUXES 3Na

RyR

Sarcolemma

Ca

2K Na

NaCaX

ATP

NaHX

ATP

3Na

Ca

H

Ca SR

PLB

ICa

ATP

Ca TnC Ca

Ca

Ca

Myofil

H

2Na Ca T-Tubule

390

H

NaCaX 3Na

Ca Na Mito

Ventricular myocyte

Figure 30-9 Diagram of Ca2+ regulation in the cardiac myocyte. Ca2+ transport and requirements for activation of myofilament force. Schematic diagram of cellular Ca2+ fluxes. (Modified from Bers DM: Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res 2000;87:275–281.)

Chapter 30 • Aging and Diastolic Heart Failure Chapter 1). This is an energy-dependent process requiring the activity of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and the sarcolemmal Na+/Ca2+ exchanger. Regulation of SERCA2a is modulated by the inhibitory subunit phospholamban. Phosphorylation of phospholamban removes inhibition of SERCA2a activity.59 Normal aging results in numerous changes of this Ca2+-regulating system, including reduced SERCA2a pumping rate, decreased SERCA2a-to-phospholamban ratio, and reduced protein levels of the sarcolemmal Na+/Ca2+ exchanger, all of which contribute to the slowing of early relaxation.59,60,64 Further supporting the role of altered Ca2+ reuptake in this regard is a series of experiments by Schmidt et al. that demonstrated restoration of Tau and −dP/dT to younger levels in senescent hearts by adenoviral gene transfer of SERCA2a, suggesting that these Ca2+-handling mechanisms could also be potential targets for therapeutic intervention in DHF (Fig. 30-10).61

Decreased Left Ventricular Compliance and Physical Deconditioning When examining the diastolic process, not only LV relaxation but also LV compliance must be considered. Animal studies have generally suggested that the heart may stiﬀen with age.65 Sophisticated analysis of contractile performance and diastolic stiﬀness in older rats demonstrated prominent decreases in cardiac compliance as assessed from pressure-volume curves.66 Our laboratory has recently studied the eﬀect of aging and lifelong ﬁtness on the end diastolic pressure-volume relationship in normal healthy adults

–dP/dt (mmHg/sec)

–5,000

–3,000

across ﬁve diﬀerent levels of cardiac ﬁlling using invasive determination of pulmonary capillary wedge pressure (PCWP) and concomitant measurement of LV end diastolic volume by echocardiography (Fig. 30-11).24 These measurements were obtained in three groups of healthy subjects that consisted of young individuals, sedentary seniors, and Masters athletes (competitive athletes over the age of 50 participating successfully in USA Masters sanctioned events, such as track and ﬁeld, swimming, and cycling). Based on the data obtained from this study, normal sedentary aging results in a marked decrease of LV compliance. When examining such data, it is important to consider the contribution of deconditioning. LV compliance is sensitive to even relatively short periods of deconditioning. For example, as little as 2 weeks of strict bed-rest deconditioning leads to a shift of the end diastolic pressure-volume relationship to the left (Fig. 30-12).67–69 Normal aging alone generally leads to reductions in physical activity, in both humans and experimental animals. It is therefore crucial to ascertain whether the loss of LV compliance is speciﬁc to the aging process or is instead the result of lifelong deconditioning, which is known to increase LV stiﬀness. If the end diastolic pressure-volume curves for the Masters athletes in Figure 30-11 are examined, it can be seen that the loss of LV compliance in the sedentary senior group is not speciﬁc for senescence and is completely prevented by lifelong endurance exercise. It should be pointed out that these data are in marked contrast to the noninvasive data for these very same subjects, which demonstrate little if any eﬀect of lifelong ﬁtness on Doppler measures of relaxation (see Figs. 30-4 and 30-5).23 The discordance between the training eﬀect on LV compliance and relaxation is best explained by the fundamental diﬀerences in cellular regulation of these two processes. LV relaxation, as controlled by Ca2+ handling, appears to be resistant to aerobic training in many species, including humans.70,71 These particular protein alterations may be speciﬁc to the aging process and not inﬂuenced by physical activity. LV compliance is regulated by a separate set of proposed pathways, which warrant some detailed discussion. The proposed pathophysiology of increased stiﬀness of the left ventricle with aging is multifactorial. Much of the focus in this

–1,000

Adult

A

Senescent Senescent Senescent + + Ad.βgal Ad.SERCA2a

30

τ (msec)

25 20 15 10

4

2 Sedentary Athletes Young 0

5

50

0

B

Estimated transmural pressure (mmHg)

6

75

100

125

150

Left ventricular end-diastolic volume (ml) Adult

Senescent

Senescent Senescent + + Ad.βgal Ad.SERCA2a

Figure 30-10 Restoration of diastolic function by adenoviral gene transfer of SERCA2a in rat hearts. Ad.β-Gal is the reporter adenovirus. Ad.SERCA2a is the adenovirus containing the gene of interest. A, −dP/dT and B, Tau. Rat hearts infected with Ad.SERCA2a demonstrate increased rate of ventricular relaxation. (Modified from Schmidt U et al: Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase. Circulation 2000;101:790–796.)

Figure 30-11 End diastolic pressure-volume relationships in young healthy sedentary subjects, healthy sedentary seniors, and senior Masters athletes. Normal sedentary aging results in a loss of ventricular compliance, while lifelong aerobic exercise prevents this loss. Estimated transmural pressure is equal to pulmonary capillary wedge pressure minus right atrial pressure; left ventricular end diastolic volume is measured by echocardiography. (Modified from Arbab-Zadeh A et al: Effect of aging and physical activity on left ventricular compliance. Circulation 2004;110:1799–1805.)

391

Chapter 30 • Aging and Diastolic Heart Failure 24 Pulmonary capillary wedge pressure (mmHg)

392

P = –Sln[(Vm–V)/(Vm–Vo)]

Fibrillar ECM

20 dP/dV = S/(Vm–V) @121 = 0.204 @139 = 0.582

16

Post bedrest S = 5.65

12

8

Stress, strain Disruption of fibrillar ECM

Pre bedrest S = 6.13

4

dP/dV = S/(Vm–V) @139 = 0.374 @121 = 0.178

*

0 0

Vo

40

Vo

80

120

160 Stress, strain

LVEDV (ml) Figure 30-12 Bedrest deconditioning leads to decreased LV compliance. Shift of the end diastolic pressure-volume (LVEDV) relationship to the left after 2 weeks of strict bedrest. (Modified from Levine BD, Zuckerman JH, Pawelczyk JA: Cardiac atrophy after bed-rest deconditioning: A nonneural mechanism for orthostatic intolerance. Circulation 1997;96:517–525.)

Figure 30-13 The extracellular matrix (ECM) is composed of a basement membrane and a fibrillar collagen network providing support and structural integrity to myocytes. (Modified from Spinale FG: Matrix metalloproteinases: Regulation and dysregulation in the failing heart. Circ Res 2002;90:520–530.)

TABLE 30-2 MMPS AND TIMPS IN VENTRICULAR REMODELING ENZYME

MMP

ENZYME (KDA LATENT/ACTIVE)

SUBSTRATE

REMODELING*

Collagenases

MMP-1

Interstitial collagenase (52/42)

+

Gelatinases

MMP-8 MMP-13 MMP-2

Neutrophil collagenase (85/64) Collagenase-3 (52/42) Gelatinase A (72/66), type IV collagenase

MMP-9

Gelatinase B (92/84), type V collagenase

Stromelysins

MMP-3

Stromelysin 1 (57/45)

Membrane type

MMP-10 MMP-11 MMP-14

Stromelysin 2 (54/44) Stromelysin 3 (64/46) MT1-MMP (66/54)

Others

... MMP-7

(MT2-MT3-MT4-MMPs) Matrilysin, PUMP-1 (28/19)

MMP-12

Matalloelastase (54/22)

Collagen type I, II, III, VII, and X; gelatins; proteoglycans; entactin Collagen type I, II, and III Collagen type I, II, and III Gelatins (type I), collagen type I, II, III, IV, V, VII, and XI; fibronectin; laminin; elastin; proteoglycans Gelatins (type I and V), collagen type I, II, III, IV, V, and VII; elastin; entactin; proteoglycans Gelatins (type I, III, IV, and V), collagen type III, IV, IX, and X; collagen telopeptides; proteoglycans; fibronectin; laminin; MMP activation Collagen type IV; proteoglycans; laminin; fibronectin Furin deavage Collagen type I, II, III, and IV; gelatin; fibronectin; laminin; activation of proMMP-2 and proMMP-13 (Not known) Proteoglycans, fibronectin, gelatins, collagen type IV, elastin, entactin Elastin (macrophage elastase)

+ + + + + ? − + ? ? ?

*Role in cardiac remodeling was classified as documented (+), probable (?), or not known (-). Modified from Jugdutt BT: Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough? Circulation 2003;108:1395–1403.

ﬁeld has centered on the extracellular matrix (ECM). The ECM is composed of a basement membrane and a ﬁbrillar collagen network providing support and structural integrity to myocytes (Fig. 30-13).72 The ECM is also highly metabolically active and serves as a source for anti-apoptotic signals and growth factors, a substrate for cell adhesion, and a determinant of myocyte mechanics.72–74 The ECM undergoes extensive turnover and remodeling. Altering the balance between collagen synthesis and degradation results in myocardial collagen accumulation, stiﬀening, and cardiac dysfunction.72,75 A common thread among diverse etiologies of CHF appears to be the dynamic remodeling of the ECM, which

in turn results in myocardial ﬁbrosis, impairing both ventricular relaxation and compliance.74 Recently, it has been recognized that the regulation of the ECM depends on an interplay between matrix metalloproteinases (MMPs), a family of enzymes present in the myocardium and responsible for degrading the matrix components of the heart, and speciﬁc tissue inhibitors of matrix metalloproteinases (TIMPs) (Table 30-2).76,77 Activity of MMPs is regulated at both pre- and posttranscriptional levels and may be modulated by inﬂammatory cytokines such as tumor necrosis factor (TNF)– alpha,76 as well as mechanical physiological signals such as load

Chapter 30 • Aging and Diastolic Heart Failure

Metabolic Hypothesis of Cardiac Aging The exact mechanism by which sedentary aging could lead to inhibition of MMPs with increases in TIMPs leading to ﬁbrosis and cardiac stiﬀening is uncertain. Another, possibly interrelated mechanism could be that relative energy imbalance, speciﬁcally insuﬃcient energy expenditure relative to caloric intake, may present a unifying hypothesis for why the heart stiﬀens with sedentary aging, yet is preserved with lifelong exercise training. For example, aged rats show clear evidence of progressive increases in collagen deposition in the left ventricle with age. However, this ﬁbrosis was substantially reduced in rats maintained on a calorierestricted diet.91 More recently, gene chip array analysis has identiﬁed prominent alterations in transcription with aging in a mouse model, including marked upregulation of the expression of ECM genes, such as procollagens.92 Similar to the aged rat, these mice demonstrated a 150% to 200% reduction in expression of these genes when fed a hypocaloric diet.92 Progressive weight gain/ obesity is one of the hallmarks of the aging process.93 For most individuals, such weight gain with age is due predominantly to reduced levels of physical activity and caloric expenditure,93 with severe health consequences.94,95 Obesity is a particularly important risk factor for the syndrome of heart failure with a normal EF.19 For example, obese individuals display increased LV mass and wall thickness coupled with reduced LV ﬁlling dynamics— maladaptations that may predispose individuals to heart failure, particularly with advancing age.96–98 Interestingly, these adverse LV adaptations appear to develop independently of hemodynamic load,99 thus pointing to a metabolic cause for these cardiac consequences.

These data suggest the possibility of a “metabolic hypothesis” of cardiac stiﬀening with sedentary aging. This hypothesis proposes that the metabolic consequences of sedentary aging— relative insulin resistance and excess caloric intake relative to expenditure, with or without obesity—lead to “lipotoxicity” and the accumulation of abnormal metabolites such as triglycerides (TGs) and advanced glycation end-products (AGEs) that separately and/or together contribute to the stiﬀening of the aged heart. Studies in animal models of human obesity have led to the development of this novel concept of “lipotoxicity,” which may explain the multiple pathological features associated with obesity.100 Speciﬁcally, in these animals the consequences of excess fat mass develop secondary to the toxic eﬀects of an accumulation of intracellular lipid within non-adipocytes.101,102 While few human data are available, evidence is emerging that an excessive accumulation of lipid within the myocardium develops in obesity and is associated with sedentary aging (Fig. 30-14). In animal models of human obesity, myocardial TG increases 2.5- and 4fold by 7 and 14 weeks of age, respectively, while lean wild-type animals display no change in myocardial TG over the same time frame.102 This increase in myocardial TG content is associated with a 15-fold increase in markers of apoptosis and profoundly depressed LV systolic performance, implying that intramyocardial TG accumulation may explain the cardiac maladaptations that develop secondary to chronic obesity. When animals are treated with an agent that lowers tissue TG, intracellular lipid content is eﬀectively diminished, markers of apoptosis are attenuated, and LV systolic performance is restored.102 In summary, substantial evidence from animal studies suggests that excessive myocardial lipid accumulation is a key feature in the pathogenesis of obesityrelated disorders and contributes to cardiac dysfunction. The close association between TG accumulation and insulin resistance/glucose intolerance in animal models as well as the clinical “metabolic syndrome” raises the additional possibility that the long-term consequences of TG accumulation could be exacerbated by the accretion of AGEs within the heart.103 When reducing sugars (such as glucose) complex nonenzymatically with amino groups on proteins, the resulting protein-protein crosslinks form a yellow-brown pigment that leads to the “browning” typically associated with the roasting of a basted turkey or steak.103 First described by Louis Maillard almost a hundred years ago, the

Myocardial triglyceride (F/W %)

and stretch.78–80 Increased MMP activity has been associated with LV enlargement and dilation,77 and inhibiting these enzymes limits the severity of pacing-induced CHF in pigs.74,81 However, these changes (expected to augment proteolysis of collagen) do not readily explain the increased ﬁbrosis and stiﬀness associated with end-stage CHF. In this regard, aged rats appear to have substantial decreases (40%–45%) in MMP activity.82 Transgenic mice that overexpress cardiac-speciﬁc TNF-alpha may help to reconcile this apparent contradiction with respect to aging.83 In this model, young mice initially demonstrated a signiﬁcant increase in MMPs associated with LV structural remodeling. However, as the mice aged, there was a time-dependent increase in TIMP-1 levels, associated with an overall reduction in the MMP/TIMP ratio and progressive ﬁbrotic stiﬀening without further enlargement.83 This time course and pattern of MMP/TIMP proﬁles has also been demonstrated in pressure overload hypertrophy84 due to aortic banding. Thus the activity of MMPs and their TIMPs may be time dependent, with diﬀering eﬀects dependent on the speciﬁc pathophysiology and phase of the life cycle.77 Aging also has prominent eﬀects on the balance between myocyte volume and the ECM. For example, the aged heart has substantially fewer myocytes than the young heart, accompanied by signiﬁcant increases in the volume fraction of collagen.85 In rats, this reduced number of myocytes is associated with increases in the size of each individual myocyte that may be adaptive.84,85 Increased myocardial ﬁbrosis has also been noted in senescent animal hearts.86–89 In otherwise “healthy” but aged human hearts, there appear to be focal areas of interstitial ﬁbrosis, predominantly in the subendocardium of the left ventricle, that increase with age and may be related to the loss of myocyte volume as “replacement ﬁbrosis.”90

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Masters athlete

Sedentaryvigorous training

Sedentary moderate training

Sedentaryno training

Figure 30-14 Intramyocardial triglyceride (TG) accumulation in elderly humans determined by 1H-MRS (magnetic resonance spectroscopy) calculations of fat/water ratio from a senior Masters athlete and three senior sedentary subjects after various levels of training. Elevated TG accumulation is associated with sedentary aging and is sensitive to physical activity.

393

394

Chapter 30 • Aging and Diastolic Heart Failure Maillard reaction104 is driven by the concentration of available sugars and is thereby also responsible for the glycation of shortlived proteins such as hemoglobin; this process is widely used clinically to monitor control of glucose in diabetic patients over several weeks to months as the concentration of hemoglobin A1c (Fig. 30-15). These Maillard reaction products (also known as Amadori products) form on other proteins in vivo and may accumulate over time in complex arrangements of crosslinked proteins, such as AGEs.105 When AGEs form on long-lived proteins such as collagen or lens crystallin proteins, they result in prominent stiﬀening of the ECM and can lead to human pathology such as cataracts or vascular and myocardial stiﬀening.106–110 Because AGEs are very stable and virtually irreversible once formed, they accumulate continuously with aging.111–113 This process therefore has been proposed as one of the key mechanisms responsible for the stiﬀening of a variety of tissues as a primary manifestation of the aging process, which may be accelerated in diseases with chronically high concentrations of blood glucose, such as diabetes.108,114 Over the last 25 years, a substantial amount of evidence has accumulated to support this hypothesis.103,112,113,115 For example, human dura mater108 and skin116 obtained at autopsy from otherwise healthy individuals showed a clear, linear increase in pigmented collagen typical of AGEs with advancing age, suggesting that these products accumulate in human tissue over time. Diabetic patients experienced an even greater accumulation of pigmented collagen, suggesting that the presence of diabetes “accelerated” the aging process.108 Diabetic patients also accumulate substantial amounts of crosslinked collagen in blood vessels, leading to increased vascular stiﬀening.117 More recently, it has been demonstrated that AGEs crosslink not only collagen, but also elastin in the aorta, further reducing arterial distensibility.106,118 Myocardial collagen also appears to be increasingly crosslinked with age,119 associated with

increased myocardial stiﬀness.120–123 It should be emphasized that these AGEs do not act simply as structural scaﬀolding. Rather, they appear to be metabolically active, binding to receptors for AGEs (RAGEs), which may precipitate endothelial dysfunction by enhancing oxidative stress and exacerbating inﬂammatory responses that may modify the ECM.124,125 Together, these multifaceted eﬀects of the accumulation of both vascular and myocardial crosslinked collagen have led to their being proposed as a unifying hypothesis to explain ventriculovascular stiﬀening in the elderly.120,121,126,127 As will be discussed later in this chapter, inhibitors of the crosslinking process may be potential treatments to prevent or even reverse ventricular stiﬀening with aging.

Role of Comorbid Conditions in the Pathophysiology of Diastolic Heart Failure The variety of cellular changes, discussed above, that occur during normal aging lead to the abnormalities in LV relaxation and compliance, which are reﬂected as abnormal Doppler parameters of diastolic function. It is clear, given the high prevalence of these abnormalities in the senior population, that the presence of diastolic abnormalities alone is not suﬃcient to cause heart failure. Instead, the superimposing of comorbid conditions upon a substrate of altered diastolic function may be the etiology of DHF in the senior population. It is unclear whether these comorbid conditions are the direct inciting stimuli for the development of CHF in this population or rather coexisting disease processes accumulated during aging. There are ample data to suggest, however, that the former may be true. The presence of HTN, atrial ﬁbrillation, diabetes, deconditioning, and CAD are all known to negatively eﬀect diastolic function.128–131 Individual comorbid conditions may inﬂuence particular deleterious eﬀects on diastolic function. For example, atrial ﬁbrillation may markedly impair late ventricular ﬁlling131;

THE MAILLARD REACTION H

O C – (CHOH)4

NH N

CH Glucose +

NH

(CHOH)4

N

O

CH2

– Schiff base AGE crosslink

Amadori product Protein amine

Δ

Δ

Figure 30-15 The Maillard reaction. (Modified from Zieman SJ, Kass DA: Advanced glycation endproduct crosslinking in the cardiovascular system: Potential therapeutic target for cardiovascular disease. Drugs 2004;64:459–470.)

Chapter 30 • Aging and Diastolic Heart Failure 40%), echoed the data from these other studies.12 More importantly, a subanalysis based on the CHARM data demonstrated that atrial ﬁbrillation in particular appeared to be a strong additive risk factor for cardiovascular mortality and hospitalization in patients with DHF.11 The additional incremental risk imposed by atrial ﬁbrillation appears to be greater for patients with preserved EF, as opposed to those with reduced EF.

diabetes, as noted earlier, is associated with increased LV stiﬀness132; and even short periods of subclinical ischemia are known to adversely impact Doppler measures of diastolic function.133 Based on these data, we can theorize that given a background of age-related slowed relaxation, loss of vigorous suction, and decreased static LV compliance, the presence of these comorbid disease states may further worsen the ability of the heart to ﬁll adequately at normal ﬁlling pressures, leading to pulmonary edema and heart failure. The proposed paradigm for this process is shown in Figure 30-16. The presence of these disorders in DHF patients is not trivial, and their prevalence in several large studies is summarized in Table 30-3. In ADHERE, for example, which examined data from over 100,000 CHF hospitalizations (26,322 with preserved systolic function), 77% of DHF patients had HTN, 45% had diabetes, and 50% had CAD.9 When the data from the Olmsted County experience are examined, similar results are observed in individual patients hospitalized for DHF, with 63% having HTN, 53% having atrial ﬁbrillation, and one third having diabetes.8 The ancillary subset of the Digitalis Investigation Group (DIG) trial, which examined the eﬀect of digoxin versus placebo in 988 patients with EF greater than 45% on cardiovascular outcomes, demonstrated that the majority of patients had HTN and ischemic disease, and one third had diabetes.14 Finally, the CHARMPreserved study, which examined the eﬀect of candesartan versus placebo on similar outcomes in 3023 patients with DHF (EF >

CLINICAL RELEVANCE Challenges in Designing Trials and Treatments for Diastolic Heart Failure The presence of the previously mentioned comorbid conditions in patients with DHF has important implications for therapeutic drug development. The divergent pathophysiological pathways we have discussed are not likely to respond to a single agent (like an angiotensin receptor blocker [ARB] alone) that may be more useful in SHF by preventing or reversing ventricular dilation and adverse remodeling. To date there are many more evidence-based therapies for SHF compared with DHF (Table 30-4) (see Chapters 32 and 34). Few large clinical trials, with the notable exception of CHARM and the ancillary DIG study, have examined patients with normal systolic function. The CHARMPreserved study demonstrated a moderate beneﬁt in prevention

TABLE 30-3 PREVALENCE OF CONDITIONS KNOWN TO NEGATIVELY IMPACT DIASTOLIC DYSFUNCTION IN DHF SAMPLES (% OF TOTAL PATIENTS)

Number of patients Hypertension, % Hx MI or CAD, % Diabetes, % Valvular disease, % Atrial fibrillation, %

OLMSTED COUNTY STUDY

ADHERE

ANCILLARY DIG TRIAL

CHARM-PRESERVED TRIAL

4596 63 53 33 3 41

26322 77 50 45 21 21

988 60 50 29 No data No data

3023 23 45 28 No data 29

DHF, diastolic heart failure; ADHERE, Acute Decompensated HEart Failure National REgistry; DIG, Digitalis Investigation Group; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; Hx, history; MI, myocardial infarction; CAD, coronary artery disease.

Diastolic “dysfunction”

Healthy sedentary aging: • Increased static ventricular end diastolic stiffness • Slowed myocardial relaxation • Loss of vigorous diastolic suction Comorbid conditions: • Hypertension (hypertrophy, increased LV stiffness) • Diabetes (increased LV stiffness) • Ischemia (slowed relaxation) • Atrial fibrillation (decreased time for filling, loss of atrial kick) • Valvular heart disease (impaired filling in mitral stenosis, LV hypertrophy in AS)

Figure 30-16 Proposed paradigm by which comorbid conditions overlaid on a substrate of slowed relaxation and decreased compliance could result in diastolic heart failure. LV, left ventricular; AS, aortic stenosis.

Diastolic heart failure

• Pulmonary edema • Dyspnea • Exercise intolerance

395

396

Chapter 30 • Aging and Diastolic Heart Failure of hospitalization for worsening CHF in the DHF population with the use of candesartan.12 In the ancillary DIG study, digoxin appeared to have little eﬀect on any substantial cardiovascular endpoint.14 More recently, there has been interest in the possible role of hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (“statins”) in DHF. The role of these drugs in DHF is unclear, but there is some evidence to suggest improved outcomes in DHF on statin therapy.134 Proposed mechanisms have focused not only on low-density lipoprotein reduction and reduction of ischemic events, but also on possible pleiotropic eﬀects involving regression or prevention of myocardial ﬁbrosis.134,135 More recently the angiotensin-converting-enzyme (ACE) inhibitor perindopril was studied in the Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) trial. This trial enrolled 850 DHF patients who were at least 70 years old with an EF of at least 45% and echo criteria for diastolic dysfunction.136,137 Patients were randomized to perindopril or placebo. The trial failed to show a signiﬁcant beneﬁt of the study drug in reaching the primary outcome of a decrease in a composite endpoint of mortality and hospitalizations. However, the investigators, using secondary endpoint data, suggested that this drug may have beneﬁcial eﬀects in those younger than 75 years of age, those with prior myocardial infarction, and those with HTN. Using such analyses, there appeared to be a beneﬁt of perindopril in improvement of the 6-minute walk distance and New York Heart

Association (NYHA) class. This study echoes prior data that suggested a beneﬁt of ACE inhibitors in DHF, but the role of such drugs in treating this disorder is far from settled.13 The PEP-CHF trial also provides several examples of the difﬁculty in designing DHF trials. The study was underpowered to address the primary endpoint. Subject enrollment was diﬃcult and did not meet the target of 1000 patients. The authors noted diﬃculty in conﬁrmation of the diagnosis of CHF in this patient population and suggested that the addition of an elevated level of brain natriuretic peptide (BNP) might help make a more deﬁnitive diagnosis. In addition, there was a signiﬁcant withdrawal of subjects during the study; 28% and 26% withdrew from the perindopril and placebo arms, respectively. Based on this and other studies in the geriatric literature, recruitment into clinical trials of older persons who have numerous comorbid conditions and more often are female can be quite challenging.138,139 The PEP-CHF trial also noted fewer clinical events than had been predicted. The relatively lower mortality in the DHF population makes it harder for investigators to show beneﬁts in survival for potential drug treatments.14 Lastly, the use of the presence of so-called diastolic dysfunction by echocardiography as a requirement for enrollment is a matter of controversy, as previously discussed in this chapter.17,140,141 Based on the experience of previous clinical trials, the treatment of comorbid conditions such as HTN alone may be of limited beneﬁt in the senior DHF patient. Years of ventricular stiﬀening and slowed relaxation are unlikely to reverse easily. These underlying changes in diastolic properties (whether primarily age associated or not) should therefore also be considered as targets for direct therapy.

TABLE 30-4 PAUCITY OF EFFECTIVE TREATMENT OPTIONS FOR DIASTOLIC HEART FAILURE SYSTOLIC HEART FAILURE

DIASTOLIC HEART FAILURE

ACE-I ARBs Beta blockers Aldosterone antagonism (aldactone, eplerenone) Isrodil/hydralazine Digoxin (symptomatic benefit)

ARBs (candesartan) ACE-I (perindopril)

Novel Therapies on the Horizon Treatments designed to improve static LV compliance may be of great beneﬁt in patients with DHF, particularly in the sedentary senior population. A new agent was recently created to speciﬁcally break already formed AGE crosslinks (see Chapter 34).112,142–144 This drug, ALT-711, is a thiazolium derivative (3-phenyacyl-4,5dimethylthiazolium chloride) that catalytically breaks established AGE crosslinks between proteins (Fig. 30-17).145 Preclinical, whole animal studies using ALT-711 have been promising. In one study, for example, the hearts of diabetic rats developed increased

ACE-I, angiotensin-converting-enzyme inhibition; ARBs, angiotensin receptor blockers.

A.G.E. crosslinked proteins

[Protein]

+

O

N H

O Ph

O X OH

Alagebrium

+

[Protein]

δ–

+

Modification imparted by alagebrium [Protein]

H N

H

O

O

HO

δ–

Cleaved products + alagebrium CHO

Ph + N

[Protein] HN

X

COOH

HO

S S *

X OH

[Protein]

+ O

[Protein]

Ph δ–

+

δ– S Figure 30-17 ALT-711 is a novel advanced glycation end-product (AGE) crosslink breaker. (Modified from Alteon Corporation Company: R&D pipeline: AGE crosslink breakers, 2006).

Chapter 30 • Aging and Diastolic Heart Failure BNP expression, decreased collagen solubility, and increased accumulation of AGEs and connective tissue growth factors.132 When the AGE crosslink breaker ALT-711 was given 4 months after diabetes was induced, collagen solubility was restored, BNP expression was reduced, and AGE accumulation was prevented.132 In a similar experimental design, AGE crosslink breakers were also shown to improve arterial compliance.146 One of the most promising animal studies researched the eﬀect of ALT-711 on aged dogs (Fig. 30-18).147 The key data from this study demonstrated the following: 1. Aged dogs had dramatically increased cardiac stiﬀness, as derived from LV end diastolic pressure-volume relationships compared with young animals, similar to what we have demonstrated in humans. 2. Four weeks of ALT-711 restored LV compliance and distensibility about halfway to normal. Similarly, other studies showed that nondiabetic aged primates had increases in LV end diastolic diameter, systolic fractional shortening, and stroke volume after ALT-711 treatment, associated with improved ventriculo-arterial coupling (50% reduction in LV end diastolic volume divided by stroke volume).148 Thus, breaking of AGE crosslinks improved ventricular function and optimized ventriculovascular coupling in healthy older primates without diabetes. Initial Phase I and Phase II human studies with this drug have been encouraging, both for their safety and for their eﬃcacy. The ﬁrst published multicenter clinical study examined 93 patients older than 50 years with systolic HTN and elevated pulse pressure145 randomized to ALT-711 or placebo in a 2 : 1 distribution for 2 months. Precise measures of arterial compliance were conducted. These ﬁndings included: ❒ ❒ ❒

Greater decrease in pulse pressure in patients treated with ALT-711 compared with placebo Increase in total arterial compliance by 15% with no change in placebo Decline in pulse wave velocity without any clear change in cardiac output or systemic vascular resistance

End diastolic pressure (mmHg)

In addition, ALT-711 appeared to be well tolerated, with few serious adverse events, and actually fewer minor adverse events

40 35 30 25 20 15 10 5 0 10

20

30

40

†

2*

†

0

†

4 weeks ALT-711

2

§ §

§

50

than placebo.145 A number of other multicenter Phase II clinical trials have been either completed or initiated, with over 1000 patients receiving ALT-711 for up to 6 months (e.g., Patients with Impaired Ejection Fraction and Diastolic Dysfunction: Eﬃcacy and Safety Trial of Alagebrium [PEDESTAL], Systolic and Pulse Pressure Hemodynamic Improvement by Restoring Elasticity/ Systolic Hypertension Interaction with Left Ventricular Remodeling [SAPPHIRE/SILVER], Systolic Pressure Eﬃcacy and Safety Trial of Alagebrium [SPECTRA]).149–151 The safety of the drug has remained consistently high, with no increase in adverse events compared with placebo, and relatively few side eﬀects. The focus of most of the clinical trials has been on patients with HTN and SHF, but one clinical study has been performed in patients with heart failure and a normal EF, the Distensibility Improvement And reMOdeliNg in Diastolic Heart Failure (DIAMOND) study.152 This open-label study used a relatively high dose of ALT-711 (210 mg b.i.d.) for 16 weeks. Primary endpoints were changes in echocardiographically derived volumes and Doppler indices of ventricular ﬁlling, NYHA functional class, exercise capacity, and quality of life. The results were mixed. There were minor improvements in some Doppler variables, such as an increase in the tissue Doppler early mitral annular velocity by about 15%, but no change in either systolic or diastolic volumes, arguing against a physiologically meaningful alteration in static ventricular compliance. The majority of patients who completed the trial increased their NYHA functional class, and the Minnesota Living with Heart Failure questionnaire improved, though these may be relatively soft endpoints in an open-label study. Exercise tolerance, blood pressure, and simple measures of aortic distensibility did not improve over the 16 weeks of the trial. The relatively limited improvement in the noninvasive clinical indicators used in the DIAMOND study were somewhat disappointing, particularly in light of the more dramatic physiological beneﬁt in the preclinical studies. This outcome does, however, emphasize an important point: that is, the short-term use of crosslink breakers alone may not be suﬃcient to alter cardiovascular compliance and improve functional capacity in hearts that have been stiﬀened by decades of accumulation of AGEs or other toxic metabolites. In this regard, the role of exercise may be particularly important. Given the marked preservation of static chamber compliance with lifelong exercise, shorter-term intensive aerobic training coupled with these crosslink breakers may be a potential treatment strategy in the senior DHF patient. Aerobic training should also be considered a preventative strategy, especially when initiated at a younger age. Whether starting intensive training later in life confers the same beneﬁts in static LV compliance as does lifelong training is unclear. Further studies examining both of these issues are currently under way.

§

1

60

70

80

90

End diastolic volume index (ml/m2) Figure 30-18 ALT-711 in dogs. Pressure-volume relationships among two groups of dogs: group 1 = young; group 2 (solid line) = aged; and group 2* (dotted line) = aged dogs following 4 weeks of therapy with the advanced glycation end-product (AGE) crosslink breaker ALT-711. (Modified from Asif M et al: An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 2000;97:2809–2813.)

FUTURE RESEARCH The population of seniors in the United States is growing, as is the incidence of DHF in this age group. DHF imposes a signiﬁcant morbidity on these individuals. While the underlying cause of DHF remains controversial, the age-associated abnormalities of LV compliance and relaxation may provide the substrate upon which a host of comorbidities, including diabetes, atrial ﬁbrillation, HTN, and CAD, may be overlaid, resulting in progression to CHF. Treatments are currently limited for DHF, and an unclear understanding of the pathophysiology and diagnosis of this disorder hampers investigational eﬀorts.. Future therapies particu-

397

398

Chapter 30 • Aging and Diastolic Heart Failure larly applicable to seniors may center on attempts to reverse the deconditioning and age-associated changes in LV diastolic properties with novel crosslink breakers. Prevention of this disorder should focus on the initiation of regular aerobic exercise during youth and early aggressive treatment of potential comorbid conditions such as HTN and ischemic disease during senescence. REFERENCES 1. Wan He MS, Velkoﬀ VA, DeBarros KA: 65+ in the United States: 2005. U.S. Census Bureau. U.S. Government Printing Oﬃce, 2005. 2. Owan TE, Redﬁeld MM: Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 2005;47:320–332. 3. Morbidity and Mortality World Report. Changes in mortality from heart failure—United States, 1980–85. MMWR 1998;47:633–636. 4. Aurigemma GP, Gaasch WH: Clinical practice. Diastolic heart failure. NEJM 2004;351:1097–1105. 5. Kitzman DW: Diastolic heart failure in the elderly. Heart Fail Rev 2002;7:17–27. 6. Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Deﬁnitions and terminology. Prog Cardiovasc Dis 2005;47:307–313. 7. Vasan RS, Benjamin EJ, Levy D: Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol 1995;26:1565–1574. 8. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. NEJM 2006;355:251– 259. 9. Yancy CW, Lopatin M, Stevenson LW, et al: Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: A report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006;47:76–84. 10. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. NEJM 2006;355:260–269. 11. Olsson LG, Swedberg K, Ducharme A, et al: Atrial ﬁbrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: Results from the Candesartan in Heart failure–Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol 2006;47:1997–2004. 12. Yusuf S, Pfeﬀer MA, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM–Preserved Trial. Lancet 2003;362(9386):777–781. 13. Philbin EF, Rocco TA Jr, Lindenmuth NW, et al: Systolic versus diastolic heart failure in community practice: Clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors. Am J Med 2000;109:605– 613. 14. Ahmed A, Rich MW, Fleg JL, et al: Eﬀects of digoxin on morbidity and mortality in diastolic heart failure: The ancillary digitalis investigation group trial. Circulation 2006;114:397–403. 15. Heart Failure Society of America: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail 2006;12:e1–e2. 16. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;112: e154–e235. 17. Yturralde RF, Gaasch WH: Diagnostic criteria for diastolic heart failure. Prog Cardiovasc Dis 2005;47:314–319. 18. Oh JK, Hatle L, Tajik AJ, Little WC: Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006;47:500–506. 19. Maurer MS, Spevack D, Burkhoﬀ D, Kronzon I: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44:1543–1549. 20. Wallerson DC, Devereux RB: Reproducibility of echocardiographic left ventricular measurements. Hypertension 1987;9(2 Pt 2):II6–II18. 21. Malm S, Frigstad S, Sagberg E, et al: Accurate and reproducible measurement of left ventricular volume and ejection fraction by contrast echocar-

22. 23. 24. 25. 26. 27. 28.

29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

42. 43. 44. 45. 46. 47.

diography: A comparison with magnetic resonance imaging. J Am Coll Cardiol 2004;44:1030–1035. Chung AK, Das SR, Leonard D, et al: Women have higher left ventricular ejection fractions than men independent of diﬀerences in left ventricular volume: The Dallas Heart Study. Circulation 2006;113:1597–1604. Prasad A, Popovic ZB, Arbab-Zadeh A, et al: The eﬀects of aging and physical activity on Doppler measures of diastolic function. Am J Cardiol 2007;99:1629–1636. Arbab-Zadeh A, Dijk E, Prasad A, et al. Eﬀect of aging and physical activity on left ventricular compliance. Circulation 2004;110:1799–1805. Varadarajan P, Pai RG: Prognosis of congestive heart failure in patients with normal versus reduced ejection fractions: Results from a cohort of 2,258 hospitalized patients. J Card Fail 2003;9:107–112. Pernenkil R, Vinson JM, Shah AS, et al: Course and prognosis in patients > or = 70 years of age with congestive heart failure and normal versus abnormal left ventricular ejection fraction. Am J Cardiol 1997;79:216–219. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiﬀness of the left ventricle. NEJM 2004;350: 1953–1959. Prasad A, Arbab-Zadeh A, Fu Q, et al: Characterization of left ventricular chamber compliance in patients with congestive heart failure and preserved systolic function. American Heart Association Scientiﬁc Sessions, New Orleans; 2004. Hirota Y: A clinical study of left ventricular relaxation. Circulation 1980;62:756–763. Yamakado T, Takagi E, Okubo S, et al: Eﬀects of aging on left ventricular relaxation in humans. Analysis of left ventricular isovolumic pressure decay. Circulation 1997;95:917–923. Harrison TR, Dixon K, Russell RO Jr, et al: The relation of age to the duration of contraction, ejection, and relaxation of the normal human heart. Am Heart J 1964;67:189–199. Gerstenblith G, Frederiksen J, Yin FC, et al: Echocardiographic assessment of a normal adult aging population. Circulation 1977;56:273–278. Arora RR, Machac J, Goldman ME, et al: Atrial kinetics and left ventricular diastolic ﬁlling in the healthy elderly. J Am Coll Cardiol 1987;9:1255– 1260. Arrighi JA, Dilsizian V, Perrone-Filardi P, et al: Improvement of the agerelated impairment in left ventricular diastolic ﬁlling with verapamil in the normal human heart. Circulation 1994;90:213–219. Bonow RO, Vitale DF, Bacharach SL, et al: Eﬀects of aging on asynchronous left ventricular regional function and global ventricular ﬁlling in normal human subjects. J Am Coll Cardiol 1988;11:50–58. Bryg RJ, Williams GA, Labovitz AJ: Eﬀect of aging on left ventricular diastolic ﬁlling in normal subjects. J Am Coll Cardiol 1987;59:971–974. Cacciapuoti F, D’Avino M, Lama D, et al: Progressive impairment of left ventricular diastolic ﬁlling with advancing age: A Doppler echocardiographic study. J Am Geriatr Soc 1992;40:245–250. Gardin JM, Henry WL, Savage DD, et al: Echocardiographic measurements in normal subjects: Evaluation of an adult population without clinically apparent heart disease. J Clin Ultrasound 1979;7:439–447. Iskandrian AS, Hakki AH: Age-related changes in left ventricular diastolic performance. Am Heart J 1986;112:75–78. Kitzman DW: Doppler assessment of diastolic function comes of age. J Am Geriatr Soc 1996;44:729–732. Kitzman DW, Sheikh KH, Beere PA, et al: Age-related alterations of Doppler left ventricular ﬁlling indexes in normal subjects are independent of left ventricular mass, heart rate, contractility and loading conditions. J Am Coll Cardiol 1991;18:1243–1250. Mantero A, Gentile F, Gualtierotti C, et al: Left ventricular diastolic parameters in 288 normal subjects from 20 to 80 years old. Eur Heart J 1995;16:94–105. Miller TR, Grossman SJ, Schectman KB, et al: Left ventricular diastolic ﬁlling and its association with age. Am J Cardiol 1986;58:531–535. Miyatake K, Okamoto M, Kinoshita N, et al: Augmentation of atrial contribution to left ventricular inﬂow with aging as assessed by intracardiac Doppler ﬂowmetry. Am J Cardiol 1984;53:586–589. Rajkumar C, Cameron JD, Christophidis N, et al: Reduced systemic arterial compliance is associated with left ventricular hypertrophy and diastolic dysfunction in older people. J Am Geriatr Soc 1997;45:803–808. Sagie A, Benjamin EJ, Galderisi M, et al: Reference values for Doppler indexes of left ventricular diastolic ﬁlling in the elderly. J Am Soc Echocardiogr 1993;6:570–576. Sartori MP, Quinones MA, Kuo LC: Relation of Doppler-derived left ventricular ﬁlling parameters to age and radius/thickness ratio in normal and pathologic states. Am J Cardiol 1987;59:1179–1182.

Chapter 30 • Aging and Diastolic Heart Failure 48. Spirito P, Maron BJ. Inﬂuence of aging on Doppler echocardiographic indices of left ventricular diastolic function. Br Heart J 1988;59:672–679. 49. Swinne CJ, Shapiro EP, Lima SD, Fleg JL: Age-associated changes in left ventricular diastolic performance during isometric exercise in normal subjects. Am J Cardiol 1992;69:823–826. 50. Yu CM, Sanderson JE: Right and left ventricular diastolic function in patients with and without heart failure: Eﬀect of age, sex, heart rate, and respiration on Doppler-derived measurements. Am Heart J Sep 1997;134: 426–434. 51. Zuccala G, Sgadari A, Cocchi A, et al: Eﬀect of age and pathology on left ventricular diastolic function: the diagnostic yield of Doppler echocardiography. J Gerontol 1995;50:M78–82. 52. Bongiovi S, Palatini P, Macor F, et al: Age and blood-pressure–related changes in left ventricular diastolic ﬁlling. J Hypertens Suppl 1992;10:S25–30. 53. Gardin JM, Arnold AM, Bild DE, et al: Left ventricular diastolic ﬁlling in the elderly: The Cardiovascular Health Study. Am J Cardiol 1998;82: 345–351. 54. Perez-David E, Garcia-Fernandez MA, Ledesma MJ, et al: Age-related intramyocardial patterns in healthy subjects evaluated with Doppler tissue imaging. Eur J Echocardiogr 2005;6:175–185. 55. Popovic ZB, Prasad A, Garcia MJ, et al: Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: Impact of age and ﬁtness. Am J Physiol 2006;290:H1454–1459. 56. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler ﬂow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 2000;35: 201–208. 57. Pacher P, Mabley JG, Liaudet L, et al: Left ventricular pressure-volume relationship in a rat model of advanced aging-associated heart failure. Am J Physiol 2004;287:H2132–2137. 58. Li SY, Du M, Dolence EK, et al: Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation end-products and protein modiﬁcation. Aging Cell 2005;4:57–64. 59. Lim CC, Liao R, Varma N, Apstein CS: Impaired lusitropy-frequency in the aging mouse: Role of Ca(2+)-handling proteins and eﬀects of isoproterenol. Am J Physiol 1999;277(5 Pt 2):H2083–H2090. 60. Cain BS, Meldrum DR, Joo KS, et al: Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol 1998;32:458–467. 61. Schmidt U, del Monte F, Miyamoto MI, et al: Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase. Circulation 2000;101:790–796. 62. He H, Giordano FJ, Hilal-Dandan R, et al: Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest 15 1997;100:380–389. 63. Vetter R, Rehfeld U, Reissfelder C, et al: Transgenic overexpression of the sarcoplasmic reticulum Ca2+ATPase improves reticular Ca2+ handling in normal and diabetic rat hearts. FASEB J 2002;16:1657–1659. 64. Froehlich JP, Lakatta EG, Beard E, et al: Studies of sarcoplasmic reticulum function and contraction duration in young adult and aged rat myocardium. J Mol Cell Cardiol 1978;10:427–438. 65. Templeton GH, Platt MR, Willerson JT, Weisfeldt ML: Inﬂuence of aging on left ventricular hemodynamics and stiﬀness in beagles. Circ Res 1979;44:189–194. 66. Bal MP, de Vries WB, van der Leij FR, et al: Left ventricular pressurevolume relationships during normal growth and development in the adult rat—studies in 8- and 50-week-old male Wistar rats. Acta Physiol Scand 2005;185:181–191. 67. Levine BD, Zuckerman JH, Pawelczyk JA: Cardiac atrophy after bed-rest deconditioning: A nonneural mechanism for orthostatic intolerance. Circulation 1997;96:517–525. 68. Perhonen MA, Franco F, Lane LD, et al: Cardiac atrophy after bed rest and spaceﬂight. J Appl Physiol 2001;91:645–653. 69. Perhonen MA, Zuckerman JH, Levine BD: Deterioration of left ventricular chamber performance after bed rest: “Cardiovascular deconditioning” or hypovolemia? Circulation 2001;103:1851–1857. 70. Fleg JL, Shapiro EP, O’Connor F, et al: Left ventricular diastolic ﬁlling performance in older male athletes. JAMA 1995;273:1371–1375. 71. Tate C, Hamra M, Shin G, et al: Canine cardiac sarcoplasmic reticulum is not altered with endurance exercise training. Med Sci Sports Exerc 1993;25:1246–1257. 72. Zannad F, Dousset B, Alla F: Treatment of congestive heart failure: Interfering with the aldosterone-cardiac extracellular matrix relationship. Hypertension 2001;38:1227–1232.

73. Kim HE, Dalal SS, Young E, et al: Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest 2000;106:857–866. 74. Spinale FG: Novel approaches to retard ventricular remodeling in heart failure. Eur J Heart Fail 1999;1:17–23. 75. Diez J, Laviades C, Mayor G, et al: Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 1995;91:1450–1456. 76. Li YY, McTiernan CF, Feldman AM: Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovasc Res 2000;46:214–224. 77. Spinale FG: Matrix metalloproteinases: Regulation and dysregulation in the failing heart. Circ Res 22 2002;90:520–530. 78. Bishop JE, Lindahl G: Regulation of cardiovascular collagen synthesis by mechanical load. Cardiovasc Res 1999;42:27–44. 79. Chesler NC, Ku DN, Galis ZS: Transmural pressure induces matrixdegrading activity in porcine arteries ex vivo. Am J Physiol 1999;277(5 Pt 2):H2002–2009. 80. Tyagi SC, Lewis K, Pikes D, et al: Stretch-induced membrane type matrix metalloproteinase and tissue plasminogen activator in cardiac ﬁbroblast cells. J Cell Physiol 1998;176:374–382. 81. Creemers EE, Davis JN, Parkhurst AM, et al: Deﬁciency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice. Am J Physiol 2003;284:H364–371. 82. Robert V, Besse S, Sabri A, et al: Diﬀerential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart. Lab Invest 1997;76:729–738. 83. Sivasubramanian N, Coker ML, Kurrelmeyer KM, et al: Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 2001;104:826–831. 84. Nagatomo Y, Carabello BA, Coker ML, et al: Diﬀerential eﬀects of pressure or volume overload on myocardial MMP levels and inhibitory control. Am J Physiol 2000;278:H151–H161. 85. Anversa P, Palackal T, Sonnenblick EH, et al: Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res 1990;67:871–885. 86. Besse S, Robert V, Assayag P, et al: Nonsynchronous changes in myocardial collagen mRNA and protein during aging: Eﬀect of DOCA-salt hypertension. Am J Physiol 1994;267(6 Pt 2):H2237–H2244. 87. Besse S, Assayag P, Delcayre C, et al: Normal and hypertrophied senescent rat heart: Mechanical and molecular characteristics. Am J Physiol 1993;265(1 Pt 2):H183–H190. 88. Eghbali M, Eghbali M, Robinson TF, et al: Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res 1989;23: 723–729. 89. Mamuya W, Chobanian A, Brecher P: Age-related changes in ﬁbronectin expression in spontaneously hypertensive, Wistar-Kyoto, and Wistar rat hearts. Circ Res 1992;71:1341–1350. 90. Olivetti G, Giordano G, Corradi D, et al: Gender diﬀerences and aging: Eﬀects on the human heart. J Am Coll Cardiol 1995;26:1068–1079. 91. Cornwell GG 3rd, Thomas BP, Snyder DL: Myocardial ﬁbrosis in aging germ-free and conventional Lobund-Wistar rats: The protective eﬀect of diet restriction. J Gerontol 1991;46:B167–170. 92. Lee CK, Allison DB, Brand J, et al: Transcriptional proﬁles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci U S A 2002;99:14988–14993. 93. Blair SN, Church TS: The ﬁtness, obesity, and health equation: Is physical activity the common denominator? JAMA Sep 8 2004;292:1232– 1234. 94. Mokdad AH, Ford ES, Bowman BA, et al: Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76–79. 95. Must A, Spadano J, Coakley EH, et al: The disease burden associated with overweight and obesity. JAMA 1999;282:1523–1529. 96. Wong CY, O’Moore-Sullivan T, Leano R, et al: Alterations of left ventricular myocardial characteristics associated with obesity. Circulation 2004;110:3081–3087. 97. Alpert MA, Lambert CR, Terry BE, et al: Eﬀect of weight loss on left ventricular diastolic ﬁlling in morbid obesity. Am J Cardiol 1995;76: 1198–1201. 98. Alpert MA, Lambert CR, Terry BE, et al: Eﬀect of weight loss on left ventricular mass in nonhypertensive morbidly obese patients. Am J Cardiol 1994;73:918–921. 99. Alexander JK, Peterson KL: Cardiovascular eﬀects of weight reduction. Circulation 1972;45:310–318. 100. Unger RH: The physiology of cellular liporegulation. Ann Rev Physiol 2003;65:333–347.

399

400

Chapter 30 • Aging and Diastolic Heart Failure 101. Lee Y, Wang MY, Kakuma T, et al: Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J Biol Chem 2001;276:5629– 5635. 102. Zhou YT, Grayburn P, Karim A, et al: Lipotoxic heart disease in obese rats: Implications for human obesity. Proc Natl Acad Sci U S A 2000;97: 1784–1789. 103. Zieman SJ, Kass DA: Advanced glycation endproduct crosslinking in the cardiovascular system: Potential therapeutic target for cardiovascular disease. Drugs 2004;64:459–470. 104. Maillard L GM: Action des acides amines sur les sucres: Formation des melanoidines par voie methodique. C R Seances Acad Sci 1912;III:66– 68. 105. Ulrich P, Cerami A: Protein glycation, diabetes, and aging. Recent Prog Horm Res 2001;56:1–21. 106. Bailey AJ: Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev 2001;122:735–755. 107. Frye EB, Degenhardt TP, Thorpe SR, Baynes JW: Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end productdependent increase in imidazolium cross-links in human lens proteins. J Biol Chem 1998;273:18714–18719. 108. Monnier VM, Kohn RR, Cerami A: Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci U S A 1984;81: 583–587. 109. Stitt AW: Advanced glycation: An important pathological event in diabetic and age related ocular disease. Br J Ophtalmol 2001;85:746–753. 110. Thorpe SR, Baynes JW: Role of the Maillard reaction in diabetes mellitus and diseases of aging. Drugs Aging 1996;9:69–77. 111. Aronson D: Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiﬀening of aging and diabetes. J Hypertens 2003;21: 3–12. 112. Redﬁeld MM: Treating diastolic heart failure with AGE crosslink breakers: Thinking outside the heart failure box. J Card Fail 2005;11:196–199. 113. Susic D, Varagic J, Ahn J, Frohlich ED: Crosslink breakers: A new approach to cardiovascular therapy. Curr Opin Cardiol 2004;19:336–340. 114. Airaksinen KE, Salmela PI, Linnaluoto MK, et al: Diminished arterial elasticity in diabetes: Association with ﬂuorescent advanced glycosylation end products in collagen. Cardiovasc Res 1993;27:942–945. 115. Bakris GL, Bank AJ, Kass DA, et al: Advanced glycation end-product crosslink breakers: A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens 2004;17(12 Pt 2):23S–30S. 116. Schnider SL, Kohn RR. Eﬀects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. J Clin Invest 1981;67:1630–1635. 117. Brownlee M, Cerami A, Vlassara H: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. NEJM 1988;318:1315–1321. 118. Winlove CP, Parker KH, Avery NC, Bailey AJ: Interactions of elastin and aorta with sugars in vitro and their eﬀects on biochemical and physical properties. Diabetologia 1996;39:1131–1139. 119. De Souza RR: Aging of myocardial collagen. Biogerontology 2002;3:325–335. 120. Lakatta EG, Levy D: Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part II: The aging heart in health: Links to heart disease. Circulation 2003;107:346–354. 121. Lakatta EG, Levy D: Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A “set up” for vascular disease. Circulation 2003;107:139–146. 122. MacKenna DA, Omens JH, McCulloch AD, Covell JW: Contribution of collagen matrix to passive left ventricular mechanics in isolated rat hearts. Am J Physiol 1994;266(3 Pt 2):H1007–H1018. 123. Avendano GF, Agarwal RK, Bashey RI, et al: Eﬀects of glucose intolerance on myocardial function and collagen-linked glycation. Diabetes 1999;48:1443–1447. 124. Wendt T, Bucciarelli L, Qu W, et al: Receptor for advanced glycation endproducts (RAGE) and vascular inﬂammation: Insights into the pathogenesis of macrovascular complications in diabetes. Curr Atheroscler Rep 2002;4:228–237. 125. Yan SD, Schmidt AM, Anderson GM, et al: Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 1994;269:9889–9897. 126. Lee AT, Cerami A: Role of glycation in aging. Ann N Y Acad Sci 1992;663:63–70. 127. Lakatta EG: Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging. Circulation 2003;107:490–497.

128. Miyamoto MI, Rose GA, Weissman NJ, et al: Abnormal global left ventricular relaxation occurs early during the development of pharmacologically induced ischemia. J Am Soc Echocardiogr 1999;12:113– 120. 129. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular ﬁlling after one year of antihypertensive treatment: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071–1076. 130. Wysokinski A, Zapolski T: [Eﬀect of atrial ﬁbrillation on left ventricle function in the elderly]. Pol Arch Med Wewn 2005;113:223–230. 131. Yu CM, Wang Q, Lau CP, et al: Reversible impairment of left and right ventricular systolic and diastolic function during short-lasting atrial ﬁbrillation in patients with an implantable atrial deﬁbrillator: A tissue Doppler imaging study. Pacing Clin Electrophysiol 2001;24:979–988. 132. Candido R, Forbes JM, Thomas MC, et al: A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ Res 2003;92:785–792. 133. De Bruyne B, Lerch R, Meier B, et al: Doppler assessment of left ventricular diastolic ﬁlling during brief coronary occlusion. Am Heart J 1989;117: 629–635. 134. Fukuta H, Sane DC, Brucks S, Little WC: Statin therapy may be associated with lower mortality in patients with diastolic heart failure: A preliminary report. Circulation 2005;112:357–363. 135. Zile MR. Treating diastolic heart failure with statins: “Phat” chance for pleiotropic beneﬁts. Circulation 2005;112:300–303. 136. Cleland JG, Tendera M, Adamus J, et al: Perindopril for Elderly People with Chronic Heart Failure: The PEP–CHF study. PEP investigators. Eur J Heart Fail 1999;1:211–217. 137. Cleland JG, Tendera M, Adamus J, et al: The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study. Eur Heart J 2006;27:2338– 2345. 138. Bayer A, Fish M: The doctor’s duty to the elderly patient in clinical trials. Drugs Aging 2003;20:1087–1097. 139. Lee PY, Alexander KP, Hammill BG, et al: Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA Aug 8 2001;286:708–713. 140. Chen HH, Lainchbury JG, Senni M, et al: Diastolic heart failure in the community: Clinical proﬁle, natural history, therapy, and impact of proposed diagnostic criteria. J Card Fail 2002;8:279–287. 141. Vasan RS, Levy D: Deﬁning diastolic heart failure: A call for standardized diagnostic criteria. Circulation 2000;101:2118–2121. 142. Vasan S, Zhang X, Zhang X, et al: An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature 1996;382(6588):275– 278. 143. Vasan S, Foiles PG, Founds HW: Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links. Expert Opin Investig Drugs 2001;10:1977–1987. 144. Vasan S, Zhang X, Kapurniotu A, et al: An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature 1996;382(6588):275– 278. 145. Kass DA, Shapiro EP, Kawaguchi M, et al: Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 2001;104:1464–1470. 146. Wolﬀenbuttel BH, Boulanger CM, Crijns FR, et al: Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci U S A 1998;95:4630–4634. 147. Asif M, Egan J, Vasan S, et al: An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiﬀness. Proc Natl Acad Sci U S A 2000;97:2809–2813. 148. Vaitkevicius PV, Lane M, Spurgeon H, et al: A cross-link breaker has sustained eﬀects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci U S A 2001;98:1171–1175. 149. Thohan V: Improvements in diastolic function among patients with advanced systolic heart failure utilizing alagebrium, an oral advanced glycation endproduct crosslink breaker. American Heart Association Scientiﬁc Sessions. New Orleans, La; 2005. 150. Susic D, Varagic J, Ahn J, Frohlich ED: Cardiovascular and renal eﬀects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats. Am J Hypertens 2004;17:328–333. 151. Alteon Corporation Company: R & D pipeline: AGE crosslink breakers. http://www.alteon.com/cross1.htm; 2006. 152. Little WC, Zile MR, Kitzman DW, et al: The eﬀect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191– 195.

Chapter 30 • Aging and Diastolic Heart Failure APPENDIX EFFECT OF AGING ON DOPPLER MEASURES OF DIASTOLIC FUNCTION STUDY

AGE RANGE (YEARS)

E : A RATIO

20–29 30–39 40–49 50–59 60–69 ≥70 All ages

0.98–3.18 0.95–2.55 0.92–1.96 0.73–1.85 0.51–1.55 0.26–1.42 0.32–2.48

Overall (>65) Women 65–69 70–74 75–79 >80 Men 65–69 70–74 75–79 >80

0.64–1.56

IVRT

DT

AFF

Framingham study (n = 127) 0.14–0.34 0.15–0.35 0.23–0.35 0.22–0.38 0.23–0.47 0.24–0.60 0.15–0.47

Cardiovascular health study (n = 980)

Mantero (n = 288)

Voutilainen (n = 93)

Klein (n = 117)

0.50–1.62 0.50–1.42 0.52–1.28 0.48–1.12 0.52–1.64 0.44–1.48 0.47–1.39 0.48–1.16

20–29 30–39 40–49 50–59 60–69 70–80

0.9–2.9 0.9–2.5 0.8–2.0 0.6–1.8 0.6–1.4 0.2–1.4

41.2–94.8 45.3–97.7 49.0–97.8 51.7–102.9 51.0–107.8 44.7–117.5

<40 40–60 >60 All

1.0–3.0 0.6–1.8 0.76–0.84 0.3–2.7

101–177 100–204 112–216 99–199

<50 >50 20–29 30–39 40–49 50–59 60–69 >70

0.7–3.1 0.5–1.7 0.8–3.6 0.9–2.5 0.8–2.4 0.9–1.7 0.6–1.4 0.2–1.8

54–98 56–124 49–93 63–95 53–105 52–124 60–128 56–116

97.2–194.4 94.2–283.8 93.2–218.8 87.5–222.3 103.5–241.1 86.5–269.7

0.04–0.44 0.07–0.47 0.10–0.50 0.14–0.54 0.17–0.57 0.19–0.59 0.11–0.35 0.20–0.48 0.27–0.63 0.08–0.56

139–219 138–282 144–220 138–214 131–223 157–245 132–296 135–303

European Study Group on Diastolic Heart Failure (review) Age <30 IVRT >92 Age 30–50 IVRT >100 Age >50 IVRT >105

Cohen (n = 107) Bryg (n = 32)

21–49 >50

1.9 (0.7–3.1*) 1.1 (0.5–1.7*)

24–29 30–49 51–68

0.92–3.04 0.80–2.24 0.25–1.89

20–29 30–49 50–74

1.3–4.1 0.8–3.2 0.4–2.0

76 (54–98*) 90 (56–124*)

179 (139–219*) 210 (138–282*)

Spirilo (n = 86) 48–96 56–104 60–108

158–278 166–274 155–287

Ranges calculated normal ranges ±2 SDs from mean and *occasional 95% confidence intervals. A, peak atrial filling; AFF, atrial filling fraction; DT, deceleration time; E, peak rapid filling; IVRT, isovolumetric relaxation time. Modified from Petrie MC, Hogg K, Caruana L, Mcmurray JJV: Poor concordance of commonly used echocardiographic measures of left ventricular diastolic function in patients with suspected heart failure but preserved systolic function: Is there a reliable echocardiographic measure of diastolic dysfunction? Heart 2004;90:511–517.

401

BARRY A. BORLAUG, MD VOJTECH MELENOVSKY, MD, PhD DAVID A. KASS, MD

31

Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction INTRODUCTION PATHOPHYSIOLOGY OF LEFT VENTRICULARARTERIAL COUPLING Ventricular-Arterial Stiffening in Heart Failure with a Preserved Ejection Fraction Mechanisms of Ventricular-Vascular Stiffening

Pathophysiology of Ventricular-Arterial Stiffening Ventricular-Arterial Stiffening and Exercise Reserve CLINICAL RELEVANCE: THERAPEUTIC STRATEGIES TARGETING STIFFNESS FUTURE RESEARCH

INTRODUCTION The mammalian cardiovascular system is designed to provide adequate ﬂow at physiologic pressures both at rest and under a broad range of demands. Since blood ﬂow is pulsatile, changes in cardiac output are accompanied by alterations in the arterial pulse wave amplitude and peak systolic pressure. To prevent wide ﬂuctuations in blood pressure that otherwise can lead to vascular and end-organ damage, the heart and arteries are compliant so that pulse and peak pressures can be buﬀered, while systemic diastolic pressures are augmented. For the vasculature, this compliance is largely contained within the proximal conduit vessels, while within the heart, it is described by the end systolic stiﬀness (elastance, inverse of compliance) that is achieved during contraction. The normal human heart develops a ventricular systolic stiﬀness of about 2.0 mmHg/ml of ventricular end systolic volume, while

arterial stiﬀness is about 1.5 mmHg/ml.1,2 These low values allow relatively large changes in volume in both the heart and the vascular bed to be achieved with only modest changes in ejected pressures. With advancing age, both ventricular and arterial stiﬀness increase, and these changes may be further exacerbated by common disorders such as hypertension, diabetes mellitus, and renal disease.3–6 Since the heart and arterial systems are coupled, such stiﬀening results in ampliﬁcation of systolic and pulse pressures during ejection, faster pressure decay during diastole, and enhanced cardiac systolic loading. Stiﬀ arteries facilitate rapid transit of the ﬂow and pressure pulse through the vasculature, increasing the velocity at which these waves encounter regions of impedance mismatch (e.g., distal arteriolar narrowings), which then increases the amplitude of reﬂected pressure waves, further exacerbating systolic load. The net eﬀect is an adverse impact on 403

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction cardiac systolic and diastolic functions, with increased myocardial oxygen consumption required to provide the body with blood ﬂow, impaired cardiovascular reserve function, labile systemic blood pressures, and diminished coronary ﬂow reserve.2,6–8 Aging is also associated with endothelial dysfunction,9 which may in part relate to mechanical stiﬀening, as reduced wall distensibility can itself compromise endothelial-dependent responses to shear stress stimulation10,11 and vasorelaxation. One can consider this adverse interaction between heart and arteries as a form of coupling disease that ultimately limits the ability of the integrated cardiovascular system to respond to stress. Abnormal ventricular-arterial stiﬀening and thus coupling may play an important role in patients with heart failure symptoms but with apparent preservation of systolic function. Such patients are typically older and female, with histories of chronic hypertension and a high prevalence of diabetes, obesity, and renal dysfunction. They often develop marked systolic hypertension under conditions of stress, and both their arterial and ventricular systolic pressures are very sensitive to blood volume status. While abnormal diastolic function is thought to contribute to heart failure symptoms by increasing congestion, it cannot explain the observed increases in systemic pressures, nor does it fully underlie limitations of cardiac reserve. Here, we review the pathophysiology of ventricular-arterial stiﬀening and its role in the syndrome of heart failure with a preserved ejection fraction (HFpEF).

PATHOPHYSIOLOGY OF LEFT VENTRICULAR-ARTERIAL COUPLING The inﬂuence of increases in ventricular systolic and vascular stiﬀness on net cardiovascular function is best depicted in the pressure-volume plane. Ventricular end systolic chamber stiﬀness is expressed as end systolic elastance (Ees) (Fig. 31-1), deﬁned by the slope of the end systolic pressure-volume relationship.12 Ventricular afterload can be represented as aortic input impedance, derived from Fourier analysis of aortic pressure and ﬂow waves.13,14 Impedance is expressed in the frequency domain and thus is more diﬃcult to match with optimal measures of ventricular systolic

Ees = Pes/Ves-V0 Ea = Pes/SV

function, which are typically determined in the time domain. One approach to this problem involves the development of a vascular parameter that shares units applicable to the heart, namely eﬀective arterial elastance (Ea).15,16 Ea combines both mean and pulsatile loading, providing a lumped parameter that reﬂects the net impact of arterial vascular load on the heart. This index was developed and validated by Sunagawa et al. in the mid 1980s and then applied and veriﬁed in humans by Kelly et al.15 The latter group conﬁrmed that the simple ratio of end systolic pressure to stroke volume (Pes/SV) could serve to estimate Ea in both hypertensive and normal humans. Graphically, Ea can be depicted as the absolute value of the slope of a line linking the coordinate points of (end systolic volume [Ves], Pes) and (end diastolic volume [Ved], P = 0) (see Fig. 31-1). Coupling of heart and artery is often then depicted by the interaction of these two relations and expressed as a ratio of Ea/ Ees.17–19 The intersection of these lines determines Pes and Ves (see Fig. 31-1). As shown in Figure 31-2, the Ea/Ees ratio is fairly preserved with normal aging to maintain optimal eﬃciency, declining somewhat in women, while both the numerator (vascular load) and the denominator (ventricular stiﬀness) increase.1 Ea is dominated by mean ventricular load, namely systemic vascular resistance,16,19 but it is also altered by artery stiﬀening to increase pulse pressure. Blood pressure pulsatility rises with aging, and this is reﬂected in the pressure-volume diagram in the elderly individual (see Fig. 31-1B) and the HFpEF patient (see Fig. 31-1C) by the rise in systolic pressure throughout ejection (arrows).2,20,21 Since Ea is determined by the ratio Pes/SV, the greater the disparity between Pes and mean arterial pressure (i.e., the more pulsatile or stiﬀ the arterial system), the higher Ea will be relative to mean resistance load. Ea also varies directly with heart rate, since for any given cardiac SV, the systolic pressure will increase or decrease proportionally with the number of strokes (i.e., cardiac output). It is important to keep these factors in mind when interpreting data reporting on Ea and Ea/Ees coupling. Eﬀective coupling of heart to artery can be deﬁned in several ways. One is the optimal transfer of blood from heart to periphery without excessive increases in pulse or systolic pressures. Another is optimal cardiovascular ﬂow reserve without compromise to

CONTROL

HF pEF 200

2.1

2.2

LV pressure

LV pressure

200

Pressure

404

150 100 50

0 Volume

40

80

100 50

0

120 160

LV Volume

B

150

0

0

A

5.6 2.8

40

80

120 160

LV Volume

C

Figure 31-1 A, Idealized pressure-volume loop in a young person. Contractility is expressed as end systolic elastance (Ees), the slope of the end systolic pressure-volume relationship. Afterload is defined by effective arterial elastance (Ea), the negative slope passing through the end systolic and end diastolic pressure-volume points. Note the loop’s rectangular shape, with little increase in pressure during systole. B, Typical pressure-volume loops obtained from a normal 65-year-old man during preload reduction. Note that the coupling ratio (Ea/Ees) is close to unity. C, Example loops from a subject with heart failure with a preserved ejection fraction (HFpEF). Ea and Ees are elevated, the coupling ratio is lower, and the loops have a more trapezoidal shape due to the gradual increase in systolic pressure during ejection (reflecting increased arterial pulse pressure), related to a decrease in arterial compliance and increase in wave reflections (arrow). Pes, end systolic pressure; Ves, end systolic volume; V0, volume intercept; SV, stroke volume. (Modified from Kawaguchi M et al: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720.)

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction 1.0

3.5

2.5

r = 0.25, p<0.0001

r = 0.26, p<0.0001

1.5

0.9

2.5

Ea/Ees

2.0

Ees (mmHg/ml)

Ea (mmHg/ml)

3.0

2.0 r = 0.17, p<0.0001

1.5

0.8

r = 0.01, p = 0.66

0.7 0.6

r = –0.10, p = 0.002

r = 0.21, p<0.0001 1.0

A

0.5

1.0 40 50 60 70 80 90 100 110

40 50 60 70 80 90 100 110

Age

40 50 60 70 80 90 100 110

Age

B

Age

C

Figure 31-2 A, B, Arterial and ventricular systolic stiffness increase with aging in both men (blue) and women (red). At each age level, stiffness is higher in women, in whom the age-dependent increase in ventricular-arterial stiffness is accentuated. C, The increase in ventricular and arterial stiffness is matched with aging in men, resulting in a stable coupling ratio, while in women this ratio decreases with age. (Modified from Redfield MM et al: Age- and gender-related ventricular-vascular stiffening: A community-based study. Circulation. 2005;112:2254–2262.)

6

3

*

Ea (mmHg/ml)

4

†

2

0

8

Con-o Con-HTN HFpEF

1

Ea/Ees ratio

6

Con-y

B

4

1.0 0.8

2

0.6

0

0.4 1

Con-o Con-HTN HFpEF

1.2

Con-y Con-O Con-HTN HFpEF

0

C

2

0 Con-y

A

Ees (mmHg/ml)

Figure 31-3 A, Ventricular systolic stiffness is elevated in hypertensive patients compared with younger and age-matched controls, but significantly higher in heart failure with a preserved ejection fraction (HFpEF). B, Arterial elastance is higher in HFpEF patients than in both hypertensive and nonhypertensive controls. C, Increases in vascular stiffness are correlated with increased ventricular systolic stiffness in all groups, with HFpEF showing an exaggerated increase in ventricular stiffness. D, Coupling ratio is lower to a similar extent in both hypertensive patients and HFpEF patients compared with controls. HFpEF is thus distinguished from hypertension by the extent of ventricular and arterial stiffening, not simply by the ratio of Ea/Ees. Con-y, young controls; Con-o, older age-matched controls; Con-HTN, hypertension-matched controls. (Modified from Kawaguchi M et al: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720.)

Ees (mmHg/ml)

*

2

3

Ea (mmHg/ml)

arterial pressures. One can mathematically express optimal coupling as the interaction that best enhances the work performed by the heart on the body (i.e., optimal external work). Lastly, one must consider the eﬃciency of the heart in performing this work—the energy consumption required to eﬀect this external work. All of these are reasonable deﬁnitions, although prior experimental and clinical studies have tended to focus on the latter two: optimizing external work and eﬃciency. For this, one can both predict22 and observe experimentally18,22 that an Ea/Ees coupling ratio of 0.6–1.2 achieves near optimal work and eﬃciency. This range is normally maintained under various physiologic stresses, as shown elegantly some years back in exercising animals.23 It can become very high, particularly in dilated cardiomyopathy, where depressed heart function (low Ees) is coupled to a high arterial impedance (high Ea).24

*

Con-Y

4

*

Con-o Con-HTN HFpEF

D

Ventricular-Arterial Stiffening in Heart Failure with a Preserved Ejection Fraction In patients with HFpEF, the Ea/Ees ratio falls compared with younger individuals but is similar to that of nonsymptomatic hypertensive elderly patients.2,20 Importantly, it still falls in a range where external work and eﬃciency are not likely compromised. However, while the ratio itself is reduced, the absolute values of both numerator and denominator are signiﬁcantly elevated (Fig. 31-3). Thus, HFpEF patients have elevated vascular stiﬀness,2,25 as well as increased ventricular stiﬀness in both systole2 and diastole.26,27 The net interaction of ventricular and arterial stiﬀness is important because it can signiﬁcantly aﬀect the ﬁrst two components of what we can consider optimal coupling—blood pressure homeostasis and preservation of adequate cardiovascular reserve.

405

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction erties of muscle cell size, wall geometry, intrasarcomeric protein composition, cytosolic and membrane distensibility, and extracellular matrix composition, ﬁbrillar crosslinking, and biophysical properties. These are discussed in detail in Chapters 2, 6, and 30. Systolic ventricular stiﬀness is related to the same determinants of stiﬀness in diastole, as well as activated myoﬁlament properties, changes in structural protein behavior shortened to smaller lengths, and interactions of the activated myocytes with the matrix. As mentioned, the latter is typically measured as chamber stiﬀness or elastance (pressure/volume), but has also been assessed invasively by transverse indentation methods or estimated based on stress-strain analysis.30,31 Vascular stiﬀening also stems from structural and muscle-tone–dependent factors. Smooth muscle tone plays an important role, as does the geometry of the vessel (e.g., dilation), elastin and collagen content, crosslinking of matrix components, and other factors. This has been recently reviewed in detail.32 How do these mechanisms relate to patients with HFpEF? Many HFpEF patients have left ventricular hypertrophy (LVH), concentric chamber remodeling, or both.33–36 While in some, this may develop from a primary sarcomeric protein defect (as with genetic hypertrophic cardiomyopathies), this cause is uncommon compared with the maladaptive response to chronically increased ventricular load, and we will focus on the latter here. In a large

Mechanisms of Ventricular-Vascular Stiffening Ventricular stiﬀening is a product of both passive and active muscle properties. Passive behavior is somewhat of a misnomer, since diastolic tone is regulated in part by calcium and also by the phosphorylation state and isoforms of various sarcomeric proteins.28,29 Nonetheless, we can ascribe diastolic stiﬀening to prop-

ΔP ΔP

A

B

Peak systolic pressure (mmHg)

As displayed in Figure 31-4, an increase in both Ea and Ees means that systolic pressures are much more sensitive to changes in cardiac preload, and thus central vascular blood volume. Small changes in volume that might accompany dietary indiscretion or diuretic usage will translate to more exaggerated changes in arterial pressure.20 This also predicts higher pressures during stress, which, in addition to requiring a greater amount of energy to deliver a given SV, can also alter both ejection and relaxation. A higher resting Ees means that there can be less eﬀective contractile reserve to call upon during stress demands (Fig. 31-5A). Higher combined ventricular and vascular stiﬀening leads to greater cardiac energy demands to provide the body with a given amount of blood ﬂow (see Fig. 31-5B).2 Lastly, increased vascular stiﬀness and thus pulsatile loading can aﬀect vascular homeostasis, coronary perfusion, and ﬂow reserve.6 We next discuss each of these mechanisms in more detail.

180

Young Elderly

150 120 90 60 40

E

ΔP ΔP

60

80

100

120

LV end diastolic volume (ml)

SBPEDV (mmHg/ml)

406

y = 0.01x + 0.3 p = 0.001, r = 0.41

2

1

0

C

D

0

F

20

40

60

80

100

Age (yrs)

Figure 31-4 The effects of varying preload and afterload on systolic blood pressure (SBP) in the presence or absence of increased ventricular systolic stiffening. A, In a normal patient, an increase in end diastolic volume (EDV) (arterial elastance [Ea] constant) leads to a corresponding increase in SBP (ΔP). B, In a typical patient with heart failure with a preserved ejection fraction with increased end systolic elastance (Ees), the same increase in preload causes a much greater increase in SBP. Similarly, while an increase in Ea causes an increase in SBP (C), this increase is amplified in the setting of elevated Ees (D), causing a much greater increase in SBP. With normal aging, the dependence of SBP on preload becomes increased, as shown by a typical younger and older patient (E). The slope of the SBP-preload relation plotted in E increases significantly with aging (F), related to increases in ventricular and arterial stiffness. LV, left ventricular. (Modified from Chen C-H et al: Coupled systolic-ventricular and vascular stiffening with age: Implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221–1227.)

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction

700

Ea = 1.4 Ea = 1.9 Ea = 2.5

80

Change in cardiac work per unit change in stroke volume (mmHg)

Percent change in stroke volume with a doubling in Ees

100

60

40

20

600 500 400 300 200

4

6

8

5

4

3 Ea (mmHg/ml)

0 2

Con y/o

10

HTN/o

100 0

0

HFpEF

2

1

1

6 5 4 3 2 Ees (mmHg/ml)

Baseline Ees (mmHg/ml)

A

B

Figure 31-5 The effects of basal end systolic elastance (Ees) on cardiovascular reserve function. A, The percent increase in stroke volume for a 100% increase in Ees (i.e., contractility increase) is quite low when the baseline Ees is high. This hyperbolic relationship shifts in parallel with changes in arterial load (arterial elastance, Ea), but this shift is modest compared to the effect of the baseline Ees value. B, The energetic cost for a given increase in cardiac stroke volume is greatly increased in the setting of increased ventricular-arterial stiffness, as is seen in HFpEF. This increases myocardial oxygen demand and may promote ischemia in addition to reducing reserve capacity. HTN/o refers to older-aged hypertensives, and Con y/o refers to young and old nonhypertensive, healthy controls, respectively. For this prediction model, oxygen consumption is estimated based on the total pressure-volume area (PVA = stroke work + potential area = SV × ESP + 0.5 × (ESV − Vo) × ESP), and this equation is resolved in terms of Ees, Ea by using two additional primary equations, one for the end-systolic elastance: ESP = Ees (ESV − Vo), and the other for effective arterial elastance: Ea = ESP/SV. SV, stroke volume; ESV, end-systolic volume; Ees, end-systolic elastance; ESP, end-systolic pressure; Vo, volume axis intercept of the end-systolic pressure-volume relationship. More complete details of the mathematics can be found in Suga H. Physiol Rev 1990;70:247–277. (Modified from Kawaguchi M, et al: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720.)

observational study of consecutive patients presenting with HFpEF, the mean LV mass index was 66.5 g/m2.7, well above cutoﬀ partition values for deﬁning LVH (46.7 g/m2.7 in women and 49.2 g/m2.7 in men).36 Myocyte hypertrophy has been documented, along with a modest rise in myoﬁbrillar content and increases in passive myocyte stiﬀness in triton-skinned cells.37,38 Myocardial ﬁbrosis is also frequently observed, although this is less clearly diﬀerent from hearts displaying dilated cardiomyopathy.38 Ventricular cellular passive stiﬀness has been found to correlate with estimates of diastolic chamber stiﬀness37 in HFpEF subjects, and indeed diastolic stiﬀening is reported in these patients.27 Not all diastolic stiﬀening is intrinsic to the chamber, however, as external loading factors also appear to contribute importantly to observed diastolic stiﬀening, as indicated by invasive pressure-volume analysis.2,39 Diastolic stiﬀening alone can contribute to ﬂuid redistribution into the lungs and limit net cardiac ﬁlling, but it cannot explain why patients with HFpEF typically present with severe, uncontrolled hypertension when they develop pulmonary edema40 and often display marked blood pressure sensitivity to vasodilator or diuretic therapy. The latter more directly relates to increased left ventricular (LV) systolic stiﬀening (Ees).2,41 In addition to arterial systolic pulse pressure and stiﬀness, which are known to increase with age,1,21,42,43 Ees also has been shown to rise in tandem (see Fig. 31-2).1,41 In subjects who develop hypertension and cardiac hypertrophy, and those who further develop HFpEF, this stiﬀening is more pronounced over age-matched controls (see Fig. 31-1B, Fig. 31-3). Since Ees also has been viewed as a measure of systolic contractile function, one might conclude that this reﬂects enhanced contractility. However, this seems unlikely, as other parameters less dependent on chamber geometry do not increase with aging.

In addition to being older and often hypertensive, the majority of HFpEF patients are female,35,36,44 and this factor may also inﬂuence abnormal ventricular-arterial stiﬀening. Women develop concentric LVH in the setting of pressure overload more often compared with men.1,45,46 In addition, in a large populationbased study of largely asymptomatic individuals, age-dependent increases in ventricular systolic and arterial stiﬀness were found to be more marked in women compared with men (see Fig. 31-2). This may underlie part of the increased prevalence of HFpEF in older women.1 The precise cause for this remains unknown but may in part relate to hormonal factors and diﬀerences in ventricular and aortic size and length. In contrast to vascular and ventricular systolic stiﬀening, mean peripheral vascular resistance does not show this age-dependent rise and is greater in men. Thus women are more likely to display accentuated increases in pulsatile loading with age, associated with greater coupled ventricular-arterial stiﬀening.

Pathophysiology of Ventricular-Arterial Stiffening There are several important physiologic consequences of combined ventricular and arterial stiﬀening, as summarized in Table 31-1, and while each of the two components confers morbidity, the combination of both leads to synergistic eﬀects. One major repercussion is increased blood pressure lability and sensitivity to volume and vascular loading.2,20 In a normal heart-artery system, a rise in Ved results in a given rise in Pes (see Fig. 31-4A). However, in a typical HFpEF patient, even if the coupling ratio is normal, the same increase in Ved will lead to an accentuated increase in systolic pressure (see Fig. 31-4B). The pressure-volume area or stroke work to achieve this given SV therefore also is higher in the HFpEF patient. Conversely, a given decrease in Ved

407

408

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction TABLE 31-1 PATHOPHYSIOLOGY OF VENTRICULAR-ARTERIAL STIFFENING UNDERLYING ABNORMALITY

HEMODYNAMIC CONSEQUENCES

CLINICAL RELEVANCE

Increased Ventricular Systolic Stiffness

1. Amplified change in blood pressure for a given change in preload or afterload 2. Lower contractile reserve 3. Lower stroke volume reserve 4. Greater energetic cost to eject a given stroke volume 1. Amplified change in blood pressure for a given change in preload or contractility 2. Greater dependence upon systolic pressure for coronary flow 3. Increased wave reflections and late systolic load 4. Abnormal endothelial mechano-transduction

1. Hypotension and oliguria with slight overdiuresis or the addition of a new vasodilator agent 2. Modest volume infusion leads to hypertension and/ or acute pulmonary edema 3. Impaired exercise tolerance and functional disability 4. Increased myocardial oxygen demand and ischemia 1. Hypotension and oliguria with slight overdiuresis or the addition of a new vasodilator agent 2. Modest volume infusion leads to hypertension and/ or acute pulmonary edema 3. Greater degree of ischemia and larger infarct size for given decrease in systolic blood pressure 4. Prolonged systole, abbreviated diastole, impaired relaxation 5. Endothelial dysfunction, further limiting vasodilation in response to stress

Increased Arterial Stiffness

will also lead to exaggerated drops in systolic pressure in this stiﬄy coupled system. Similarly, an isolated increase in afterload (Ea) in an HFpEF patient will lead to a much more exaggerated increase in blood pressure because of the higher baseline Ees (see Fig. 31-4C and D). Increased ventricular-arterial stiﬀening explains why systolic blood pressure is much more preload dependent in older versus younger patients (see Fig. 31-4E and F). In addition to increased preload and afterload sensitivity, systolic reserve also becomes limited with increased stiﬀening. A high basal Ees means that there is less eﬀective change in systolic performance for a given percent rise in Ees during stress demands. Increases in Ees reﬂect contractility reserve, but the eﬀect of a change in Ees on net cardiac output is nonlinear, being much greater when the starting value is low than when it rises (see Fig. 31-5). If you link a heart with a high Ees to a stiﬀ arterial system, the net eﬀect on systolic pressure is exacerbated,20 and thus ejection is further compromised. Since exercise duration is determined predominantly by cardiac output reserve,47 combined systolic ventricular and vascular stiﬀening can be an important contributor to exertional incapacity. A third consequence of combined arterial-ventricular systolic stiﬀening is that the cardiac work required to deliver a given cardiac output increases. As shown in Figure 31-5B, using a previously validated model, one can estimate the required rise in cardiac work to achieve a given change in SV (heart rate constant) as a function of ventricular (Ees) and arterial (Ea) properties.2 This is depicted as a three-dimensional surface—with the lowest cost to the heart when both ventricular and arterial net elastances are low, and increasing cost as these rise. Mean values for both parameters are depicted for four patient groups, including subjects with HFpEF, who have double or more the energetic cost to the heart compared with younger controls, and age-matched hypertensive subjects without LVH. Patients with chronic LVH and hypertension but without heart failure symptoms had elevation of both25 and an increased energy cost to the heart (data not shown). The heart normally depends upon diastolic arterial pressure as the driving force for coronary artery perfusion, with more than 70% of coronary ﬂow provided during diastole. However, when the heart ejects into a stiﬀ vasculature, it becomes more dependent upon ﬂow entering the circulation during systole.7,48 Animal studies have revealed that this change in pulse perfusion pattern

has consequences, as it can render the heart more sensitive to declines in systolic performance. Consider a heart exposed to coronary artery occlusion to induce acute ischemia (Fig. 31-6). When the heart ejects into a compliant arterial system, the occlusion is well compensated for by moderate chamber dilation, and there is little decline in systolic pressure. However, when the same heart ejects into a stiﬀ system by means of an in vivo aortic bypass tube,7 the results are markedly diﬀerent. In this case, the heart dilates much more with the same occlusion, and the magnitudes of both the ischemic bed size and the resulting decline in function are exacerbated. Cardiac interaction with a stiﬀ arterial system also ampliﬁes late systolic pressure loading, and this can aﬀect both the net amount of volume ejected and diastolic processes.49 Elevation of afterload prolongs relaxation,50–53 an eﬀect that can be mitigated in the setting of β-adrenergic activation.54 Progressive increases in late systolic load, induced by timed inﬂation of intra-aortic balloons in animal models, have been shown to prolong LV relaxation.53 The increase in loading required to elicit a prolongation was rather marked, at nearly 80% of maximum (i.e., isovolumic contraction). However, we have found that in patients with HFpEF, acute increases in afterload induced by isometric handgrip can also slow isovolumic relaxation rate,2 and this could contribute to elevated diastolic pressures and disease pathophysiology. A sixth mechanism whereby loss of arterial compliance and thus distensibility with vascular stiﬀening may contribute to disease pathophysiology lies in endothelial mechanosignaling. The endothelium is a major physical force transducer that registers local changes in shear stress (ﬂow) and vessel distension (stretch) and translates these signals to alterations in endothelial function and vascular tone. Pulsatile perfusion combines both stimuli, and recent studies from our laboratory have revealed that these two signals combined provide additive stimulation for nitric oxide synthase (NOS), a primary upstream kinase activator (Akt), and cytoprotective eﬀects against oxidant stress.10,11 The latter appear mediated primarily by the augmented rise in Akt activation. However, pulse perfusion in the relative absence of wall cyclic distension yields a diﬀerent response. Here, Akt activation is blunted and there is correspondingly less rise in NOS activation and a substantial blunting of the protection to oxidant stress. This

200

200

150

150

Pressure (mmHg)

Pressure (mmHg)

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction

100

50

0

50

0 0

A

100

30

60

90

Volume (ml)

0

B

30

60

90

Volume (ml)

Figure 31-6 The effects of acute ischemia in the setting of increased arterial stiffening. A, If the heart ejects into a normally compliant system, acute occlusion of the left anterior descending induces a rightward shift in the pressure-volume loop, with an increase in end diastolic and systolic volumes, and a slight decrease in systolic pressure. B, If the same experiment is performed with the heart ejecting into a stiff vasculature, the heart dilates more, end systolic volume shifts more to the right, and there is a greater diminution in the systolic blood pressure developed. (Modified from Kass DA et al: Adverse influence of systemic vascular stiffening on cardiac dysfunction and adaptation to acute coronary occlusion. Circulation 1996;93:1533–1541.)

signaling appears speciﬁcally coupled to stretch stimulation (rather than shear), and although the exact cascade responsible remains to be elucidated, it has intriguing implications. One is that reduced arterial compliance can blunt the normal ﬂowmediated dilatory response that is a central component of vasodilator reserve under stress. While this direct link has yet to be proven in vivo, it may indeed contribute to vasodilator reserve limitations in the elderly, and in particular in individuals with HFpEF, who require such reserve as a compensation for the loss of other cardiovascular mechanisms.55

Ventricular-Arterial Stiffening and Exercise Reserve Increases in ventricular and vascular stiﬀness aﬀect cardiovascular reserve function with exercise stress. Warner et al. studied the eﬀects of losartan on exercise performance in 20 asymptomatic hypertensive subjects with echo-Doppler diastolic dysfunction and a hypertensive response to exercise, suggesting increased ventricular-vascular stiﬀness.56 While losartan had no eﬀect on resting blood pressure, it decreased peak systolic pressure during exercise, increased the time for blood pressure to exceed 190 mmHg, and was associated with an approximately 10% increase in peak oxygen consumption. The authors speculated that losartan therapy improved diastolic performance, but this was not directly demonstrated. An equally plausible explanation is that losartan provided for a greater reduction in aortic input impedance during stress, improving the cardiac output response to exercise. In a more recent study from this group, 6 months of losartan compared with hydrochlorothiazide treatment found similar reductions in exercise-induced hypertension in this population, while only losartan improved exercise performance and quality of life measures, suggesting that direct ventricular and vascular eﬀects, rather than blood pressure change per se, are critical in determining cardiovascular reserve function.57 Hundley et al. studied the relationship between proximal aortic distensibility derived from magnetic resonance imaging (MRI) and exercise performance in 10 young, 10 older, and 10 HFpEF subjects.58 They demonstrated that aortic distensibility is highest in the young and most compromised in HFpEF patients, even compared with healthy older subjects (although the HFpEF

group was signiﬁcantly older than the healthy older volunteers). The authors went on to show that changes in aortic distensibility and cross-sectional area strongly predict exercise performance (peak oxygen consumption) (Fig. 31-7), even after adjusting for age and gender in multivariate regression analysis. Aortic wall thickness was signiﬁcantly greater in HFpEF subjects compared with both groups, supporting the notion that exaggerated vascular remodeling contributes to increased arterial stiﬀening in these patients, independent of or in addition to normal aging. We recently showed that compared with hypertensive subjects with LVH, patients with HFpEF display a markedly blunted ability to augment cardiac output with upright exercise, despite a similar increase in LV Ved.55 Their inability to increase cardiac output with stress correlated with chronotropic incompetence and an inability to properly vasodilate and reduce systemic vascular resistance during exercise. Baseline blood pressure and vascular stiﬀness were similarly elevated in both groups, and only by measuring changes with exercise was the deﬁcit in vasodilator reserve function observed.

CLINICAL RELEVANCE: THERAPEUTIC STRATEGIES TARGETING STIFFNESS Ventricular-vascular stiﬀening can be treated with agents that acutely modulate ventricular systolic and diastolic performance, vascular smooth muscle tone, and endothelial function. Interventions such as verapamil that acutely reduce ventricular and vascular stiﬀness have been shown to improve exercise capacity in patients with HFpEF59 and hypertrophic cardiomyopathy60,61 and in elderly patients with hypertension and hypertrophy.62 A large part of the mechanistic beneﬁt has been believed to be related to improvements in ventricular peak ﬁlling rate (PFR), assessed by nuclear gated blood pool study.59–61 However, a more recent trial in older hypertensive patients found that verapamil did not produce a consistent increase in PFR.62 In contrast, it was associated with signiﬁcant reductions in ventricular systolic stiﬀness (contractility/peak cardiac power index) and vascular stiﬀness (Ea, pulse wave velocity, augmentation index), and these changes were in turn associated with a 50% improvement in aerobic exercise performance. In subjects with lower resting PFR, verapamil

409

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction 7

150

6

125

5 4 3 2

y = 0.003x – 1.54 r = 0.79

1

Area change (mm2)

Distensibility (10–3 mmHg–1)

410

75 50 y = 0.056x – 21.08 r = 0.82

25

0

0 0

A

100

1000

2000

3000

PkV02 (ml/min)

4000

0

B

1000

2000

3000

4000

PkV02 (ml/min)

tended to increase it, but if PFR was higher at rest, verapamil tended to diminish it. However, it is important to note that exercise performance improved similarly in both groups of patients. In a recent study of HFpEF subjects, we found that resting PFR was elevated compared with hypertensive/LVH controls because of volume overload, suggesting that verapamil may have less beneﬁt in this population.55 It is noteworthy that all of these trials were limited by relatively small sample sizes and did not involve chronic administration of study drug. Pure vasodilators may have more variable eﬀects. Two weeks and 6 months of treatment with the angiotensin receptor antagonist losartan improved exercise performance in subjects with a hypertensive response to exercise,56,57 while acute vasodilation with sodium nitroprusside did not share such beneﬁcial eﬀects.63 The latter is somewhat predictable, since a given reduction in Ea results in more exaggerated decreases in blood pressure with relatively less increase in stroke volume in the setting of high baseline Ees (see Fig. 31-4D). Propranolol, which decreases Ees but increases Ea, also does not improve net exercise performance.64 However, none of these small trials were performed in patients with HFpEF. Given the extent of chronotropic incompetence in HFpEF patients,55,65 drugs such as calcium channel antagonists and beta blockers require more study to compare oﬀsetting eﬀects on ventricular and arterial stiﬀness and heart rate.

FUTURE RESEARCH Many of the increases in ventricular-arterial stiﬀness in HFpEF are chronic in nature, due to changes in the material properties of the cardiovascular system.6 In the largest randomized trial of heart failure with near-normal EF (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity [CHARM]– Preserved), there was a borderline-signiﬁcant treatment eﬀect driven by a reduction in hospitalizations for heart failure.66 However, this trial enrolled subjects with heart failure and EF greater than 40%, which is not typical of the garden-variety HFpEF patient with LVH and LV ejection fraction greater than 60%.33,35,36,44 Other therapies targeting these chronic changes include aldosterone,67,68 transforming growth factor–β,69 and chymase antagonists.70 A large-scale randomized trial funded by the National Institutes of Health was initiated in 2006 to test the eﬃcacy of the aldosterone antagonist spironolactone in HFpEF (TOPCAT-NCT00094302). This study is ongoing.

Figure 31-7 Increased vascular stiffness impairs metabolic exercise performance in heart failure with a preserved ejection fraction (HFpEF). Both A, aortic distensibility and B, change in cross-sectional area correlate strongly with peak oxygen consumption (PkVO2) during metabolic exercise testing in young (green diamonds), older (red squares), and HFpEF subjects (blue triangles). (Modified from Hundley WG et al: Cardiac cycle–dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802.)

Drugs speciﬁcally targeting ventricular hypertrophy may also prove very useful. An emerging player in hypertrophy signaling, rho kinase,71 is a key downstream eﬀector of Gq-protein–coupled angiotensin-II signaling. Rho kinase increases vascular smooth muscle cell tone, and the rho kinase inhibitor fasudil is being evaluated as an anti-anginal drug. Fasudil also attenuates angiotensinII–induced cardiac hypertrophy, thus therapies interfering with rho kinase may prove synergistically useful relative to its vasodilatory and antihypertrophic properties.72 Intriguingly, hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (statins), which are known to inhibit rho kinase activation,73 have also been shown to be associated with improved survival in a retrospective analysis of patients with HFpEF.74 We recently demonstrated that the phosphodiesterase (PDE)-5 inhibitor sildenaﬁl markedly attenuated the hypertrophic response to pressure overload in mice.75 In humans, sildenaﬁl suppresses acute β-adrenergic–stimulated contractility,76 and ongoing studies, including an NIH-sponsored multicenter trial (RELAX trial), are evaluating whether it can blunt or even reverse hypertrophic responses in patients with HFpEF. Since both rho kinase and PDE-5 inhibitors can reduce LVH and arterial stiﬀness and cause modest vasodilation, they present attractive approaches to treat multiple potentially synergistic abnormalities in HFpEF patients. As basic research continues to deﬁne more of the cellular mechanisms contributing to increases in ventricular and arterial stiﬀness, remodeling, and hypertrophy, we will increasingly be able to target HFpEF more speciﬁcally and eﬃcaciously at its pathophysiologic foundations. Such basic ﬁndings will be more eﬀectively translated to the bedside as additional clinical hemodynamic studies are performed to distill how each component of ventricular-arterial stiﬀening speciﬁcally modiﬁes systolic and diastolic performance in patients with HFpEF. REFERENCES 1. Redﬁeld MM, Jacobsen SJ, Borlaug BA, et al: Age- and gender-related ventricular-vascular stiﬀening: A community-based study. Circulation 2005;112:2254–2262. 2. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and arterial stiﬀening in patients with heart failure and preserved ejection fraction: Implications for systolic and diastolic reserve limitations. Circulation 2003;107:714–720. 3. Kass DA: Age-related changes in ventricular-arterial coupling: Pathophysiologic implications. Heart Fail Rev 2002;7:51–62. 4. Avolio AP, Fa-Quan D, Wei-Qiang L, et al: Eﬀects of aging on arterial distensibility in populations with high and low prevalence of hypertension:

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

25.

26. 27. 28. 29. 30. 31.

Comparison between urban and rural communities in China. Circulation 1985;71:202–210. Avolio AP, Chen SG, Wang RP, et al: Eﬀects of age on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 1983;68:50–58. Kass DA: Ventricular arterial stiﬀening: Integrating the pathophysiology. Hypertension 2005;46:185–193. Kass DA, Saeki A, Tunin RS, Recchia FA: Adverse inﬂuence of systemic vascular stiﬀening on cardiac dysfunction and adaptation to acute coronary occlusion. Circulation 1996;93:1533–1541. Kelly RP, Tunin R, Kass DA: Eﬀect of reduced aortic compliance on cardiac eﬃciency and contractile function of in situ canine left ventricle. Circ Res 1992;71:490–502. Najjar SS, Scuteri A, Lakatta EG: Arterial aging: Is it an immutable cardiovascular risk factor? Hypertension 2005;46:454–462. Li M, Chiou KR, Bugayenko A, et al: Reduced wall compliance suppresses Akt-dependent apoptosis protection stimulated by pulse perfusion. Circ Res 2005;97:587–595. Peng X, Haldar S, Deshpande S, et al: Wall stiﬀness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium. Hypertension 2003;41:378–381. Suga H, Sagawa K: Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 1974;35: 117–128. Murgo JP, Westerhof N, Giolma JP, Altobelli SA: Aortic input impedance in normal man: Relationship to pressure waveforms. Circulation 1980;62: 105–116. Nichols WW, Pepine CJ, Geiser EA, Conti R: Vascular load deﬁned by the aortic input impedance spectrum. Fed Proc 1980;39:196–201. Kelly RP, Ting CT, Yang TM, et al: Eﬀective arterial elastance as index of arterial vascular load in humans. Circulation 1992;86:513–521. Sunagawa K, Maughan WL, Burkhoﬀ D, Sagawa K: Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H773–H780. Asanoi H, Sasayama S, Kameyama T: Ventriculoarterial coupling in normal and failing heart in humans. Circ Res 1989;65:483–493. De Tombe PP, Jones S, Burkhoﬀ D, et al: Ventricular stroke work and eﬃciency both remain nearly optimal despite altered vascular loading. Am J Physiol 1993;264:H1817–H1824. Kass DA, Kelly RP: Ventriculo-arterial coupling: Concepts, assumptions, and applications. Ann Biomed Eng 1992;20:41–62. Chen C-H, Nakayama M, Nevo E, et al: Coupled systolic-ventricular and vascular stiﬀening with age implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221–1227. Nichols WW, O’Rourke MF, Avolio AP, et al: Eﬀects of age on ventricularvascular coupling. Am J Cardiol 1985;55:1179–1184. Sunagawa K, Maughan WL, Sagawa K: Optimal arterial resistance for the maximal stroke work studied in isolated canine left ventricle. Circ Res 1985;56:586. Little WC, Cheng CP: Eﬀect of exercise on left ventricular-vascular coupling assessed in the pressure-volume plane. Am J Physiol 1993;264: H1629–H1633. Feldman MD, Pak PH, Wu CC, et al: Acute cardiovascular eﬀects of OPC18790 in patients with congestive heart failure. Time- and dose-dependence analysis based on pressure-volume relations. Circulation 1996;93:474– 483. Melenovsky V, Borlaug BA, Rosen B, et al: Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: Role for atrial remodeling/dysfunction. J Am Coll Cardiol 2007;49:198–207. Liu CP, Ting CT, Lawrence W, et al: Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy: Systolic versus diastolic determinants. Circulation 1993;88(Pt 1):1893–1906. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiﬀness of the left ventricle. N Engl J Med 2004;350:1953–1959. Kass DA, Bronzwaer JG, Paulus WJ: What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 2004;94:1533–1542. Granzier HL, Labeit S: The giant protein titin: A major player in myocardial mechanics, signaling, and disease. Circ Res 2004;94:284–295. Halperin HR, Chew PH, Weisfeldt ML, et al: Transverse stiﬀness: A method for estimation of myocardial wall stress. Circ Res 1987;61: 695–703. Miyaji K, Sugiura S, Omata S, et al: Myocardial tactile stiﬀness: A variable of regional myocardial function. J Am Coll Cardiol 1998;31:1165–1173.

32. Zieman SJ, Melenovsky V, Kass DA: Mechanisms, pathophysiology, and therapy of arterial stiﬀness. Arterioscler Thromb Vasc Biol 2005;25: 932–943. 33. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–259. 34. Devereux RB, Roman MJ, Liu JE, Welty TK, Lee ET, Rodeheﬀer R, Fabsitz RR, Howard BV Congestive heart failure despite normal left ventricular systolic function in a population–based sample: the Strong Heart Study. Am J Cardiol 2000;86:1090–1096. 35. Owan TE, Redﬁeld MM. Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 2005;47:320–332. 36. Klapholz M, Maurer M, Lowe AM, et al: Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: Results of the New York Heart Failure Registry. J Am Coll Cardiol 2004;43:1432– 1438. 37. Borbely A, van der Velden J, Papp Z, et al: Cardiomyocyte stiﬀness in diastolic heart failure. Circulation 2005;111:774–781. 38. Van Heerebeek L, Borbely A, Niessen HW, et al: Myocardial structure and function diﬀer in systolic and diastolic heart failure. Circulation 2006;113: 1966–1973. 39. Dauterman K, Pak PH, Nussbacher A, et al: Contribution of external forces to left ventricle diastolic pressure: Implications for the clinical use of the Frank-Starling law. Ann Intern Med 1995;122:737–742. 40. Gandhi SK, Powers JC, Nomeir AM, et al: The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344: 17–22. 41. Chen CH, Nakayama M, Nevo E, et al: Coupled systolic-ventricular and vascular stiﬀening with age: Implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221–1227. 42. Avolio AP, Fa-Quan D, Wei-Qiang L, et al: Eﬀects of aging on arterial distensibility in populations with high and low prevalence of hypertension: Comparison between urban and rural communities in China. Hypertension 1985;71:202–210. 43. Kelly R, Hayward C, Avolio A, O’Rourke M: Noninvasive determination of age-related changes in the human arterial pulse. Circulation 1989;80:1652– 1659. 44. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355: 260–269. 45. Carroll JD, Carroll EP, Feldman T, et al: Sex-associated diﬀerences in left ventricular function in aortic stenosis of the elderly. Circulation 1992;86:1099– 1107. 46. Villari B, Campbell SE, Schneider J, et al: Sex-dependent diﬀerences in left ventricular function and structure in chronic pressure overload. Eur Heart J 1995;16:1410–1419. 47. Franciosa JA, Leddy CL, Wilen M, Schwartz DE: Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure. Am J Cardiol 1984;53:127–134. 48. Saeki A, Recchia F, Kass DA: Systolic ﬂow augmentation in hearts ejecting into a model of stiﬀ aging vasculature: Inﬂuence on myocardial perfusiondemand balance. Circ Res 1995;76:132–141. 49. Nichols WW, O’Rourke MF, Avolio AP, et al: Ventricular/vascular interaction in patients with mild systemic hypertension and normal peripheral resistance. Circulation 1986;74:455–462. 50. Gillebert TC, Leite-Moreira AF, De Hert SG: Load dependent diastolic dysfunction in heart failure. Heart Fail Rev 2000;5:345–355. 51. Borlaug BA, Kass DA: Mechanisms of diastolic dysfunction in heart failure. Trends Cardiovasc Med 2006;16:273–279. 52. Leite-Moreira AF, Correia-Pinto J: Load as an acute determinant of enddiastolic pressure-volume relation. Am J Physiol Heart Circ Physiol 2001;280:H51–H59. 53. Leite-Moreira AF, Correia-Pinto J, Gillebert TC: Afterload induced changes in myocardial relaxation: A mechanism for diastolic dysfunction. Cardiovasc Res 1999;43:344–353. 54. Takimoto E, Soergel DG, Janssen PM, et al: Frequency- and afterloaddependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites. Circ Res 2004;94:496–504. 55. Borlaug BA, Melenovsky V, Russell SD, et al: Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006;114:2138– 2147. 56. Warner JG Jr, Metzger DC, Kitzman DW, et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572.

411

412

Chapter 31 • Ventricular-Arterial Interaction in Patients with Heart Failure and a Preserved Ejection Fraction 57. Little WC, Zile MR, Klein A, et al: Eﬀect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol 2006;98:383–385. 58. Hundley WG, Kitzman DW, Morgan TM, et al: Cardiac cycle–dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802. 59. Setaro JF, Zaret BL, Schulman DS, et al: Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic ﬁlling and normal left ventricular systolic performance. Am J Cardiol 1990;66: 981–986. 60. Bonow RO: Eﬀects of calcium-channel blocking agents on left ventricular diastolic function in hypertrophic cardiomyopathy and in coronary artery disease. Am J Cardiol 1985;55:172B–178B. 61. Bonow RO, Rosing DR, Bacharach SL, et al: Eﬀects of verapamil on left ventricular systolic function and diastolic ﬁlling in patients with hypertrophic cardiomyopathy. Circulation 1981;64:787–796. 62. Chen C-H, Nakayama M, Talbot M, et al: Verapamil acutely reduces ventricular-vascular stiﬀening and improves aerobic exercise performance in elderly individuals. J Am Coll Cardiol 1999;33:1602–1609. 63. Nussbacher A, Gerstenblith G, O’Connor FC, et al: Hemodynamic eﬀects of unloading the old heart. Am J Physiol 1999;277:H1863–H1871. 64. Fleg JL, Schulman S, O’Connor F, et al: Eﬀects of acute beta-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise. Circulation 1994;90:2333–2341. 65. Brubaker PH, Joo KC, Stewart KP, et al: Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil 2006;26:86–89. 66. Yusuf S, Pfeﬀer MA, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781.

67. Pitt B, Reichek N, Willenbrock R, et al: Eﬀects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: The 4E-left ventricular hypertrophy study. Circulation 2003;108:1831–1838. 68. Pitt B, Zannad F, Remme WJ, et al: The eﬀect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–717. 69. Kuwahara F, Kai H, Tokuda K, et al: Transforming growth factor–beta function blocking prevents myocardial ﬁbrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 2002;106:130–135. 70. Matsumoto T, Wada A, Tsutamoto T, et al: Chymase inhibition prevents cardiac ﬁbrosis and improves diastolic dysfunction in the progression of heart failure. Circulation 2003;107:2555–2558. 71. Brown JH, Del Re DP, Sussman MA: The Rac and Rho hall of fame: A decade of hypertrophic signaling hits. Circ Res 2006;98:730–742. 72. Higashi M, Shimokawa H, Hattori T, et al: Long-term inhibition of Rhokinase suppresses angiotensin II–induced cardiovascular hypertrophy in rats in vivo: Eﬀect on endothelial NAD(P)H oxidase system. Circ Res 2003;93:767–775. 73. Liao JK: Statin therapy for cardiac hypertrophy and heart failure. J Investig Med 2004;52:248–253. 74. Fukuta H, Sane DC, Brucks S, Little WC: Statin therapy may be associated with lower mortality in patients with diastolic heart failure: A preliminary report. Circulation 2005;112:357–363. 75. Takimoto E, Champion HC, Li M, et al: Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005;11:214–222. 76. Borlaug BA, Melenovsky V, Marhin T, et al: Sildenaﬁl inhibits betaadrenergic–stimulated cardiac contractility in humans. Circulation 2005;112:2642–2649. 77. Suga H: Ventricular energetics. Physiol Rev 1990;70:247–277.

ANNE S. KANDERIAN, MD AJAY BHARGAVA, MD GARY S. FRANCIS, MD

32

General Treatment of Diastolic Heart Failure INTRODUCTION BACKGROUND PATHOPHYSIOLOGY CLINICAL RELEVANCE General Treatment Guidelines Treatment of Underlying Disease and Contributing Factors Specific Therapies FUTURE RESEARCH SUMMARY

INTRODUCTION Even the language of “diastolic heart failure” is controversial.1 The phrase “heart failure with preserved left ventricular function” is preferred by many. When there is uncertainty about the name of a disorder and ambiguity regarding its pathophysiology, you can be almost certain that there will be little agreement about its treatment. However, there is general, although not universal, agreement that the fundamental problem of diastolic heart failure is impaired left ventricular (LV) ﬁlling. The left ventricle is often thickened and stiﬀ, and the ﬁlling pressures are increased relative to the LV volume. This leads to the cardinal features of heart failure, including pulmonary congestion, dyspnea, exercise intolerance, and edema. In fact, systolic and diastolic failure are usually clinically indistinguishable at the bedside. In most cases, a detailed imaging or even a hemodynamic study is necessary to understand the underlying structural and functional distinction between systolic and diastolic heart failure. Moreover, systolic and diastolic functions are intertwined and usually don’t occur in isolation.2 These observations have in part obscured the development of a speciﬁc therapy designed to treat diastolic heart failure. There currently is no targeted therapy for diastolic heart failure. This may change as old concepts of pathophysiology are challenged.3,4

BACKGROUND There are several trials that are ongoing or under consideration to test diﬀerent therapies in patients with diastolic heart failure. Only two large trials have been completed. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved) trial5 demonstrated a trend toward improvement as measured by fewer hospitalizations for heart failure when candesartan was added to conventional therapy. More recently, the perindopril in elderly people with chronic heart failure (PEP-CHF) study was published. This study did not show a mortality beneﬁt with perindopril, but similarly, there was a signiﬁcant reduction in heart failure related hospitalizations at one year.5a However, the cardiovascular event rate in patients with diastolic heart failure is relatively low compared with patients with systolic heart failure. There are more noncardiovascular deaths and non–heart failure hospitalizations in patients with diastolic heart failure, as they tend to be older and have more comorbid conditions. Elderly women with hypertension, LV hypertrophy (LVH), and ischemic heart disease are the prototypical patients. This makes it much more diﬃcult to demonstrate a clear reduction in all-cause death and all-cause hospitalizations in a clinical trial that focuses on treatment of diastolic heart failure, unless the sample size is very large and the follow-up is quite long. Recognition of this problem has probably hampered the design and implementation of large clinical trials for the treatment of diastolic heart failure. Because the language and pathophysiology of diastolic heart failure are complex,6–8 it is not unexpected that the treatment would also be ambiguous. Nevertheless, certain general principles of treatment can be applied. One should initially target therapy toward reducing pulmonary congestion, maintaining synchronous atrial contraction, and increasing the duration of diastole by reducing heart rate. Sodium restriction, reduction of total blood volume, and reduction of central blood volume are generally useful. Blunting neurohormonal activation (both the sympathetic nervous system [SNS] and the renin-angiotensin-aldosterone system [RAAS]) seems helpful. Hypotension should be avoided by cautious use of low-dose diuretics, so as to maintain blood 415

416

Chapter 32 • General Treatment of Diastolic Heart Failure pressure and cardiac output. Interventions should include drugs designed to prevent and treat myocardial ischemia and foster prevention and regression of LVH. Preservation of exercise tolerance is an important clinical goal.7 Nevertheless, it should be reiterated that there are no large randomized clinical trials to guide our therapy, with the exception of CHARM-Preserved and PEP-CHF, and both of these trials failed to show a survival beneﬁt. Despite a lack of clinical trial data, physicians are faced on a daily basis with patients who have severe diastolic heart failure. The question remains, how should we manage them? This chapter will outline a number of conventional treatment options currently available. We may lack objective data from large clinical trials, but we have years of observational data. These treatment options are outlined in Table 32-1.

PATHOPHYSIOLOGY To date, the pathophysiology of diastolic heart failure is incompletely understood and is not directly addressed by any drugs currently available. The core feature of diastolic heart failure is inadequate LV diastolic ﬁlling, which is a consequence of both impaired LV relaxation and increased LV stiﬀness.6,8–10 Several mechanisms contribute to these processes, including increased

myocardial mass and changes in the extracellular matrix caused by excess ﬁbrillar collagen.7,10 Ventricular relaxation is an energydependent process and is often impaired when myocardial ischemia is present.11 Hypertension, LVH, and ﬁbrosis caused by scarring from myocardial infarction (MI), dilated cardiomyopathy, or aging all lead to increased myocardial stiﬀness.12 Additional etiologies include pericardial diseases, inﬁltrative cardiomyopathies, and hypertrophic cardiomyopathy. Each increases myocardial stiﬀness and produces diastolic dysfunction.9 Just as in heart failure with impaired LV function, neurohormonal and endothelial activity play important roles in diastolic heart failure.7,13 Activation of the RAAS contributes to increased myocardial stiﬀness, partly by increasing reactive collagen deposition.7 The collagen matrix is particularly active in heart failure, leading to both enhanced collagen synthesis and a higher turnover of collagen.7 The ratio of myocardial ﬁbroblasts to myocytes is 4 : 1, implying the important role of collagen in myocardial growth and hypertrophy. Angiotensin II and aldosterone stimulate hypertrophy and proliferation of cells and stimulate collagen synthesis by ﬁbroblasts, leading to LV remodeling, including hypertrophy.7,14 Therefore, one could postulate that reducing RAAS activity with agents such as angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor blockers is beneﬁcial in patients with diastolic heart failure, just as in systolic heart failure.

TABLE 32-1 MANAGEMENT OF PATIENTS WITH DIASTOLIC HEART FAILURE OBJECTIVE

TREATMENT

DAILY MEDICATION DOSE

Control congestion

Salt restriction Diuretics

Control hypertension and regress LVH

Diuretics

<2 g of sodium per day Furosemide 10–120 mg Hydrochlorothiazide 12.5–25 mg Chlorthalidone 12.5–25 mg Hydrochlorothiazide 12.5–25 mg Atenolol 12.5–100 mg Metoprolol 12.5–200 mg Propranolol 20–80 mg Carvedilol 3.126–50 mg Enalapril 2.5–40 mg Lisinopril 10–40 mg Ramipril 5–20 mg Captopril 25–150 mg Losartan 50–100 mg Candesartan 4–32 mg Spironolactone 25–75 mg Amlodipine 2.5–10 mg Felodipine 2.5–20 mg

Beta blockers

ACE inhibitors

ARBs Aldosterone blockers CCBs Maintain sinus rhythm and control tachycardia

Cardioversion of atrial fibrillation Radiofrequency ablation of atrial fibrillation Beta blockers CCBs

Treat myocardial ischemia

Coronary revascularization (coronary artery bypass surgery or percutaneous coronary intervention) Nitrates Beta blockers CCBs

LVH, left ventricular hypertrophy; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker. Modified from Aurigemma GP, Gaasch WH: Diastolic heart failure. NEJM 2004;351:1097–1105.

Atenolol 12.5–100 mg Metoprolol 12.5–200 mg Verapamil 120–360 mg Diltiazem 120–540 mg Isosorbide dinitrate 30–180 mg Isosorbide mononitrate 30–90 mg Atenolol 12.5–100 mg Metoprolol 12.5–200 mg Amlodipine 2.5–10 mg Verapamil 120–360 mg Diltiazem 120–540 mg

Chapter 32 • General Treatment of Diastolic Heart Failure Increased LV stiﬀness and decreased compliance of the ventricle are reﬂected in the pressure-volume loop curve such that for any given LV volume, a higher LV diastolic pressure is observed. Likewise, for any pressure, the LV end diastolic volume is much smaller.8,12 Pulmonary congestion ensues when the higher pressures are transmitted back to the lungs.12,13 All these lead to the typical symptoms of heart failure, including exertional dyspnea and diminished exercise tolerance. An exaggerated hypertensive response to exercise is often observed when patients with diastolic heart failure undergo exercise stress testing.11 This may be due to the high frequency of concomitant systemic hypertension.

CLINICAL RELEVANCE General Treatment Guidelines The goals of treatment of diastolic heart failure are similar to those of systolic heart failure. Not only do we seek to improve survival in our patients, but we also aim to improve our patients’ quality of life by reducing symptoms, increasing exercise tolerance, and decreasing hospitalizations. Like most disease states, treatment should be based on evidence derived from clinical trials. Practice guidelines are generally data driven, but when there are few data, consensus or expert opinion is provided. Most of the data from clinical trials have been exclusive to systolic heart failure. Although the mortality rate of patients with diastolic heart failure is not quite as high as that of systolic heart failure, it is nevertheless higher than in patients without heart failure.8,13,15 Moreover, there is signiﬁcant morbidity associated with diastolic heart failure, and the hospitalization rate in the elderly remains close to that of systolic heart failure.8,10,16 Approximately one third to one half of all patients with manifest heart failure have preserved ejection fraction (EF).8,10,13,16,17 The incidence of diastolic heart failure depends on the local demographics. Hospitals in large inner-city neighborhoods will see much more diastolic heart failure, as poorly treated hypertension and elderly people are more common. Therefore it remains crucial that we learn more about eﬀective treatment strategies for patients with diastolic heart failure. However, lack of data from large clinical trials is reﬂected in the practice guidelines set forth by the experts. The practice guidelines on chronic heart failure of the American College of Cardiology/American Heart Association (ACC/ AHA) were revised in 200518 and include a section on patients with heart failure and normal LVEF. The recommendations listed by the task force are presented in Table 32-2. Class I recommendations include control of hypertension, control of ventricular rate in patients with atrial ﬁbrillation, and use of diuretics to control pulmonary congestion and peripheral edema. Coronary revascularization in patients with heart failure and normal EF and coronary artery disease is a class IIa recommendation. Restoration and maintenance of sinus rhythm in patients with atrial ﬁbrillation, heart failure, and normal EF may improve symptoms and is a class IIb recommendation. Due to a paucity of data to guide management of patients with diastolic heart failure, a class IIb recommendation is given to beta blockers, ACE inhibitors, ARBs, and calcium channel blockers (CCBs). Eﬃcacy of digitalis to minimize symptoms of heart failure in patients with a normal EF is not well established, and its use is also a class IIb recommendation. The task force emphasized the need to eliminate other conditions that may contribute to heart failure with a normal EF.

TABLE 32-2 AMERICAN COLLEGE OF CARDIOLOGY/AMERICAN HEART ASSOCIATION RECOMMENDATIONS FOR TREATMENT OF PATIENTS WITH HEART FAILURE AND NORMAL LEFT VENTRICULAR EJECTION FRACTION Class I 1. Control of systolic and diastolic hypertension in accordance with published guidelines 2. Control of ventricular rate in patients with atrial fibrillation 3. Use of diuretics to control pulmonary congestion and peripheral edema Class IIa 1. Coronary revascularization in patients with coronary artery disease in whom symptomatic or demonstrable myocardial ischemia is judged to be having an adverse effect on cardiac function Class IIb 1. Restoration and maintenance of sinus rhythm in patients with atrial fibrillation 2. Use of beta blockers, ACE inhibitors, ARBs, or CCBs in patients with controlled hypertension to minimize symptoms of heart failure 3. Use of digitalis to minimize symptoms of heart failure is not well established.

Level of Evidence A C C Level of Evidence C

Level of Evidence C C

C

ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.

The Heart Failure Society of America (HFSA) also produced an executive summary on its Heart Failure Practice Guidelines.19 These too include a section on evaluation and management of patients with heart failure and preserved LVEF (Table 32-3). The guidelines highlight the necessity to obtain a diﬀerential diagnosis in these patients, as treatment may vary for diﬀering conditions. The HFSA recommendations are similar to those of the ACC/ AHA task force and stress the importance of evaluating for myocardial ischemia, controlling blood pressure, and counseling on salt restriction. Diuretic therapy is recommended in those patients with evidence of volume overload. ACE inhibitors are recommended in all patients with heart failure and preserved EF who have diabetes or atherosclerotic cardiovascular disease and one additional risk factor. The guidelines recommend that ARBs be used in patients who are intolerant of ACE inhibitors. Beta blockers are recommended in patients who have a history of MI, hypertension, or atrial ﬁbrillation with rapid ventricular rate. CCBs are recommended in those patients who have atrial ﬁbrillation but are intolerant to beta blockers, those with symptom-limiting angina, and those with hypertension. Finally, the guidelines recommend that sinus rhythm be restored and maintained in patients who have symptomatic atrial ﬁbrillation or ﬂutter. These guidelines are essentially based on observational studies. Other than for the ACC/AHA and HFSA guidelines, there are few recommendations to oﬀer patients with diastolic heart failure. While there is no standardized treatment, attention needs to be paid to the individual patient and to potential etiologies of diastolic heart failure. Since no patient is quite like another, treatment strategies should be targeted to underlying mechanisms that could be contributing to heart failure in each individual.

417

Chapter 32 • General Treatment of Diastolic Heart Failure 18

TABLE 32-3 THE HEART FAILURE SOCIETY OF AMERICA RECOMMENDATIONS FOR MANAGEMENT OF PATIENTS WITH HEART FAILURE AND PRESERVED LEFT VENTRICULAR EJECTION FRACTION RECOMMENDATION 1. Detailed approach to differential diagnosis by use of echocardiography, electrocardiography, and stress imaging 2. Evaluate for possible myocardial ischemia 3. Aggressive blood pressure management 4. Low sodium diet 5. Diuretic recommended in all patients with clinical evidence of volume overload (thiazide or loop diuretic), with avoidance of excessive diuresis 6. ARBs or ACE inhibitors should be considered 7. ACE inhibitors should be considered in patients with symptomatic atherosclerotic cardiovascular disease or diabetes and 1 additional risk factor 8. ARBs should be considered in patients who meet the above criteria but are intolerant to ACE inhibitors 9. Beta blockers recommended in patients with: a. Prior MI b. Hypertension c. Atrial fibrillation requiring rate control 10. CCBs should be considered in: a. Atrial fibrillation requiring rate control in patients intolerant to beta blockers (diltiazem or verapamil) b. Symptom-limiting angina c. Hypertension (amlodipine) 11. Restore and maintain sinus rhythm in patients with symptomatic atrial flutter/ fibrillation

STRENGTH OF EVIDENCE C C C C C

B or C respectively C

Reduction in left ventricular mass index (%)

418

16 14

*

12

*

10

†

8 6 4 2 0 ARBs

CCBs

Diuretics ACE Beta inhibitors blockers

Figure 32-1 Reduction in left ventricular (LV) mass index (percentage from baseline) associated with antihypertensive therapy from different drug classes. The results are based on a meta-analysis of eight trials and over 4100 patients. The reduction of LV mass index was significantly higher with angiotensin II receptor blockers (ARBs) (13%), calcium channel blockers (CCBs) (11%), and angiotensin-converting-enzyme (ACE) inhibitors (10%) compared with beta blockers (6%). * indicates p < 0.05 versus beta blockers; † indicates p < 0.01 versus beta blockers. (From Klingbeil AU et al: A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 2003;115:41–46.)

C

C B B C A C C

ARB, angiotensin receptor blocker; ACE, angiotensin converting enzyme; MI, myocardial infarction; CCB, calcium channel blocker.

Treatment of Underlying Disease and Contributing Factors There are several conditions that contribute to or exacerbate diastolic heart failure. These include hypertension, LVH, myocardial ischemia, increased vascular stiﬀness, diabetes mellitus, renal failure, anemia, obesity, and pulmonary diseases.12,20 Furthermore, there may be external constraints on the myocardium and pericardium that render the left ventricle incapable of ﬁlling adequately,11 thereby mimicking diastolic heart failure. It is crucial to consider these conditions, as treatment of constrictive pericarditis is obviously quite diﬀerent than that of systemic hypertension with LVH.

Hypertension Hypertension is associated with an increase in left atrial (LA) pressure that contributes to increased LV diastolic pressure and delays early diastolic ﬁlling (see Chapter 19).11 Lowering the blood pressure allows the ventricle to relax more adequately, thereby increasing early diastolic ﬁlling.11 Furthermore, treating hypertension may reduce myocardial ischemia, which can also contribute to diastolic heart failure. Chronic hypertension leads

to LVH, causing impaired LV compliance because of a stiﬀer ventricle. Antihypertensive therapy is critical in diastolic heart failure, as it induces LVH regression, improving diastolic performance and LV distensibility.11 Klingbeil et al. published a meta-analysis of the eﬀects of treatment on LV mass in essential hypertension.21 This meta-analysis of 80 clinical trials and over 4000 patients showed that anti-hypertensive drug classes had diﬀering eﬀects on LV mass reduction. ARBs produced a 13% reduction of LV mass index; CCBs, 11%; ACE inhibitors, 10%; diuretics, 8%; and beta blockers, 6% (Fig. 32-1). ARBs, CCBs, and ACE inhibitors all reduced LV mass index more signiﬁcantly than beta blockers. It is intuitive that with LVH regression, diastolic function might improve; however, it remains to be determined whether a greater reduction in LV mass improves clinical outcomes. Nevertheless, in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, regression of Cornell product LVH was associated with 35% to 45% reductions in the risk of cardiovascular death, stroke, or MI, a 37% reduction in the composite endpoint, and a 28% reduction in all-cause mortality.22 It is very infrequent that single drug therapy is eﬀective in reducing blood pressure, and we are often left to employ multiple agents to achieve goal blood pressure, especially in patients with concomitant diabetes mellitus. While medical therapy and lower blood pressure contribute to LVH regression, one must not forget that weight loss, reduced salt intake, and exercise can also play roles in managing hypertension. A recent cross-sectional study showed that long-term caloric restriction ameliorates the decline in diastolic function in humans.23 Twenty-ﬁve patients with caloric restriction were compared with 25 age- and gender-matched healthy subjects on a standard Western diet and were found to have lower body mass index, systolic and diastolic blood pressures, and levels of inﬂammatory markers. Indices of diastolic function were improved in patients with caloric restriction compared with the matched controls on a Western diet; however, no change was found with respect to systolic function. It is unclear whether the eﬀect of caloric restriction on diastolic function is independent of blood pressure; nevertheless, emphasis should be placed on targeting dietary modiﬁcations when advising patients.

Chapter 32 • General Treatment of Diastolic Heart Failure

Coronary Artery Disease Myocardial ischemia or infarction is a major contributor to diastolic heart failure (see Chapter 22). One of the ﬁrst hemodynamic parameters observed when a coronary artery is acutely occluded by angioplasty is a reduction in negative change in pressure versus time (−dp/dt). This change is manifested by an abrupt increase in LV end diastolic pressure before there are any changes in systolic function.11 These observations suggest that diastolic relaxation, known to be energy dependent, is exquisitely sensitive to myo-cardial ischemia, even more so than systolic function.11 The pressure-volume relationship is shifted up and to the left.24 The chamber stiﬀness constant, k, achieves a greater slope. Fibrosis produced by scarring from a prior infarction also contributes to LV stiﬀening.9,25 Diastolic heart failure is primarily a disease of the elderly, and it is in this population that the prevalence of coronary artery disease is most high. There are no data demonstrating that coronary revascularization leads to an improvement in diastolic heart failure outcomes. Revascularization alone, without further medical therapy, has not been shown to reduce the incidence of pulmonary edema.10,11 In fact, one study showed that pulmonary edema occurred in 50% of patients within 6 months after revascularization.26 Despite this, it is essential that screening for coronary artery disease be performed, either by invasive or noninvasive techniques, as myocardial ischemia is a wellestablished cause of diastolic heart failure.

Diabetes Diabetes mellitus and impaired glucose metabolism contribute to LVH and arterial stiﬀness, which impair LV relaxation and distensibility (see Chapter 26).11,27 Furthermore, the prevalence of coronary artery disease is higher in patients with diabetes, and there may be more underlying microvascular disease. The advanced glycation of proteins forms complex compounds known as advanced glycation end-products (AGEs), which cross-link and polymerize with other proteins. These cross-links with collagen alter vascular compliance, resulting in loss of elasticity and increased vascular stiﬀness.28 This process occurs with normal aging but is often accelerated in the presence of diabetes. In hypertensive patients without diabetes, fasting plasma glucose is associated with adverse diastolic function independent of LVH.29 Several studies have reported that insulin resistance in nondiabetic patients with hypertension is associated with diastolic dysfunction.30–33 In fact, hypertension and diabetes mellitus are a dominant force in the development of systolic and diastolic heart failure, and the combination of the two is associated with more severe abnormal LV relaxation.27 It is not unreasonable to conclude that treating diabetes and improving glucose control may be favorable in patients with diastolic heart failure. Nevertheless, some studies have shown that an improvement in glycemic control in patients with type II diabetes mellitus does not ameliorate diastolic function in spite of regression of LVH.34,35 It may be that improved glycemic control has little eﬀect on the already present AGEs responsible for collagen cross-linking and ﬁbrosis. The LIFE study noted that patients with diabetes have less regression of LVH than those without diabetes in response to antihypertensive therapy.36 Additionally, regression of Cornell product LVH with antihypertensive therapy was associated with a reduction in the composite endpoint in the nondiabetic population, but this did not appear to be the case in patients with diabetes. These observations stress the importance of prevention, early strict glycemic control, and blood pressure control.

Some experimental studies have been conducted on diabetic animal models. Studies in prediabetic rats as well as in advanced diabetic rats have consistently demonstrated that peroxisome proliferator–activated receptor (PPAR) ligands improve glucose and lipid metabolism, as well as prevent LV diastolic dysfunction.37–39 PPAR-α agonists such as pioglitazone or rosiglitazone not only improve insulin resistance but facilitate endothelial function.40–42 Recent studies have conﬁrmed the existence of endothelial dysfunction in patients with systolic heart failure,43 and we can perhaps assume that this is altered in patients with diastolic heart failure as well. Nonetheless, endothelial dysfunction has been implicated in the pathophysiology of hypertension,43 which is closely associated with development of diastolic heart failure. It is plausible that PPAR ligands may be useful in diabetic patients with diastolic heart failure, although randomized double-blind studies are needed, especially since PPAR agonists have been noted to promote ﬂuid retention and exacerbation of heart failure. Patients with impaired diastolic function can remain asymptomatic for years without evident heart failure. LA hypertrophy and forceful LA contraction can augment late diastolic ﬁlling.11 However, in patients with atrial ﬁbrillation, this useful mechanism is absent, invoking an augmentation of LA pressure. The left atrium then acts more as a simple conduit and cannot propel blood easily into the thickened, nondistensible left ventricle. Pulmonary congestion ensues and consequently symptomatic heart failure. Therefore, it is usually advantageous to restore and maintain sinus rhythm in patients with diastolic heart failure. When this is not feasible, it is important to at least control ventricular rate, as tachycardia reduces the time for complete relaxation and may be hazardous to patients with diastolic dysfunction. Slowing the heart rate enables more time for diastolic ﬁlling and thus better coronary perfusion and LV performance.10

Specific Therapies Diuretics Life-threatening pulmonary edema can occur in patients with diastolic heart failure. It can be a dramatic presentation and should be promptly treated, as in any case of acute pulmonary edema. Severe systemic hypertension is frequently present and must be aggressively treated. Acute myocardial ischemia, mycardial infarction, and rapid atrial ﬁbrillation must also be identiﬁed, and if evident, promptly treated. Intravenous diuretics, nitrates, oxygen, and in some cases morphine sulfate are frequently employed. Intubation and ventilatory support may be necessary, and patients with chronic or acute renal failure may sometimes need urgent dialysis. Intravenous furosemide and nitrates should be employed judiciously, as patients with diastolic heart failure and small LV chambers may be more easily volume depleted than patients with large, dilated, poorly contracting hearts.11 This is particularly the case when there is an absence of systemic hypertension, making diastolic heart failure diﬃcult to treat. The diastolic pressure-volume curve is steep, implying that small changes in volume result in large changes in pressure, and therefore a signiﬁcant drop in cardiac volume can produce hypotension and reduced cardiac output. Diuretics have no direct eﬀect on actual diastolic function, but they can reduce central blood volume. Loop diuretics preferentially are utilized in treating volume overload, whereas thiazide diuretics are more useful for control of blood pressure. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart

419

420

Chapter 32 • General Treatment of Diastolic Heart Failure Attack Trial (ALLHAT) demonstrated that chlorthalidone was superior to both amlodipine and lisinopril in hypertensive patients.44 Interestingly, this beneﬁt was even more prominent in African-American participants. Several studies have conﬁrmed that African-American patients do not respond as well to blockers of the RAAS; this may be due to inherent lower plasma renin levels.45,46 However, a substantial number of patients with heart failure have some degree of renal insuﬃciency, and thiazide diuretics are well known to be ineﬀective when there is reduced glomerular ﬁltration.

Nitrates Nitrates are frequently used along with diuretics in the treatment of acute pulmonary edema. They assist in alleviating pulmonary congestion while acting primarily as venodilators. Unlike diuretics, however, nitrates may also exert their action on the ventricle by releasing endothelial nitric oxide, thereby improving ventricular distensibility. Nitrates are predominantly useful in cases of hypertensive pulmonary edema and are often used either sublingually or intravenously. Like diuretics, nitrates must be cautiously used, as hypotension can occur. Large doses of nitroglycerin must be given to achieve arteriolar dilation (i.e., to lower blood pressure), whereas smaller doses of nitroglycerin (i.e., 40 μg/min) lower venous pressure through dilation of large-capacitance veins and thereby reduce pulmonary congestion without reducing blood pressure.

Beta Blockers It has become standard practice to incorporate beta blockers into the treatment of coronary artery disease, hypertension, and more recently systolic heart failure. Prior studies have shown that beta blocker treatment in patients with systolic heart failure is associated with improved ventricular performance, a higher EF, and increased survival.47–50 Despite the paucity of data with beta blockade and diastolic heart failure, it is not unreasonable to infer that beta blockade is also valuable in the treatment of diastolic heart failure. Beta blockade may exert its actions on diastolic heart failure via several distinct mechanisms. Coronary artery disease is a common comorbidity in the elderly hypertensive patient manifesting with heart failure and a preserved EF. Myocardial ischemia may instigate heart failure, and it has been shown that beta blockers improve symptoms and survival in patients with coronary artery disease.51–54 Administration of beta blockers likely relieves ischemia and may play a role in preventing diastolic heart failure. Additionally, beta blockers are eﬀective in reducing tachycardia. Tachycardia is generally not well tolerated in patients with diastolic dysfunction, as it reduces diastolic time, thereby reducing the time for complete relaxation and LV ﬁlling, thus contributing to elevated diastolic pressure. Furthermore, tachycardia is not well tolerated in myocardial ischemia, due to increased myocardial oxygen demand and decreased time allowed for coronary perfusion. For these reasons, beta blockers are also advantageous in the setting of atrial ﬁbrillation and a rapid ventricular rate. As with systolic heart failure, beta blockers can suppress the deleterious eﬀects of chronic activation of the sympathetic nervous system, thereby improving autonomic balance and reducing ventricular wall stress. Beta blockers, still useful as eﬀective antihypertensive agents, elicit LVH regression, though not to the same degree as other antihypertensive agents.21 The analysis of the LIFE study, in which atenolol was shown to be inferior to

losartan with regard to the composite primary endpoint of cardiovascular death, stroke, and MI, supports the contention that beta blockers are less eﬀective in LVH regression than ARBs.22 Although there are no large-scale randomized trials assessing the eﬃcacy of beta blockers in patients with heart failure and preserved EF, a few smaller-scale trials have been performed. Diﬀering patient populations and small sample sizes have produced conﬂicting results, and there are essentially no serious outcomes data. One of the earlier studies randomized 158 elderly patients with a prior history of MI, heart failure, and an EF greater than 40% to propranolol or placebo.55 All patients were treated with ACE inhibitors and diuretics and followed for 32 months. The authors demonstrated that there was a 35% reduction in total mortality and a 37% reduction in combined total mortality and nonfatal MI in patients randomly allocated to propranolol. The mortality reduction seems quite high in the face of the small sample size and portrays a higher beneﬁt of beta blockers than was reported in the larger-scale Study of Eﬀects of Nebivolol Intervention on Outcomes and Rehospitalizations in Seniors with Heart Failure (SENIORS). It may very well be that the mortality beneﬁt observed with propranolol is attributable to these patients having underlying coronary artery disease, with improvement of myocardial ischemia driving the beneﬁt rather than direct improvement in actual diastolic function. The SENIORS trial randomized 2128 elderly patients with heart failure to nebivolol versus placebo.56 Nebivolol is a beta-1selective blocker that modulates nitric oxide and serves as a vasodilator but is not yet approved for use in the United States. This study was not exclusive to diastolic heart failure, with a mean EF of 36%. Only 35% of patients had an EF greater than 35%. The primary outcome consisted of a composite of all-cause mortality or cardiovascular hospitalizations. These endpoints occurred in 31.1% of patients receiving nebivolol compared with 35.3% of patients receiving placebo. The hazard ratio in favor of nebivolol was 0.86, with a p value of nominal signiﬁcance (p = 0.039). In SENIORS, 68% of patients had documented coronary artery disease. Subgroup analyses were performed in patients with EFs less than and greater than 35%. The hazard ratios for the primary outcome were 0.87 and 0.82, respectively, indicating no diﬀerential eﬀect on preserved or low EF. The beneﬁt of nebivolol was not as robust as that observed with beta blockers in systolic heart failure, such as was demonstrated with carvedilol in the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS)49 and bisoprolol in the Cardiac Insuﬃciency Bisoprolol Study (CIBIS) II.50 The population studied in the SENIORS trial was older; the inclusion criteria was age older than 70 years, which produced a mean age of 76 years. Subgroup analysis demonstrated that patients younger than 75 years had a greater reduction in all-cause mortality or cardiovascular hospitalizations with nebivolol (17.4%) than placebo (22.5%) compared with those older (24.6% vs. 26.7%). These observations support the contention that large clinical trials in older patients will have many noncardiovascular deaths, making “all-cause mortality” a poor choice for an endpoint. These studies looked primarily at clinical outcomes of patients with diastolic heart failure and did not focus on actual diastolic function. However, there are studies that sought to ascertain this notion. Echocardiographic parameters are utilized to determine stages of diastolic dysfunction, and studies have consistently conﬁrmed that beta blocker usage is associated with improved diastolic function. A study published in 2000 showed that in 45

Chapter 32 • General Treatment of Diastolic Heart Failure patients with depressed EF, administration of carvedilol signiﬁcantly increased deceleration time of early diastolic ﬁlling.57 The authors demonstrated an improvement in diastolic function: 77% of patients with a baseline restrictive ﬁlling pattern reverted to normal or pseudonormal ﬁlling patterns after carvedilol therapy, and 71% of patients with an abnormal relaxation pattern changed to a normal ﬁlling pattern. The Swedish Dopplerechocardiographic study (SWEDIC) was comprised solely of patients with heart failure and preserved systolic function.58 In this study, 113 patients were randomized to carvedilol or placebo for 6 months. The primary endpoint was change in the integrated quantitative assessment of all four Doppler variables of diastolic function. These are (1) E/A ratio (early diastolic ﬁlling velocity to atrial late diastolic ﬁlling velocity), (2) mitral atrial (A)-wave duration compared with pulmonary venous atrial duration, (3) isovolumic relaxation time, and (4) pulmonary venous systolic/ diastolic velocity. Although there was no eﬀect on the primary endpoint, there appeared to be a trend toward improved diastolic function in patients treated with carvedilol. A statistically signiﬁcant improvement in E/A ratio was found in patients treated with carvedilol (p = 0.046). This ﬁnding may be purely a result of lowering the heart rate. As expected, heart rate decreased signiﬁcantly in the carvedilol group (from 74 to 60 bpm), although there was no signiﬁcant reduction in systolic and diastolic blood pressure. When subgroup analysis was performed, the beneﬁt of carvedilol on E/A ratio was exclusive to patients with baseline heart rates greater than 71 bpm (p = 0.002). In those with low heart rates (<71 bpm), there was no eﬀect. Although the study was not powered for mortality, other measurements were assessed. A trend toward worsening New York Heart Association (NYHA) class with carvedilol treatment was observed, though it was not statistically signiﬁcant. Patients likely to beneﬁt from beta blocker therapy include those with known coronary artery disease, myocardial ischemia, and tachycardia. Lowering the heart rate to less than 71 bpm may not provide any incremental beneﬁt of improved diastolic ﬁlling and diastolic function as seen in the SWEDIC trial. Beta blockers may also be valuable in patients with atrial ﬁbrillation to control heart rate, lower blood pressure, and alleviate myocardial ischemia. Finally, beta blockers are still widely used in the treatment of hypertension, though other agents have been shown to provide more LVH regression.

Angiotensin-Converting-Enzyme Inhibitors It has been well established that ACE inhibitors are beneﬁcial in patients with chronic heart failure and reduced EF. Landmark trials such as the Studies of Left Ventricular Dysfunction (SOLVD)59 and the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)60 demonstrated that ACE inhibitors improve survival as well as slow the progression of heart failure in patients with depressed EF.59–61 Most of the clinical trials that have shown a beneﬁt in patients with heart failure have excluded those with preserved EF, as a low EF was usually a criteria for entry. Several randomized studies have also shown a beneﬁt of ACE inhibitors in patients post-MI, as in the Survival and Ventricular Enlargement (SAVE) trial,61 as well as in patients with high-risk factors, as in the European Trial of Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA)62 and the Heart Outcomes Prevention Evaluation (HOPE) study.63 These trials have consistently demonstrated an improvement in survival and EF and a reduction in

heart failure. ACE inhibitors may be beneﬁcial in that they improve compliance of blood vessels, cause regression of LVH, restore ﬂow-mediated dilation in blood vessels, and improve endothelial function in patients with heart failure. Additionally, ACE inhibitors play a vital role in modifying myocardial remodeling that occurs with systolic heart failure, LVH, post-MI, and activation of the RAAS.64 Theoretically, agents that block the RAAS should likewise be beneﬁcial in patients with heart failure and preserved EF. Very little data exist on the utility of ACE inhibitors in heart failure patients with preserved EF. Despite this, several observational studies have demonstrated that patients with diastolic heart failure prescribed ACE inhibitors had longer survival as well as a shorter length of stay during index hospitalization.65,66 To address this issue, the Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) clinical trial is under way.67 In the PEP-CHF study, 850 elederly patients with LVEF between 40% and 50% and a history of heart failure and abnormal diastolic dysfunction were randomized either to perindopril or to placebo. The primary endpoint was a composite of all-cause mortality and heart failure hospitalizations and was achieved in 25.1% of patients randomized to placebo versus 23.6% of patients randomized to perindopril (p = 0.545). However, when analysis was conducted at one-year follow-up, patients randomized to perindopril had signiﬁcantly fewer heart failure hospitalizations, improvement in NYHA class, and an increase in six minute walking distance. The mean follow-up of the study was 26.2 months; however, after one year, a large percentage of the patients were unblinded, and over one third of patients were taking openlabel ACE inhibitors by the end of the study. This could explain why there was no statistical diﬀerence in the overall primary endpoint in spite of a diﬀerence in subgroup analysis at one year follow-up. A small study conducted in 1993 examined the eﬀect of enalapril on congestive heart failure in elderly patients with prior MI and normal LVEF.68 In this study, 21 patients with NYHA class III heart failure who required diuretics were randomized to 3 months treatment with enalapril or placebo. Enalapril was found to signiﬁcantly improve NYHA functional class, systolic and diastolic blood pressure, EF, and exercise tolerance and to reduce LV mass. Enalapril also led to improvement in diastolic parameters such as increased peak mitral E/A ratios. Another trial examined the long-term Eﬀects of Amlodipine and Lisinopril on LV Mass and Diastolic Function: E/A Ratio (ELVERA) in elderly, previously untreated hypertensive patients.69 This study randomized 166 patients to either amlodipine or lisinopril. Both drug therapies led to equivalent reductions in systolic and diastolic blood pressures, reduction in the LV mass index, and improvement in the E/A ratio. The authors demonstrated that even when blood pressures were stabilized in the second year of drug treatment, reduction of LV mass continued to take place. Although there appeared to be an improvement in diastolic function based on echocardiographic parameters, clinical outcomes were not assessed in this study. It is well known that patients with chronic kidney disease have a propensity to develop LVH and diastolic heart failure.70,71 In fact, several reports have documented that diastolic dysfunction exists in children with chronic kidney disease on hemodialysis.72 Diastolic dysfunction poses a problem for the individual with chronic kidney disease, since hypotension during dialysis is a common occurrence.70 There are conﬂicting reports on whether kidney transplantation serves to improve diastolic dysfunction or

421

Chapter 32 • General Treatment of Diastolic Heart Failure not. Nevertheless, there may be a role for drug therapy. ACE inhibitors have been shown to be eﬀective in slowing the progression of renal disease in both the diabetic and nondiabetic populations, as well as reducing protein excretion in diabetics by 35% to 40%. Additionally, ACE inhibitors have been shown to induce regression of LVH that is associated with a signiﬁcant improvement in diastolic function in hypertensive patients with chronic renal failure.73 It may be challenging to interpret diastolic dysfunction in patients with renal failure because the Doppler indices of diastolic dysfunction are preload dependent and have been known to change during hemodialysis.74–77 Controversy exists over whether ACE inhibitors are equally eﬃcacious in diﬀering population subgroups. Most of the patients enrolled in clinical trials are Caucasian males, and we should not assume that these beneﬁts will apply to women and non-Caucasians. Several studies have indicated that African-American patients are less likely to beneﬁt from monotherapy with ACE inhibitors and ARBs than diuretics and CCBs compared with Caucasians.78,79 A pooled analysis from the SOLVD prevention and treatment trials demonstrated that enalapril therapy was associated with a signiﬁcant reduction of heart failure hospitalizations among Caucasian patients with LV dysfunction, but not among African-American patients.78 Additionally, this analysis showed that both systolic and diastolic blood pressure reduction was more eﬀective in Caucasian patients, whereas there was no signiﬁcant diﬀerence in African-American patients. A meta-analysis of the ACE inhibitor trials indicates that women are not as likely to beneﬁt from these agents as men.79 It appears that men have a signiﬁcant mortality reduction from treatment with ACE inhibitors (relative risk, 0.82), whereas women have a more modest mortality beneﬁt (relative risk, 0.92). Women with symptomatic LV dysfunction have a slight mortality beneﬁt (relative risk, 0.90), although not to the same degree as men. Mortality beneﬁt is not observed in women with asymptomatic LV dysfunction (relative risk, 0.96). In men, there is a signiﬁcant mortality beneﬁt in both symptomatic and asymptomatic LV dysfunction groups. It is unclear why these diﬀerences exist, and evidently future studies are warranted. Despite the paucity of data on ACE inhibitors in patients with heart failure and preserved EF, we still advocate their use in the treatment of diastolic heart failure. ACE inhibitors are eﬀective in patients with hypertension as well as in those with vascular disease, both of which associate with diastolic heart failure. ACE inhibitors may be eﬀective tools for primary prevention in that their use has been related to prevention of heart failure, diabetes, and even new or recurrent atrial ﬁbrillation.62,63,80–82 Eﬃcacy of ACE inhibitors is related to higher dosages. However, it is best to start at a lower dose and carefully uptitrate monthly, as hypotension continues to remain a risk in patients with diastolic heart failure receiving vasodilator therapy. Similarly, renal function must be closely monitored, as a substantial rise in blood urea nitrogen (BUN) and creatinine can occur when there is baseline renal insuﬃciency or simultaneous renovascular disease. Serum potassium should also be monitored frequently as hyperkalemia can frequently occur. Special consideration should be given in the elderly, as their creatinine clearance is usually lower, with even mild elevations in serum creatinine levels.

Angiotensin Receptor Blockers ACE inhibitors are historically preferred over ARBs when treating patients with heart failure and depressed EF because the former have been available longer. ARBs are usually reserved for

use in those who are intolerant of ACE inhibitors. There is little evidence to support one or the other in heart failure with preserved EF. The ACC/AHA guidelines give both drug classes a class IIb recommendation.18 To date, the largest randomized clinical trial in patients with heart failure and preserved EF conducted is the CHARM-Preserved trial.5 CHARM-Preserved examined the eﬀects of candesartan in patients with chronic heart failure and preserved LVEF. This trial was part of the overall CHARM program. CHARM-Preserved enrolled 3023 patients, randomizing them to either candesartan or placebo with a mean follow-up of 36.6 months. The primary endpoint consisted of combined cardiovascular death and hospitalizations related to heart failure. There was a slight relative risk reduction of 11% in the primary outcome among LV preserved patients treated with candesartan; however, this improvement was marginal (unadjusted p = 0.118, covariate adjusted p = 0.051) (Fig. 32-2). Although cardiovascular death did not diﬀer between the two groups, there did appear to be a signiﬁcant reduction in heart failure hospitalizations with use of candesartan (p = 0.017). There was also a trend toward reduced cardiovascular events with candesartan, although the results were not signiﬁcant. The CHARM-Preserved trial failed to demonstrate a survival beneﬁt because of several possible reasons, the most likely being that the study was insuﬃciently powered. The number of cardiovascular events was relatively small. The curves were beginning to separate, and had the study a larger sample size or a longer followup period, the results may have unambiguously favored candesartan. Patients were enrolled if they had heart failure based on a physician’s judgment rather than absolute diagnostic criteria. It is conceivable, therefore, that some enrolled patients might not have had heart failure and therefore were not as likely to beneﬁt from drug intervention. Another observation is that the patients studied in this trial were younger, with a mean age of 67 years. The increased morbidity and mortality that is associated with diastolic heart failure generally aﬀects the elderly more than their younger counterparts. The younger age of the patients and fewer endpoints may have contributed to the lack of survival beneﬁt observed with candesartan in the CHARM-Preserved trial. A smaller, randomized study of surrogate endpoints by Little et al. demonstrated that treatment with losartan signiﬁcantly improved exercise tolerance and quality of life in patients with diastolic dysfunction and a hypertensive response to exercise.83 As Proportion with cardiovascular death or hospital admission for CHF (%)

422

50

Hazard ratio 0.89 (95% CI 0.77–1.03), p = 0.118 Adjusted hazard ratio 0.86, p = 0.051

40 30

Placebo 20

Candesartan

10 0 0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Time (years) Number at risk Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195 Figure 32-2 The CHARM-Preserved trial: Kaplan-Meier curve of the time to cardiovascular death or hospital admission for congestive heart failure (CHF). (From Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781. With permission from Elsevier.)

Chapter 32 • General Treatment of Diastolic Heart Failure angiotensin II impairs LV relaxation, the authors decided to ascertain whether losartan, an ARB, could improve diastolic function during exercise, and thereby improve exercise tolerance. They noted that at baseline, the mitral E/A ratio increased with a shortened mitral deceleration time after exercise. Although there did not appear to be any signiﬁcant change in echocardiographic diastolic parameters with administration of losartan, there was an increase in exercise tolerance as well as quality of life. Losartan did not alter the resting blood pressure and slightly decreased peak systolic blood pressure during exercise, although this was not signiﬁcant. In this study, losartan was administered for only 2 weeks, and this duration of treatment may have been insuﬃcient to show any meaningful clinical change, yet exercise tolerance and quality of life did improve. The initial LIFE study demonstrated that for equivalent blood pressure reduction, losartan was superior to atenolol in preventing cardiovascular morbidity and death in hypertensive patients, a group known to be at risk to develop diastolic heart failure. A substudy from LIFE examined the changes in diastolic LV ﬁlling after one year of antihypertensive treatment.84 Echocardiograms and Doppler measurements were performed at baseline and one year in 728 patients. The authors demonstrated that antihypertensive therapy reduced mean LV mass by 12% and LA diameter by 3% and improved diastolic LV ﬁlling patterns signiﬁcantly. The E/A ratio and the deceleration time both increased, and there appeared to be an improvement in ﬂow patterns. The LIFE substudy also noted that improvement in diastolic function was related only to reduction in LV mass. There appeared to be no changes in diastolic ﬁlling parameters in patients without LV mass reduction. Since the study was blind and the main LIFE study was still in progress, no comparison was made between losartan and atenolol. Nevertheless, the study conﬁrms that blood pressure control by losartan or atenolol can promote regression of LVH and improve diastolic function. ARBs have consistently demonstrated an improvement in LVH regression; in fact, the greatest reduction (13%) of LV mass index in a meta-analysis on antihypertensive therapy was observed with ARBs.21 A study of hypertensive patients conﬁrmed that there is a strong association between myocardial collagen content and LV chamber stiﬀness.85 In this study, all patients were given losartan for 12 months, and endomyocardial biopsies were obtained. The authors demonstrated that losartan caused signiﬁcant regression of myocardial ﬁbrosis (reduced collagen content) and that this was associated with reduction of LV chamber stiﬀness, assessed echocardiographically. This further conﬁrms the role of angiotensin II in invoking myocardial ﬁbrosis. Diﬀering opinions exist on whether ARBs should be added to ACE inhibitors in the treatment of heart failure. Several studies of systolic heart failure, such as the Randomized Evaluation of Strategies for LV Dysfunction (RESOLVD) pilot study, the CHARM-Added trial,86 and the Valsartan in Chronic Heart Failure Trial (Val-HeFT),87 demonstrated that addition of an ARB to treatment of patients already being treated with ACE inhibitors further reduced mortality or morbidity or both in those with heart failure and depressed EF. However, there appears to be a discrepancy between the latter two trials. In Val-HeFT, 35% of patients were treated with beta blockers, and the addition of valsartan to patients treated with an ACE inhibitor and a beta blocker was associated with adverse eﬀects of morbidity and mortality. This was probably a statistical anomaly and was not observed in the CHARM-Added trial, in which 55% of patients were treated with beta blockers, and addition of candesartan was associated with a further reduced risk of cardiovascular death or heart

failure hospitalizations. Patients require careful monitoring as they tend to develop more hyperkalemia and renal dysfunction with the combined use of ACE inhibitors and ARBs, even in the absence of aldosterone antagonists. The use of concomitant ACE inhibitors and ARBs needs to be validated in patients with diastolic heart failure. In the CHARM-Preserved trial, less than 20% of patients were on ACE inhibitors, so an eﬀective analysis could not be conducted.5 A recent animal study demonstrated that addition of an ARB to an ACE inhibitor in hypertensive rats induced more regression of LVH and myocardial ﬁbrosis.88 This led to reduced myocardial stiﬀening and improved ventricular relaxation that was independent of blood pressure. Although we do not have data to suggest that ARBs provide a clear and unambiguous survival beneﬁt to patients with diastolic heart failure, we advocate their use, as they have been shown to eﬀectively lower blood pressure and reduce LVH and heart failure hospitalizations and to enhance exercise tolerance. These are all important goals in the treatment of heart failure. Additionally, like ACE inhibitors, ARBs have been shown to consistently reduce the development of new-onset diabetes mellitus, a determinant of diastolic dysfunction. The cardioprotective eﬀects of ARBs are wide in that they block the actions of angiotensin II and the RAAS, leading to improved hemodynamics, reduced LV remodeling, improved endothelial function, arterial compliance, and tone. Either an ACE inhibitor or an ARB is a reasonable treatment option for diastolic heart failure.

Aldosterone Receptor Blockers Aldosterone is released from the adrenal glands in response to angiotensin II and multiple other stimuli, including hyperkalemia. It plays an important role in promoting myocardial ﬁbrosis.11 ACE inhibitors and ARBs have only a partial eﬀect on aldosterone release inhibition, since other factors, such as serum potassium levels, catecholamines, endothelin, and corticotrophin, are not blocked. There are no current studies regarding aldosterone receptor blockers in patients with diastolic heart failure, though one is currently being planned. However, aldosterone blockers improve mortality in patients with heart failure and depressed EF, as in the case of spironolactone in the Randomized Aldactone Evaluation Study (RALES)89 and eplerenone in post-MI patients in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Eﬃcacy and Survival Study (EPHESUS).90 Based on this, it is attractive to consider aldosterone blockers to be likewise beneﬁcial in patients with heart failure and preserved EF. Although these agents are clearly appealing, we have no compelling data for their use in patients with diastolic heart failure. They require regular monitoring of serum potassium and renal function and should probably not be used in patients with serum creatinine levels greater than 2.5 mg/dL. We have little information about the combined use of ACE inhibitors, ARBs, and aldosterone receptor blockers, and this triple combination cannot be recommended until the safety record of their coadministration is established.

Calcium Channel Blockers One of the ﬁrst studies looking at treatment eﬀects in patients with diastolic heart failure utilized a CCB, verapamil.91 This study was a placebo-controlled, double-blind, 5-week crossover trial in 20 men with EFs greater than 45%, heart failure, and documented abnormal LV peak ﬁlling rates. Verapamil improved the LV peak ﬁlling rate by 30%. Furthermore, there seemed to be an improve-

423

424

Chapter 32 • General Treatment of Diastolic Heart Failure ment in the mean congestive heart failure score. The small sample size and the fact that all patients were men greatly limit the study, as diastolic heart failure is particularly prevalent in elderly women. The study was likely too brief to measure an eﬀect on LVH regression. Another study showed that verapamil was eﬀective in improving LV diastolic ﬁlling and exercise tolerance in patients with hypertrophic cardiomyopathy.92 CCBs are valuable agents that also ameliorate angina. The nondihydropyridine CCBs may be of utility in diastolic heart failure in that like beta blockers, they serve to lower the heart rate and increase ventricular diastolic ﬁlling. One must be mindful when prescribing verapamil in the elderly, as it tends to cause constipation. In animal models with diastolic heart failure, amlodipine was shown to prevent myocardial stiﬀening through amelioration of collagen remodeling.93 CCBs are highly eﬀective antihypertensive agents, and since control of high blood pressure is a major goal in the treatment of diastolic heart failure, they are widely used in this syndrome.

Digitalis The ACC/AHA practice guidelines state that the usefulness of digitalis to minimize symptoms of heart failure in patients with normal EF is not well established and is given a class IIb recommendation. The Digitalis Investigation Group (DIG) examined the eﬀect of digoxin on mortality and morbidity in patients with heart failure.94 The overall study showed that digoxin did not reduce overall mortality but did reduce the rate of overall hospitalizations, as well as hospitalizations for worsening heart failure. The main study randomized patients with EFs less than 45%; however, an ancillary trial was conducted in 988 patients with EFs greater than 45%. The results were similar to the main trial in that there was no signiﬁcant diﬀerence with respect to overall mortality. There was, however, a reduction in the combined outcome of death or hospitalization due to worsening heart failure, with a risk ratio of 0.82. The subpopulation studied in DIG may have been too small, and a false positive result may have been observed. Despite the subset ﬁndings in the DIG trial, digitalis is not widely used to treat patients with diastolic heart failure, and other agents may be more beneﬁcial.

Statins The use of statins in the last decade has been expanding, mainly because of the vast number of clinical trials that demonstrate their eﬃcacy in various disease states. The contemporary thinking is that statins have pleiotropic eﬀects that go beyond pure lipid-lowering mechanisms.95–97 In addition to their antiinﬂammatory and antioxidant properties, statins may reduce LV remodeling, increase arterial distensibility, improve endothelial function, and favorably aﬀect the neurohormonal systems.98–103 Additionally, few animal studies have shown that statins reduce or prevent LVH and ﬁbrosis.104–106 One clinical study also demonstrated that use of statins induced regression of LVH in patients with angina.107 Several retrospective analyses of large databases have observed that statins improve survival in patients with heart failure and depressed EF, irrespective of whether the heart failure is due to ischemia.108–110 Although no large prospective trials in diastolic heart failure have been performed, an observational study demonstrated that statin therapy may be associated with lower mortality in patients with diastolic heart failure.111

A retrospective analysis by Little’s group evaluated 137 patients with heart failure and a preserved EF.111 Use of statin therapy was associated with an improvement in survival, with a relative risk of death of 0.22. Interestingly, treatment with an ACE inhibitor, ARB, beta blocker, or CCB had no signiﬁcant eﬀect on survival. Propensity analysis conﬁrmed that statin therapy was indeed associated with improved survival. Nevertheless, these studies should be considered exploratory or hypothesis generating, not deﬁnitive.

FUTURE RESEARCH Diastolic heart failure is common and lethal. As the population continues to age and coronary revascularization becomes more readily available, we are seeing more patients with heart failure who have preserved EF. Clearly, it would be advantageous to have large-scale clinical trials to guide our therapy with this condition. To date, most large-scale clinical trials in patients with heart failure have focused on those with depressed EF. The largest trial of patients with heart failure and preserved EF is the CHARMPreserved trial, which indicated only a marginal beneﬁt of candesartan, probably because it was underpowered. There are several ongoing large-scale clinical trials. These include the Irbesartan in Heart Failure with Preserved EF trial (I-Preserve) and Treatment of Preserved Cardiac function heart failure with an Aldosterone antagonist (TOPCAT), a trial of spironolactone in patients with heart failure and preserved EF funded by the National Heart, Lung, and Blood Institute. However, it should be reiterated that patients with diastolic heart failure likely have fewer lethal cardiovascular endpoints and more noncardiovascular morbidity endpoints than patients with systolic heart failure. As such, trials focusing on diastolic heart failure will require large sample sizes and very long follow-ups to provide an unambiguous conclusion. Such trials may be beyond the reach of contemporary designs and costs.

SUMMARY Heart failure is one of the most common causes for elderly patients to be admitted to the hospital, and diastolic heart failure probably accounts for one half of all these patients. To date, treatment of heart failure has focused primarily on patients with a depressed EF. Although the mortality of diastolic heart failure is perhaps not as severe as systolic heart failure, it is nevertheless high and should be taken into account. In the absence of clinical trial data, we are without clear guidelines regarding eﬀective therapy. The practice guidelines provided by the ACC/AHA and HFSA serve as roadmaps of how to approach patients with diastolic heart failure but cannot recommend deﬁnitive drug treatment. As with systolic heart failure, treatment of acute symptoms of heart failure should be targeted at reducing congestion and volume overload with the aid of diuretics and possibly nitrates. Several known causes of diastolic heart failure, such as hypertension, underlying ischemia, atrial ﬁbrillation, valvular heart disease, and diabetes need to be considered, as their management may diﬀer. Every eﬀort should be made to ensure that patients are compliant with medications and that they maintain salt restriction. Up to 80% of patients with diastolic heart failure have evidence of LVH determined echocardiographically,14 and treatment of hypertension should always be a primary concern. It usually takes more than one drug to eﬀec-

Chapter 32 • General Treatment of Diastolic Heart Failure tively control blood pressure. Beta blockers may be useful to slow heart rate, prolong diastole, and allow for enhanced ventricular diastolic ﬁlling. ACE inhibitors and ARBs may be beneﬁcial, as they block the RAAS and the deleterious eﬀects of angiotensin II, which has been implicated in the pathophysology of diastolic heart failure. Even though the largest trial conducted to date, CHARM-Preserved, did not demonstrate a clear survival beneﬁt with candesartan, there was a reduction in heart failure hospitalizations; this remains a valid goal in the chronic treatment of heart failure. Just as in the treatment of hypertension and systolic heart failure, various agents with diﬀering mechanisms of action should be employed in the treatment of diastolic heart failure (see Table 32-1). It bears mentioning that the pathophysiology of diastolic heart failure is not similar to that of systolic heart failure, and new molecular mechanisms in diastolic heart failure are being uncovered.112,113 Caution should be exercised in assuming that treatment of systolic heart failure produces the same eﬀects as in diastolic heart failure. Clearly, novel agents that target the underlying molecular mechanisms in diastolic heart failure should be sought. That being said, the management of patients with diastolic heart failure is complex and not always eﬀective. Careful follow-up is warranted, and control of concomitant problems such as hypertension and diabetes mellitus is essential. In the ﬁnal analysis, prevention will prove to be the most powerful interdiction. If we can prevent hypertension and LVH, ischemic heart disease, and type II diabetes mellitus, much of what we term “diastolic heart failure” will cease to exist. REFERENCES 1. Konstam MA: “Systolic and diastolic dysfunction” in heart failure? Time for a new paradigm. J Card Fail 2003;9:1–3. 2. Eichhorn EJ, Willard JE, Alvarez L, et al: Are contraction and relaxation coupled in patients with and without congestive heart failure? Circulation 1992;85:2132–2139. 3. Burkhoﬀ D, Maurer MS, Packer M: Heart failure with a normal ejection fraction: Is it really a disorder of diastolic function? Circulation 2003;107: 656–658. 4. Maurer MS, Spevack D, Burkhoﬀ D, Kronzon I: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44:1543–1549. 5. Yusuf S, Pfeﬀer MA, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781. 5a. Cleland JG, Tendera M, Adamus J, et al: The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27(19):2338–2345. 6. Zile MR, Baicu CF, Gaasch WH: Diastolic heart failure—abnormalities in active relaxation and passive stiﬀness of the left ventricle. N Engl J Med 2004;350:1953–1959. 7. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment. Circulation 2002;105:1503–1508. 8. Zile MR, Brutsaert DL: New concepts in diastolic dysfunction and diastolic heart failure: Part I: Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387–1393. 9. Angeja BG, Grossman W: Evaluation and management of diastolic heart failure. Circulation 2003;107:659–663. 10. Aurigemma GP, Gaasch WH: Clinical practice. Diastolic heart failure. N Engl J Med 2004;351:1097–1105. 11. Little WC, Brucks S: Therapy for diastolic heart failure. Prog Cardiovasc Dis 2005;47:380–388. 12. Cody RJ: The treatment of diastolic heart failure. Cardiol Clin 2000;18:589– 596. 13. Vasan RS: Diastolic heart failure. BMJ 2003;327:1181–1182. 14. Chinnaiyan KM, Alexander D, McCullough PA: Role of angiotensin II in the evolution of diastolic heart failure. J Clin Hypertens (Greenwich) 2005;7:740–747.

15. McCullough PA, Khandelwal AK, McKinnon JE, et al: Outcomes and prognostic factors of systolic as compared with diastolic heart failure in urban America. Congest Heart Fail 2005;11:6–11. 16. Wu EB, Yu CM: Management of diastolic heart failure—a practical review of pathophysiology and treatment trial data. Int J Clin Pract 2005;59:1239– 1246. 17. Yancy CW, Lopatin M, Stevenson LW, et al: Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: A report from the Acute Decompensated Heart Failure National Registry (ADHERE) database. J Am Coll Cardiol 2006;47:76–84. 18. Hunt SA: ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46: e1–e82. 19. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail 2006;12:10–38. 20. Massie BM, Fabi MR: Clinical trials in diastolic heart failure. Prog Cardiovasc Dis 2005;47:389–395. 21. Klingbeil AU, Schneider M, Martus P, et al: A meta-analysis of the eﬀects of treatment on left ventricular mass in essential hypertension. Am J Med 2003;115:41–46. 22. Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 2002;359:995–1003. 23. Meyer TE, Kovacs SJ, Ehsani AA, et al: Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 2006;47:398–402. 24. Aroesty JM, McKay RG, Heller GV, et al: Simultaneous assessment of left ventricular systolic and diastolic dysfunction during pacing-induced ischemia. Circulation 1985;71:889–900. 25. Mandinov L, Eberli FR, Seiler C, Hess OM: Diastolic heart failure. Cardiovasc Res 2000;45:813–825. 26. Kramer K, Kirkman P, Kitzman D, Little WC: Flash pulmonary edema: Association with hypertension and reoccurrence despite coronary revascularization. Am Heart J 2000;140:451–455. 27. Liu JE, Palmieri V, Roman MJ, et al: The impact of diabetes on left ventricular ﬁlling pattern in normotensive and hypertensive adults: The Strong Heart Study. J Am Coll Cardiol 2001;37:1943–1949. 28. Aronson D: Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiﬀening of aging and diabetes. J Hypertens 2003;21: 3–12. 29. Miyazato J, Horio T, Takishita S, Kawano Y: Fasting plasma glucose is an independent determinant of left ventricular diastolic dysfunction in nondiabetic patients with treated essential hypertension. Hypertens Res 2002;25:403–409. 30. Andersson B, Svealv BG, Tang MS, Mobini R: Longitudinal myocardial contraction improves early during titration with metoprolol CR/XL in patients with heart failure. Heart 2002;87:23–28. 31. Nagano N, Nagano M, Yo Y, et al: Role of glucose intolerance in cardiac diastolic function in essential hypertension. Hypertension 1994;23(6 Pt 2):1002–1005. 32. Kamide K, Nagano M, Nakano N, et al: Insulin resistance and cardiovascular complications in patients with essential hypertension. Am J Hypertens 1996;9(12 Pt 1):1165–1171. 33. Watanabe K, Sekiya M, Tsuruoka T, et al: Eﬀect of insulin resistance on left ventricular hypertrophy and dysfunction in essential hypertension. J Hypertens 1999;17:1153–1160. 34. Felicio JS, Ferreira SR, Plavnik FL, et al: Eﬀect of blood glucose on left ventricular mass in patients with hypertension and type 2 diabetes mellitus. Am J Hypertens 2000;13:1149–1154. 35. Pitale SU, Abraira C, Emanuele NV, et al: Two years of intensive glycemic control and left ventricular function in the Veterans Aﬀairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM). Diabetes Care 2000;23:1316–1320. 36. Okin PM, Devereux RB, Gerdts E, et al: Impact of diabetes mellitus on regression of electrocardiographic left ventricular hypertrophy and the prediction of outcome during antihypertensive therapy: The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study. Circulation 2006;113:1588–1596. 37. Aronoﬀ S, Rosenblatt S, Braithwaite S, et al: Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with

425

426

Chapter 32 • General Treatment of Diastolic Heart Failure

38.

39. 40. 41. 42. 43. 44.

45. 46.

47. 48.

49.

50. 51. 52. 53. 54.

55.

56.

57. 58.

type 2 diabetes: A 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000;23: 1605–1611. Kim SK, Zhao ZS, Lee YJ, et al: Left-ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR-alpha or -gamma agonists in a type 2 diabetic animal model. Diabetes Metab Res Rev 2003;19:487– 493. Tsuji T, Mizushige K, Noma T, et al: Pioglitazone improves left ventricular diastolic function and decreases collagen accumulation in prediabetic stage of a type II diabetic rat. J Cardiovasc Pharmacol 2001;38:868–874. Tao L, Liu HR, Gao E, et al: Antioxidative, antinitrative, and vasculoprotective eﬀects of a peroxisome proliferator-activated receptor–gamma agonist in hypercholesterolemia. Circulation 2003;108:2805–2811. Pistrosch F, Passauer J, Fischer S, et al: In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control. Diabetes Care 2004;27:484–490. Hetzel J, Balletshofer B, Rittig K, et al: Rapid eﬀects of rosiglitazone treatment on endothelial function and inﬂammatory biomarkers. Arterioscler Thromb Vasc Biol 2005;25:1804–1809. Boulanger CM: Secondary endothelial dysfunction: Hypertension and heart failure. J Mol Cell Cardiol 1999;31:39–49. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997. Wright JT Jr, Dunn JK, Cutler JA, et al: Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA 2005;293:1595–1608. Weir MR, Gray JM, Paster R, Saunders E: Diﬀering mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. The Trandolapril Multicenter Study Group. Hypertension 1995;26:124–130. Waagstein F, Bristow MR, Swedberg K, et al: Beneﬁcial eﬀects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993;342:1441–1446. Hjalmarson A, Goldstein S, Fagerberg B, et al: Eﬀects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000;283:1295–1302. Packer M, Fowler MB, Roecker EB, et al: Eﬀect of carvedilol on the morbidity of patients with severe chronic heart failure: Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. Circulation 2002;106:2194–2199. The Cardiac Insuﬃciency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999;353:9–13. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801– 807. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. The MIAMI Trial Research Group. Eur Heart J 1985;6:199–226. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet 1986;2:57–66. Halkin A, Grines CL, Cox DA, et al: Impact of intravenous beta-blockade before primary angioplasty on survival in patients undergoing mechanical reperfusion therapy for acute myocardial infarction. J Am Coll Cardiol 2004;43:1780–1787. Aronow WS, Ahn C, Kronzon I: Eﬀect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction > or = 40% treated with diuretics plus angiotensinconverting enzyme inhibitors. Am J Cardiol 1997;80:207–209. Flather MD, Shibata MC, Coats AJ, et al: Randomized trial to determine the eﬀect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215– 225. Capomolla S, Febo O, Gnemmi M, et al: Beta-blockade therapy in chronic heart failure: Diastolic function and mitral regurgitation improvement by carvedilol. Am Heart J 2000;139:596–608. Bergstrom A, Andersson B, Edner M, et al: Eﬀect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail 2004;6:453–461.

59. Eﬀect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293–302. 60. Eﬀects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429–1435. 61. Pfeﬀer MA, Braunwald E, Moye LA, et al: Eﬀect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival And Ventricular Enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669–677. 62. Fox KM. Eﬃcacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362:782–788. 63. Yusuf S, Sleight P, Pogue J, et al: Eﬀects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–153. 64. Hayashida W, Van Eyll C, Rousseau MF, Pouleur H: Regional remodeling and nonuniform changes in diastolic function in patients with left ventricular dysfunction: Modiﬁcation by long-term enalapril treatment. The SOLVD Investigators. J Am Coll Cardiol 1993;22:1403–1410. 65. Philbin EF, Rocco TA Jr, Lindenmuth NW, et al: Systolic versus diastolic heart failure in community practice: Clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors. Am J Med 2000;109:605– 613. 66. Grigorian Shamagian L, Roman AV, Ramos PM, et al: Angiotensin-converting enzyme inhibitors prescription is associated with longer survival among patients hospitalized for congestive heart failure who have preserved systolic function: A long-term follow-up study. J Card Fail 2006;12:128– 133. 67. Cleland JG, Tendera M, Adamus J, et al: Perindopril for elderly people with chronic heart failure: The PEP-CHF study. The PEP investigators. Eur J Heart Fail 1999;1:211–217. 68. Aronow WS, Kronzon I. Eﬀect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993;71:602– 604. 69. Terpstra WF, May JF, Smit AJ, et al: Long–term eﬀects of amlodipine and lisinopril on left ventricular mass and diastolic function in elderly, previously untreated hypertensive patients: the ELVERA trial. J Hypertens 2001;19: 303–309. 70. Manes MT, Gagliardi M, Misuraca G, et al: Left ventricular geometric patterns and cardiac function in patients with chronic renal failure undergoing hemodialysis. Monaldi Arch Chest Dis 2005;64:27–32. 71. Roux E, Pieri B, Bergeri I, et al: Precipitating factors associated with diastolic heart failure in the elderly. Ann Cardiol Angeiol (Paris) 2003;52:308– 312. 72. Mitsnefes MM, Kimball TR, Border WL, et al: Impaired left ventricular diastolic function in children with chronic renal failure. Kidney Int 2004;65:1461–1456. 73. Dyadyk AI, Bagriy AE, Lebed IA, et al: ACE inhibitors captopril and enalapril induce regression of left ventricular hypertrophy in hypertensive patients with chronic renal failure. Nephrol Dial Transplant 1997;12:945– 951. 74. Oguzhan A, Arinc H, Abaci A, et al: Preload dependence of Doppler tissue imaging derived indexes of left ventricular diastolic function. Echocardiography 2005;22:320–325. 75. Hung KC, Huang HL, Chu CM, et al: Evaluating preload dependence of a novel Doppler application in assessment of left ventricular diastolic function during hemodialysis. Am J Kidney Dis 2004;43:1040–1046. 76. Fatema K, Hirono O, Takeishi Y, et al: Hemodialysis improves myocardial interstitial edema and left ventricular diastolic function in patients with end-stage renal disease: Noninvasive assessment by ultrasonic tissue characterization. Heart Vessels 2002;16:227–231. 77. Chakko S, Girgis I, Contreras G, et al: Eﬀects of hemodialysis on left ventricular diastolic ﬁlling. Am J Cardiol 1997;79:106–108. 78. Exner DV, Dries DL, Domanski MJ, Cohn JN: Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001;344: 1351–1357. 79. Shekelle PG, Rich MW, Morton SC, et al: Eﬃcacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: A

Chapter 32 • General Treatment of Diastolic Heart Failure

80. 81.

82.

83. 84.

85.

86.

87. 88. 89.

90. 91.

92.

93. 94.

meta-analysis of major clinical trials. J Am Coll Cardiol 2003;41:1529– 1538. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C: Trandolapril reduces the incidence of atrial ﬁbrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999;100:376–380. Vermes E, Ducharme A, Bourassa MG, et al: Enalapril reduces the incidence of diabetes in patients with chronic heart failure: Insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003;107: 1291–1296. Vermes E, Tardif JC, Bourassa MG, et al: Enalapril decreases the incidence of atrial ﬁbrillation in patients with left ventricular dysfunction: Insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation 2003;107:2926–2931. Warner JG Jr, Metzger DC, Kitzman DW, et al: Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–1572. Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular ﬁlling after one year of antihypertensive treatment: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071–1076. Diez J, Querejeta R, Lopez B, et al: Losartan-dependent regression of myocardial ﬁbrosis is associated with reduction of left ventricular chamber stiﬀness in hypertensive patients. Circulation 2002;105:2512– 2517. McMurray JJ, Ostergren J, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARMAdded trial. Lancet 2003;362:767–771. Cohn JN, Tognoni G: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667– 1675. Yoshida J, Yamamoto K, Mano T, et al: AT1 receptor blocker added to ACE inhibitor provides beneﬁts at advanced stage of hypertensive diastolic heart failure. Hypertension 2004;43:686–691. Pitt B, Zannad F, Remme WJ, et al: The eﬀect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709– 717. Pitt B, Remme W, Zannad F, et al: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–1321. Setaro JF, Zaret BL, Schulman DS, et al: Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic ﬁlling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981– 986. Bonow RO, Dilsizian V, Rosing DR, et al: Verapamil-induced improvement in left ventricular diastolic ﬁlling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term eﬀects. Circulation 1985;72:853–864. Nishikawa N, Masuyama T, Yamamoto K, et al: Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats. J Am Coll Cardiol 2001;38:1539–1545. The eﬀect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525– 533.

95. Nissen SE. High–dose statins in acute coronary syndromes: not just lipid levels. Jama 2004;292:1365–1367. 96. Zile MR. Treating diastolic heart failure with statins: “phat” chance for pleiotropic beneﬁts. Circulation 2005;112:300–303. 97. Davignon J: Beneﬁcial cardiovascular pleiotropic eﬀects of statins. Circulation 2004;109(23 Suppl 1):III39–III43. 98. Treasure CB, Klein JL, Weintraub WS, et al: Beneﬁcial eﬀects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481–487. 99. Ridker PM, Rifai N, Pfeﬀer MA, et al: Long-term eﬀects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230–235. 100. Plenge JK, Hernandez TL, Weil KM, et al: Simvastatin lowers C-reactive protein within 14 days: An eﬀect independent of low-density lipoprotein cholesterol reduction. Circulation 2002;106:1447–1452. 101. Egashira K, Hirooka Y, Kai H, et al: Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994;89:2519–2524. 102. Ferrier KE, Muhlmann MH, Baguet JP, et al: Intensive cholesterol reduction lowers blood pressure and large artery stiﬀness in isolated systolic hypertension. J Am Coll Cardiol 2002;39:1020–1025. 103. Hayashidani S, Tsutsui H, Shiomi T, et al: Fluvastatin, a 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2002;105:868–873. 104. Patel R, Nagueh SF, Tsybouleva N, et al: Simvastatin induces regression of cardiac hypertrophy and ﬁbrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2001;104:317–324. 105. Indolﬁ C, Di Lorenzo E, Perrino C, et al: Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation. Circulation 2002;106:2118–2124. 106. Oi S, Haneda T, Osaki J, et al: Lovastatin prevents angiotensin II–induced cardiac hypertrophy in cultured neonatal rat heart cells. Eur J Pharmacol 1999;376:139–148. 107. Nishikawa H, Miura S, Zhang B, et al: Statins induce the regression of left ventricular mass in patients with angina. Circ J 2004;68:121–125. 108. Folkeringa RJ, Van Kraaij DJ, Tieleman RG, et al: Statins associated with reduced mortality in patients admitted for congestive heart failure. J Card Fail 2006;12:134–138. 109. Horwich TB, MacLellan WR, Fonarow GC: Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol 2004;43:642–648. 110. Mozaﬀarian D, Nye R, Levy WC: Statin therapy is associated with lower mortality among patients with severe heart failure. Am J Cardiol 2004;93:1124–1129. 111. Fukuta H, Sane DC, Brucks S, Little WC: Statin therapy may be associated with lower mortality in patients with diastolic heart failure: A preliminary report. Circulation 2005;112:357–363. 112. van Heerebeek L, Borbely A, Niessen HW, et al: Myocardial structure and function diﬀer in systolic and diastolic heart failure. Circulation 2006;113:1966–1973. 113. Katz AM, Zile MR: New molecular mechanism in diastolic heart failure. Circulation 2006;113:1922–1925.

427

STEVEN J. LESTER, MD A. JAMIL TAJIK, MD

33

Echo-Based Approach to the Management of Diastolic Heart Failure INTRODUCTION PATHOPHYSIOLOGY CLINICAL RELEVANCE Primary Prevention of Diastolic Dysfunction Secondary Prevention and Treatment of Diastolic Heart Failure FUTURE DIRECTIONS

INTRODUCTION Heart failure is a clinical syndrome of signs and symptoms resulting from cessation of normal heart function whereby the heart is not able to pump enough blood to meet the body’s energy demands. Hence, heart failure is not a speciﬁc disease entity; instead, the development of heart failure represents the ﬁnal common pathway of any and all forms of cardiovascular disease. The diagnosis of heart failure is incomplete without assignment of a speciﬁc etiology. The components of the cardiac cycle provide an intellectual framework for the appropriation of the breakdown in heart function. As a result, terms such as “diastolic heart failure” or heart failure in the setting of “normal systolic function” have crept into the medical nomenclature. Although it is practical to classify heart failure patients as those with either normal or abnormal systolic function, such a classiﬁcation is based on physiologic principles destitute of virtue. Each component of the cardiac cycle is functionally dependent on the other. Unlike two-dimensional (2D) echocardiography, where crude parameters of cardiac performance such as ejection fraction are used, Doppler echocardiography is able to detect and quantitatively display minor amplitude and temporal subtleties that may occur in ventricular mechanical function. Traditionally, parameters of diastolic function have been derived from Doppler, and

those of systolic function from 2D variables. This may create the illusion that individuals with heart failure have “normal systolic function.” The interrogation of cardiac function with derived parameters of deformation such as strain and strain rate conﬁrm the illusion despite frequent pronouncements and mutual citation. Despite its incipient limitations, for the purpose of further discussion the term diastolic heart failure (DHF) will be used in this chapter to refer to the syndrome of heart failure in the setting of normal ejection fraction. Individuals with heart failure, whether associated with a normal or a reduced ejection fraction, may be equally disabled and have a similarly poor prognosis.1–3 In individuals with heart failure, independent of etiology, the New York Heart Association (NYHA) functional classiﬁcation is useful in deﬁning prognosis and monitoring response to treatment. Similarly, a comprehensive evaluation and staging of diastolic function, independent of disease, is useful in deﬁning prognosis, monitoring response to treatment, and developing new treatment strategies.4–10 Diagnosis and staging of diastolic dysfunction provide a framework for the approach to management of individuals with DHF (see Chapter 10). The echocardiogram is a powerful tool enabling the clinician to noninvasively obtain parameters of ﬂow, pressure, and resistance and thus evaluate intracardiac hemodynamics inﬂuenced by ailments in the diastolic phase of the cardiac cycle.

PATHOPHYSIOLOGY The mitral valve is the door that when opened exposes the left atrium to the hemodynamic elements of the left ventricle. Prolonged exposure to elevated ﬁlling pressure results in structural remodeling of the left atrium. Therefore, the comprehensive evaluation of diastolic function should begin with a measure of left atrial (LA) size. The anteroposterior dimension of the left atrium obtained by M-mode echocardiography was initially the 429

430

Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure only available method to determine LA size. However, for this unidimensional measurement to accurately represent the true LA size, it must be assumed that it bears a consistent relation to other LA dimensions. This assumption is not accurate, and thus LA size should be represented by a volume-based method of evaluation.11,12 As diastolic function is staged from mild to moderate to severe, so will there be mild, moderate, and severe increases in LA volume in the absence of atrial arrhythmias or valvular heart disease. LA volume may therefore be considered the “morphophysiologic” expression of left ventricular (LV) diastolic function.13 LA volume reﬂects the cumulative eﬀect of exposure to increased LV ﬁlling pressure over time. An increase in LA volume has profound clinical implications. LA volume has been found to be a robust predictor of cardiovascular outcomes, not the least of which is an increased risk for the development of heart failure.14–17

CLINICAL RELEVANCE Primary Prevention of Diastolic Dysfunction Identiﬁcation of risk and intervention prior to overt disease is essentially the ﬁrst therapeutic target for all disease and no less our ﬁrst strategy in the management of DHF. The age distribution of DHF incidence is skewed toward the elderly, and in individuals over 70 years of age the incidence of DHF exceeds that of heart failure with reduced ejection fraction.1 A primary prevention strategy becomes even more germane as society is faced with a burgeoning elderly population creating a social and health care economic crisis. Echocardiography, with its ability to reliably and reproducibly measure LA volume, provides a window of opportunity to identify individuals at risk for DHF and potentially provide therapeutic intervention. The intervention for prevention is based on little clinical trial data and requires the art of medicine to intervene. DHF is a pathophysiologic manifestation of a heterogeneous group of diseases. Common underlying etiologies of DHF include hypertension, ischemic and diabetic heart disease, metabolic syndrome, and obesity. Less common but important considerations are diagnoses of valvular heart disease, inﬁltrative and storage diseases, hypertrophic cardiomyopathy, pericardial disease, and other restrictive cardiomyopathies. Another very important but underappreciated etiology for DHF is sleep apnea. Ventriculararterial stiﬀening contributes importantly to the development of DHF. Precipitating factors (acute decompensation) of DHF may include sudden elevation in blood pressure, tachycardia (commonly atrial ﬁbrillation with an uncontrolled ventricular response), acute ischemia, renal failure, anemia, the institution of nonsteroidal antiinﬂammatory medication, and other factors, such as excessive salt load that may increase intravascular volume. Early identiﬁcation and aggressive targeted treatment of underlying eti-

Normal

Abnormal relaxation

Pseudorestrictive normalization (reversible)

ologies and potential precipitating conditions, as mentioned above, must be the goal of short- and long-term management strategies. Neurohormonal modulation of the renin-angiotensinaldosterone system (RAAS) has a proven salutary eﬀect on each of the above-mentioned conditions.18–33 Angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin I receptor antagonists (ARBs), and aldosterone receptor antagonists (ARAs), independently of their hemodynamic eﬀect, mediate potentially favorable eﬀects of reduced smooth muscle cell growth, prevention of collagen deposition, and reduced growth factor expression.34–37 Statins have touted similar pleiotropic eﬀects.38,39 Intellectually intriguing is the low threshold to the use of statins and consideration of therapy targeting the RAAS in individuals with an increased LA volume and/or a subclinical history of coronary disease (positive coronary artery calciﬁcation score by computed tomography or increased carotid intima-media thickness) or prediabetes in an eﬀort to prevent eventual development of DHF. Limited data in patients with hypertension suggest that favorable remodeling of the left atrium can be inﬂuenced.40 ACEIs may also result in favorable remodeling of the left atrium (the morphophysiologic expression of diastolic function) independently of their inﬂuence on blood pressure.41 Opportunities exist for these hypotheses to be tested in clinical trials (see Chapters 32 and 34). Until furnished with data, deﬁnitive therapeutic recommendations are null, and potential therapeutic approaches are based on prophecy.

Secondary Prevention and Treatment of Diastolic Heart Failure In individuals with DHF, the question is generally not what the cumulative eﬀect of ﬁlling pressure over time has been, but rather what the ﬁlling pressures at the instant in time of the evaluation are. The echocardiogram reliably provides us with this information through the integration of data obtained from blood ﬂow velocities with those of wall motion analysis. This integrative evaluation also allows for staging of disease severity (Fig. 33-1) (see Chapter 10). Here the evaluation often begins with measures of the mitral inﬂow velocity proﬁle (Fig. 33-2). Annular excursion interrogated generally with Doppler tissue imaging techniques provides an evaluation of wall motion (Fig. 33-3). Notwithstanding constrictive pericarditis, ubiquitous to individuals with diastolic dysfunction is a relaxation abnormality of the left ventricle. This is characterized by a low early mitral inﬂow velocity (E) and E/A ratio (A = the atrial component of mitral inﬂow), with a prolonged deceleration time and a low early mitral annular velocity (E′). With progression to more severe diastolic dysfunction, the association of reduced LV compliance with increased LA pressure will result in an increase in the E velocity and E/A ratio

Restrictive (irreversible)

Mean LAP Normal

↑

↑↑

↑↑↑

↑↑↑

Grade of diastolic dysfunction

I

II

III

IV

Figure 33-1 Natural history of diastolic dysfunction. Wave form represents the mitral inflow velocity profile. A “restrictive (reversible)” condition would represent a conformational change in the mitral inflow velocity profile during the strain phase of the Valsalva maneuver from III to I. LAP, left atrial pressure.

Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure E vel = 90cm/sec A vel = 40cm/sec E/A = 2.2 DT = 222msec

E

A

Figure 33-2 Mitral inflow velocity profile with the pulsed wave sample volume placed at the mitral leaflet tips. E, early rapid filling wave; A, late filling wave due to atrial contraction; DT, deceleration time, the time interval from the peak of the E velocity to its extrapolation to baseline.

A¢ E¢

Figure 33-3 Septal annular Doppler tissue image. E′, early diastolic annular velocity (away from the apex or transducer); A′, late diastolic annular velocity secondary to atrial contraction.

and a reduction in deceleration time. The mitral blood ﬂow velocity proﬁle may now appear normal. However, the E′ velocity will remain reduced, identifying the underlying LV relaxation abnormality. The E/E′ ratio can therefore be used to discriminate an individual with normal versus grade II diastolic dysfunction. Similarly, individuals with a restrictive mitral inﬂow pattern, E/A greater than 2, and deceleration time less than 150 msec who are able to favorably inﬂuence the mitral inﬂow velocity proﬁle with hemodynamic manipulation (often the Valsalva maneuver) declare themselves of less severe diastolic dysfunction than those with an irreversible restrictive pattern. The former are designated with grade III diastolic dysfunction and the latter are designated with grade IV. Beyond the scope of this chapter but worthy of note is that the evaluation of the pulmonary venous blood ﬂow velocity proﬁle, the mitral inﬂow ﬂow propagation

velocity, and a measure of the isovolumic relaxation time may also be helpful in the evaluation and staging of diastolic dysfunction. The absence of clinical trial data makes treatment of DHF largely empirical and generally based on therapeutic strategies thought to favorably target the underlying causative etiologies and precipitating factors. As the etiologic classiﬁcation of individuals with DHF is varied, so are recommended treatment strategies. For example, the need to individualize the therapeutic approach to DHF is highlighted by judicious blood pressure control in hypertensive patients, anti-ischemic therapy (pharmacologic and/ or revascularization) in patients with ischemic heart disease, treatment of sleep apnea, deﬁnitive management of valvular heart disease, gradient reduction therapy in individuals with hypertrophic cardiomyopathy, surgical treatment of constrictive pericarditis, control of ventricular rate, restoration and maintenance of sinus rhythm in individuals with atrial ﬁbrillation, and appropriate targeted therapies for disorders such as hemachromatosis, Fabry’s disease, and amyloidosis. As one cannot categorize individuals with DHF into a homogeneous etiologic classiﬁcation, should one create a simple unifying treatment strategy? This is a consideration often overlooked in the design of heart failure trials. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved) trial, a prospective outcome trial evaluating a treatment strategy (candesartan) solely for individuals with DHF, included a heterogeneous etiologic classiﬁcation of DHF.42 The ﬁndings, however, were promising, showing a signiﬁcant reduction in hospitalization for heart failure and a strong trend toward signiﬁcance in the primary outcome of death or hospital admission for heart failure. We await the results of the Irbesartan in Heart Failure with Preserved Systolic Function (I-Preserve) trial, in which inclusion deﬁned a more discriminate patient population.43 A number of small studies have evaluated the eﬃcacy of ACEIs, ARBs, beta blockers, digoxin, and calcium channel blockers in the management of patients with DHF. These studies have yielded dichotomous outcomes and little conclusive insight into deﬁnitive treatment strategies. The echocardiographic staging of diastolic dysfunction (see Fig. 33-1) may provide a useful guide for therapeutic intervention. Congestive symptoms can often be ameliorated with the judicious use of venodilators and diuretics. Medications that modify atrioventricular (AV) nodes can be used to slow heart rate and increase the diastolic ﬁlling time. Additional neurohormonal modulation is intellectually intriguing. Treatment may be tailored to a deﬁned success of a reduction in diastolic dysfunction grade and NYHA functional class. Individuals with grade 1 diastolic dysfunction are generally asymptomatic at rest but may complain of dyspnea on mild exertion. In the normal heart, as heart rate increases, there is an increase in contractility and faster relaxation. In myocardial disease, there is incomplete restitution, less LV pressure decline, reduced coronary ﬂow reserve, and thus higher LV diastolic pressure (Fig. 33-4). For these individuals, the duration of diastole is critical, and beta blockers or rate-slowing calcium channel blockers often provide a favorable symptomatic response. In Figure 33-5, intracardiac hemodynamics are favorably inﬂuenced with diuresis, and better blood pressure control is characterized echocardiographically by a change to a grade I mitral inﬂow velocity proﬁle and reduced E/E′ ratio. The persistent and unchanged reduced E′ velocity suggests that myocardial mechanical properties are in fact unaltered, but with hemodynamic manipulation a more favorable position of the end diastolic pressure-volume rela-

431

Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure 50

W

40 LV pressure (mmHg)

432

Normal B

30

20

10

0 0

50

100

150

200

250

LV end diastolic volume (ml) Figure 33-4 Top, unfavorable mitral inflow velocity profile with fusion of the mitral E and A waves. Bottom, with heart rate slowing there is now a more favorable mitral inflow velocity profile.

E=1.4m/sec

E¢=.04m/sec

E/E¢=35

e¢

E=.40m/sec

E¢=.04m/sec

E/E¢=10

e¢ Figure 33-5 Top two images, before treatment; and bottom two images, posttreatment. Following treatment, there has been a conformational change in the mitral inflow velocity profile to a grade 1 pattern and a marked reduction in the E/E′ ratio. Note that before and after treatment, the E′ velocity remains unchanged and significantly depressed.

tionship has been achieved. In patients with grade 3 or 4 diastolic dysfunction, LV ﬁlling may be complete in middiastole. Such patients have a ﬁxed stroke volume, and empirically slowing the heart rate to between 50 and 70 bpm may result in a further reduction in cardiac output and a worsening of the clinical symptom complex. Therefore, in these patients, the initiation of beta blocker therapy should be monitored closely and done with small doses.

FUTURE DIRECTIONS It must be emphasized that heart failure is not a diagnosis but rather a constellation of signs and symptoms representing a ﬁnal common pathway of a heterogeneous group of diseases.10 The

Figure 33-6 The left ventricular (LV) end diastolic pressure-volume relationship (EDPVR). W, worsening of the EDPVR; B, better EDPVR. (Modified from Maurer MS et al: Diastolic dysfunction: Can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol 2004;44:1543–1549.)

diagnosis of heart failure must not be made without appropriation of the underlying etiology and precipitant cause. This is the fundamental limitation of many heart failure trials, where patient inclusion is granted based on signs and symptoms of heart failure and either an ejection fraction of greater than 40%–45% or less than 35%–40% without consideration of an underlying causative mechanism. This limits the external validity of much of the published literature deﬁning management of patients with heart failure. The need for more rigid criteria deﬁning study populations for heart failure trials is needed, and as we embark on deﬁning therapeutic strategies for DHF, this consideration is paramount. In clinical medicine there are fundamentally only two therapeutic targets; improvement in symptoms and quality of life and improvement in survival. The salutary eﬀects on symptoms as a result of strategies that merely alter loading conditions (see Figs. 33-4 and 33-5) do not directly inﬂuence the diastolic properties of the myocardium but rather direct the myocardium to a more favorable position on the end diastolic pressure-volume curve. A true change in diastolic function is characterized by a rightward/ downward shift in the end diastolic pressure-volume relationship (Fig. 33-6). Either a more favorable position on a deﬁned end diastolic pressure-volume curve or a true change in the end diastolic pressure-volume relationship will result in improvement in symptoms. It is diﬃcult, however, to conceptualize how survival may be aﬀected without a true change in myocardial performance. Therefore, as treatment strategies evolve for DHF, endpoints need to include not only symptoms but also the inﬂuence on myocardial mechanics. Echocardiography is evolving novel mechanisms with which to evaluate subtle changes in myocardial performance. The paradigm of myocardial motion is shifting from simple unidirectional comments of longitudinal, circumferential, or radial motion to those of rotation, twist, and torsion, which better reﬂect the complexity of myocardial mechanics (see Chapter 12). Along with standard Doppler techniques, this may prove echocardiography to be an even more important tool in the evaluation of new treatment strategies. The heart is not a pump that works in isolation. The heart has an intimate relationship with the arterial vasculature (see Chapters 7 and 31). Increases in vascular and ventricular stiﬀness

Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure along with DHF appear to be associated with the privilege of aging.44 Vascular stiﬀness results in an increase in pulse pressure. The decrease in diastolic pressure may decrease coronary blood ﬂow, incite microvascular abnormalities, and begin a cascade resulting in abnormal diastolic function.45 Insight into these mechanisms may inﬂuence novel therapeutic strategies targeting the vasculature with endpoints of stiﬀness and central aortic pressure. Preliminary strategies focused in this direction hold promise.46 REFERENCES 1. Senni M, Tribouilloy CM, Rodeheﬀer RJ, et al: Congestive heart failure in the community: A study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–2289. 2. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355: 251–259. 3. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355: 260–269. 4. Wang M, Yip G, Yu CM, et al: Independent and incremental prognostic value of early mitral annulus velocity in patients with impaired left ventricular systolic function. J Am Coll Cardiol 2005;45:272–277. 5. Dokainish H, Zoghbi WA, Lakkis NM, et al: Incremental predictive power of B-type natriuretic peptide and tissue Doppler echocardiography in the prognosis of patients with congestive heart failure. J Am Coll Cardiol 2005;45:1223–1236. 6. Bruch C, Gotzmann M, Stypmann J, et al: Electrocardiography and Doppler echocardiography for risk stratiﬁcation in patients with chronic heart failure: Incremental prognostic value of QRS duration and a restrictive mitral ﬁlling pattern. J Am Coll Cardiol 2005;45:1072–1075. 7. Pozzoli M, Traversi E, Cioﬃ G, et al: Loading manipulations improve the prognostic value of Doppler evaluation of mitral ﬂow in patients with chronic heart failure. Circulation 1997;95:1222–1230. 8. Temporelli PL, Corra U, Imparato A, et al: Reversible restrictive left ventricular diastolic ﬁlling with optimized oral therapy predicts a more favorable prognosis in patients with chronic heart failure. J Am Coll Cardiol 1998;31:1591–1597. 9. Nishimura RA, Tajik AJ: Evaluation of diastolic ﬁlling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. 10. Tajik AJ: Guest lecture in full: New horizons in the management of cardiovascular disease. Heart Views 2004;5:135–144. 11. Lester SJ, Ryan EW, Schiller NB, et al: Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol 1999;84:829– 832. 12. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantiﬁcation: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantiﬁcation Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463. 13. Tsang TS, Barnes ME, Gersh BJ, et al: Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284–1289. 14. Abhayaratna WP, Seward JB, Appleton CP, et al: Left atrial size: Physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47: 2357–2363. 15. Miyasaka Y, Barnes ME, Gersh BJ, et al: Incidence and mortality risk of congestive heart failure in atrial ﬁbrillation patients: A community-based study over two decades. Eur Heart J 2006;27:936–941. 16. Takemoto Y, Barnes ME, Seward JB, et al: Usefulness of left atrial volume in predicting ﬁrst congestive heart failure in patients > or = 65 years of age with well-preserved left ventricular systolic function. Am J Cardiol 2005;96:832–836. 17. Tsang TS, Barnes ME, Gersh BJ, et al: Prediction of risk for ﬁrst age-related cardiovascular events in an elderly population: The incremental value of echocardiography. J Am Coll Cardiol 2003;42:1199–205. 18. Silver MA, Peacock WF 4th, Diercks DB: Optimizing treatment and outcomes in acute heart failure: Beyond initial triage. Congest Heart Fail 2006;12:137–145. 19. Touyz RM: Highlights and summary of the 2006 Canadian Hypertension Education Program recommendations. Can J Cardiol 2006;22:565–571.

20. Tsouli SG, Liberopoulos EN, Kiortsis DN, et al: Combined treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: A review of the current evidence. J Cardiovasc Pharmacol Ther 2006;11:1–15. 21. Pitt B, Fonarow GC, Gheorghiade M, et al: Improving outcomes in post– acute myocardial infarction heart failure: Incorporation of aldosterone blockade into combination therapy to optimize neurohormonal blockade. Am J Cardiol 2006;97:26F–33F. 22. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, et al: Angiotensinconverting enzyme inhibitors in coronary artery disease and preserved left ventricular systolic function: A systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol 2006;47:1576– 1583. 23. Danchin N, Cucherat M, Thuillez C, et al: Angiotensin-converting enzyme inhibitors in patients with coronary artery disease and absence of heart failure or left ventricular systolic dysfunction: An overview of longterm randomized controlled trials. Arch Intern Med 2006;166:787– 796. 24. Ostergren JB: Angiotensin receptor blockade with candesartan in heart failure: Findings from the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) programme. J Hypertens 2006;24(Suppl):S3–S7. 25. Pitt B, Rajagopalan S: Aldosterone receptor antagonists for heart failure: Current status, future indications. Cleve Clin J Med 2006;73:257–260, 264–268. 26. McMurray J, Solomon S, Pieper K, et al: The eﬀect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: An analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). J Am Coll Cardiol 2006;47:726–733. 27. Mann JF: Cardiovascular risk in patients with mild renal insuﬃciency: Implications for the use of ACE inhibitors. Presse Med 2005;34:1303–1308. 28. Bosch J, Lonn E, Pogue J, et al: Long-term eﬀects of ramipril on cardiovascular events and on diabetes: Results of the HOPE study extension. Circulation 2005;112:1339–1346. 29. Gerstein HC, Pogue J, Mann JF, et al: The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE study: A prospective epidemiological analysis. Diabetologia 2005;48:1749–1755. 30. Mann JF, Gerstein HC, Pogue J, et al: Cardiovascular risk in patients with early renal insuﬃciency: Implications for the use of ACE inhibitors. Am J Cardiovasc Drugs 2002;2:157–162. 31. Fuller JA: Combine EUROPA and HOPE. Lancet 2003;362:1937. 32. Mann JF, Gerstein HC, Yi QL, et al: Progression of renal insuﬃciency in type 2 diabetes with and without microalbuminuria: Results of the Heart Outcomes and Prevention Evaluation (HOPE) randomized study. Am J Kidney Dis 2003;42:936–942. 33. Arnold JM, Yusuf S, Young J, et al: Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation 2003;107:1284–1290. 34. Brilla CG, Funck RC, Rupp H: Lisinopril-mediated regression of myocardial ﬁbrosis in patients with hypertensive heart disease. Circulation 2000;102:1388–1393. 35. Brilla CG: Aldosterone and myocardial ﬁbrosis in heart failure. Herz 2000;25:299–306. 36. Peng H, Carretero OA, Vuljaj N, et al: Angiotensin-converting enzyme inhibitors: A new mechanism of action. Circulation 2005;112:2436– 2445. 37. Kumar A, Meyerrose G, Sood V, et al: Diastolic heart failure in the elderly and the potential role of aldosterone antagonists. Drugs Aging 2006;23:299–308. 38. Ito MK, Talbert RL, Tsimikas S: Statin-associated pleiotropy: Possible beneﬁcial eﬀects beyond cholesterol reduction. Pharmacotherapy 2006;26:85S–97S. 39. Zile MR: Treating diastolic heart failure with statins: “Phat” chance for pleiotropic beneﬁts. Circulation 2005;112:300–303. 40. Mottram PM, Haluska B, Leano R, et al: Eﬀect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558–565. 41. Tsang TS, Barnes ME, Abhayaratna WP, et al: Eﬀects of quinapril on left atrial structural remodeling and arterial stiﬀness. Am J Cardiol 2006; 97:916–920. 42. Yusuf S, Pfeﬀer MA, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777–781.

433

434

Chapter 33 • Echo-Based Approach to the Management of Diastolic Heart Failure 43. Carson P, Massie BM, McKelvie R, et al: The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial: Rationale and design. J Card Fail 2005;11:576–85. 44. Redﬁeld MM, Jacobsen SJ, Borlaug BA, et al: Age- and gender-related ventricular-vascular stiﬀening: A community-based study. Circulation 2005;112:2254–2262.

45. Schwartzkopﬀ B, Motz W, Frenzel H, et al: Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension. Circulation 1993;88:993–1003. 46. Little WC, Zile MR, Kitzman DW, et al: The eﬀect of alagebrium chloride (ALT–711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191–195.

34

W. H. WILSON TANG, MD

Future Therapies in Diastolic Heart Failure INTRODUCTION

PATHOPHYSIOLOGY AND CLINICAL RELEVANCE

PATHOPHYSIOLOGY AND CLINICAL RELEVANCE Targeting Extrinsic Factors: Antagonizing Neurohormonal Upregulation Targeting Intracellular Intrinsic Factors: Metabolic Modulation Targeting Extracellular Intrinsic Factors: Inhibiting Collagen, Crosslinks, and Matrix Deposition Novel Device Therapies

Targeting Extrinsic Factors: Antagonizing Neurohormonal Upregulation

FUTURE RESEARCH

INTRODUCTION The treatment of diastolic heart failure (also known as “heart failure with preserved systolic function”) has been challenging, partly because there is a lack of consensus regarding the deﬁnition of the disease entity, as well as a paucity of large-scale clinical trials to demonstrate eﬀective therapeutic strategies.1 Diastolic and systolic heart failure may have certain similar pathophysiologic processes in common, but there are also distinct diﬀerences in myocardial structure and function.2 Most treatment strategies for diastolic heart failure strive to alleviate signs and symptoms or prevent exacerbating factors, rather than alter the underlying pathophysiologic abnormalities (such as improving active relaxation or reducing passive stiﬀness). Several lines of new investigations have identiﬁed regression of left ventricular (LV) hypertrophy as a potential target of therapy, while others hope to improve outcomes in patients with features of diastolic heart failure via novel targets. Some of these drugs have already been approved for other indications, and improvement in diastolic dysfunction is considered an ancillary property that may have potential for further clinical development. This chapter summarizes the ongoing eﬀorts to develop future therapies targeting extrinsic or intrinsic factors in diastolic heart failure.

It has been postulated that neurohormonal upregulation in the heart failure syndrome is a nonspeciﬁc homeostatic response to adverse hemodynamic perturbations in both preserved and impaired systolic function.3 Although current guidelines have recognized the potential beneﬁt of angiotensin-converting-enzyme (ACE) inhibitors and aldosterone receptor blockers in the treatment of diastolic heart failure,4 outcome trials are still ongoing. The modest beneﬁts of add-on aldosterone receptor blockers to ACE inhibitors or β-adrenergic blockers in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)–Preserved study has provided some reassurance that this approach is safe and potentially beneﬁcial.5 Results from the European Perindopril for Elderly Persons with Chronic Heart Failure (PEP-CHF) study have recently been reported.6 However, enrollment and event rates were lower than anticipated and many subjects withdrew from the study or started to take open-label ACE inhibitors, thereby reducing the power of the study to show a diﬀerence in the primary endpoint to 35%. Nevertheless, by one year follow-up, reductions in the primary outcome (HR 0.692: 95% CI 0.474–1.010; P = 0.055) and hospitalization for heart failure (HR 0.628: 95% CI 0.408–0.966; P = 0.033) were observed, and functional class (P < 0.030) and six minute corridor walk distance (P = 0.011) improved in those assigned to perindopril. Meanwhile, the Valsartan in Diastolic Dysfunction (VALIDD) study did not show statistically signiﬁcant diﬀerences in changes of diastolic relaxation velocity between valsartan or matched placebo when similar target blood pressure lowering was achieved.7 This raised a question of reliability regarding echocardiographic variables as surrogate endpoints and the beneﬁts of these agents beyond their blood pressure control. The Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE)8 study is still underway, and we hope it will shed important insight into whether ACE inhibitors and aldosterone receptor blockers improve clinical outcomes in this population. However, the wide acceptance of these agents in the treatment of hypertension and 435

436

Chapter 34 • Future Therapies in Diastolic Heart Failure diabetes already may have lessened the impact of these large-scale clinical trials on changing the treatment patterns in this population, since the majority of patients suﬀering from diastolic heart failure may already be treated with ACE inhibitors, aldosterone receptor blockers, or both. Ongoing clinical developments of renin inhibitors and aldose reductase inhibitors will likely provide more complete blockade of the renin-angiotensin-aldosterone system and potential therapies for diastolic heart failure.

Aldosterone Receptor Antagonists A growing body of evidence suggests that aldosterone plays an important role in the pathophysiology of diastolic heart failure (see Chapters 27 and 32). Myocardial aldosterone has been implicated in myocyte hypertrophy and cardiac ﬁbrosis leading to diastolic dysfunction.9 In patients with systolic heart failure, treatment with aldosterone receptor antagonists resulted in reduction in collagen turnover and in cardiac ﬁbrosis.10,11 Several small-scale investigations have demonstrated that in hypertensive subjects, treatment with spironolactone can lead to improvement in myocardial strain and strain rate, measured by echocardiography,12 as well as reduction in LV mass, measured by magnetic resonance imaging.13 These results appear to be synergistic with the use of ACE inhibitors, or even with angiotensin receptor blockers (ARBs). For now, aldosterone receptor antagonists are not indicated for treating diastolic heart failure, and their broad adoption has been hampered by their risks of developing hyperkalemia and renal insuﬃciency. Several mechanistic clinical studies are under way to better identify changes in various clinical and echocardiographic features with either spironolactone or eplerenone. A large, National Institutes of Health–sponsored multicenter clinical trial is currently under way to study whether spironolactone can reduce morbidity and mortality. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study will enroll 4500 adult patients with heart failure and preserved systolic function (LV ejection fraction >45%, plus heart failure hospitalization within 12 months or elevated natriuretic peptides). Patients will be recruited over 21/2 years, treated, and followed for a minimum of 2 years, with the primary endpoint being a composite of cardiovascular mortality, aborted cardiac arrest, and hospitalization for the management of heart failure (i.e., hospitalization for nonfatal myocardial infarction or nonfatal stroke). This is, however, quite a challenging task, because the study population will primarily be elderly patients with a wide range of comorbid conditions that may confound the endpoints.

Endothelin Receptor Antagonists Researchers have had a long-standing interest in the development of endothelin receptor antagonists for the treatment of heart failure (see Chapter 27). However, attempts to use bosentan, darusentan, and tezosentan in patients with systolic heart failure have not been successful.14–16 More recently, it has been recognized that endothelin may play an important role in the development of diastolic dysfunction. Endothelin interacts with the renin-angiotensin-aldosterone system and matrix metalloproteinases (MMPs) in the development of diastolic dysfunction, and this pathophysiology can be attenuated by endothelin type A receptor antagonists.17–19 Sitaxsentan sodium, a potent antagonist of the endothelin receptor (isoform ETA), is currently being evaluated in a Phase II multicenter clinical trial in patients with diastolic heart failure, deﬁned as symptoms of chronic heart failure, with a left ventricular ejection fraction (LVEF) greater than 50%

and abnormal diastolic function on echocardiography. Although the primary objective of this exploratory study is to demonstrate improvement in impaired exercise tolerance with sitaxsentan sodium in patients with diastolic heart failure, it will provide valuable data to assess the safety of a drug class that has previously raised concerns in the systolic heart failure population.

Vasopressin Receptor Antagonists Arginine vasopressin levels have been found to be elevated in patients with clinical evidence of both systolic and diastolic heart failure (see Chapter 27). Since patients with diastolic heart failure demonstrate the same clinical presentation of ﬂuid retention and functional impairment, antagonizing vasopressin V2 receptors may provide some added beneﬁts. However, current clinical trials of vasopressin receptor antagonists such as tolvaptan and lixivaptan are limited either to those with LV systolic dysfunction or to those with evidence of hyponatremia. If beneﬁcial in these settings, it will be logical to explore the potential beneﬁts of these agents in patients with diastolic heart failure, although there have been no speciﬁc studies to address the role of vasopressin and its antagonist in diastolic heart failure.

Targeting Intracellular Intrinsic Factors: Restoring Calcium Homeostasis Targeting calcium homeostasis to improve lusitropy has been a long-standing goal in treating diastolic heart failure. During cardiac ischemia, an increase in intracellular calcium is proposed to impair myocyte contraction and may alter myocyte recovery following reperfusion. Many of the agents that improve calcium sensitization have demonstrated improvement in lusitropy in animal models and in mechanistic studies.

MCC-135 (Calderet) MCC-135 is an agent for cardiac diseases, including heart failure or myocardial infarction, that demonstrates improving eﬀects for cardiac diastolic dysfunction and protective eﬀects for cardiac necrosis by enhancing Ca2+ uptake by the sarcoplasmic reticulum and inhibiting the sarcolemmal Na+/Ca2+ exchange.20 These eﬀects have been shown mainly in animal models21 and were thought to reduce calcium overload at the sarcoplasmic reticulum, thereby preserving myocardial function in diastolic heart failure and reducing the incidence of fatal reperfusion arrhythmias in the setting of ischemia. However, published human data on this compound is limited. The Phase II randomized, double-blind, placebo-controlled, parallel-assignment, safety/eﬃcacy MCC135 GO1 study has been performed in patients with symptomatic diastolic heart failure22; the results of the study have not yet been presented. The future clinical development of MCC-135 for diastolic heart failure is currently unclear.

Ranolazine Ranolazine has been safe and eﬀective in reducing angina in patients with refractory chronic stable angina (currently approved indication) without any alterations in hemodynamic proﬁles.23 Ranolazine also has inhibitory eﬀects on the late sodium channel, which has prompted interest in using ranolazine for treatment of diastolic dysfunction.24 Animal studies have identiﬁed improvements in LV function following ranolazine therapy,25 and early human studies have shown improvement in diastolic indices fol-

Chapter 34 • Future Therapies in Diastolic Heart Failure lowing intravenous administration of ranolazine in humans.26 Through its inhibition of the late sodium current, ranolazine reduces the activity of sodium-calcium exchange (NCX) and lowers intracellular calcium overload.23 However, such eﬀects have been limited to in vitro and animal studies,27 and their beneﬁts are yet to be conﬁrmed in humans. Nevertheless, as an approved drug, there is good potential for ranolazine to be developed in the area of diastolic heart failure.

Gene Therapy Direct gene transfer has yielded some success in experimental models of diastolic heart failure. The concept is straightforward: Overexpression of a gene that encodes a speciﬁc protein to enhance or replace an abnormality in calcium handling may improve excitation-contraction coupling and result in improvement in diastolic function.28,29 Genes that improve calcium homeostasis, such as Ca2+-ATPase (SERCA2a)30,31 and parvalbumin,32 phospholamban (S16EPLN),33 protein phosphatase 1,34 and NCX,35 have been prime targets for this type of strategy in animal models. Most of the studies demonstrated hemodynamic improvement of LV relaxation but not necessarily reduction in LV end diastolic pressures. Various other cell therapies, antisense therapies,36 and other targets, such as Akt and ryanodine receptor–stabilizing proteins (FKBP12.6), have also been reported.37,38 However, human data regarding the safety and eﬃcacy of gene therapy remain scarce. It should be emphasized that not all strategies targeting calcium homeostasis can result in diastolic improvement. One such innovative device therapy modulates intracellular calcium levels using noncontractile repetitive pacing, so-called cardiac contractility modulation.39 Clinical trials are currently under way to determine its eﬃcacy in improving cardiac performance, but so far there has not been any noticeable improvement in diastology, despite an impressive increase in cardiac contractility in symptomatic patients with impaired cardiac function.

Targeting Intracellular Intrinsic Factors: Metabolic Modulation The role of metabolic derangements in progression of the heart failure syndrome is not well understood despite decades of basic science research. Hyperglycemia has been associated with worsening diastolic dysfunction in patients with type 1 diabetes mellitus.40 Metabolism, contraction, and relaxation of the heart are inseparably linked, and a constant resynthesis of adenosine triphosphate (ATP) by oxidative phosphorylation in the mitochondria is a prerequisite for normal cardiac function. In heart failure, the heart adapts by switching from fatty acid to glucose oxidation.41 Restoring the balance between fatty acid and glucose metabolism represents an exciting and promising novel strategy in heart failure, although the eﬀects of metabolic modulation in diastolic heart failure have not been explored.

Insulin Sensitizers Several new diabetic medications have been evaluated in the improvement of diastolic dysfunction in long-term therapy (see Chapter 26). The number of studies on this topic is limited. Hyperglycemia has been associated with increased diastolic abnormalities, and metformin has been shown to reduce diastolic dysfunction in diabetic myocardium.42 Pioglitazone has also been shown to improve diastolic indices in patients with essential

hypertension.43 However, no clinical studies have been performed to speciﬁcally examine the role of these agents in improving diastolic indices beyond the setting of diabetes mellitus. While there are limited peroxisome proliferator-activated receptors–gamma (PPARγ) in the myocardium, abundant receptors for another “sensitizer,” glucagon-like peptide 1 (GLP-1), may indicate potential direct metabolic eﬀects on the myocardium. Short-term infusion of GLP-1 in diabetic patients with no history of heart failure has also resulted in improvement in invasive hemodynamic measurements of diastolic dysfunction44; mechanistic human trials are currently ongoing in patients with advanced systolic heart failure, and an injectable form of GLP-1 is currently approved for glycemic control in patients with diabetes mellitus.

Fatty Acid Oxidation Inhibitor Improving cardiac metabolism can also be achieved by reducing fatty acid oxidation, thereby restoring the balance of glucose and fatty acid utilization in the failing heart. Both perhexiline and oxfenicine inhibit fatty acid oxidation and reduce the rise in diastolic tension during ischemia.45 Several existing drugs, such as trimetazidine and perhexiline, have been tested in patients with heart failure in the setting of impaired LVEF, and echocardiographic indices of diastolic dysfunction (E/A ratio, diastolic strain, or strain rate) improved in parallel with alterations in phosphocreatine/ATP ratios.46 While there have been some safety concerns with renal and hepatic drug toxicities for perhexiline, trimetazidine has been widely used in Europe for treating angina.

Copper Chelating Therapy (Trientine) Another intriguing concept that has emerged over the past few years is the role of copper metabolism in the development of diabetic cardiomyopathy. Cooper et al. published several key papers illustrating the eﬃcacy of trientine, a copper chelating agent for Wilson’s disease, in reversing LV remodeling (predominantly regression of hypertrophy) without lowering blood sugar.47,48 It was also shown to substantially improve cardiomyocyte structure and to reverse elevation in LV collagen and β-1 integrin. These data are believed to implicate accumulation of elevated loosely bound copper in the mechanism of diabetic cardiomyopathy and to support the use of selective copper chelation in the treatment of this condition. This hypothesis is now being tested in a new formulation of trientine (under the name LaszarinTM, Protemix Inc). Early-phase reports of oral treatment with trientine show elevations in copper excretion in humans with type 2 diabetes, and following 6 months of treatment, it caused elevated LV mass to decline signiﬁcantly toward normal.48 To date, trientine has been well tolerated by patients in clinical trials, and it has a long safety proﬁle in the treatment of Wilson’s disease. A Phase IIb clinical trial of trientine administration in patients with diabetic heart failure with a quality of life (exercise tolerance) outcome is currently under way. Larger clinical trials are in the planning stages. Nevertheless, our understanding of why copper chelation may work is rudimentary; it is unclear whether it will work outside the setting of diabetes mellitus, and whether structural changes may directly translate into clinical beneﬁts.

Statins and Coenzyme Q10 Statins have been widely used to treat hypercholesterolemia. Interestingly, their anti-inﬂammatory and pleiotropic eﬀects have

437

438

Chapter 34 • Future Therapies in Diastolic Heart Failure been considered as potential treatments in the setting of diastolic heart failure (see Chapter 32). Treatment with statins in non– heart failure patients has been associated with reduction in markers of oxidative and nitrosative stress.49 Fukuta et al. conducted an exploratory study of statin therapy in patients with diastolic heart failure.50 This study evaluated 137 patients with heart failure and preserved LV function. Use of statin therapy was associated with an improvement in survival and a relative risk of death of 0.22. In contrast, treatment with an ACE inhibitor, aldosterone receptor blocker, beta blocker, or calcium channel blocker had no signiﬁcant eﬀect on survival. Propensity analysis conﬁrmed that statin therapy was associated with improved survival and a trend toward improved survival without cardiovascular hospitalization.50 Interpretation of these results must take into consideration that this was not a randomized clinical trial. Nevertheless, other prospective studies have identiﬁed potential beneﬁts of statin use on LV remodeling.51 There have been several plausible explanations for the potential beneﬁts of statins in this population, including prevention of hypertrophy and ﬁbrosis, providing ancillary anti-inﬂammatory and antioxidative eﬀects, and of progression of coronary ischemia. With broad use of statins in the at-risk population (particularly in diabetic patients), large-scale exploration of eﬃcacy with statin therapy in this setting will be challenging. It will be interesting to see if the ongoing clinical trials using rosuvastatin have any eﬀects on diastolic remodeling or mortality beneﬁts. The issues are further complicated by the phenomenon known as “statin cardiomyopathy.” In some studies diastolic parameters have become more impaired following statin therapy and can be improved by coenzyme (Co) Q10 administration.52 Indeed, CoQ10 has been widely used as a nutriceutical agent due to its antioxidant eﬀects. Claims have been made that CoQ10 may possess some eﬀects on improving diastolic dysfunction in small clinical studies,53 but no deﬁnitive evidence for diastolic improvement is available.

Thyroid Hormone Analog The connection between thyroid hormone and the cardiovascular system has been well recognized. In hyperthyroidism, cardiac contractility and cardiac output are enhanced and systemic vascular resistance is decreased, whereas the opposite is true in hypothyroidism. Furthermore, signiﬁcant correlations were found between pulse-wave tissue Doppler imaging parameters and serum-free T3 and T4 and concentrations of thyroid-stimulating hormone in both subclinical hypothyroid and in euthyroid patients.54 Treatment with thyroid hormones and their analogs may restore diminished expression of sarcoplasmic reticulum proteins, including GLUT-4 and SERCA2.55 A recently developed T3 analog, 3,5-diiodothyropropionic acid (DITPA), has been shown to improve diastolic indices,56 but current ongoing Phase II heart failure studies have been limited to those with chronic systolic heart failure.

Targeting Extracellular Intrinsic Factors: Inhibiting Collagen, Crosslinks, and Matrix Deposition Advanced Glycation End-Product Crosslink Breakers Advanced glycation end-products (AGEs) are permanent carbohydrate structures that form when carbohydrates bind to pro-

teins, lipids, and DNA (see Chapter 30). Many proteins, including the structural proteins collagen and elastin, play an integral role in the architecture of tissues and organs and in the maintenance of cardiovascular elasticity and vascular wall integrity. By irreversibly crosslinking collagen molecules in the setting of aging or diabetes, AGEs may increase the tensile strength of the collagen and also may make it less susceptible to degradation by MMPs. The formation of AGE “crosslink” therefore leads to increased stiﬀness, and abnormal protein accumulation may cause further complications of aging and diabetes. AGEs are also known to induce oxidative stress, in which reactive molecules provoke the underlying component of inﬂammation. Pharmacologic intervention with alagebrium, the prototype AGE crosslink breaker, directly targets the biochemical pathway leading to myocardial and vascular stiﬀness. Removal of the AGEs by cleavage of the abnormal crosslinking bonds has been associated with diminished inﬂammatory and sclerotic signaling pathways. These pathways are responsible for the deposition of abnormal amounts of matrix proteins that physically stiﬀen tissues. The presence of AGE crosslinks also renders tissues and organs less susceptible to normal turnover, thus enhancing the presence of these abnormal bonds on various molecules. Importantly, alagebrium does not disrupt the natural carbohydrate modiﬁcation to proteins, intramolecular crosslinking, or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function are preserved, while abnormal crosslinking is reduced. Preliminary studies have indicated that alagebrium can partially reverse some of the constellation of functional deﬁcits and structural abnormalities of diastolic dysfunction and may be able to modify some aspects of chronic heart failure. Most importantly, alagebrium modiﬁes the underlying disease pathology rather than treating the symptoms of disease. Distensibility Improvement and Remodeling in Diastolic Heart Failure (DIAMOND), a Phase IIa clinical study, was conducted to evaluate the potential eﬀects of alagebrium in patients with diastolic heart failure.57 In this open-label study, 23 patients (New York Heart Association [NYHA] classes II–III, LVEF >50%, age ≥60 years) received 210 mg of alagebrium twice daily for 16 weeks in addition to their current medications. Patients who received alagebrium had a statistically signiﬁcant reduction in LV mass, as well as a marked improvement in the initial phase of LV diastolic ﬁlling and better quality of life in the absence of blood pressure reduction. The results from the parallel, open-label Patients with Impaired Ejection Fraction and Diastolic Dysfunction: Eﬃcacy and Safety Trial of Alagebrium (PEDESTAL) study on patients with systolic heart failure and diastolic dysfunction were presented at the 2005 American Heart Association scientiﬁc sessions and showed trends consistent with the DIAMOND study results. However, recent safety concerns have emerged regarding liver toxicity in male rats treated with alagebrium, and the clinical development of this drug class in hypertension and erectile dysfunction has been discontinued. Nevertheless, if the beneﬁts outweigh the risks, this novel approach will be highly promising.

Matrix Metalloproteinase Inhibitors Collagen deposition leading to increased stiﬀness can result from alterations in the balance of promoters and inhibitors of MMPs.58 However, this concept of inhibiting MMPs to reduce collagen deposition suﬀers from the problem of using a therapeutic target

Chapter 34 • Future Therapies in Diastolic Heart Failure that has widespread eﬀects that extend beyond the failing myocardium. Recent results from the Prevention of Myocardial Infarction Early Remodeling (PREMIER) study showed that the prototype MMP inhibitor, PG-116800, did not show signiﬁcant beneﬁts in preventing LV remodeling over placebo following myocardial infarction.59 This inhibitor has yet to be tested in the setting of diastolic heart failure. Several other drugs are also being considered to target MMPs and tissue inhibitors of metalloproteinases (TIMPs) in this population; but until a more speciﬁc target can be identiﬁed, this strategy remains largely theoretical.

Novel Device Therapies Cardiac Resynchronization Therapy As in many other areas in cardiology, innovative device therapies have emerged. One of them is cardiac resynchronization therapy (CRT), for patients with systolic heart failure with dyssynchrony (see Chapter 29). When properly optimized, CRT has been shown to improve systolic as well as diastolic dysfunction.60 We still have very limited experience regarding the role of dyssynchrony in pure diastolic heart failure, and the signiﬁcance of dyssynchrony (especially diastolic dyssynchrony) in patients with preserved systolic function remains unclear. While studies to date have limited CRT to patients with systolic heart failure, patients with atrial ﬁbrillation who may be dependent on cardiac pacing have been shown to beneﬁt in the Post Atrioventricular Nodal Ablation Evaluation (PAVE) LV-based cardiac stimulation trial.61 Furthermore, regional wall thickness62 and diastolic indices63 appear to improve following CRT, especially in non-ischemic cardiomyopathy.

Implantable Hemodynamic Monitoring Devices One strategy to improve care for patients with diastolic heart failure targets improved monitoring of diastolic parameters to guide therapy. Since the common end result of passive stiﬀness and abnormal relaxation is elevated LV end diastolic pressure, proactive intracardiac hemodynamic monitoring is a theoretical solution to guide optimal drug therapy. Over the past two decades, implantable hemodynamic monitoring (IHM) devices have undergone signiﬁcant reﬁnements, and the recent multicenter Chronicle Oﬀers Management to Patients with Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) safety study, utilizing the Chronicle device (Medtronic Inc.), resulted in signiﬁcant reduction in heart failure hospitalizations and mortality in patients with NYHA class III heart failure (approximately 30% of the study population had preserved cardiac function).59 Several other hemodynamic monitoring devices are currently undergoing early clinical development, and it is likely that IHM devices will guide drug management in selected patients with diastolic heart failure.

Novel Mechanical Assist Devices Mechanical assist devices have focused on improving forward ﬂow by providing either pulsatile or nonpulsatile pumps as “replacements” for myocardial function. However, currently available mechanical devices are invasive and focus mainly on salvaging patients with end-stage systolic dysfunction. Most of these strate-

gies are highly invasive, with potential complications that can be extensive and devastating, which has limited their broad adoption. Two devices speciﬁcally designed to enhance diastolic ﬁlling are now in preclinical phases of testing. Although these devices require invasive surgical implantation through a simple oﬀ-pump closed-heart procedure, preclinical data have been promising. The ImCardia (CorAssist Cardiovascular Inc.) is an elastic, selfexpanding device with a special silicon lattice material attached to the external surface of the left ventricle.64 The ImCardia harnesses the heart’s systolic energy during recoil from systole in order to reduce diastolic intracardiac pressure. The device operates without the need for an external source of energy. In contrast, the Levram Physiological Cardiac Assist Device (PCAD) (Levram Medical Systems) utilizes a single blood displacement chamber and a single cannula.65 The cannula is inserted into the failing ventricle cavity via the LV apex and is connected to a blood displacement actuator. Instead of the traditional “rerouting” concept of ventricular assist devices, the Levram PCAD utilizes the residual power of the cardiac muscle and works with its dynamics in a synchronized manner, thereby providing direct add-on mechanical pumping assistance during systole and diastole. Both studies will begin human feasibility trials in the near future, but the concept for surgical interdiction is still in early development, largely due to its invasive nature.

FUTURE RESEARCH Drugs and devices developed to treat diastolic heart failure are thought to hold limited commercial promise because they are primarily add-on therapies in a study population in which treatment goals and treatment outcomes are not well deﬁned. The therapeutic options discussed in this chapter are just some of the examples on which there are published data or that are currently in active clinical development. The fact that there are a limited number of “pipeline” drugs that speciﬁcally target diastolic heart failure brings home the point that we are still in the infancy of understanding the underlying pathophysiology of diastolic heart failure. Furthermore, the association between improvements of echocardiographic indices of diastolic dysfunction may not relate directly to clinical eﬃcacy. Although LV hypertrophy regression appears to be a good surrogate endpoint for diastolic heart failure, deﬁnitive proof for this is not yet available. From what we understand now, drugs that aﬀect calcium homeostasis will emerge as important players in this ﬁeld, although existing neurohormonal antagonists will maintain their presence in the diastolic heart failure regimen. New targets will emerge, and new drug classes (like AGE crosslink breakers) will be tested as we broaden our understanding of the diversity of diastolic heart failure. Metabolic modulation has also shown great promise as we begin to understand the close connections between myocardial and vascular metabolic derangements and diastolic dysfunction. Device implantation for treating diastolic heart failure will need further development to reduce the procedural risks, invasiveness, and expense. Nevertheless, intracardiac hemodynamic monitoring devices will likely play an important role in guiding therapy in this population. The road to clinical development in diastolic heart failure is tortuous and demanding, but at the same time exciting and rewarding, as it brings new ideas, new challenges, and new hopes.

439

440

Chapter 34 • Future Therapies in Diastolic Heart Failure REFERENCES 1. Zile MR, Baicu CF, Bonnema DD: Diastolic heart failure: Deﬁnitions and terminology. Prog Cardiovasc Dis 2005;47:307–313. 2. van Heerebeek L, Borbely A, Niessen HW, et al: Myocardial structure and function diﬀer in systolic and diastolic heart failure. Circulation 25 2006;113: 1966–1973. 3. Packer M: The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20: 248–254. 4. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail 2006;12:10–38. 5. Yusuf S, Pfeﬀer MA, Swedberg K, et al: Eﬀects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362(9386):777–781. 6. Cleland JG, Tendera M, Adamus J, et al: The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27: 2338–2345. 7. Solomon SD, Janardhanan R, Verma A, et al: Eﬀect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: A randomized trial. Lancet 2007;369(9579):2079–2087. 8. Carson P, Massie BM, McKelvie R, et al: The Irbesartan in Heart Failure with Preserved Systolic Function (I–Preserve) trial: Rationale and design. J Card Fail 2005;11:576–585. 9. Tang WH, Parameswaran AC, Maroo AP, Francis GS: Aldosterone receptor antagonists in the medical management of chronic heart failure. Mayo Clin Proc 2005;80:1623–1630. 10. Izawa H, Murohara T, Nagata K, et al: Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial ﬁbrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: A pilot study. Circulation 2005;112:2940–2945. 11. Zannad F, Alla F, Dousset B, et al: Limitation of excessive extracellular matrix turnover contribute to survival beneﬁt of spironolactone therapy in patients with congestive heart failure: Insights from the Randomized Aldactone Evaluation Study (RALES). Rales investigators. Circulation 2000;102:2700–2706. 12. Mottram PM, Haluska B, Leano R, et al: Eﬀect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558–565. 13. Pitt B, Reichek N, Willenbrock R, et al: Eﬀects of eplerenone, enalil, and eplerenone/enalil in patients with essential hypertension and left ventricular hypertrophy: The 4E–left ventricular hypertrophy study. Circulation 2003;108:1831–1838. 14. Packer M, McMurray J, Massie BM, et al: Clinical eﬀects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: Results of a pilot study. J Card Fail 2005;11:12–20. 15. Kalra PR, Moon JC, Coats AJ: Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol 2002;85:195–197. 16. Anand I, McMurray J, Cohn JN, et al: Long-term eﬀects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): Randomised, double-blind, placebo-controlled trial. Lancet 2004;364:347–354. 17. Yamamoto K, Masuyama T, Sakata Y, et al: Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts. Cardiovasc Res 2000;47:274–283. 18. Yamamoto K, Masuyama T, Sakata Y, et al: Prevention of diastolic heart failure by endothelin type A receptor antagonist through inhibition of ventricular structural remodeling in hypertensive heart. J Hypertens 2002;20: 753–761. 19. Podesser BK, Siwik DA, Eberli FR, et al: ET(A)-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat. Am J Physiol Heart Circ Physiol 2001;280:H984–H991. 20. Satoh N, Kitada Y: Eﬀects of MCC-135 on Ca2+ uptake by sarcoplasmic reticulum and myoﬁlament sensitivity to Ca2+ in isolated ventricular muscles of rats with diabetic cardiomyopathy. Mol Cell Biochem 2003;249: 45–51. 21. Satoh N, Sato T, Shimada M, et al: Lusitropic eﬀect of MCC-135 is associated with improvement of sarcoplasmic reticulum function in ventricular muscles of rats with diabetic cardiomyopathy. J Pharmacol Exp Ther 2001;298:1161–1166. 22. Zile M, Gaasch W, Little W, et al: A phase II, double-blind, randomized, placebo-controlled, dose comparative study of the eﬃcacy, tolerability, and

23. 24.

25. 26. 28. 29. 30. 31. 32.

33. 34. 35. 36. 37. 38. 39.

40.

41. 42. 43. 44.

45.

46.

safety of MCC-135 in subjects with chronic heart failure, NYHA class II/ III (MCC-135-GO1 study): Rationale and design. J Card Fail 2004; 10:193–199. Chaitman BR: Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 2006;113:2462– 2472. Undrovinas AI, Belardinelli L, Undrovinas NA, Sabbah HN: Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J Cardiovasc Electrophysiol 2006;17(Suppl 1):S169–S177. Sabbah HN, Chandler MP, Mishima T, et al: Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 2002;8:416–422. Hayashida W, van Eyll C, Rousseau MF, Pouleur H: Eﬀects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther 1994;8:741–747. Hoshijima M: Gene therapy targeted at calcium handling as an approach to the treatment of heart failure. Pharmacol Ther 2005;105:211–228. Hunter WC: Role of myoﬁlaments and calcium handling in left ventricular relaxation. Cardiol Clin 2000;18:443–457. Miyamoto MI, del Monte F, Schmidt U, et al: Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci USA 2000;97:793–798. Schmidt U, del Monte F, Miyamoto MI, et al: Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase. Circulation 2000;101:790–796. Hirsch JC, Borton AR, Albayya FP, et al: Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction. Am J Physiol Heart Circ Physiol 2004;286: H2314–H2321. del Monte F, Harding SE, Dec GW, et al: Targeting phospholamban by gene transfer in human heart failure. Circulation 2002;105:904–907. Pathak A, del Monte F, Zhao W, et al: Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circ Res 2005;96:756–766. Munch G, Rosport K, Baumgartner C, et al: Functional alterations following cardiac sodium-calcium exchanger overexpression in heart failure. Am J Physiol Heart Circ Physiol 2006;291:H488–H495. Harding SE, del Monte F, Hajjar RJ: Antisense strategies for treatment of heart failure. Methods Mol Med 2005;106:69–82. Cittadini A, Monti MG, Iaccarino G, et al: Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling. Gene Ther 2006;13:8–19. Yano M, Kobayashi S, Kohno M, et al: FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. Circulation 2003;107:477–484. Lawo T, Borggrefe M, Butter C, et al: Electrical signals applied during the absolute refractory period: An investigational treatment for advanced heart failure in patients with normal QRS duration. J Am Coll Cardiol 2005;46:2229–2236. Shishehbor MH, Hoogwerf BJ, Schoenhagen P, et al: Relation of hemoglobin A1c to left ventricular relaxation in patients with type 1 diabetes mellitus and without overt heart disease. Am J Cardiol 2003;91:1514–1517, A1519. Morrow DA, Givertz MM: Modulation of myocardial energetics: Emerging evidence for a therapeutic target in cardiovascular disease. Circulation 2005;112:3218–3221. Jyothiri GN, Soni BJ, Masurekar M, et al: Eﬀects of metformin on collagen glycation and diastolic dysfunction in diabetic myocardium. J Cardiovasc Pharmacol Ther 1998;3:319–326. Horio T, Suzuki M, Suzuki K, et al: Pioglitazone improves left ventricular diastolic function in patients with essential hypertension. Am J Hypertens 2005;18:949–957. Thrainsdottir I, Malmberg K, Olsson A, et al: Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure. Diab Vasc Dis Res 2004;1:40–43. Kennedy JA, Kiosoglous AJ, Murphy GA, et al: Eﬀect of perhexiline and oxfenicine on myocardial function and metabolism during low-ﬂow ischemia/reperfusion in the isolated rat heart. J Cardiovasc Pharmacol 2000;36:794–801. Lee L, Campbell R, Scheuermann-Freestone M, et al: Metabolic modulation with perhexiline in chronic heart failure: A randomized, controlled trial of short-term use of a novel treatment. Circulation 2005;112:3280– 3288.

Chapter 34 • Future Therapies in Diastolic Heart Failure 47. Cooper GJ, Chan YK, Dissanayake AM, et al: Demonstration of a hyperglycemia-driven pathogenic abnormality of copper homeostasis in diabetes and its reversibility by selective chelation: Quantitative comparisons between the biology of copper and eight other nutritionally essential elements in normal and diabetic individuals. Diabetes 2005;54:1468–1476. 48. Cooper GJ, Phillips AR, Choong SY, et al: Regeneration of the heart in diabetes by selective copper chelation. Diabetes 2004;53:2501–2508. 49. Shishehbor MH, Brennan ML, Aviles RJ, et al: Statins promote potent systemic antioxidant eﬀects through speciﬁc inﬂammatory pathways. Circulation 2003;108:426–431. 50. Fukuta H, Sane DC, Brucks S, Little WC: Statin therapy may be associated with lower mortality in patients with diastolic heart failure: A preliminary report. Circulation 2005;112:357–363. 51. Sola S, Mir MQ, Lerakis S, et al: Atorvastatin improves left ventricular systolic function and serum markers of inﬂammation in nonischemic heart failure. J Am Coll Cardiol 2006;47:332–337. 52. Silver MA, Langsjoen PH, Szabo S, et al: Eﬀect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction. Am J Cardiol 2004;94:1306–1310. 53. Oda T: Recovery of load-induced left ventricular diastolic dysfunction by coenzyme Q10: Echocardiographic study. Mol Aspects Med 1994;15(Suppl): S149–S154. 54. Zoncu S, Pigliaru F, Putzu C, et al: Cardiac function in borderline hypothyroidism: A study by pulsed wave tissue Doppler imaging. Eur J Endocrinol 2005;152:527–533. 55. Minakawa M, Takeuchi K, Ito K, et al: Restoration of sarcoplasmic reticulum protein level by thyroid hormone contributes to partial improvement of myocardial function, but not to glucose metabolism in an early failing heart. Eur J Cardiothorac Surg 2003;24:493–501. 56. Morkin E, Pennock G, Spooner PH, et al: Pilot studies on the use of 3,5diiodothyropropionic acid, a thyroid hormone analog, in the treatment of congestive heart failure. Cardiology 2002;97:218–225.

57. Little WC, Zile MR, Kitzman DW, et al: The eﬀect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191– 195. 58. Ahmed SH, Clark LL, Pennington WR, et al: Matrix metalloproteinases/ tissue inhibitors of metalloproteinases: Relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006;113:2089–2096. 59. Cleland JG, Coletta AP, Freemantle N, et al: Clinical trials update from the American College of Cardiology meeting: CARE-HF and the remission of heart failure, Women’s Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER. Eur J Heart Fail 2005;7:931–936. 60. Waggoner AD, Faddis MN, Gleva MJ, et al: Improvements in left ventricular diastolic function after cardiac resynchronization therapy are coupled to response in systolic performance. J Am Coll Cardiol 2005;46:2244– 2249. 61. Doshi RN, Daoud EG, Fellows C, et al: Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005;16:1160–1165. 62. Zhang Q, Fung JW, Auricchio A, et al: Diﬀerential change in left ventricular mass and regional wall thickness after cardiac resynchronization therapy for heart failure. Eur Heart J 2006;27:1423–1430. 63. Waggoner AD, Rovner A, de las Fuentes L, et al: Clinical outcomes after cardiac resynchronization therapy: Importance of left ventricular diastolic function and origin of heart failure. J Am Soc Echocardiogr 2006;19: 307–313. 64. Feld Y, Dubi S, Reisner Y, et al: Future strategies for the treatment of diastolic heart failure. Acute Card Care 2006;8:13–20. 65. Landesberg A, Konyukhov E, Shofti R, et al: Augmentation of dilated failing left ventricular stroke work by a physiological cardiac assist device. Ann N Y Acad Sci 2004;1015:379–390.

441

Index

Page numbers followed by b denote boxes, those followed by f denote figures, and those followed by t denote tables.

A ACE inhibitors. See Angiotensin-converting enzyme (ACE) inhibitors Action potential, 5–6 Acute aortic insuﬃciency, 240 Acute chamber dilation, 30 Acute coronary syndromes, 357 Acute decompensated diastolic heart failure, 24 Acute heart failure, 356–357 Acute ischemia description of, 55, 278 transmitral inﬂow in, 280t Acute myocardial infarction Doppler ﬁlling proﬁles in, 282–285, 283t left ventricular remodeling after, 278 Acute pulmonary edema, 20 Adrenergic receptors, 4 Adrenergic signaling abnormalities, 4 Adrenocorticotropic hormone, 348 Adrenomedullin, 345, 349 Advanced glycation end-products (AGEs), 160, 393–394, 419, 438 Aerobic exercise training, 211 Afterload arterial, age-associated increases in, 85 in chronic aortic regurgitation, 240 ejection fraction aﬀected by, 63 left ventricular geometry aﬀected by increases in, 323 systolic blood pressure aﬀected by, 406f tissue Doppler imaging aﬀected by increases in, 324t AGEs. See Advanced glycation end-products Aging. See also Seniors arterial stiﬀening and, 84 Doppler measures of diastolic function aﬀected by, 401 left ventricular diastolic function and, 84 left ventricular ﬁlling and, 111, 120 left ventricular relaxation aﬀected by, 111, 388–389 metabolic hypothesis of, 393–394 mitral ﬂow velocity and, 120t, 120–121 pulmonary venous ﬂow velocity and, 123 sedentary, 388, 393 A-kinase anchoring proteins, 4 Alagebrium, 438 Aldosterone, 253, 296, 348, 435 Aldosterone inhibitors, 210 Aldosterone receptor antagonists, 339, 423, 435–436 ALT-711, 396f, 396–397 Amlodipine, 416t, 421 Amyloid deposits, 305 Amyloidosis. See Cardiac amyloidosis

Angina, 424 Angiotensin II, 253, 347 Angiotensin II inhibitors, 268 Angiotensin receptor blockers, 210, 422–423 Angiotensin-converting enzyme (ACE) inhibitors angiotensin receptor blockers and, 423 indications for, 338t, 353, 396, 417, 421–422, 435 Annular velocity, 187f Annulus paradoxus, 308 Aortic distensibility, 208, 208f Aortic insuﬃciency, 240–241 Aortic stenosis diastolic dysfunction in, 241 left ventricular untwisting delays associated with, 157 Tei index aﬀected by, 195 Apical acoustic window, 153 Arginine vasopressin, 346, 348 Arterial compliance, 208, 209f Arterial elastance, 78, 82 Arterial stiﬀening. See also Ventricular-arterial stiﬀening age-associated increase in, 84 description of, 78, 82–83 Arterial-ventricular coupling, 82 Arterial-ventricular stiﬀening. See Ventriculararterial stiﬀening Arteriovenous oxygen, 204 Ascites, 304 Atenolol, 416t Athlete’s heart, 293 Atrial conduit function, 37 Atrial ﬁbrillation constrictive pericarditis and, 308 description of, 138 hypertrophic cardiomyopathy and, 290–291 Atrial ﬂutter, 138 Atrial natriuretic peptide description of, 237, 346 NT-proANP, 358 structure of, 350f Atrial septal defects, 323 Atrial systole, 106 Atrioventricular conduction disease, 378 Atrioventricular delay, 377–379, 379, 379f Atrioventricular synchrony, 378 Augmentation index, 236

B Bernoulli equation, 46, 134 Beta blockers diastolic heart failure treated with, 420–421 dilated cardiomyopathy treated with, 254 hypertrophic cardiomyopathy treated with, 294–295

Biopsy, endomyocardial description of, 250 in restrictive cardiomyopathy, 310 Biventricular pacing, 374, 375t B-mode echocardiography, 163 Brain natriuretic peptide administration of, 357–358 in chronic renal failure, 358 in constrictive pericarditis, 304–305, 358 description of, 67, 148, 190, 345 diastolic dysfunction and, 355 exogenous administration of, 357–358 half-life of, 351 in heart failure, 351–352 immunoassays for, 352 left ventricular function and, 351f, 354f, 355t left ventricular remodeling and, 351 NT-proBNP, 351, 357 plasma levels of, 351, 353, 356, 359 restrictive cardiomyopathy levels of, 304–305 secretion of, 351 structure of, 350f synthesis of, 350–351 Brain perfusion, 84 Buﬀered beat acquisition, 108

C Calcium early diastole inﬂuenced by reuptake of, 390f, 390–391 homeostasis of, 334–335, 436 mitochondrial sequestration of, 84 in myocardial relaxation impairments, 3 myoﬁlament responsiveness to, 6–7 regulation abnormalities, 4 Calcium channel blockers, 294–296, 417, 423–424 Calcium release calcium-induced, 4 sarcoplasmic membrane protein regulation of, 6 Calcium sensitizers, 7 Calcium-induced calcium release, 4 Calmodulin-dependent protein kinase II, 6 Candesartan, 210, 211f, 338, 386, 395, 415, 416t, 431 Capillary basement membrane, 335 Capillary resistance, 83 Capillary wedge pressure, 148 Captopril, 416t Carbon dioxide, 203–204 Cardiac amyloid, 358 Cardiac amyloidosis case study of, 262 classiﬁcation of, 262–263 clinical presentation of, 263–264 description of, 100, 100f

443

444

Index Cardiac amyloidosis (Continued) diagnosis of, 265–266 echocardiography of, 264–265 end-stage chronic heart failure caused by, 193, 194f etiology of, 262 familial, 262–263 ﬂow diagram of, 267f forms of, 263t left atrial strain in, 168 orthostatic hypotension in, 263 secondary, 263 senile systemic, 263 Cardiac cachexia, 263 Cardiac cycle, 13f, 116 Cardiac natriuretic peptides. See Natriuretic peptides Cardiac output exercise-related increases in, 16–17 Fick principle used to determine, 204 left ventricular relaxation eﬀects on, 119 Cardiac resynchronization therapy basics of, 374 description of, 157–158, 439 diastolic dysfunction aﬀected by, 377t diastolic function aﬀected by, 376–377 diastolic heart failure treated with, 381 mechanisms of, 374 modalities, 381 Tei index aﬀected by, 376 Cardiac sarcoidosis, 100, 101f Cardiac tamponade acute, 301 constrictive pericarditis and, 311 Cardiac transplantation cardiac noncompliance after, 251 description of, 178, 179f diastolic dysfunction in, 250–252 hemodynamic abnormalities associated with, 254 pulmonary capillary wedge pressure after, 251 rejection after, 196, 251–252 survival rates after, 250 technique of, 251 Cardiomyocytes. See also Myocytes age-related changes in, 390 calcium regulation in, 390f diastolic disorders caused by dysfunction of, 81 diastolic function, 19 hypertrophy of, 86 stiﬀness of, 86 in systolic heart failure, 17 Cardiomyopathy. See Diabetic cardiomyopathy; Dilated cardiomyopathy; Hypertrophic cardiomyopathy Cardiopulmonary exercise testing hemodynamic alterations during arterial compliance, 208, 209f chronotropic response, 208–209, 209f left ventricular compliance, 206 left ventricular ﬁlling pressures, 206 stroke volume, 205–206, 207f submaximal exercise capacity, 204 variables measured during, 203 Cardiotrophin-1, 349 Cardiovascular risk, 85–86 Cardiovascular system arterial-ventricular coupling, 82 description of, 82 stiﬀening of, 82 Carvedilol, 197, 416t Central pulse pressure, 84–85 Chamber stiﬀness, 43–44 CHARM, 338, 386, 395, 415, 422, 431, 435 Chest x-rays, 308, 309f, 310f

Children diastolic dysfunction in, 313–319 dilated cardiomyopathy in, 324 hypertrophic cardiomyopathy in, 323–324, 325f left ventricular diastolic function in color M-mode ﬂow propagation velocity, 318–319 description of, 314 mitral inﬂow Doppler assessments, 314–316 pulmonary venous Doppler assessments, 316 tissue Doppler imaging of, 316–318 left ventricular hypertrophy in, 323 single ventricle palliation, 325–326, 327f tetralogy of Fallot in, 324–325 Chlorthalidone, 416t Chronic aortic insuﬃciency, 240–241 Chronic renal failure, 358, 421 Chronotropic incompetence, 209f, 211 Chronotropic response, 208–209, 209f C-hump, 248 Circulation lumped parameter model of, 49–50 neurohormonal regulation of, 346 Coenzyme Q10, 437–438 Colchicine, 268 Collagen aldosterone blockade eﬀects on, 348 crosslinked, 394 in diastolic heart failure, 17, 19f Color kinesis, 250 Color M-mode Doppler echocardiography background of, 145–148 in children, 318–319 clinical uses of, 148–149 description of, 145 diastolic function evaluations, 148 ﬂow propagation, 146 ﬂow propagation velocity measurements, 322f future research of, 149–150 intraventricular pressure gradients, 146–147, 149 left atrial pressure estimates using, 148 left ventricular ﬁlling evaluations, 219 left ventricular inﬂow evaluation, 219f, 219–220, 220f mitral inﬂow, 146f pathophysiologic evaluations, 147–148 pseudonormal ﬁlling patterns, 148 technique of, 216 Computational ﬂuid models, 53–54 Computed tomography, 308, 309f Concentric left ventricular hypertrophy, 23–24, 65, 182, 235 Conduit stiﬀness, 85 Congenital heart disease atrial septal defects, 323 left ventricular diastolic function in children color M-mode ﬂow propagation velocity, 318–319 description of, 314 mitral inﬂow Doppler assessments, 314–316 pulmonary venous Doppler assessments, 316 tissue Doppler imaging of, 316–318 left ventricular hypertrophy in, 323 patent ductus arteriosus, 320 postoperative, 326–327 single ventricle palliation, 325–326 tetralogy of Fallot, 324–325 ventricular pressure overload in, 323 ventricular septal defects, 320 ventricular volume overload in, 319–323 Constrictive pericarditis ascites in, 304 atrial ﬁbrillation and, 308 brain natriuretic peptide in, 304–305, 358 cardiac tamponade and, 311

Constrictive pericarditis (Continued) case studies of, 308–311 chest x-ray evaluations, 308, 309f, 310f clinical presentation of, 304 computed tomography of, 308, 309f description of, 98–99, 99f diagnosis of, 302 diastolic dysfunction in, 158 diastolic forward ﬂow in, 306f echocardiography evaluations M-mode, 305f pulsed Doppler, 305–307, 306f, 307f tissue Doppler, 307–308 two-dimensional, 305, 305f eﬀusive-, 311 electrocardiographic ﬁndings, 304–305 future research of, 311 hepatic vein diastolic ﬂow in, 306, 307f interventricular dependence in, 303–304 intrathoracic-intracardiac pressures, dissociation in, 303 jugular venous pressure in, 304 left ventricular ﬁlling in, 317 magnetic resonance imaging of, 308 mitral annulus velocity, 307, 310 mitral inﬂow velocity in, 305, 306f occult, 307 pathology of, 302, 302f pathophysiology of, 302–308 pericardial thickness associated with, 305 physical examination ﬁndings, 304 pulmonary capillary wedge pressure ﬂuctuations in, 303–304, 304f restrictive cardiomyopathy versus, 303–304, 358 tissue Doppler imaging of, 158, 307–308 treatment of, 308 ventricular septal motion in, 305 Continuous wave Doppler isovolumic relaxation time measurement, 217 pulmonary regurgitation, 173 tricuspid regurgitation, 173 Contractility myoﬁlament responsiveness to calcium eﬀects on, 6 sympathetic stimulation eﬀects on, 3 Convective deceleration, 80–81 Copper chelating therapy, 437 Coronary artery disease diabetes mellitus and, 336 Doppler echocardiography diagnosis of, 278–285 equilibrium radionuclide angiocardiography detection of, 109–110 magnetic resonance imaging applications, 98 prevalence of, 277 radionuclide techniques for, 110–111 treatment of, 110–111, 419 Coronary circulation, 84 Coronary perfusion, 84–85 Corticotrophin-releasing factor, 349 Coupling disease, 82 Crosslink breakers, 438 Crosslinked collagen, 394 C-type natriuretic peptide, 350–351 Cyclic adenosine monophosphate, 4

D Danon’s disease, 270 Decompensated diastolic heart failure acute, 24 causes of, 21 comorbid conditions, 21–22 diastolic function abnormalities in, 20–22 trigger mechanisms of noncardiac factors in, 24

Index Deconditioning, 391–393 Deferoxamine, 271 Deformation of myocardium, 223 Delayed hyperenhancement, 96, 97f Demand ischemia, 22 Diabetes mellitus cardiovascular disease associated with, 333 complications of, 337 coronary artery disease and, 336 crosslinked collagen in, 394 diastolic heart failure in angiotensin-converting enzyme inhibitors for, 338t prevalence of, 339 risks of, 333–334 studies of, 339 treatments for, 337–338, 419 epidemiology of, 333 glycemic control in, 419 hypertension and, 336 tissue Doppler evaluations, 160 treatment of, 419 Diabetic cardiomyopathy calcium homeostatic regulation abnormalities in, 334–335 cardiac autonomic dysfunction in, 336 cellular mechanisms involved in, 335f clinical relevance of, 336–339 free fatty acid metabolism in, 334 insulin resistance in, 336 left ventricular diastolic dysfunction in, 336–337 metabolic disturbances associated with, 334–335 myocardial ﬁbrosis, 335 pathophysiology of, 334f, 334–335, 335f progression of, 336, 337t small vessel disease in, 335–336 stages of, 337t Diastasis, 106, 117 Diastole atrial contraction at end of, 12–13 deﬁnition of, 4 description of, 313 left ventricular chamber, 43–44 left ventricular stiﬀness and, 16, 83 measurements of, 13 myocardial relaxation during, 12 phases of, 12–13, 106 Diastolic distensibility, 17 Diastolic dysfunction. See also Left ventricular diastolic dysfunction; Right ventricular diastolic dysfunction arterial stiﬀness and, 82 assessment of, 132 brain natriuretic peptide and, 355 cardiac resynchronization therapy eﬀects on, 377t in cardiac transplantation, 250–252 causes of, 3 cellular mechanisms of, 4, 5f characteristics of, 374 in children, 313–319 in constrictive pericarditis, 158 deﬁnition of, 11–12, 12b, 64, 74, 85, 367 in dilated cardiomyopathy, 98 Doppler echocardiography assessments, 67–68 epidemiology of, 68–69, 116 exercise intolerance associated with, 205, 337 grading of, 121–123, 124f, 431 in hypertrophic cardiomyopathy, 97, 296 ischemic causes of, 22 left atrial size and, 166–168 left ventricular end diastolic pressure, 78–79 manifestations of, 313 mitral ﬁlling pattern associated with, 14 myocardial relaxation abnormalities associated with, 77

Diastolic dysfunction (Continued) natural history of, 430f pericardium and, 27–30 prevalence of, 68 primary prevention of, 430 prognosis of, 68–69 reperfusion as cause of, 22 secondary prevention of, 430–432 in seniors. See Seniors, diastolic dysfunction in stages of, 65t, 216t systolic dysfunction and, 79 tachycardia eﬀects on, 338 in transplanted heart, 250–252 Diastolic function atrioventricular delay and, 377–379 cardiac resynchronization therapy eﬀects on, 376–377 deﬁnition of, 355 in hypertrophic cardiomyopathy, 159, 296 left ventricular. See Left ventricular diastolic function pacing eﬀects on, 375–376 right ventricular, 138–9 Diastolic heart failure cardiac resynchronization therapy for, 381 cardiac structure in, 367–368 cardiomyocytes in diastolic function, 19 gene products from, 86 hypertrophy of, 86 remodeling of, 17 characteristics of, 11, 65, 277, 368t, 373 collagen in, 17, 19f conditions associated with, 64, 339 decompensated, 20–21 deﬁnition of, 12, 12b, 64, 74, 85, 233, 367, 429 in diabetes mellitus. See Diabetes mellitus diagnostic criteria for, 12b, 65–66, 70, 386 Doppler echocardiography ﬁndings, 15f epidemiology of, 69–70, 81, 373 during exercise, diastolic function abnormalities in, 22 exercise intolerance in, 205 hospitalization rates for, 339 incidence of, 430 left ventricular ejection fraction in, 367 left ventricular ﬁlling in, 338 left ventricular remodeling in, 17, 18f, 21f, 367 left ventricular systolic function in, 19–20, 367– 371, 368t mechanical asynchrony in, 375f mortality rates, 277 with normal ejection fraction, 85–86 novel therapies for, 396–397 pathophysiology of, 416–417, 430 precipitating factors, 430 prevalence of, 69–70, 386f prognosis of, 70 in seniors. See Seniors, diastolic heart failure in stroke volume alterations in, during exercise, 206, 207f substrate in, 21 systolic heart failure versus, 65, 66t, 86 treatment of ACC/AHA recommendations for, 417t aldosterone receptor blockers, 423 angiotensin receptor blockers, 422–423 angiotensin-converting enzyme inhibitors, 421–422 background, 415–416 beta blockers, 420–421 calcium channel blockers, 423–424 description of, 396t, 396–397 digitalis, 424

Diastolic heart failure (Continued) diuretics, 416t, 419–420 goals, 417 guidelines for, 417 nitrates, 420 overview of, 416t statins, 424 summary of, 424 ventricular myocardium in, 373 Diastolic mitral regurgitation, 138 Diastolic pressure-volume relationships, 45f Diastolic stiﬀening, 407 Diastolic suction description of, 80 left ventricular, 17 left ventricular geometry abnormalities and, 81 models of, 81 pericardial contribution to, 29 ventricular ﬁlling aﬀected by, 80 Diastolic tricuspid regurgitation, 138 Digital ﬁltering, 108 Digitalis, 424 Digoxin, 338 Dihydropyridine receptors (DHPRs), 3–4 3,5-Diiodothyropropionic acid, 438 Dilated cardiomyopathy beta blockers for, 253–254 cardiac resynchronization therapy for, 157–158 in children, 324 deﬁnition of, 247 diuretics for, 254 exercise tolerance in, 252 familial, 247 incidence of, 247 left ventricular diastolic dysfunction in description of, 98, 247–248 echocardiographic indices of, 248–250 prognostic signiﬁcance of, 252–253 tissue Doppler imaging of, 250 left ventricular end diastolic pressure in, 248 magnetic resonance imaging applications, 98 pathogenesis of, 248 pressure-volume relationship abnormalities in, 248, 249f right ventricular diastolic dysfunction in, 253 survival rate for, 254 Tei index in, 195 tissue Doppler evaluations, 157–158, 250 treatment of, 253–254 Diltiazem, 295–296, 416t Direct His bundle pacing, 381 Disopyramide, 296 Diuretics, 254, 416t, 419–420 DHRs. See Dihydropyridine receptives Dobutamine stress echocardiography, 196 Doppler echocardiography acute myocardial infarction, 282–285, 283t aging eﬀects on, 401 cardiac transplantation rejection, 250 color M-mode. See Color M-mode Doppler echocardiography description of, 429 diastolic dysfunction assessments, 67–68 diastolic function assessments, 70, 135–136 diastolic heart failure ﬁndings, 15f hypertrophic cardiomyopathy, 291–293 isovolumic relaxation time, 217, 218f, 313 left atrial size evaluations, 216, 216f left ventricular ﬁlling assessments using, 13 left ventricular inﬂow measurements, 216–217, 217f, 219–220 leg raising maneuver, 228, 228f limitations of, 140 management uses of, 429–433 maneuvers used with, 226–228

445

446

Index Doppler echocardiography (Continued) myocardial velocity gradients, 308 noninvasive, 78 preload increase eﬀects on, 322t pulsed wave constrictive pericarditis evaluations, 305–307, 306f, 307f hepatic veins, 221–222 pulmonary venous ﬂow evaluations, 217–218, 219f right ventricular inﬂow, 221, 222f superior vena cava, 223, 223f waveform, 218, 219f respiratory maneuvers, 228 respirometer use, 225, 226f, 228 in seniors, 387 technique of, 215–216 Tei index measurements, 194 tetralogy of Fallot, 324–325 tissue. See Tissue Doppler Dual-chamber implantable cardioverterdeﬁbrillators, 381 Dual-chamber pacemakers, 374, 378 Dyspnea, 191 Dyssynchronous pacing, 376t

E E/A wave velocity ratio aging eﬀects, 388f description of, 131–132, 136, 430 pseudonormalization of, 238 Ea/Ees ratio, 404 Early annular diastolic velocity, 186 Eccentric left ventricular hypertrophy, 235 Echocardiography amyloidosis evaluations, 264–265 color kinesis, 250 color M-mode Doppler. See Color M-mode Doppler echocardiography description of, 105 Doppler. See Doppler echocardiography left atrial area measurement using, 163, 164f, 164t myocardial contrast, 225–226 E/Ea ratio, 188–189, 318 Eﬀective arterial elastance, 78, 82 Eﬀusive-constrictive pericarditis, 311 Ejection fraction deﬁnition of, 63 determinants of, 75, 368 diastolic heart failure prognosis and, 70 in heart failure, 81, 405–406, 417 left ventricular. See Left ventricular ejection fraction left ventricular ﬁlling pressure measurements and, 190 limiting factors, 75 preserved, 352 timing of measurements, 66 in women, 386, 387f Ejection phase, 35 Elastance index, 237 Electrocardiogram, 304–305 Enalapril, 416t End diastolic pressure volume, 75, 76f, 279f, 289, 391f End systolic elastance, 78 End systolic pressure to stroke volume ratio, 404 End systolic volume, 17 Endomyocardial biopsy description of, 250 in restrictive cardiomyopathy, 310 End-organ pulsatility, 83–84 Endothelin, 345

Endothelin-1, 348–349 Endothelin receptor antagonists, 436 Endothelium, 408 End-stage chronic heart failure, 193, 194f, 349 Energy-dependent diastolic relaxation, 86 Energy-dependent myocardial relaxation, 81 Equilibrium radionuclide angiocardiography buﬀered beat acquisition, 108 coronary artery disease evaluations, 109–110 data analysis, 108–109 description of, 105 diastolic function analysis using, 107–109 digital ﬁltering, 108 frame mode, 107 list mode acquisition, 107–108 mathematical curve ﬁtting, 108 E/Vp, 187–188 E-wave velocity description of, 47, 128–129 in mitral regurgitation and stenosis, 136 Excitation-contraction coupling, 3–4 Exercise diastolic function during, 16–17, 118–119 left ventricle response to, 370–371 left ventricular ﬁlling eﬀects, 13f myocyte relaxation during, 17 Exercise intolerance description of, 203, 211 in diastolic heart failure, 205 pathophysiology of, 204–209, 211 severity of, 203 in systolic heart failure, 205 Exercise tolerance in diastolic dysfunction, 337 in dilated cardiomyopathy, 252 interventions to increase, 210–211 Exercise training, 211 Expired ventilation/carbon dioxide generation, 203 Extracellular matrix composition of, 392, 392f myocyte volume and, 393 regulation of, 392 remodeling of, 17, 19f

F Fabry’s disease, 268–270 Familial amyloidosis, 262–263 Fatty acid oxidation inhibitors, 340, 437 Felodipine, 416t Fibrosis, myocardial, 235, 239, 241, 335 Fibrous pericardium, 301, 302f Fick equation, 204, 206f Filling. See Left ventricular ﬁlling First pass radionuclide angiography, 105, 109–110 Flow propagation velocity, 187f Fluid-structure interaction models, 54 Fontan operation, 326, 327f Forward continuity disease, 85 Frank-Starling relationship, 29, 116, 166 Free fatty acid metabolism, 334 Furosemide, 416t

G Gene expression proﬁling, 254 Gene therapy, 7, 436–437 Glucagon-like peptide 1, 437 Glucose cross-link breakers, 210 Glucose cross-linkers, 339

Glucosidase acid alpha trinucleotide repeat expansion, 159 Glycemic control, 419 Glycogen storage disorders, 269–270 Glycated hemoglobin, 160, 333 GNB3 gene, 237 Gradient echo sequences, 94–95

H Heart anatomic features of, in diastolic heart failure, 367–368 compliance of, 403 diastolic arterial pressure in, 408 lumped parameter model of, 49–50 Heart failure acute, 356–357 brain natriuretic peptide levels in, 351–352 conditions that cause, 64 deﬁnition of, 11, 63, 203, 429 demographic features of, 352 diagnosis of, 356–357, 432 diastolic. See Diastolic heart failure ejection fraction in, 81, 405–406 epidemiology of, 215, 373 incidence of, 3 left ventricular hypertrophy and, 346 model of, 346f monitoring of, 357 mortality rates, 81 after myocardial infarction, 357, 358f natural history of, 203 neurohormonal model of, 345 normal systolic function in, 111 predictors of, 277 with preserved ejection fraction, 405–406, 417, 421 renin-angiotensin system in, 347–348 symptoms of, 81 systolic. See Systolic heart failure treatment of, 357 Heart transplantation. See Cardiac transplantation Hemochromatosis, 100, 101f, 270–271 Hepatic venous ﬂow, 175–176, 177f HMG-CoA reductase inhibitors, 396, 410, 424. See also Statins Hydrochlorothiazide, 210, 416t Hydropericardium, noncompressing, 29 Hyperglycemia, 335 Hyperinsulinemia, 336 Hypertension antihypertensive therapies for, 354, 418–419 aortic stiﬀness in, 236–237, 237f cardiac ﬁbrosis in, 239 cardiac natriuretic peptide and, 352 description of, 111 diabetes mellitus and, 336 diastolic dysfunction in, 235, 242 epidemiology of, 237–238 future research for, 242 left atrial function in, 235–236 left atrial pressure aﬀected by, 418 left ventricular geometry and, 235 left ventricular hypertrophy, 238–239, 293 left ventricular mass in, 234–235 left ventricular remodeling secondary to, 233 mitral inﬂow parameters, 238–239 neurohormones for, 354 renin-angiotensin system in, 347–348 signaling pathways activated in, 237 systolic heart failure and, 397 treatment of, 239, 242, 418–419

Index Hypertensive hypertrophic cardiomyopathy of the elderly, 238 Hypertrophic cardiomyopathy athlete’s heart versus, 293 atrial ﬁbrillation in, 290–291 beta blockers for, 294–295 calcium diastolic levels, 287–288 sensitivity changes, 288–289 calcium channel blockers for, 294–296 in children, 323–324, 325f clinical presentation of, 290–291 deﬁnition of, 287 diagnosis of, 291–293 diastolic dysfunction in, 97, 296 diastolic function in, 159, 296 diﬀerential diagnosis, 293 Doppler echocardiographic indices, 291–293 dual-chamber pacing in, 378 exercise-induced ischemia in, 289 hypertensive left ventricular hypertrophy versus, 293 hypertrophy associated with, 97, 289 left atrial enlargement and, 294 left ventricular hypertrophy and, 358 left ventricular outﬂow tract obstruction, 287 longitudinal strain in, 294f magnetic resonance imaging of, 97–98 mitral ﬂow velocity in, 291, 292f mortality causes, 291 mutations in, 287–288, 288f myocardial velocity gradients in, 291–292, 293f myosin heavy chain mutations in, 287–288, 290 obstructive, 290 phenotypic heterogeneity of, 290 prognosis of, 291 progression of, 290 radionuclide techniques for, 111 rapid ﬁlling volume index in, 289 subclinical disease, 293–294 symptoms of, 290–291 tissue annular velocities in, 292f tissue Doppler evaluations, 159 treatment of, 294–296 Hypotension, 415

I Implantable hemodynamic monitoring devices, 439 Infective endocarditis, 240 Inferior vena cava diameter, 172–173, 173f, 222– 223, 223f Insulin resistance, 334, 336 Insulin sensitizers, 437 Interventricular interval, 379 Interventricular septum, 317f Intracardiac blood ﬂow determinants, 44–46 Intracellular calcium, 4 Intraventricular ﬂow description of, 50–51 ﬂuid-mechanical computer modeling of, 53–55 Intraventricular pressure gradients color M-mode Doppler echocardiography of, 146–147, 149 description of, 54–55, 57, 207 left ventricular torsion and, 156 Irbesartan, 339 Ischemia acute. See Acute ischemia demand, 22 diastolic dysfunction caused by, 22 Doppler inﬂow patterns aﬀected by, 279, 281–282 experimental studies of, 55

Ischemia (Continued) in hypertrophic cardiomyopathy, 289 left ventricular hypertrophy and, 23 pulmonary symptoms induced by, 23 subendocardial, 23 supply, 22 Ischemic heart disease, 157 Isometric hand exercise, 227–228 Isosorbide dinitrate, 416t Isosorbide mononitrate, 416t Isovolumic relaxation duration of, 106 initiation of, 106 quantiﬁcation of, 13 Isovolumic relaxation time cardiac transplant rejection eﬀects on, 251 deﬁnition of, 182, 217, 313 description of, 126–127 Doppler measurement of, 174, 217, 218f, 313 duration of, 127 left ventricular intracavitary ﬂow during, 127–128 in mid-left ventricular cavity, 128f

J J-receptors, 209 Jugular venous pressure, 304

K Kirchoﬀ ’s ﬁrst law, 49 Kussmaul sign, 304

L LAMP2, 269 Laplace’s law, 234 Left atrial appendage description of, 33, 39f distensibility of, 85 Left atrial diameter measurement of, 164f, 164t, 167 in obese patients, 236 Left atrial dimension, 182f Left atrial function assessment of, 165–166 diastolic left ventricular dysfunction and, 38 in hypertension, 235–236 left ventricular systolic dysfunction and, 38–39 Left atrial pressure color M-mode Doppler echocardiography estimation of, 148 description of, 80–81 diastolic ﬁlling rates aﬀected by, 279 diastolic properties that aﬀect, 117, 118f hypertension eﬀects on, 418 mean, 117, 189 in restrictive cardiomyopathy, 305 transmitral velocity aﬀected by, 182–183 Left atrial relaxation, 123 Left atrial size diastolic dysfunction and, 166–168 Doppler echocardiography of, 216, 216f, 429–430 prognosis associated with, 167 quantiﬁcation of, 163–165 Left atrial strain, 168 Left atrial systolic force, 235 Left atrial volume, 164–165, 165f, 167, 291 Left atrial volume index, 167t

Left atrium area of, echocardiography measurement of, 163, 164f, 164t booster pump function, 34 conduit function, 37 contractility of, 236 deﬁnition of, 163 distensibility of, 85 enlargement of, 167, 294 function of, 34 future research of, 168 physiologic functions of, 165–166 pressure-volume loops, 38f pressure-volume relations of, 34–35, 64, 166f reservoir function, 36–37 tissue velocity of, 168f Left hepatic vein, 172 Left ventricle chronic hemodynamic loading adaptation, 37 circumferential shortening of, 370 contractile behavior of, 368–370 contractility of, 369 contraction of, 79 distensibility of, 248 exercise response by, 370–371 ﬂow propagation inside, 54 longitudinal shortening of, 370 narrowing of, 128 pacing eﬀects on, 374–375 passive diastolic properties of, 48–49 pressure propagation inside, 54–55 pressure-volume loops, 240f pumping ability of, 368 regional contractile behavior of, 369–370 relaxation of, 44 systolic performance of, 63–64 Left ventricular chamber diastole, 43–44 Left ventricular compliance, 119 Left ventricular diastolic dysfunction. See also Diastolic dysfunction cellular bases of, 237 in diabetes cardiomyopathy, 336–337 in dilated cardiomyopathy. See Dilated cardiomyopathy, left ventricular diastolic dysfunction in grading of, 121–123, 124f hypertension and, 235 left atrial function and, 38–39 left atrial pressure in, 316 metabolic risk factors, 236 molecular bases of, 237 symptoms of, 11 Left ventricular diastolic function abnormalities in, 18 age-related changes, 84 assessment of, 64, 66, 74–76, 79 in children color M-mode ﬂow propagation velocity, 318–319 description of, 314 mitral inﬂow Doppler assessments, 314–316 pulmonary venous Doppler assessments, 316 tissue Doppler imaging of, 316–318 deﬁnition of, 64 in diastolic heart failure, 17–19 Doppler echocardiography assessments color M-mode, 148 description of, 70, 135–136, 313–314 equilibrium radionuclide angiocardiography assessment of, 107–109 exercise eﬀects, 16–17, 119 heart failure symptoms and, 67 hypertension eﬀects on, 111 measurement of, 66–67 metabolic risk factors on, 236

447

448

Index Left ventricular diastolic function (Continued) obesity on, 236 radionuclide assessments of, 106, 106b time-activity curve, 106, 107f tissue Doppler imaging assessments, 254 Left ventricular diastolic pressure, 12 Left ventricular diastolic pressure-volume relation, 368 Left ventricular diastolic suction eﬀect, 17 Left ventricular dilation, 54, 55f Left ventricular ejection fraction description of, 337, 357 in diastolic heart failure, 367 “normal,” 386t Left ventricular ejection time, 194 Left ventricular end diastolic pressure description of, 74, 75f, 76f, 78, 117, 181 in dilated cardiomyopathy, 248 estimation of, 184 Left ventricular end diastolic pressure-volume relationship, 279f Left ventricular end systolic elastance, 370f Left ventricular ﬁlling age-related changes in, 111 cardiac loading conditions eﬀect on, 121 color M-mode Doppler echocardiography of, 219 computer modeling of, 54f determinants of, 117f diagram of, 80f diastolic function measurements, 13–14 in diastolic heart failure, 338 diastolic suction eﬀects, 80 Doppler echocardiographic assessment of, 13, 64 exercise eﬀects on, 13f historical perspectives of, 116–117 left ventricular relaxation eﬀects on, 118f pseudonormalized, 64 relaxation during, 49, 134 right ventricular ﬁlling and, 303 sinus tachycardia eﬀects on, 136 variations in, 137 velocity of, 46–47 Left ventricular ﬁlling patterns abnormal, 81, 120f age-related changes in, 120 baseline, 54, 56f natural history of, 121f normal, 120f patient management uses of, 139 preload eﬀects, 227 Left ventricular ﬁlling pressures deﬁnition of, 181 description of, 78–79 ejection fraction and, 190 estimation of, 184–191 exercise-related alterations in, 206 noninvasive measures of, 206–207 tissue Doppler evaluation of, 157 two-dimensional echocardiography of, 181–182 Left ventricular geometry afterload increase eﬀects on, 323 description of, 55, 57f hypertension and, 235 Left ventricular hypertrophy angiotensin receptor blockers for regression of, 423 in children, 323 chronic kidney disease and, 421 concentric, 23–24, 65, 182, 235 in congenital heart disease, 323 eccentric, 235 heart failure and, 346 hypertensive, 233–235, 238–239, 293

Left ventricular hypertrophy (Continued) in hypertrophic cardiomyopathy, 97, 358 ischemia and, 23 M-mode echocardiography of, 133 ventricular time-volume curves in, 98 Left ventricular inﬂow color M-mode Doppler measurement of, 220f Doppler measurement of, 216–217, 217f Left ventricular intracavitary ﬂow, 127–128 Left ventricular isovolumic relaxation time. See Isovolumic relaxation time Left ventricular mass, 233–235 Left ventricular mass-to-volume ratio, 326 Left ventricular outﬂow tract obstruction of, 323 time-velocity integral, 128 verapamil eﬀects on, 295 Left ventricular pacing, 375t Left ventricular pressure declines in, 13, 250 volume and, 78f Left ventricular relaxation abnormal, 374 aging eﬀects on, 111, 388–389 cardiac output aﬀected by, 119 diastolic ﬁlling time aﬀected by, 118 impaired, 184t isovolumic period of, 55 in seniors, 388–389 slowing of, 117 tissue Doppler assessments, 156–157 transmitral velocity and, 185–186 Left ventricular remodeling brain natriuretic peptide and, 351 concentric, 235–236 deﬁnition of, 278 in diastolic heart failure, 17, 18f, 21f, 367 hypertension as cause of, 233 post-infarction, 278 Left ventricular stiﬀness abnormal, 404 age-related increases in, 403, 405f assessment of, 77–78 deﬁnition of, 374 diastolic function and, 16, 83 noninvasive assessment of, 78 quantiﬁcation of, 16 Left ventricular stroke volume, 36 Left ventricular stroke work, 369f Left ventricular suction, 80–81 Left ventricular systolic dysfunction deﬁnition of, 63 left atrial function and, 38 symptoms of, 11 Left ventricular systolic function, 19–20, 367–371 Left ventricular torsion, 156, 223–224 Left ventricular untwisting catecholamines and, 156 delayed, 156 description of, 55, 57f Left ventricular wall segments of, 225f stress, 359 thickness of description of, 193, 238 in restrictive cardiomyopathy, 303 Left ventricular-arterial coupling, 404–409 Leg raising maneuver, 228, 228f Lisinopril, 416t, 421 List mode acquisition, 107–108 Loop diuretics, 420 Losartan, 210, 409, 416t Lumped parameter model, 49–50 Lungs, ﬂuid redistribution into, 407

M Magnetic resonance imaging amyloidosis, 100, 100f artifacts, 100 constrictive pericarditis, 98–99, 99f, 308 contraindications, 100, 101t coronary artery disease evaluations, 98 delayed hyperenhancement, 96, 97f description of, 93 dilated cardiomyopathy evaluations, 98 gradient echo sequence, 94–95 hemochromatosis, 100, 101f hypertrophic cardiomyopathy evaluations, 97–98 imaging sequences of, 94–97 limitations of, 100, 102 myocardial tagging, 95–96, 96f pericardium, 98, 99f phase contrast, 95 phase velocity, 95 physics of, 93–94 restrictive cardiomyopathy, 99–100 sarcoidosis, 100, 101f spin-echo sequence, 94, 94f Magnetic resonance spectroscopy, 96–97 Maillard reaction, 394, 394f Matrix metalloproteinases description of, 236, 392t, 392–393, 436 inhibitors of, 438 MCC-135, 436 Mean arterial blood pressure, 84 Mechanical assist devices, 439 Mechanoreceptors, 28 Metabolic equivalents, 203 Metabolic hypothesis, 393–394 Metoprolol, 416t Microalbuminuria, 337 Middiastolic ﬂow reversal, 326 Mineralocorticoid receptors, 348 Mitral annular velocity in constrictive pericarditis, 307, 310 septal ablation eﬀects on, 296, 297f tissue Doppler imaging of, 133–134 Mitral A-wave duration of, 130–131 velocity of, 130 Mitral deceleration time, 129 Mitral E wave, 314, 316 Mitral ﬁlling in diastolic dysfunction, 14 pseudonormal, 148 Mitral ﬂow acceleration of, 46–47 deceleration of, 47 Doppler tracings of, 316f modeling of, 47–49 peak, 80 preload eﬀects on, 49 relaxation eﬀects on, 48, 48f Mitral ﬂow velocity age-related changes in, 120t, 120–121 disease eﬀects on, 120–121 Doppler measurement of, 130f Doppler patterns, 119–123 in hypertrophic cardiomyopathy, 291, 292f left ventricular diastolic dysfunction graded by, 121–122 patterns abnormal, 137 interpretation of, 136–138 M-mode echocardiography of, 132–133 tricuspid ﬂow velocity patterns versus, 133

Index Mitral ﬂow velocity (Continued) two-dimensional echocardiography of, 132–133 at start of atrial contraction, 129–130 variables of description of, 119f left ventricular isovolumic relaxation time, 126–127 Mitral inertance, 46, 49, 49f Mitral inﬂow ischemia eﬀects on, 279, 281–282 left ventricular dilation eﬀects on, 54, 55f Mitral inﬂow velocity, 305, 306f, 431f Mitral peak E/A wave velocity ratio, 131–132 Mitral regurgitation acute, 241 chronic, 241–242 diastolic, 138 diastolic dysfunction in, 241–242 E-wave velocities in, 129, 136 Mitral respiratory ﬂow velocity, 137 Mitral stenosis E-wave velocities in, 129, 136 pulmonary hypertension secondary to, 242 Mitral time-velocity integral, 128 Mitral to pulmonary venous A-wave duration, 124, 126, 126f Mitral valve regurgitation, 50 M-mode echocardiography color. See Color M-mode Doppler echocardiography constrictive pericarditis, 305f inferior vena cava diameter measurements, 222– 223, 223f left atrial size measurement using, 163 mitral ﬂow velocity patterns evaluated with, 132–133 strain rate, 156f Myocardial compliance, 30 Myocardial contrast echocardiography, 225–226 Myocardial ﬁbrosis, 235, 239, 241, 335 Myocardial infarction, 357, 358f, 419 Myocardial ischemia, 419 Myocardial relaxation assessment of, 76–77 causes of, 44 factors that aﬀect, 375 impaired, 98 magnetic resonance spectroscopy of, 96–97 mitral ﬂow aﬀected by, 48 myocyte control of, 3 noninvasive assessment of, 77 pressure decrease during, 44 ventricular compliance and, 49 Myocardial strain, 155, 223, 292–293 Myocardial tagging, 95–96, 96f Myocardial velocity gradients, 291–292, 293f, 308 Myocardium atrial, 33 deformation of, 223 neonatal, 314 Myocyte relaxation diastolic dysfunction caused by, 3 during exercise, 17 Myocytes. See also Cardiomyocytes action-potential duration in, 5–6 in atrial myocardium, 33 hypertrophy of, 278 remodeling of, 17, 19f Myoﬁlaments, 6 Myosin binding protein C, 288 Myosin heavy chains description of, 37 mutations, 159, 287–288, 290 Myosin regulatory light chains, 289

N Na+-Ca2+ exchanger calcium regulation by, 7 description of, 4–5 in reverse mode, 5, 7 sarcolemmal, 5 summary of, 7 sympathetic stimulation regulation of, 5 Natriuretic peptide(s) atrial. See Atrial natriuretic peptide brain. See Brain natriuretic peptide cardiac dysfunction screening and, 354–356 C-type, 350–351 description of, 349–350 hypertension and, 352 structure of, 350 Natriuretic peptide receptor, 350 Navier-Stokes equations, 44 Neonatal myocardium, 314 Neurohormones adrenomedullin, 349 aldosterone, 253, 296, 348 arginine vasopressin, 346, 348 blockade of, 359 cardiotrophin-1, 349 circulation regulation by, 346 endothelin-1, 348–349 future research of, 359 in heart failure, 352–354 natriuretic peptides. See Natriuretic peptides overview of, 345–346 prostaglandins, 352 renin-angiotensin system, 345, 347–348 summary of, 359 sympathetic nervous system, 345–347 tissue necrosis factor-alpha, 349 types of, 345 urocortin, 349 ventricular hypertrophy transition to heart failure, 346 Nicorandil, 296 Nitrates, 420 Noncompressing hydropericardium, 29 Norepinephrine, 347, 353

O Obesity, 236 Obstructive hypertrophic cardiomyopathy, 290 Oxygen consumption, 204–205

P Pacing adverse eﬀects of, 379–381 atrial, 375t basics of, 374 biventricular, 374, 375t cardiac condition eﬀects on, 380 cardiac function aﬀected by, 374–375 diastolic dysfunction, 374 diastolic function and, 375–376 direct His bundle, 381 dual-chamber, 374, 378 duration of, 380 dyssynchronous, 376t left ventricular, 375t mechanism of action, 374 modes of, 381 right ventricular, 375, 375t right ventricular outﬂow tract, 381 sites of, 376t, 380–381

Pacing (Continued) synchronous, 376t ventricle-to-ventricle timing, 379 ventricular dyssynchrony, 380 Parvalbumin, 437 Passive relaxation, 77 Patent ductus arteriosus, 320 Peak E/A wave velocity ratio, 131–132 Peak ﬁlling rate, 94, 106, 409 Peak forward ﬂow velocity in early systole, 123 Peak mitral A-wave velocity, 130 Peak mitral E-wave velocity, 47, 128–129, 133 Peak oxygen consumption, 203 Peak systolic blood pressure, 210f Percutaneous coronary interventions, 284 Percutaneous transluminal coronary angioplasty, 279, 281 Pericardial eﬀusion, 301–302 Pericardial knock, 304 Pericardiectomy description of, 27–28 pathophysiologic eﬀects of, 28 transmural pressures after, 29 Pericardiocentesis, 311 Pericardium anatomy of, 301 calciﬁed, 308, 309f ﬁbrous, 301, 302f historical studies of, 302 magnetic resonance imaging of, 98, 99f pathophysiology of, 27–30 serous, 301, 302f ventricular volume and, 301 Perindopril, 338, 396, 421, 435 Peroxisome proliferator-activated receptor-γ, 236, 419, 437 Phase contrast imaging, 95 Phosphodiesterase-5A, 237, 410 Phospholamban, 6, 237, 391, 437 Post-infarction left ventricular remodeling, 278 P-R interval, 131 Preload description of, 49 Doppler echocardiography aﬀected by increases in, 322t left ventricular ﬁlling patterns aﬀected by, 227 systolic blood pressure aﬀected by, 406f during Valsalva maneuver, 121 Pre-pro-endothelin, 348 Pressure half-time, 313 Pressure pulsatility, 84 Pressure relaxation, 76 Pressure-volume loop, 74, 75f, 404f Pressure-volume relations description of, 34–35 diastolic, 45f in dilated cardiomyopathy, 248, 249f Primary pulmonary hypertension, 197, 242 Propranolol, 416t Prostaglandins, 352 Protein kinase A, 4 Protein phosphatase 1, 437 Pseudonormal mitral ﬁlling, 148, 248 Pulmonary artery pressures, 134 Pulmonary artery systolic pressure, 191 Pulmonary capillary wedge pressure after cardiac transplantation, 250–251 in constrictive pericarditis, 303–304 description of, 181, 184, 185f, 188f, 198f, 391 intrathoracic-intracardiac dissociation eﬀects on, 303, 303f Pulmonary congestion, 66 Pulmonary edema, 419 Pulmonary regurgitation, 173

449

450

Index Pulmonary vein(s) description of, 33 modeling of, 52f velocity description of, 183–184 limitation of, 185 Pulmonary vein ﬂow, 49, 316f Pulmonary vein–left atrial pressure gradient, 50 Pulmonary venous diastolic ﬂow velocity, 123 Pulmonary venous ﬂow Doppler measurement of, 217–218, 219f, 226f, 316 velocity age-related changes in, 123 mitral to pulmonary venous A-wave duration, 124, 126, 126f Pulmonary venous stiﬀness, 85 Pulse pressure, 84–85 Pulse wave velocity, 236

Q

Right atrial appendage, 33 Right atrial pressure, 176f, 177t Right atrium, 172 Right ventricle dimension of, 172 isovolumic acceleration, 323 pressure-volume loops, 35 Right ventricular diastolic dysfunction, 253. See also Diastolic dysfunction Right ventricular diastolic function description of, 138–139 determinants of, 171 evaluation of, 178–179 Right ventricular end diastolic pressure-dimension, 28 Right ventricular ﬁlling, 171, 303 Right ventricular function, 197 Right ventricular inﬂow, 221, 222f Right ventricular outﬂow tract pacing, 381 Right ventricular pacing, 375, 375t Right ventricular relaxation, 171 Ryanodine receptor 2, 4–5

Q-Ea, 189 QRS prolongation, 374

S

R Radionuclide techniques advantages of, 105 coronary artery disease applications, 110–111 diastolic function assessments, 106, 106b equilibrium radionuclide angiocardiography. See Equilibrium radionuclide angiocardiography ﬁrst pass radionuclide angiography, 105, 109–110 future research for, 112 history of, 105–106 hypertension evaluations, 111 hypertrophic cardiomyopathy evaluations, 111 limitations of, 111–112 Ramipril, 416t Ranolazine, 436 Rapid ﬁlling volume index, 289 Receptor activator modifying proteins, 349 Regulatory light chains, 289 Remodeling. See Left ventricular remodeling Renal perfusion, during diastole, 84 Renin, 347 Renin-aldosterone-angiotensin system, 416 Renin-angiotensin system, 345, 347–348 Reperfusion, 22 Repolarization-relaxation coupling, 3–4 Reservoir function, 36–37 Respiratory collapse, 172–173 Respiratory maneuvers, 228 Respirometer, 225, 226f, 228 Restrictive cardiomyopathy brain natriuretic peptide levels in, 304–305 constrictive pericarditis versus, 303–304, 358 deﬁnition of, 303 description of, 99–100 endomyocardial biopsy in, 310 hemodynamics of, 302 hepatic vein diastolic ﬂow in, 306, 307f idiopathic, 310 left atrial pressure in, 305 left ventricular ﬁlling in, 317 left ventricular wall thickness in, 303, 305 morphologic features of, 302f, 303 secondary causes of, 303 tissue Doppler evaluations, 158 Restrictive ﬁlling, 248 Reverse continuity disease, 84 Rho kinase, 410

Sarcoidosis, 100, 101f Sarcolemma, 5 Sarcolemmal receptors, 5–6 Sarcoplasmic membrane proteins, 6 Sarcoplasmic reticulum calcium release from, 4, 7 description of, 6 Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, 7, 237, 288, 334, 391 Secondary amyloidosis, 263 Sedentary aging, 388, 393 Senile systemic amyloidosis, 263 Seniors. See also Aging coronary artery disease in, 419 diastolic dysfunction in description of, 388 left ventricular compliance decreases, 391–393 slowing of myocardial relaxation as cause of, 388–391 diastolic heart failure in clinical presentation of, 385–386 comorbid conditions, 394–395, 395f diagnosis of, 386–387 Doppler echocardiography, 387 future research of, 397–398 hypertension and, 395–396 prognosis of, 387–388 trials and treatments for, 395–396 epidemiology of, 385 myocardial relaxation in, 388–389 population growth of, 385 Septal ablation, 296 SERCA, 5–6 Serous pericardium, 301, 302f Sildenaﬁl, 237, 410 Simpson’s method, 164, 165f Single photon emission computed tomography, 107 Single ventricle palliation, 325–326 Sinus tachycardia, 136 Sitaxsentan sodium, 436 Sleep apnea, 430 Small vessel disease, 335–336 Speckle tracking, 224 Sphygmomanometer, 227, 227f Spin-echo sequence, 94, 94f Spironolactone, 416t Statins, 424, 430, 437–438. See also HMG-CoA reductase inhibitors

Stiﬀening arterial-ventricular. See Ventricular-arterial stiﬀening cardiovascular system, 82–83 left ventricular. See Left ventricular stiﬀness Storage cardiomyopathies, 268–269, 272 Strain, 155, 223 Strain rate, 155, 168, 191, 223, 292–293 Strain rate imaging, 224, 225t, 292 Stroke volume diastolic distensibility and, 17 exercise-related alterations in, 205–206, 207f Subendocardial ischemia, 23 Submaximal exercise capacity description of, 204 heart rate, 205 Superior vena cava, 223, 223f, 307f Supply ischemia, 22 Sympathetic nervous system, 345–347 Synchronous pacing, 376t Systolic anterior motion, 266 Systolic arterial pressure, 66, 67f Systolic blood pressure, 406f Systolic dysfunction deﬁnition of, 85 left ventricular deﬁnition of, 63 left atrial function and, 38 symptoms of, 11 Systolic function assessment of, 75–76 echocardiographic measures of, 319–320 in heart failure, 111 heart failure symptoms and, 67 Systolic heart failure aldosterone and, 348 cardiomyocytes in, 17, 86 characteristics of, 11, 65, 86, 368t deﬁnition of, 64, 85–86 diastolic heart failure versus, 65, 66t, 86 endothelial dysfunction in, 419 epidemiology of, 70 exercise intolerance in, 205 hypertension and, 397 treatment of, 396t ventricular myocardium in, 373 Systolic performance, 63–64 Systolic strain, 369 Systolic torsion, 55

T Tachycardia, 136, 198, 338 Tc-99m radiolabeled agents, 109, 112 Tei index aortic stenosis eﬀects on, 195 cardiac resynchronization therapy eﬀects on, 376 carvedilol eﬀects on, 197 deﬁnition of, 250 description of, 193–194 in dilated cardiomyopathy, 195 Doppler echocardiography measurements, 194 formula for, 194 left ventricular diastolic ﬁlling pressure, 196 limitations of, 198 load dependency of, 195 measurement of, 194–195 primary pulmonary hypertension and, 197 prognostic utility of, 195–196 pulmonary capillary wedge pressure and, 198f right ventricular function evaluations, 197 tachycardia evaluations, 198

Index Tetralogy of Fallot, 324–325 Thermodilution catheter, 284 Thiazide diuretics, 420 Thyroid hormone analog, 438 Tissue Doppler imaging afterload increase eﬀects on, 323, 324t age eﬀects on, 320f in children, 316–318 constrictive pericarditis evaluations, 158, 307–308 conventional Doppler versus, 220 deﬁnition of, 220 description of, 16, 16f diabetes mellitus evaluations, 160 diastolic function evaluations, 220 dilated cardiomyopathy evaluations, 157–158, 250 formats of, 220 hypertrophic cardiomyopathy evaluations, 159 ischemic heart disease evaluations, 157 left ventricular diastolic function assessments, 254 left ventricular end diastolic dimension eﬀects on, 321f left ventricular ﬁlling pressure evaluations, 157 left ventricular relaxation assessments, 156–157 mitral annular velocities evaluated with, 133–134 myocardial velocities, 158 myocardial velocity recording using, 176 parameters, 160 preload increase eﬀects on, 322t restrictive cardiomyopathy evaluations, 158 subclinical disease versus hypertrophic cardiomyopathy, 293 transplant rejection evaluations, 160 velocities, 153–155, 154f Tissue inhibitors of metalloproteinases, 236, 392, 392t, 438 Tissue necrosis factor-alpha, 349 Titin, 86 Torsion imaging, 224 Transesophageal echocardiography, 175 Transmitral A velocity, 184 Transmitral E velocity, 186 Transmitral ﬂow, 51f Transmitral gradient, 47, 49 Transmitral velocity deceleration time, 77 determinants of, 182–183 Doppler recording of, 183f inﬂow, 65f left atrial pressure eﬀects on, 182–183

Transmitral velocity (Continued) left ventricular relaxation and, 185–186 limitation of, 185 relaxation eﬀects on, 182–183 Transmural pressures, 28 Transplant rejection, 160 Transplantation. See Cardiac transplantation Transthyretin, 262 Treppe eﬀect, 17, 119 Tricuspid annular plane systolic excursion, 253 Tricuspid ﬂow velocity, 133 Tricuspid inﬂow, 174–175, 175f Tricuspid regurgitation continuous wave Doppler of, 173 description of, 134 diastolic, 138 hepatic venous ﬂow in, 177f jet velocity, 173, 174f Trientine, 437 Triglycerides, 393 α-Tropomyosin, 289 Troponin C, 4 Troponin I, 289 Troponin T, 288–289 Troponin-tropomyosin complex, 4 T-tubules, 5 Tumor necrosis factor-alpha, 392 Two-dimensional echocardiography constrictive pericarditis evaluations, 305, 305f Fabry’s disease, 270f left ventricular ﬁlling pressure evaluations, 181–182 mitral ﬂow velocity patterns evaluated with, 132–133

U Urocortin, 349

V Valsalva maneuver, 121, 226f, 227f, 226–227 Valvular heart disease aortic insuﬃciency, 240–241 aortic stenosis, 241 description of, 239–240, 358 mitral stenosis, 242 Vascular stiﬀness, 82, 84 Vasoactive hormones, 345 Vasodilators, 352, 410 Vasopressin, 347 Vasopressin receptor antagonists, 436

Ventricular compliance, 49 Ventricular contractility, 369 Ventricular dyssynchrony, 380 Ventricular function deﬁnition of, 368 left ventricular ejection fraction. See Left ventricular ejection fraction Ventricular hypertrophy. See also Left ventricular hypertrophy in congenital heart disease, 323 drugs that target, 410 Ventricular remodeling. See Left ventricular remodeling Ventricular septal defects, 320 Ventricular stiﬀness abnormal, 404 age-related increases in, 403, 405f assessment of, 77–78 causes of, 406 deﬁnition of, 374 diastolic function and, 16, 83 future research of, 410 noninvasive assessment of, 78 quantiﬁcation of, 16 therapeutic strategies for, 409–410 Ventricular-arterial stiﬀening. See also Arterial stiﬀening abnormal, 404 cardiac work aﬀected by, 408 endothelial mechanosignaling, 408 exercise reserve and, 409 future research of, 410 in heart failure with preserved ejection fraction, 405–406 pathophysiology of, 407–409 Ventricular-vascular stiﬀening mechanisms of, 406–407 treatment of, 409–410 Verapamil, 111, 210, 211f, 295, 416t, 423 Voltage-gated L-type channels calcium inﬂux through, 4 description of, 3 phosphorylation of, 4

W Wilson’s disease, 437 Women angiotensin-converting enzyme inhibitor use in, 422 ejection fraction in, 386, 387f heart failure with preserved ejection fraction in, 407

451