Myocardial protection

Myocardial Protection

This book is dedicated to our wives Michelle Ricci and Helen Salerno

MyocardialT Protection EDITED BY

Tomas A. Salerno, MD Professor and Chief Division of Cardiothoracic Surgery University of Miami Jackson Memorial Hospital Miami, Florida

and

Marco Ricci, MD Assistant Professor of Surgery Division of Cardiothoracic Surgery Staff Surgeon, Section of Pediatric Cardiac Surgery University of Miami Jackson Memorial Hospital Miami, Florida

Blackwell Publishing

Futura, an imprint of Blackwell Publishing

© 2004 by Futura, an imprint of Blackwell Publishing Blackwell Publishing, Inc./Futura Division, 3 West Main Street, Elmsford, New York 10523, USA Blackwell Publishing, Inc., 350 Main Street, Maiden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia All rights reserved. No part of this publication may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review. 0304050654321 ISBN: 1-4051-1643-9 Library of Congress Cataloging-in-Publication Data Myocardial protection / edited by Tomas A. Salerno and Marco Ricci. — Isted. p.; cm. Includes bibliographical references and index. ISBN 1-4051-1643-9 1. Heart—Surgery—Complications—Prevention. 2. Myocardium. 3. Cardiac arrest, Induced. 4. Myocardial reperfusion. 5. Re-perfusion injury—Prevention. I. Salerno, Tomas A. II. Ricci, Marco, M.D. [DNLM: 1. Cardiovascular Surgical Procedures—methods. WG168M99582004] RD598.M9152004 617.4'l-dc21 2003009294 A catalogue record for this title is available from the British Library Acquisitions: Steven Korn Production: Julie Elliott Typesetter: Graphicraft Ltd, Hong Kong Printed and bound in Great Britain by CPI Bath, Bath For further information on Blackwell Publishing, visit our website: www.futuraco.com www.blackwellpublishing.com Notice: The indications and dosages of all drugs in this book have been recommended in the medical literature and conform to the practices of the general community. The medications described do not necessarily have specific approval by the Food and Drug Administration for use in the diseases and dosages for which they are recommended. The package insert for each drug should be consulted for use and dosage as approved by the FDA. Because standards for usage change, it is advisable to keep abreast of revised recommendations, particularly those concerning new drugs.

Contents

List of Contributors, vii Foreword, xi W. Gerard Rainer, MD Preface, xii 1 The History of Myocardial Protection, 1 Anthony L Panos, MD, MSc, FRCSC, FACS 2 The Duality of Cardiac Surgery: Mechanical and Metabolic Objective, 13 Gerald D. Buckberg, MD 3 Modification of Ischemia-Reperfusion-Induced Injury by Cardioprotective Interventions, 18 Ming Zhang, MD, Tamer Sallam, BS, BA, Yan-Jun Xu, PhD, andNaranjan S. Dhalla, PhD, MD (Hon), DSc (Hon) 4 Anesthetic Preconditioning: A New Horizon in Myocardial Protection, 33 Nader D. Nader, MD, PhD, FCCP 5 Myocardial Protection During Acute Myocardial Infarction and Angioplasty, 43 Alexandre C. Ferreira, MD, FACC and Eduardo deMarchena, MD, FACC 6 Intermittent Aortic Cross-Clamping for Myocardial Protection, 53 Fabio Biscegli Jatene, MD, PhD, Paulo M. Pego-Fernandes, MD, PhD, and Alexandre Ciappina Hueb, MD 7 Intermittent Warm Blood Cardioplegia: The Biochemical Background, 59 Ganghong Tian, MD, PhD, TomasA. Salerno, MD, and Roxanne Deslauriers, PhD 8 Warm Heart Surgery, 70 Hassan Tehrani, MB, BCh, Atiq Rehman, MD, Pierluca Lombardi, MD, Mohan Thanikachalam, MD, and Tomas Salerno, MD

9 Intermittent Antegrade Warm Blood Cardioplegia, 75 Antonio Maria Calafiore, MD, Giuseppe Vitolla, MD, and Angela laco, MD 10 Antegrade, Retrograde, or Both?, 82 Frank G. Scholl, MD and Davis C. Drinkwater, MD 11 Miniplegia: Biological Basis, Surgical Techniques, and Clinical Results, 88 Giuseppe D'Ancona, MD, Hratch Karamanoukian, MD, LuigiMartinelli, MD, Michael O. Sigler, MD, and TomasA. Salerno, MD 12 Substrate Enhancement in Cardioplegia, 94 Shafie Fazel, MD, Marc P. Pelletier, MD, and Bernard S. Goldman, MD 13 Is There a Place for On-Pump, Beating Heart Coronary Artery Bypass Grafting Surgery? The Pros and Cons, 119 Simon Fortier, MD, Roland G. Demaria, MD, PhD, FETCS, and Louis P. Perrault, MD, PhD, FRCSC, FACS 14 Myocardial Protection in Beating Heart Coronary Artery Surgery, 126 Vinod H. Thourani, MD and John D. Puskas, MD, MSc 15 Beating Heart Coronary Artery Bypass Grafting: Intraoperative Strategies to Avoid Myocardial Ischemia, 134 Kushagra Katariya, MD, Michael O. Sigler, MD and Tomas A. Salerno, MD 16 Beating Heart Coronary Artery Bypass in Patients with Acute Myocardial Infarction: A New Strategy to Protect the Myocardium, 144 Jan F. Gummert, MD, PhD, Michael A. Borger, MD, PhD, Ardawan Rastan, MD, and Friedrich W. Mohr, MD, PhD

Contents

VI

17 Beating Heart Coronary Artery Bypass with Continuous Perfusion Through the Coronary Sinus, 152 Harinder Singh Bedi, MCh, FIACS 18 On-Pump Beating Heart Surgery for Dilated Cardiomyopathy and Myocardial Protection, 160 Tadashi Isomura, MD and Hisayoshi Suma, MD 19 Myocardial Protection with Beta-Blockers in Valvular Surgery, 167 Nawwar Al Attar, FRCS, MSc, FETCS, Marcio Scorsin, MD, PhD, andArrigo Lessana, MD, FETCS 20 Myocardial Protection in Minimally Invasive Valvular Surgery, 174 Rene Pretre, MD and Marko I. Turina, MD 21 Intermittent Warm Blood Cardioplegia in Aortic Valve Surgery: An Update, 181 M. Saadah Suleiman, PhD, Raimondo Ascione, MD, and Gianni D. Angelini, MD, FRCS 22 Myocardial Protection in Surgery of the Aortic Root, 189 Stephen Westaby, PhD, MS, FETCS 23 Myocardial Protection in Major Aortic Surgery, 193 Marc A. Schepens, MD, PhD and Andrea Nocchi, MD 24 Recent Advances in Myocardial Protection for Coronary Reoperations, 196 Jan T. Christenson, MA, MD, PhD, PD, FETCS and Afksendiyos Kalangos, MD, PhD, PD, FETCS 25 Myocardial Protection During Minimally Invasive Cardiac Surgery, 203 Saqib Masroor, MD, MHS and Kushagra Katariya, MD 26 Current Concepts in Pediatric Myocardial Protection, 207 Bradley S. Allen, MD

27 Myocardial Preconditioning in the Experimental Model: A New Strategy to Improve Myocardial Protection, 230 Eliot R. Rosenkranz, MD, Jun Feng, MD, PhD, and Hong-Ling Li, MD, MSc 28 New Concepts in Myocardial Protection in Pediatric Cardiac Surgery, 264 Bindu Bittira, MD, MSc, Dominique Shum-Tim, MD, MSc, and Christo I. Tchervenkov, MD 29 Extracardiac Fontan: The Importance of Avoiding Cardioplegic Arrest, 275 Carlo F. Marcelletti, MD and Raul F. Abella, MD 30 Preservative Cardioplegic Solutions in Cardiac Transplantation: Recent Advances, 282 Romualdo J. Segurola Jr., MD and Rosemary F. Kelly, MD 31 Myocardial Preservation in Clinical Cardiac Transplantation: An Update, 292 Louis B. Louis IV, MD, Xiao-Shi Qi, MD, PhD, and Si M. Pham, MD, FACS 32 Myocardial Protection During Left Ventricular Assist Device Implantation, 301 Aftab R. Kherani, MD, Mehmet C. Oz, MD, and YoshifumiNaka, MD, PhD 33 Gene Therapy for Myocardial Protection, 304 Said F. Yassin, MD and Christopher G. McGregor, MD 34 Aortic and Mitral Valve Surgery on the Beating Heart, 311 Marco Ricci, MD, Pierluca Lombardi, MD, Michael O. Sigler, MD, Giuseppe D'Ancona, MD and TomasA. Salerno, MD Index, 321

List of Contributors

Raul F. Abel la, MD

Jan T. Christenson, MA, MD, PHD,

Consultant in Cardiac Surgery, Division of Pediatric Cardiovascular Surgery, Ospedale Civico di Palermo, Palermo, Sicily, Italy

PD, FETCS Chief of Clinic, Department of Surgery, Clinic for Cardiovascular Surgery, University Hospital of Geneva, Geneva, Switzerland

Nawwar Al Attar, FRCS, MSc, FETCS Cardiac Surgeon, Department of Cardiac Surgery, Centre Cardiologique du Nord, St. Denis, France

Bradley S. Allen, MD Chief, Division of Pediatric Cardiac Surgery, University of Texas, Houston; Memorial Hermann Children's Hospital, Houston Texas, USA

Gianni D. Angelini, MD, FRCS Bristol Heart Institute, University of Bristol, Bristol, United Kingdom

Raimondo Ascione, MD Bristol Heart Institute, University of Bristol, Bristol, United Kingdom

Harinder Singh Bedi, MCH, FIACS Chief Cardiac Surgeon and Chairman, Cardiovascular Surgery, Metro Heart Institute, Noida, New Delhi, India

Giuseppe D'Ancona, MD Hospital San Martino Geneva, University of Geneva Medical School, Geneva, Italy

Eduardo deMarchena, MD, FACC Professor of Medicine and Surgery, Chief, Interventional Cardiology, University of Miami School of Medicine, Miami, FL, USA

Roland G. Demaria, MD, PHD, FETCS Department of Surgery and Research Center, Montreal Heart Institute, Montreal, Quebec, Canada

Roxanne Deslauriers, PHD Director of Research, Institute for Biodiagnostics, National Research Council, Winnipeg, Manitoba, Canada

Naranjan S. Dhalla, PHD, MD(Hon), DSc (Hon) Distinguished Professor and Director, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada

Bindu Bittira, MD, MSC Chief Resident, Thoracic Surgery, Division of Cardiothoracic Surgery, The Montreal General Hospital, McGill University, Montreal, Quebec, Canada

Davis C. Drinkwater, MD Department of Cardiothoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Michael A. Borger, MD, PHD

Shaf ie Fazel, MD

Leipzig Heart Center, University of Leipzig, Leipzig, Germany

Resident, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada

Gerald D. Buckberg, MD

Alexandre C. Ferreira, MD, FACC

Division of Thoracic and Cardiovascular Surgery, University of California, Los Angeles, Los Angeles, CA, USA

Assistant Professor of Medicine, Coordinator, Interventional Training Program, University of Miami School of Medicine, Miami, FL

Antonio Maria Calaf iore, MD

Simon Fortier, MD

Professor and Chief, Department of Cardiac Surgery, "G. D'Annunzio" Chieti University, Chieti, Italy

Department of Surgery and Research Center, Montreal Heart Institute, Montreal, Quebec, Canada

VII

List of Contributors

VIM

Bernard S. Goldman, MD

Pierluca Lombard!, MD

Surgeon, Division of Cardiovascular Surgery, Sunnybrook and Women's College Health Sciences Centre, Toronto; Professor, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Editor-in-Chief, Journal of Cardiac Surgery

Fellow in Cardiothoracic Surgery, Division of Cardiothoracic Surgery, Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA

Jan F. Gummert, MD, PHD

Louis B. Louis IV, MD Division of Cardiothoracic Surgery, University of Miami School of Medicine, Miami, FL, USA

Leipzig Heart Center, University of Leipzig, Leipzig, Germany

Carlo F. Marcel letti, MD

Alexandre Ciappina Hueb, MD

Cardiovascular Surgeon-in-Chief, Division of Pediatric Cardiovascular Surgery, Ospedale Civico di Palermo, Palermo, Sicily, Italy

Department of Thoracic and Cardiovascular Surgery, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil

Angela lacd, MD Staff Surgeon, Department of Cardiac Surgery, "G. D'Annunzio" Chieti University, Chieti, Italy

Tadashi Isomura, MD Director, Cardiovascular Surgery, Hayama Heart Center, Hayama, Kanagawa, Japan

Fabio Biscegli Jatene, MD, PHD Department of Thoracic and Cardiovascular Surgery, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil

Luigi Martinelli, MD Hospital San Martino Genova, University of Geneva Medical School, Genova, Italy

Saqib Masroor, MD, MHS Division of Thoracic and Cardiovascular Surgery, University of Miami, Jackson Memorial Hospital, Miami, FL, USA

Christopher G. McGregor, MD Mayo Clinic Foundation, Rochester, MN, USA

Friedrich W. Mohr, MD, PHD Leipzig Heart Center, University of Leipzig, Leipzig, Germany

Af ksendiyos Kalangos, MD, PHD,

Nader D. Nader, MD, PHD, FCCP

PD, FETCS Chief of Service, Department of Surgery, Clinic for Cardiovascular Surgery, University Hospital of Geneva, Geneva, Switzerland

Associate Professor of Anesthesiology, Surgery, Pathology, and Anatomical Sciences, State University of New York at Buffalo; Chief, Perioperative Care and Anesthesia, Upstate VA Healthcare System, Buffalo, NY, USA

Hratch Karamanoukian, MD

Yoshifumi Naka, MD, PHD

Center for Less Invasive and Robotic Heart Surgery, Kaleida Health, Buffalo, NY, USA

Kushagra Katariya, MD Division of Cardiothoracic Surgery, University of Miami, Jackson Memorial Hospital, Miami, FL, USA

Rosemary F. Kelly, MD

Herbert Irving Assistant Professor of Surgery, Director, Mechanical Circulatory Support, Columbia University, College of Physicians and Surgeons, New York, NY, USA

Andrea Nocchi, MD Cardiothoracic Surgeon, Department of Cardiac Surgery, Ospedale Carlo Poma, Mantova, Italy

Mehmet C. Oz, MD

Assistant Professor of Surgery, University of Minnesota, Cardiovascular and Thoracic Surgery, Minneapolis, MN, USA

Associate Professor of Surgery, Director, The Cardiovascular Institute, Columbia University, College of Physicians and Surgeons, New York, NY, USA

Aftab R. Kherani, MD

Anthony L. Panos, MD, MSC, FRCSC,

Resident in General Surgery, Duke University Medical Center, Durham, NC; Research Fellow, Division of Cardiothoracic Surgery, Columbia University, College of Physicians and Surgeons, New York, NY, USA

FACS Division of Cardiothoracic Surgery, William S. Middleton VA Medical Center; Associate Professor, University of Wisconsin at Madison, Madison, WI, USA

Arrigo Lessana, MD, FETCS

Paulo M. Pego-Fernandes, MD, PHD

Chief of Surgery, Department of Cardiac Surgery, Centre Cardiologique du Nord, St. Denis, France

Department of Thoracic and Cardiovascular Surgery, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil

List of Contributors

IX

Marc P. Pel letter, MD

Tamer Sal lam, BS, BA

Surgeon, Division of Cardiovascular Surgery, Sunnybrook and Women's College Health Sciences Centre, Toronto; Assistant Professor, Department of Surgery, University of Toronto, Toronto, Ontario, Canada

Research Fellow, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada

Louis P. Perrault, MD, PHD, FRCSC, FACS

Department of Cardiothoracic Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands

Department of Surgery and Research Center, Montreal Heart Institute, Montreal, Quebec, Canada

Si M. Pham, MD, FACS Director, Section of Cardiopulmonary Transplantation, Division of Cardiothoracic Surgery, University of Miami School of Medicine, Miami, FL

Rene Pretre, MD Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland

John D. Puskas, MD, MSC Associate Professor of Surgery, Carlyle Fraser Heart Center, Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA

Marc A. Schepens, MD, PHD Frank G. Scholl, MD Department of Cardiothoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Marcio Scorsin, MD, PHD Cardiac Surgeon, Department of Cardiac Surgery, Centre Cardiologique du Nord, St. Denis, France

Romualdo J. Segurola Jr., MD Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, MN, USA

Michael O. Sigler, MD Department of Surgery, University of Miami, Jackson Memorial Hospital, Miami, FL, USA

Xiao-Shi Qi, MD, PHD

Dominique Shum-Tim, MD, MSC

Division of Cardiothoracic Surgery, University of Miami School of Medicine, Miami, FL, USA

Staff Surgeon, The Montreal Children's Hospital; Staff Surgeon, The Montreal General Hospital; Assistant Professor of Surgery, McGill University, Montreal, Quebec, Canada

W. Gerard Rainer, MD Distinguished Clinical Professor of Surgery, University of Colorado Health Sciences Center; Past President and Historian, Society of Thoracic Surgeons

Ardawan Rastan, MD Leipzig Heart Center, University of Leipzig, Leipzig, Germany

Atiq Rehman, MD Fellow in Cardiothoracic Surgery, Division of Cardiothoracic Surgery, Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA

Marco Ricci, MD Assistant Professor of Surgery, Division of Cardiothoracic Surgery, University of Miami, Jackson Memorial Hospital, Miami, FL, USA

Eliot R. Rosenkranz, MD Director, Section of Pediatric Cardiac Surgery, Associate Professor of Surgery, University of Miami, Jackson Memorial Hospital, Miami, FL, USA

Tomas A. Salerno, MD Professor and Chief, Division of Cardiothoracic Surgery University of Miami, Jackson Memorial Hospital, Miami, FL, USA

M. Saadah Suleiman, PHD Bristol Heart Institute, University of Bristol, Bristol, United Kingdom

Hisayoshi Suma, MD Honored Director, Cardiovascular Surgery, Hayama Heart Center, Hayama, Kanagawa, Japan

Christo I. Tchervenkov, MD Director, Cardiovascular Surgery, The Montreal Children's Hospital, Montreal, Quebec, Canada

Hassan Tehrani, MB, BCH Fellow in Cardiothoracic Surgery, Division of Cardiothoracic Surgery, Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA

Mohan Thanikachalam, MD Fellow in Cardiothoracic Surgery, Division of Cardiothoracic Surgery, Daughtry Family Department of Surgery, University of Miami, Miami, FL, USA

Vinod H. Thourani, MD Resident in Cardiothoracic Surgery, Carlyle Fraser Heart Center, Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA

List of Contributors

Ganghong Tian, MD, PHD

Yan-Jun Xu, PHD

Associate Research Officer, Institute for Biodiagnostics, National Research Council, Winnipeg, Manitoba, Canada

Research Scientist, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada

Marko I. Turina, MD Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland

Giuseppe Vitolla, MD Staff Surgeon, Department of Cardiac Surgery, "G. D'Annunzio" Chieti University, Chieti, Italy

Stephen Westaby, PHD, MS, FETCS Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom

Said F. Yassin, MD Division of Cardiothoracic Surgery, University of Miami School of Medicine, Miami, FL, USA

Ming Zhang, MD Research Fellow, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada

Foreword

When open heart surgery became a possibility onehalf century ago, it seems that considerable attention was directed toward protection of the body as a whole (perhaps it was assumed that this would take care of the needs of the heart as well). Hypothermia, partial perfusion, intermittent aortic cross-clamping and a variety of other techniques were thought to suffice until careful observers noted occurrence of such events as "stone heart," subendocardial ischemia, and other manifestations of inadequate myocardial protection. This dramatically demonstrated that the heart could not be treated as just any other organ or part of the body. Its function is so different because of its intricate neuromuscular structure that investigations were begun (and continue until the present) to define the cellular metabolic needs of the heart and to develop ways to meet those needs so that, hopefully, minimal cardiac function will be lost following correction of the underlying abnormality.

Salerno and Ricci have admirably filled a needed niche by pulling together various approaches and modalities for myocardial protection applicable to many different scenarios—the chapter titles speak for themselves in exhibiting the array of situations discussed in detail along with au courant data regarding various methods of protection based upon pioneering investigations by contributors such as Kirklin, Buckberg, and others. This volume is an absolute necessity for cardiac surgeons in training and in practice and is so designed to be an invaluable teaching tool and reference into the foreseeable future. W. Gerard Rainer, MD Distinguished Clinical Professor of Surgery University of Colorado Health Sciences Center Past President and Historian, Society of Thoracic Surgeons

XI

Preface

Cardiac surgery has undergone major changes in the recent past. With changes came new knowledge, technology and progress, all aimed at providing better care to our patients. Fundamentally, however, cardiac surgery "is myocardial protection," the realization that no matter how perfect the reparative surgery, myocardial function has to be preserved for a short and long-term successful outcome. The pace of technological advancements has accelerated over the last five years, allowing surgeons to perform cardiac surgery differently and more comfortably. For each procedure, there is the need for different technology, such as devices, valves, suture materials, stabilizers, shunts, blowers, and others. One factor, however, has remained constant, i.e. the need for individualization for a specific method of myocardial protection tailored to each operation. It is in this spirit that the editors of this book felt the

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need to put together a collection of manuscripts written by experts in the different fields of myocardial protection. The idea is to give the reader an up-to-date view of how myocardial protective strategies are being utilized by surgeons performing different procedures. Although it was recognized that the past plays a major role in current methods of myocardial protection, the book was intentionally aimed at the present and the future. The editors are grateful to all the authors and co-authors who wrote this modern book. Their tasks were time consuming, aside from their daily work as clinicians and scientists. It is a tribute to them that the publishers were able to print a textbook that is up to date with current knowledge regarding myocardial protection. TomasA. Salerno, MD Marco Ricci, MD

CHAPTER 1

The history of myocardial protection Anthony L Panos, MD, MSC, FRCSC, FAGS

Introduction The history of myocardial protection is a rich and varied story that encompasses the work of basic scientists and clinicians working in different countries over many years. It is an excellent example of clinical problems stimulating basic research and then translating that knowledge back "from the bench to the bedside." Many surgeons are aware of the famous quotation by the great 19th century surgeon Theodore Billroth, that "any surgeon who operates upon the heart, should lose the respect of his colleagues." At the time that Billroth made that statement, cardiac surgery was indeed very hazardous because knowledge and techniques were not available to make it safe. The ensuing years saw a growth in knowledge and new technology that led to the development of modern cardiac surgery as we currently practice it. Myocardial protection was a key part of these developments that allowed safe cardiac surgery to be performed. The term myocardial protection encompasses more than just cardioplegia, and can be said to include things such as the perioperative management of patients with medical treatment (such as beta-blockers, etc.), or support devices (such as intraaortic balloon pumps), better anesthetic agents, and better hemodynamic management. All of these treatments contribute to making cardiac surgery safer, and to get a sick patient through a major operation. However, for the purposes of our discussion we will focus more on the development of cardioplegia. This is a very large field of research and has been reviewed in several books [1-5] and review articles [6]. In one chapter we will only be able to go over some of the important highlights, and give a general

outline of the work that has brought us to where we are today.

Early cardiac physiology The whole of biologic and medical sciences flowered at the end of the 19th century, as exemplified by the microbiologic discoveries of Pasteur, Koch's postulates, and Claude Bernard's emphasis on homeostasis as a principle, to maintain the "internal milieu" [7]. There were also great advances in physiology, especially cardiac physiology and the understanding of muscle mechanics by Otto Frank [8-10], and Starling [11]. The pioneering work of Sydney Ringer on the effects of electrolytes on the regulation of the heart beat [12-15] is summarized by Toledo-Pereyra [16]. Physiologists in the late 19th century thought about control of cardiac function in terms of myogenic versus neurogenic theories. It was in this atmosphere that Ringer conducted his elegant experiments and showed the effects of various ions on the heartbeat. Ringer's work was initally not appreciated in Europe, but was followed by American physiologists, who extended it [17-21]. As early as 1935, Zwikster and Boyd had shown that the heart could be reversibly arrested using potassium [22]. However, surgeons did not appreciate this physiological research, and the clinical application of this knowledge would occur 20 years later. Cardiovascular physiology continued to expand through the early years of the 20th century, but was carried on largely by zoologists, and physiologists working on problems of basic science. For example, there were studies of the thebesian vein system that would later become especially important to the

CHAPTER 1

technique of retrograde cardioplegia [23-31]. Others studied the electrophysiology [21,32] of the heart, the physiology of coronary blood flow [33-38], myocardial energetics [31,39-41], and the relationships between coronary blood flow and cardiac mechanics [42-44]. All of this important basic science work was crucial to later clinical applications.

Early operations—closed Surgeons returned from the second world war after exposure to military surgery, and had developed an interest in the treatment of traumatic chest wounds [45]. This renewed interest in cardiac surgery led to a great expansion of the specialty in the 1950s. Cardiac surgery developed later than other surgical specialties, largely due to the technical difficulties of operating on the heart. The surgeon could not support the circulation while working on the heart, and this limited the kinds of surgery that could be done upon the heart. As a result, the early operations for cardiac disease consisted mostly of extracardiac procedures, such as the ligation of a patent ductus arteriosus by Gross and Hubbard [46], and the revolutionary work of Blalock and Taussig to create palliative shunts for the treatment of cyanotic congenital heart disease [47]. There were other early attempts to operate on the surface of the heart. These operations included methods to treat ischemic heart disease by increasing the blood flow to the myocardium by creating noncoronary collateral blood supply to the heart. Pericardial adhesions were created, for example, by means of pericardial irritation, or by covering the heart with omentum after epicardial and pericardial abrasion [48-50]. Some investigators studied the effects of coronary sinus ligation in animal models in an effort to impede venous outflow and thereby improve coronary artery perfusion of myocardium [27-29,51]. Dr Claude Beck developed an operation to "revascularize" the heart using the cardiac venous system [48-50]. The Beck operation created a venous bypass to the epicardial veins of the heart and subsequent ligation of the coronary sinus [52-56]. It is remarkable how much Beck achieved with the limited technology available to him, and how prescient his work was, predicting that surgery would become important in the treatment of angina pectoris. There were also some closed operations performed, such as mitral commissurotomy for the treatment

of mitral valve stenosis [57-59] or pulmonary valve stenosis [60]. There were a variety of ingenious operations done through artificial "wells," for example, to allow closure of an atrial septal defect "underwater" [61]. All of these operations reflected the limits of the technology of their time. Most were very ingenious, and in many ways ahead of their time. However, in the final analysis they all required the ability to support the circulation to make the breakthroughs that they were seeking.

Early operations—open Experimental work using inflow occlusion to allow work within the heart (i.e. "open" operations) found that brain injury occurred when the cerebral blood flow was interrupted. The irreversible brain injury occurred with interruptions of about 4 min duration. Bigelow first proposed the use of hypothermia during cardiac surgery in 1950 [62]. This led Bigelow, Swan, Boerema, and others to investigate the use of hypothermia in cardiac surgery [39,62-71]. This laboratory work was then taken into the clinical world and the first intracardiac repairs using systemic hypothermia were reported [67,69,70,72]. However, it is important to note that in these early papers the original intention for the use of hypothermia was to protect primarily the brain, and not the heart. In 1950 Bigelow found that in experimental models the total body oxygen consumption decreased with temperature, and this included myocardial metabolism [62,63]. This data was later expanded and became the rationale for the use of hypothermia as a technique to protect the heart. The crucial technology of artificial circulatory support was developed, principally by the perseverance of Dr John Gibbon [73-75]. The "heart-lung machine" of Gibbon could support the circulation, and this development really allowed cardiac surgery to be done [76]. Surgeons could at last safely support the patient's circulation while working within the heart. However, in order to provide the body's oxygen requirements, high flow rates were needed. This was initially a difficult problem, and stressed the available technology of early oxygenators. Investigators reassessed Bigelow's earlier findings for total body oxygen consumption and temperature dependence. They found that by adding hypothermia, the total body requirements for

History of myocardial protection oxygen were greatly decreased in patients. Therefore, the total flow rates needed to provide the body's oxygen requirements could also be decreased greatly.

Cardioplegia The first use of "elective cardiac arrest" was by Melrose in 1955, who also coined the term "cardioplegia" for the technique [77]. Melrose used a solution containing potassium to remove the transmembrane electrical potential and hence to stop the cardiac impulse and arrest the heart in diastole. However, once again, the paper by Melrose makes it clear that his initial impetus to devise the technique was to reduce the foaming that occurred with the cardiopulmonary machines he was using, in order to reduce air emboli, and not to protect the heart. Also, during the 1950s there was the first use of alternate routes of cardioplegia administration and various temperatures [78-80]. Gott et al. used retrograde perfusion of the heart via the coronary sinus using warm blood with Melrose solution, both experimentally and clinically [78,79]. Lillehei's group also used retrograde perfusion of the coronary sinus with blood during aortic valve surgery [80]. Gradually as experience with the technique increased [81], the long-term effects of Melrose solution became known. Surgeons found that there was late vascular and myocardial injury in these patients [82-88]. As a result, surgeons abandoned the technique. Some surgeons used direct ostial cannulation of the coronary ostia in order to perfuse the heart during surgery. However, reports of ostial stenoses discouraged most surgeons from using this technique [89,90]. In the late 1950s and early 1960s Shumway and Lower reported their work using hypothermic methods to protect the heart [91]. The use of hypothermia became widespread, and combined with intermittent ischemia became the dominant method of myocardial management during cardiac surgery in the USA during the 1960s. Despite the problems with Melrose solution, some surgeons in Europe continued to use and develop cardioplegia [92]. Bretschneider and others continued to develop the methods of cardioplegia based on an "intracellular" electrolyte solution, which reduced transmembrane gradients, and arrested the heart [93-95]. Others, such as Hoelscher, studied the effects of magnesium-procainamide as compared to potassium citrate cardioplegia, and

found that there was no ultrastructural damage with the magnesium-procainamide method [96,97]. Bretschneider also developed the idea of buffering of the cardioplegic solution as an important principle of myocardial protection [92,94]. This continuing work on cardioplegia in Europe was important to the eventual resurgence of interest in America in the 1970s.

Reassessment of myocardial damage In the 1960s surgeons reviewing the complications of cardiac surgery did not consider that the complications were due to the surgery itself. Slowly data accumulated that questioned this prevailing concept. In 1967, Taber's group reported that there was myocardial necrosis following cardiac surgery [98]. He found that patchy necrosis affected as much as 30% of the myocardium. In a paper by Najafi's group, the authors found that there was subendocardial necrosis seen in patients who underwent valve surgery, with normal coronary arteries [99]. In the setting of double valve operations Cooley et al. first described the condition of "stone heart" [100]. This was seen when the ischemic time was prolonged, and the hearts went into a state of ischemic contracture. Other investigators also found that patients undergoing valve surgery, who had otherwise normal coronary arteries, had perioperative myocardial infarction [101,102]. Storstein et al. studied the mechanisms of these infarctions [103]. In other studies, patients undergoing atrial septal defect repair had enzyme evidence of myocardial infarction [104]. This gradually led surgeons to once again question whether the intraoperative myocardial protection was effectively protecting the heart, and whether they could improve their techniques.

Reintroduction of cardioplegia Some investigators, such as Tyers, identified the problems with Melrose solution as toxicity due to inappropriately high ionic concentrations, rather than due to the idea of electromechanical arrest in and of itself [105,106]. In 1973 Gay and Ebert pioneered the reintroduction of cardioplegia using crystalloid solutions with much lower concentrations of KC1, which were just sufficient to give electromechanical arrest [107]. In 1974 Hearse's group reported their experimental work with a potassium chloride solution

CHAPTER 1

[108]. In 1976 another paper extended this work [109]. These experimental papers led to the development of cardioplegic solutions for clinical use, such as the St Thomas' solution [108-112], which was first used clinically in 1976 [ 110]. A great deal of work ensued on the various components of cardioplegia solutions, on what should be included in the solutions, and in what concentrations. Many papers were written on the proper use and concentrations of buffers, Mg2+, Ca2+, acid-base balance, local anesthetics, and even oxygen. Some investigators wanted to deliver oxygen during the arrest period and introduced oxygen into the cardioplegia solutions to "oxygenate" them [113,114]. There was even interest in the use of artificial solutions such as fluorocarbons for cardioplegia because of their oxygen-carrying capacity [115-118].

Blood cardioplegia The interest in delivering oxygen and buffering the cardioplegia solution led investigators to question whether the best buffer and oxygen-carrying could be achieved by blood itself. Dr Gerald Buckberg's group working at UCLA did a large amount of experimental work that led to the development of blood cardioplegia in the late 1970s [119]. Other surgeons were also interested in the technique [120-122], its use spread, and it became widely adopted as a cardioplegic method during the 1980s. Nevertheless, there are many proponents of crystalloid cardioplegia [113,114,123], and other methods of myocardial protection such as fibrillatory arrest [124,125], who continue to use their methods with good results. Dr Buckberg's group continued to work on myocardial protection and developed several very important techniques. Their work asked whether we could use cardioplegia not merely to prevent damage, but also to act as a form of treatment, and to reverse injury to the myocardium. They reported the use of warm blood cardioplegia given to induce cardiac arrest and replenish highenergy phosphates in energy-depleted hearts before giving cold cardioplegia [126]. This is important in chronically ill patients, and also those suffering from acute ischemia [127]. This led to investigations altering the conditions of reperfusion (pressure, temperature, etc.) at the end of the arrest period. The use of terminal warm

cardioplegia, the so-called terminal "hot-shot," was confirmed experimentally [128] and clinically [129] to be advantageous to myocardial metabolism. Buckberg's group also investigated the use of amino acids in the cardioplegia to provide substrates for Kreb's cycle [ 130]. This method of substrate enhancement has been shown to be beneficial clinically, reducing the need for inotropic support or the use of the intraaortic balloon pump [131-133]. This work also led to the development of "secondary" blood cardioplegia to resuscitate poorly functioning injured hearts at the end of the operation with a further period of warm cardioplegic arrest [ 134,135].

Continuous cardioplegia Salerno's group at the University of Toronto was interested in myocardial protection, both experimentally and clinically. They questioned whether surgeons could avoid ischemia altogether [136]. Several investigators had used continuous cold blood cardioplegia, in patients undergoing valve surgery [137], in acute postinfarction mitral regurgitation [138], and in patients with ventricular hypertrophy [139]. The use of continuous blood cardioplegia was done in an effort to provide oxygen and substrate throughout the operation. This eventually led to questions about the ability to deliver oxygen at lower temperatures. It was well known that the oxygen-hemoglobin dissociation curve was shifted to the right by hypothermia, and interfered with unloading of oxygen at the cellular level. The question was "Did we need hypothermia"? If we used a warm induction dose of cardioplegia, cold in the middle, and a "hot-shot" at the end, did we really need the cold in the middle? Ali has summarized the theoretical background and rationale of the technique [ 140,141 ]. After Salerno reintroduced the use of continuous normothermic blood cardioplegia [142], initial experimental [143] and clinical [144-146] work led to renewed interest in the technique. It led to the development of new technology in order to use the technique to advantage. Visualization could be difficult, so a variety of "blowers" were developed to aid the surgeon [147,148]. Some investigators developed the use of equipment to monitor the adequacy of perfusion during the operation. Other groups explored the physiological limits of the technique. Could the flow be interrupted, and if so, for how long? This was studied experimentally [149,150] and clinically [151-154].

History of myocardial protection performed from the aorta to the coronary sinus. This was modified by the ligation of the coronary sinus to facilitate retroperfusion of the myocardium (the Beck II operation). By 1954 Beck had performed the operation on 43 patients and symptoms of angina were improved in 88% [176]. However, it was a difficult operation to perform using the technology then available. The difficulty of the operation, early surgical failures, and deaths led to the abandonment of the procedure. In 1956 the pioneering work in cardiac surgery from the University of Minnesota extended to the Retrograde cardioplegia investigation of cardiac perfusion and cardioplegia. There was a resurgence of interest in coronary sinus Gott and Lillehei first used retrograde continuous retroperfusion of the heart in the early 1980s, led by normothermic blood cardioplegia in a dog model Gundry, Chitwood, Menasche, Fabiani, Carpentier, [78] using potassium citrate blood cardioplegia as Fuentes, and Chiu, among others. Coronary sinus per- described by Melrose. They also went on to use the fusion was used initially with crystalloid cardioplegia, technique clinically in valve surgery [79,80]. However, and then with blood cardioplegia, and both were used as outlined above, other technical developments "cold." However, the need to deliver cardioplegia in superceded this technique. Work continued on retroperfusion in experimental a near continuous fashion for the normothermic techniques of warm heart surgery led some surgeons models. In 1967 Hammond et al. found that retroto reexamine the retrograde route of administration perfusion provided some myocardial protection dur[161,162]. It had been used by surgeons sporadic- ing coronary artery ligation in dogs [177]. In 1973 ally over the years [163—169], but became much more Lolley et al. found that retroperfusion with substrate wide-spread after the upsurge in interest in normo- enhancement gave better protection during normothermic ischemic arrest [178]. The technique of thermic techniques. Thebesius first described the anatomy of the coro- retroperfusion of the heart was picked up again clinicnary veins in 1708 [170], and this was studied further ally in the following decade. There were several studies done to assess the by Abernathy in 1798 and Langer in 1880. This led to the work by Pratt in 1898, in which the feline heart adequacy of retrograde coronary sinus perfusion for was supported with retrograde perfusion alone for protection of the heart, and it was especially important up to 1 h [23]. In 1928 Wearn showed that coronary with the normothermic blood cardioplegia technique veins communicate with thebesian veins [24-26], and because of the question of right ventricle protection in 1929 Grant found that effluent drained into both [163,179-182]. Most surgeons today have had some ventricles. Katz showed great variability in venous experience with the retrograde route of cardioplegia anatomy in 1938 [38]. In the same year, Gregg showed administration, and many would advocate its use that there was increased backflow through the coron- in redo surgery or valvular surgery. Some surgeons, ary arteries when the coronary sinus was ligated [27]. such as Buckberg and Salerno, have also advocated the In 1943 Roberts performed dye injection of the coron- use of simultaneous antegrade and retrograde delivery ary sinus, and found filling of the coronary arteries of cardioplegia to better perfuse all capillary beds [171,172]. This suggested that the heart could be [181,183-185]. nourished via retrograde perfusion, and maybe useful in the treatment of myocardial ischemia. Other subgroups of patients Dr Claude Beck tested these hypotheses in 1945. Beck was an early proponent of coronary sinus inter- The growth of cardiac surgery led investigators to try vention [48,52-55,173-175]. He found a decrease to improve myocardial protection in various subin the size of an experimental myocardial infarction groups of patients. In particular, some subgroups with ligation of the coronary veins to that area. This have a higher mortality rate, such as patients at the led to the "Beck operation," in which a bypass was extremes of age, both the very young and the very old. There was initially some concern about the issue of neurologic protection [155]. However, other investigators found that the neurologic threat was not seen in their studies [156-160]. A great deal of work ensued concerning the use of normothermic techniques. This was summarized in a monograph [5]. After the initial flush of enthusiasm, the technique has found its niche, and shown that myocardial protection can be achieved with methods other than hypothermia, which had become so deeply entrenched.

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There has been research in optimizing the methods of myocardial protection in these more extreme groups. Patients undergoing the repair of congenital heart defects often have multiple abnormalities, not just cardiac ones. In addition, there is some evidence that the myocardium of these patients may be different from normal on a cellular level. Pediatric heart surgeons have carried out work to improve the protection of the heart during repair of congenital lesions in immature and newborn children [186-196]. The population in western countries is increasingly aging. Cardiac surgeons are operating on older patients, with more comorbidities. This group of patients also poses special challenges for myocardial protection. Several investigators have studied the changes associated with aging, and the effects on myocardial protection [197-201]. The "senescent" myocardium changes as it ages, and several studies suggest we may get better myocardial protection in this age group by altering the cardioplegia ingredients, or by changing our strategy. There was also an enthusiasm for alternative methods of achieving cardiac arrest that use potassium channel "openers" to remove the transmembrane potential [202-206]. Further work needs to be done before we better understand the role of this technique.

Summary One could consider that the whole field of myocardial protection has gone almost full circle as the emphasis has returned to the avoidance of ischemia. The other chapters in this book will address each topic more fully, but one might view the return of beating heart surgery as the best way to avoid ischemia altogether. This is certainly a promising area for research, both with regards to myocardial protection and neurological functioning. We may see a change in emphasis as we adopt the new paradigm of "off-pump" surgery, but we will still need the basic concepts of myocardial protection, even in that setting. We will also need to use methods of circulatory support and myocardial protection for "open" procedures, such as valve surgery or intracardiac repairs of congenital defects, for the foreseeable future. There will still be a need for myocardial protection. The topic of myocardial protection is very large. In this chapter we have given only an overview. It is a story that continues to evolve, and is not yet com-

pleted. The history of this topic was written, and continues to be written, by the contributors to this book.

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61 Gross RE, Watkins E, Pomeranz AA, Goldsmith El. A method for surgical closure of interauricular septal defects. Surg Gynecol Obstet 1953; 96:1-24. 62 Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia its possible role in cardiac surgery. An investigation of factors governing survival in dogs at low body temperatures. Ann Surg 1950; 132: 849-66. 63 Bigelow WG, Lindsay WK, Harrison RC, Gordon RA, Greenwood WF. Oxygen transport and utilization in dogs at low body temperature. Am J Physiol 1950; 160: 125-37. 64 Bigelow WG, Callaghan JC, Hopps JA. General hypothermia for experimental intracardiac surgery. Ann Surg 1950; 132: 531-40. 65 Boerema I, Wildschut A, Schmidt WJH, Broekhuysen L. Experimental researches into hypothermia as an aid in the surgery of the heart. Arch Chir (Neerl) 1951; 3: 25-34. 66 Cookson BA, Neptune WB, Bailey CP. Hypothermia as a means of performing intracardiac surgery under direct vision. Dis Chest 1952; 22: 245-60. 67 Swan H, Zeavin I, Blount SG, Jr, Virtue RW. Surgery by direct vision in the open heart during hypothermia. JAMA 1953; 153:1081-5. 68 Swan H, Zeavin I, Holmes JH, Montgomery V. Cessation of circulation in general hypothermia. I. Physiologic changes and their control. Ann Surg 1953; 138:360-76. 69 Bigelow WG, Mustard WT, Evans JG. Some physiological concepts of hypothermia and their application to cardiac surgery. / Thorac Cardiovasc Surg 1954; 28:463. 70 Swan H, Zeavin I. Cessation of circulation in general hypothermia: techniques of intracardiac surgery under direct vision. Ann Surg 1954; 139: 385. 71 Andjus RK, Smith AN. Reanimation of adult rats from body temperatures between 0 and +2°C. / Physiol 1955; 128:446. 72 Lewis FJ, Taufic M. Closure of atrial septal defects with the aid of hypothermia: experimental accomplishments and the report of one successful case. Surgery 1953; 33: 52-9. 73 Gibbon JH. Artificial maintenance of circulation during experimental occlusion of pulmonary artery. Arch Surg 1937;34:1105-31. 74 Gibbon JH. Application of mechanical heart and lung apparatus to cardiac surgery. Minn Med 1954; 37: 171-85. 75 Miller BJ, Gibbon JH, Gibbon MH. Recent advances in the development of a mechanical heart and lung apparatus. Ann Surg 1951; 134: 694. 76 Melrose DG. A history of cardiopulmonary bypass. In: Taylor KM, ed. Cardiopulmonary Bypass: principles and management. Baltimore: Williams & Wilkins, 1986: 1-12. 77 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Elective cardiac arrest. Lancet 1955; ii: 21-2. 78 Gott VL, Gonzalez JL, Paneth M et al. Cardiac retroperfusion with induced asystole for open surgery upon the aortic valve or coronary arteries. Proc Soc Exp Biol Med 1957; 94:689-92.

79 Gott VL, Gonzalez JL, Zuhdi MN, Varco RL, Lillehei CW. Retrograde perfusion of the coronary sinus for direct vision aortic surgery. Surg Gynecol Obstet 1957; 104:319-28. 80 Lillehei CW, DeWall RA, Gott VL, Varco RL. The direct vision correction of calcine aortic stenosis by means of a pump-oxygenator and retrograde coronary sinus perfusion. Dis Chest 1956; 30:123-32. 81 Gerbode F, Melrose DG. The use of potassium arrest in open cardiac surgery. Am J Surg 1958; 96:221-7. 82 Allen P, Lillehei CW. Use of induced cardiac arrest in open-heart surgery. Minn Med 1957; 40:672. 83 Bjork VO, Fors B. Induced cardiac arrest. / Thorac Cardiovasc Surg 1961; 41: 387-94. 84 MacFarland JA, Thomas LB, Gilbert JW, Morrow AG. Myocardial necrosis following elective cardiac arrest induced with potassium citrate. / Thorac Cardiovasc Surg 1960; 40:200-8. 85 Nunn DD, Belisle CA, Lee WH. A comparative study of aortic occlusion alone and of potassium citrate arrest during cardiopulmonary bypass. Surgery 1959; 45: 848. 86 Waldhausen JA, Braunwald NS, Bloodwell RD, Cornwell WP, Morrow AG. Left ventricular function following elective cardiac arrest. / Thorac Cardiovasc Surg 1960; 39: 799-807. 87 Willman VL, Cooper T, Zafiracopoulos P, Hanlon CR. Depression of ventricular function following elective cardiac arrest with potassium citrate. Surgery 1959; 46: 792-6. 88 Hoelscher B, Just OH, Merker HF. Studies by electron microscopy on various forms of induced cardiac arrest in dog and rabbit. Surgery 1961; 49:492-9. 89 Midell AI, Deboer A, Bermudez G. Post perfusion coronary ostial stenosis. / Thorac Cardiovasc Surg 1976; 72:80-5. 90 Pennington DG, Dencer B, Beshiti H et al. Coronary artery stenosis following aortic valve replacement and intermittent intracoronary cardioplegia. Ann Thorac Surg 1982; 33:576-84. 91 Shumway NE, Lower RR. Hypothermia for extended periods of anoxic arrest. SurgForum 1959; 10: 563. 92 Gebhard MM, Bretschneider HJ, Gersing E, Schnabel PA. Bretschneider's histidine-buffered cardioplegic solution. Concept, application and efficiency. In: Roberts AJ, ed. Myocardial Protection in Cardiac Surgery. New York: Marcel Dekker, 1987:95-119. 93 Bretschneider HJ. Uberlenszeit und, Weiderbelebungszeit des, Herzens bei Normo- und Hypothermie. Verh Dtsch GesKreisl-Forsch 1964; 30:11-34. 94 Bretschneider J, Hubner G, Knoll D et al. Myocardial resistance and tolerance to ischemia: Physiological and biochemical basis. J Cardiovasc Surg 1975; 16:241-60. 95 Sondergaard T, Berg E, Staffeldt I, Szcezepanski K. Cardioplegia cardiac arrest in aortic surgery. / Cardiovasc Surg 1975; 16:228-90. 96 Hoelscher B. Studies by electron microscopy on the effects of magnesium chloride-procainamide or potassium citrate on the myocardium in induced cardiac arrest. / Cardiovasc Surg 1967; 8:163-6.

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97 Hoelscher B. Studies by electron microscopy on various forms of induced cardiac arrest in dog and rabbit. Surgery 1967; 49:492-9. 98 Morales AR, Fine G, Taber RE. Cardiac surgery and myocardial necrosis. Arch Pathol 1967; 83: 71-9. 99 Henson DE, Najafi H, Callaghan R et al. Myocardial lesions following open heart surgery. Arch Pathol 1969; 88:423-30. 100 Cooley DA, Reul GJ, Wikasch DC. Ischemic contracture of the heart: "stone heart." Am J Cardiol 1972; 29: 5757. 101 Hultgren HN, Miyagawa M, Buch W, Angell WW. Ischemic myocardial injury during cardiopulmonary bypass surgery. Am Heart} 1973; 85:167-76. 102 Rossiter SJ, Hultgren HN, Kosek JC, Wuerflein RD, Angell WW. Ischemic myocardial injury with aortic valve replacement and coronary bypass. Arch Surg 1974; 109:652-8. 103 Storstein O, Efskind L, Torgersen O. The mechanism of myocardial infarction following prosthetic aortic valve replacement. ActaMedScand 1973; 193:103-8. 104 Hairston P, Parker EF, Arrants JE, Bradham RR, Lee WH, Jr. The adult atrial septal defect: results of surgical repair. Ann Surg 1974; 179: 799-804. 105 Tyers GFO, Todd GJ, Neibauer IM, Manley NJ, Waldhausen JA. The mechanism of myocardial damage following potassium citrate (Melrose) cardioplegia. Surgery 1975; 78:45-53. 106 Todd GJ, Tyers GFO. Potassium induced arrest of the heart: effect of low potassium concentrations. Surg Forum 1975; 26:255-6. 107 Gay WA, Ebert PA. Functional metabolic, and morphologic effects of potassium-induced cardioplegia. Surgery 1973; 74:284-90. 108 Hearse DJ, Stewart DA, Chain EB. Recovery from cardiac bypass and elective cardiac arrest. CircRes 1974; 35: 448-57. 109 Hearse DJ, Stewart DA, Braimbridge MV. Cellular protection during myocardial ischaemia: the development and characterization of a procedure for the induction of reversible ischaemic arrest. Circulation 1976; 54: 193-202. 110 Braimbridge MV, Chayen J, Bitensky L et al. Cold cardioplegia or continuous coronary perfusion? / Thorac Cardiovasc Surg 1977; 74:900-6. 111 Hearse DJ, Stewart DA, Braimbridge MV. Hypothermic arrest and potassium arrest: metabolic and myocardial protection during elective cardiac arrest. Circ Res 1975; 36:481-9. 112 Ledingham SJN, Braimbridge MV, Hearse DJ. The St Thomas' Hospital cardioplegic solution: a comparison of the efficacy of the two formulations. / Thorac Cardiovasc Surg 1987; 93:240-6. 113 Guyton RA, Dorsey LMA, Graver JN et al. Improved myocardial recovery after cardioplegic arrest with an oxygenated crystalloid solution. / Thorac Cardiovasc Surg 1985; 89:877-87. 114 Guyton RA. Oxygenated crystalloid cardioplegia. Sem Thorac Cardiovasc Surg 1993; 5:114-21.

115 Moores WY. The role of blood substitutes in myocardial protection. In: Roberts AJ, ed. Myocardial Protection in Cardiac Surgery. New York: Marcel Dekker, 1987:475-93. 116 Novick RJ, Stefaniszyn HJ, Michel RP, Burdon FD, Salerno TA. Protection of the hypertrophied pig myocardium. A comparison of crystalloid, blood, and Fluosol-DA cardioplegia during prolonged aortic clamping. / Thorac Cardiovasc Surg 1985; 89: 547-66. 117 Stefaniszyn HJ, Novick RJ, Michel RP, Salerno TA. Reaction of subcutaneous tissues to injection of FluosolDA, 20%. Can]Surg 1984; 27:176-8. 118 Stefaniszyn HJ, Wynands JE, Salerno TA. Initial Canadian experience with artificial blood (Fluosol-DA20%) in severely anemic patients. / Cardiovasc Surg 1985; 26: 337-42. 119 Follette DM, Mulder DG, Maloney JV, Jr, Buckberg GD. Advantages of blood cardioplegia over continuous coronary perfusion and intermittent ischemia. / Thorac Cardiovasc Surg 1978; 76:604-19. 120 Earner HB, Laks H, Codd JE et al. Cold blood as the vehicle for potassium cardioplegia. Ann Thorac Surg 1979; 28: 509-16. 121 Earner HB, Kaiser GC, Tyras DH et al. Cold blood as the vehicle for hypothermic potassium cardioplegia. Ann Thorac Surg 1980; 29: 224-30. 122 Engelman RM, Rousou JH, Dobbs W, Pals MA, Longo F. The superiority of blood cardioplegia in myocardial preservation. Circulation 1980; 62 (SupplI): 62-6. 123 Hendry PJ, Masters RG, Haspect A. Is there a place for cold crystalloid cardioplegia in the 1990s? Ann Thorac Surg 1994; 58:1690-4. 124 Akins CW. Noncardioplegic myocardial preservation for coronary revascularization. / Thorac Cardiovasc Surg 1984; 88:174-81. 125 Akins CW. Hypothermic fibrillatory arrest for coronary artery bypass grafting. / Cardiac Surg 1992; 7: 342—7. 126 Rosenkranz ER, Vinten-Johansen J, Buckberg GD et al. Benefits of normothermic induction of cardioplegia in energy-depleted hearts, with maintenance of arrest by multidose cold blood cardioplegic infusions. / Thorac Cardiovasc Surg 1982; 84:667-77. 127 Rosenkranz ER, Buckberg GD, Mulder DG, Laks H. Warm-glutamate blood cardioplegia induction in inotropic, intra-aortic balloon dependent coronary patients in cardiogenic shock. Initial experience and operative strategy. / Thorac Cardiovasc Surg 1983; 86: 507-18. 128 Follette D, Steed D, Foglia R, Fey K, Buckberg GD. Reduction of post ischemic myocardial damage by maintaining arrest during initial reperfusion. Surg forwm!977;28:281-3. 129 Teoh KH, Christakis GT, Weisel RD et al. Accelerated myocardial metabolic recovery with warm blood cardioplegia. / Thorac Cardiovasc Surg 1986; 91: 888-95. 130 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safety of prolonged aortic clamping with blood cardioplegia. Aspartate enrichment of glutamate blood cardioplegia in energy depleted hearts after ischemic and reperfusion injury. / Thorac Cardiovasc Surg 1986; 91:428-35.

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131 Allen BS, Buckberg GD, Schwaiger M et al. Studies of controlled reperfusion after ischemia. XVI. Early recovery of regional wall motion in patients following surgical revascularization after eight hours of acute coronary occlusion. / Thome Cardiovasc Surg 1986; 92: 636-48. 132 Laks H, Rosenkranz ER, Buckberg GD. Surgical treatment of cardiogenic shock after myocardial infarction. Circulation 1986; 74 (Suppl 3): 16-22. 133 Rosenkranz ER, Buckberg GD, Laks H, Mulder DG. Warm induction of cardioplegia with glutamateenriched blood in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intraaortic balloon support. / Thorac Cardiovasc Surg 1983; 86:507-18. 134 Lazar HL, Buckberg GD, Manganaro AM, Becker H. Myocardial energy replenishment and reversal of ischemic damage by substrate enhancement of secondary blood cardioplegia with amino acids during reperfusion. / Thorac Cardiovasc Surg 1980; 80: 350-9. 135 Lazar HL, Buckberg GD, Manganaro AM, Becker H, Maloney JV, Jr Reversal of ischemic damage with amino acid substrate enhancement during reperfusion. Surgery 1980; 88: 702-9. 136 Cusimano RJ, Ashe KA, Salerno PR, Lichtenstein SV, Salerno TA. Oxygenated solutions in myocardial preservation. Cardiac Surg 1988; 2:167-80. 137 Bomfim V, Kaijser L, Bendz R, Sylven C, Olen C. Myocardial protection during aortic valve replacement. Cardiac metabolism and enzyme release following continuous blood cardioplegia. Scand J Thorac Cardiovasc Surg 1981; 15:141-7. 138 Panos A, Christakis GT, Lichtenstein SV et al. Operation for acute postinfarction mitral insufficiency using continuous oxygenated blood cardioplegia. Ann Thorac Surg 1989; 48: 816-19. 139 Khuri SF, Warner KG, Josa M et al. The superiority of continuous cold blood cardioplegia in the metabolic protection of the hypertrophied human heart. / Thorac Cardiovasc Surg 1988; 95:442-54. 140 Ali IS, Al-Nowaiser O, Deslauriers R et al. Continuous normothermic blood cardioplegia. Sem Thorac Cardiovasc Surg 1993; 5:141-50. 141 Ali IS, Panos AL. Origins and conceptual framework of warm heart surgery. In: Salerno TA, ed. Warm Heart Surgery. London: Arnold, 1995:16-25. 142 Salerno TA. Continuous blood cardioplegia. option for the future or return to the past? / Mo/ Cell Cardiol 1990; 22 (Suppl V):S49. 143 Panos A, Kingsley SJ, Hong AP, Salerno TA, Lichtenstein SV. Continuous warm blood cardioplegia. Surg Forum 1990; 41:233-5. 144 Panos A, Ashe K, El-Dalati H et al. Heart surgery with long cross-clamp times. Clin Invest Med 1989; 12 (5 Suppl): C55. 145 Panos A, Ashe K, El-Dalati H et al. Clinical comparison of continuous warm (37°C) versus continuous cold (10°C) blood cardioplegia in CABG surgery. Clin Invest Med 1989; 12(5 Suppl): C55.

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146 Panos A, Abel J, Slutsky AS, Salerno TA, Lichtenstein SV. Warm aerobic arrest: a new approach to myocardial protection. /Mo/ Cell Cardiol 1990; 22 (Suppl V): S31. 147 Maddaus M, Ali IS, Birnbaum PL, Panos AL, Salerno TA. Coronary artery surgery without cardiopulmonary bypass. Usefulness of the surgical blower-humidifier. J Cardiac Surg 1992; 7: 348-50. 148 Teoh KHT, Panos AL, Harmantas AA, Lichtenstein SV, Salerno TA. Optimal visualization of coronary artery anastomoses by gas jet. Ann Thorac Surg 1991; 52:564. 149 Tian G, Xiang B, Butler KW et al. A 31-P nuclear magnetic resonance study of intermittent warm blood cardioplegia. J Thorac Cardiovasc Surg 1995; 108:1155-63. 150 Misare BD, Krukenkamp IB, Caldarone CA, Levitsky S. Can continuous warm blood cardioplegia be safely interrupted. SurgForum 1992; 43:208-10. 151 Ali IM, Kinley CE. The safety of intermittent warm blood cardioplegia. Eur J Cardiothorac Surg 1994; 8: 554-6. 152 Doyle D, Dagenais F, Poirier N, Normandin D, Cartier P. La cardioplegie sanguine «chaude» intermittente. Ann Chir 1992; 46: 800-4. 153 Calafiore AM, Teodori G, Mezzetti A et al. Intermittent antegrade warm blood cardioplegia. Ann Thorac Surg 1995; 59:398-402. 154 Calafiore AM, Mezzetti A. Intermittent antegrade normothermic blood cardioplegia. In: Salerno TA, ed. Warm Heart Surgery. London: Arnold, 1995: 77-89. 155 Martin TD, Graver JM, Gott JP et al. Prospective, randomized trial of retrograde warm blood cardioplegia: myocardial benefit and neurologic threat. Ann Thorac Surg 1994; 57:298-304. 156 Warm Heart Investigators. Randomised trial of normothermic versus hypothermic coronary bypass surgery. Lancet 1994; 343 (8897): 559-63. 157 Wong BI, McLean RF, Naylor CD et al. Centralnervous-system dysfunction after warm or hypothermic cardiopulmonary bypass. Lancet 1992; 339 (8806): 1383-4. 158 Singh AK, Bert AA, Feng WC. Neurological complications during myocardial revascularization using warmbody, cold-heart surgery. Eur J Cardiothorac Surg 1994; 8:259-64. 159 Singh AK, Feng WC, Bert AA, Rotenberg FA. Warm body, cold heart surgery: clinical experience in 2817 patients. Eur J Cardiothorac Surg 1994; 7:225—30. 160 Laursen H, Waaben J, Gefke K et al. Brain histology, blood—brain barrier and brain water after normothermic and hypothermic cardiopulmonary bypass in pigs. Eur] Cardiothorac Surg 1989; 3:539-43. 161 Rashid A, Fabri BM, Jackson M et al. A prospective randomised study of continuous warm versus intermittent cold blood cardioplegia for coronary artery surgery: preliminary report. Eur J Cardiothorac Surg 1994; 8: 265-9. 162 Salerno TA, Houck JP, Barrozo CAM et al. Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection. Ann Thorac Surg 1991; 51: 245-7.

History of myocardial protection

163 Menasche P, Kural S, Fauchet M et al. Retrograde coronary sinus perfusion: a safe alternative for ensuring cardioplegic delivery in aortic valve surgery. Ann Thome Surg 1982; 34:647-58. 164 Fabiani JN, Romano M, Chapelon C et al. La cardioplegie retrograde: etude experimentale et clinique. [Retrograde cardioplegia. experimental and clinical study.] Ann Chir 1984; 38: 513-16. 165 Gundry SR, Kirsh MM. A comparison of retrograde cardioplegia versus antegrade cardioplegia in the presence of coronary artery obstruction. Ann Thome Surg 1984; 38:124-7. 166 Gundry SR, Sequiera A, Razzouk AM, McLaughlin JS, Bailey LL. Facile retrograde cardioplegia. transatrial cannulation of the coronary sinus. Ann Thome Surg 1990; 50: 882-6. 167 Fabiani JN, Deloche A, Swanson J, Carpentier A. Retrograde cardioplegia through the right atrium. Ann Thome Surg 1986; 41:101-2. 168 Guiraudon GM, Campbell CS, McLellan DG et al. Retrograde coronary sinus versus aortic root perfusion with cold cardioplegia. Randomized study of levels of cardiac enzymes in 40 patients. Circulation 1986; 74 (Suppl III): 105-15. 169 Chitwood WR, Jr. Myocardial protection by retrograde cardioplegia: coronary sinus and right atrial methods. Cardiac Surg 1988; 2:197-218. 170 Langer L. Die foramina Thebesii im herzen des menschen. Sitzungsb D KAkad Wissensch Math-Naturw 1880; 82 (3 Abth): 25-39. 171 Roberts JT. Experimental studies on the nourishment of the left ventricle by the luminal (Thebesial) vessels. Fed Prod 943; 2:90. 172 Roberts JT, Browne RS, Roberts G. Nourishment of the myocardium by way of the coronary sinus. Fed Proc 1943; 2:90. 173 Beck CS. The development of a new blood supply to the heart by operation. Ann Surg 1935; 102:801-13. 174 Beck CS. A new blood supply to the heart by operation [editorial]. Surg Gynecol Obstet 1935; 61:407-10. 175 Beck CS. Further data on the establishment of a new blood supply to the heart by operation. / Thome Surg 1936;5:604-11. 176 Beck CS, Leighninger DS. Operations for coronary artery disease. JAMA 1954; 156:1226-33. 177 Hammond GL, Davies AL, Austen WG. Retrograde coronary sinus perfusion. A method of myocardial protection in the dog during left coronary artery occlusion. Ann Surg 1967; 166: 39-47. 178 Lolley DM, Hewitt RL, Drapanas T. Retroperfusion of the heart with a solution of glucose, insulin, and potassium during anoxic arrest. / Thome Cardiovasc Surg 1974; 67: 364-70. 179 Gundry SR, Wang N, Bannon D et al. Retrograde continuous warm blood cardioplegia: maintenance of myocardial homeostasis in humans. Ann Thome Surg 1993;55:358-61. 180 Menasche P, Fleury JP, Droc L etal. Metabolic and functional evidence that retrograde warm blood cardioplegia

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does not injure the right ventricle in human beings. Circulation 1994; 90:11310-15. 181 Partington MT, Acar C, Buckberg GD, Julia PL. Studies of retrograde cardioplegia. II. Advantages of antegrade/ retrograde cardioplegia to optimize distribution in jeopardized myocardium. / Thome Cardiovasc Surg 1989;97:613-22. 182 Stirling MC, McClanahan TB, Schott RJ et al. Distribution of cardioplegic solution infused antegradely and retrogradely in normal canine hearts. / Thome Cardiovasc Surg 1989; 98:1066-76. 183 Ihnken K, Morita K, Buckberg GD et al. The safety of simultaneous arterial and coronary sinus perfusion: experimental background and initial clinical results. J Cardiac Surg 1994; 9:15-25. 184 Hoffenberg EF, YeJ, Sun J, Ghomeshi HR, Salerno TA, Deslauriers R. Antegrade and retrograde continuous warm blood cardioplegia: a 31P magnetic resonance study. Ann ThoracSurg 1995; 60:1203-9. 185 Tian G, Shen J, Sun J et al. Does simultaneous antegrade/retrograde cardioplegia improve myocardial perfusion in the areas at risk? A magnetic resonance perfusion imaging study in isolated pig hearts. / Thome Cardiovasc Surg 1998; 115:913-24. 186 del Nido PJ. Myocardial protection and cardio pulmonary bypass in neonates and infants. Ann Thorac Surg 1997; 64:878-9. 187 Takeuchi K, Nagashima M, Itoh K et al. Improving glucose metabolism and/or sarcoplasmic reticulum Ca2+-ATPase function is warranted for immature pressure overload hypertrophied myocardium. Jpn Circ J 2001;65:1064-70. 188 Gundry SR. Retrograde cardioplegia in infants and children. In: Mohl, W, ed. Coronary Sinus Interventions in Cardiac Surgery. Austin TX: RG Landes, 1994: 6770. 189 Hammon JW, Jr. Myocardial protection in the immature heart. Ann Thorac Surg 1995; 60:839-42. 190 McMahon WS, Gillette PC, Hinton RB et al. Developmental differences in myocyte contractile response after cardioplegic arrest. / Thorac Cardiovasc Surg 1996; 111:1257-66. 191 Rebeyka IM, Hanan SA, Borges MR et al. Rapid cooling contracture of the myocardium. The adverse effect of prearrest cardiac hypothermia. / Thorac Cardiovasc Surg 1990; 100:240-9. 192 Williams WG, Rebeyka IM, Tibshirani RJ et al. Warm induction blood cardioplegia in the infant. A technique to avoid rapid cooling myocardial contracture. / Thorac Cardiovasc Surg 1990; 100: 896-901. 193 Jessen ME, Abd-Elfattah AS, Wechsler AS. Neonatal myocardial oxygen consumption during ventricular fibrillation, hypothermia, and potassium arrest. Ann Thorac Surg 1996; 61:82-7. 194 Abd-Elfattah AS, Ding M, Wechsler AS. Myocardial stunning and preconditioning: age, species, and model related differences: role of AMP-5'-nucleotidase in myocardial injury and protection. / Card Surg 1993; 8 (2 Suppl): 257-61.

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195 Rebeyka IM, Yeh T, Jr, Hanan SA et al Altered contractile response in neonatal myocardium to citratephosphate-dextrose infusion. Circulation 1990; 82 (5 Suppl): IV367-IV370. 196 Mask WK, Abd-Elfattah AS, Jessen M et al. Embryonic versus adult myocardium: adenine nucleotide degradation during ischemia. Ann Thome Surg 1989; 48:109-12. 197 Blanche C, Khan SS, Chaux A et al. Cardiac reoperations in octogenarians, analysis of outcomes. Ann Thorac Surg 1999; 67:93-8. 198 Burns PG, Krukenkamp IB, Caldarone CA et al. Is the preconditioning response conserved in senescent myocardium? Ann Thorac Surg 1996; 61:925—9. 199 Caldarone CA, Krukenkamp IB, Burns PG et al. Blood cardioplegia in the senescent heart. / Thorac Cardiovasc Surg 1995; 109:269-74. 200 Panos AL, Khan SI, Del Rizzo DF et al. Results of cardiac surgery in the elderly using normothermic techniques. Cardiol Elderly 1995; 3:189-92. 201 Amrani M, Chester AH, layakumar J, Yacoub MH. Aging reduces postischemic recovery of coronary

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endothelial function. / Thorac Cardiovasc Surg 1996; 111:238-45. Cason BA, Gordon HI, Avery IVEG, Hickey RF. The role of ATP sensitive potassium channels in myocardial protection. / Card Surg 1995; 10 (4 Suppl): 441-4. Cohen NM, Wise RM, Wechsler AS, Damiano RJ, Ir Elective cardiac arrest with a hyperpolarizing adenosine triphosphate-sensitive, potassium channel opener. A novel form of myocardial protection? ) Thorac Cardiovasc Surg 1993; 106:317-28. Cohen NM, Damiano RJ, Jr, Wechsler AS. Is there an alternative to potassium arrest? Ann Thorac Surg 1995; 60:858-63. Maskal SL, Cohen NM, Hsia PW, Wechsler AS, Damiano RJ, Jr. Hyperpolarized cardiac arrest with a potassium-channel opener, aprikalim. / Thorac Cardiovasc Surg 1995; 110 (4 Part 1): 1083-95. Menasche P, Mouas C, Grousset C. Is potassium channel opening an effective form of preconditioning before cardioplegia? Ann Thorac Surg 1996; 61: 1764-8.

CHAPTER 2

The duality of cardiac surgery: mechanical and metabolic objective Gerald D. Buckberg, MD

There are dual objectives at operation, and the two fundamental components are technical success and absence of iatrogenic injury due to inadequate myocardial protection. We have entered a new millennium, and the spectrum of surgical procedures used to correct abnormal structure is expanding. Intervals of aortic clamping need to be longer, so that we make the correct diagnosis and implement a more natural correction (i.e. mitral valve repair, Ross procedure, aortic reconstruction with stentless valves, homografts). In addition, our patients' vulnerability to injury has increased, so we need to improve our methods of protection as well as learn new operative techniques. This chapter deals both with the evolution of current methods and the recognition of newer methods of protection, so that the dual relationship between protection and procedures is not separated. Technical success and the avoidance of intraoperative damage are our dual surgical objectives. The early and late success of a cardiac surgical procedure is related to how well the operation corrected the mechanical problem, and how carefully myocardial protection avoided the secondary dysfunctional effects of aortic clamping for technical repair. There is no separation between these two central events. The mechanically perfect heart cannot undergo early or late survival if operative damage from protection is severe. An example is the development of "stone" heart after 30 min of normothermic aortic clamping for aortic stenosis, or late dilatation from evolving scar from intraoperative ischemic damage. Conversely, the normal myocardium on bypass, with preserved structural and biochemical integrity, cannot maintain cardiac output if there is a technical operative error,

such as a closed coronary anastomosis or iatrogenic valvar insufficiency. The need for these vital elements to be in harmony is well known, yet there are important differences in the cardiac surgical approaches to these two fundamental determinants of outcome. On one level, the meticulous pursuit of mechanical perfection is unending; for example, through cardiac vision (i.e. eye glasses, 2-5-3-5 loops, 4-5 loops, 6-0 loops, the microscope, and finally robotic magnification away from the direct operative field). Surgical suture techniques, starting at 5-0 prolene, progress to 10-0 to secure a perfect anastomosis or repair. Major interventional changes in mitral valve repair are developed to avoid replacement, and novel mechanical methods are introduced to return the ventricle in a normal elliptical cardiac position. This structural goal is the technical belief of cardiac surgery and the pursuit of excellent technology will never end. Focal examples of this drive come from the ongoing search for perfection, through learning the Ross procedure for aortic valve replacement and repeated visits to valvuloplasty clinics to enlarge our concepts of valve repair to avoid mechanical replacement. The undercurrent theme is that sufficient time must be spent during aortic clamping, in an unhurried way to: (i) inspect the functional anatomy; and then (ii) accomplish a novel technical repair. There is an enlarging body of surgeons wanting to utilize these creative technical approaches, but the numbers of clinical centers dealing with these more difficult valvular problems is limited. The surgical restriction, despite an available cadre of patients, is underlying concern about producing extended intraoperative

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damage during the prolonged aortic clamping times required for novel technical success. On a second level, these more extensive procedures are often withheld from patients with underlying impairment of ventricular function due to: (i) recognized increased vulnerability to damage in hearts with hypertrophy and/or coronary disease; (ii) limited functional reserve if protection is marginal; and/or (iii) use of a shorter procedure (i.e. using an artificial valve) to avoid the prolonged intra-aortic clamping needed to be used for correcting the lesion in a more natural way. The performance of evolving operative techniques is halted in many centers by the conceptual barrier that "prolonged aortic clamping will cause progressive tissue damage" when the new task is undertaken, because of the knowledge that repair "burns extra minutes" into our efforts to achieve mechanical success. The barrier is the uncertainty of the value of current techniques of myocardial protection during prolonged aortic clamping in patients with advanced cardiac disease when there is diminished preoperative function. Unfortunately, unbridled progress to learn new techniques is unaccompanied, in many centers, with a similarly more intensive understanding, looking for reasons why more damage is invoked if the interval of clamping is prolonged. A fundamental reason is that techniques of improved protection have made slower educational progress during our ongoing pursuit of the evolution of improved technique. I will cite several examples of evolving methods of protection, to bring into focus this disparity between mechanical and metabolic excellence. So that all surgeons can have the freedom to use their technical skills to the full, this disparity should be dissolved. The first method of protection is hypothermia, provided by cold perfusate and surface cooling based upon findings by Shumway in 1959 to limit damage from normothermia. To some, this became the historic "end stop" of myocardial protective strategies. This may reflect the "iceberg age," and restricted focus upon this method alone has arrested progress toward a full understanding of the mechanics of ischemic damage, and how to reverse these changes. Our progress becomes cushioned by the classic statement "we have good results, why change"? The reason to change methods of protection is obvious, unless current protective methods provide complete avoidance of massive inotropic support, assist devices, or

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transplantation, following technically successful repair. Hopefully, a "rigid" concept that cold is everything "will not veil" any further development of our knowledge in cardiac protection. Our capacity to stop metabolic demands quickly, and simultaneously limit progressive extension of damage over time, has been enhanced by cardioplegic techniques that retard metabolism, and are now used almost universally. Hypothermia is a vital component, but reflects an addition, rather the unifying force that becomes the only solution. Further progress has developed by general agreement that blood contains natural benefits over conceptual crystalloid techniques, red blood cells are a fundamental component of most cardioplegic solutions. Those who externally create a crystalloid component and exclude blood must now address the well-proven benefits of restoring the blood vehicle that normally nourishes the nonbypassed heart that must function when bypass is discontinued. In addition, strategic methods to distribute solution, both antegrade, retrograde, and simultaneously antegrade/retrograde, have been developed, and are used commonly throughout the world. More importantly, new methods to prevent ischemic damage (i.e. buffering, hypocalcemia, oxygen radical scavengers, reducing complement) under more favorable conditions have been added. However, few centers are now involved with the surgical adoption of these new protective techniques. Many use methods that were developed 20 years ago. The injury could be limited if we addressed the newer metabolic and delivery changes that have been initiated. Consequently, there has been a mechanical leap in technical skills, but only "microsteps" taken in advancing and using efforts for protection. The recognition that temperature and cardiologic vehicle do not insure adequate distribution has allowed the evolution of retrograde delivery. These methods of retroperfusion are used in greater than 60% of patients in the United States and somewhat less worldwide. However, this is not a universal vehicle for cardioplegic delivery, despite evidence that different areas of diseased hearts are perfused by antegrade and retrograde techniques. This is very important because of the limited capacity of retrograde methods to consistently protect the right ventricle, and is especially important in reoperative coronary procedures. The ready clinical demonstration that different regions are perfused by retrograde perfusion (i.e.

Duality of cardiac surgery coronary sinus effluent during antegrade perfusions starting blue and becoming red, then with retrograde perfusion, aortic effluent starting blue and then becoming red), indicates that different areas are perfused during the period of aortic clamping. This shows that some regions were imperfectly perfused using one technique only. Clinical evidence has gradually attained general acceptance that these antegrade and retrograde delivery methodologies should be combined. These changes are further limited by those who have not yet "made this step of transatrial cannulation." To many, a slight prolongation of operation to open the right atrium and directly cannulate the coronary sinus provides a sufficient reason to limit pursuing retrograde methodology. Little attention is given to the prolonged inotropic and metabolic support that is needed when this potential 5-min supplement is excluded. Some accept the prolonged intensive care unit and increased hospital stay, and mortality is due to the nature of the disease rather than the potential consequence of not using this methodology. The value in morbidity of consecutive hospital cases and reduced cost was shown nicely in a study by Loop several years ago at the Cleveland Clinic

[1]. The aforementioned applications of cold blood cardioplegia and retrograde perfusion are simply the start of the advanced techniques of myocardial protection, as many centers have made physiologic variances in the cardioplegic temperature while using blood cardioplegic protection. Evidence is clear that the jeopardized heart has increased vulnerability to damage, and that this injury can be modified, both experimentally, and clinically, by a warm controlled blood cardioplegic reperfusion, especially if there is amino acid enrichment [2-4]. Despite this knowledge, there is much slower adaptation to using proven concepts of controlled reperfusion before releasing the aortic clamp. Warm reperfusion is used in less than 50% of centers, with fewer participants in Europe. Furthermore, it should be recognized that ongoing ischemia during aortic clamping is not needed when the procedure is ongoing and direct heart visualization is unimpaired (i.e. doing proximal anastomosis, placing sutures from the valve ring to the valve, and closing the aorta or atrium) as the procedure progresses. During these times, continuous cold blood perfusion is available, yet is not commonly used. The result is that ischemia is prolonged unnecessarily. The

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potential injury could be limited if there was understanding of the availability of reperfusion, especially retrograde, when operative vision does not become impaired by ongoing perfusion while the aorta is clamped. The "blending" of methods of protection can be used to avoid the arbitrary "alternative position stance," where there is an unnecessary introduction of a surgically imposed contrast between "warm versus cold, antegrade versus retrograde, intermittent versus continuous," which now becomes an "integrated method." This integrated approach takes advantage of the benefits of each method, rather than pitting one method against the other. The result is that each patient receives warm induction, cold blood cardioplegia, and a warm reperfusate, with delivery antegrade, retrograde, and sometimes simultaneously antegrade and retrograde, in either an intermittent delivery, and in a continuous way if vision is not impaired by perfusion. The cold arrested heart remains stopped by hypothermia, so that the blood delivery can be with either a cardioplegia solution, or with cold regular blood, or a nonpotassiumcontaining solution with the cardioplegic constituents [5,6]. The benefits of this combined approach were shown, recently, in more than 1500 patients with advanced heart disease, and even more extensively in an alternate subset of patients with valve complex mitral valve disease [5] or Ross procedures with damaged ventricles, where ischemic times were greater than 180-250 min without inotropic support [7]. Further supplemental steps like white blood cell filtration, oxygen radical scavenger addition, magnesium supplementation, low Po2 to limit reoxygenation damage, short-acting calcium antagonists to reduce and prevent calcium-related injury, adding sodium hydrogen ion exchangers, and other evolving regions are at the frontier of better techniques to protect the heart. These concepts have been developed, yet there is a slower pathway among surgeons towards incorporating these procedures into the operation. Some think change is "living with the university." That is simply the wrong idea. We must advance in our learning of myocardial protection modalities, in the same way as we progress with mechanical matters to provide our patients with many of the benefits of each aspect that should be in the armamentarium of the cardiac surgeon, just as in the natural evolution of mechanical methods of repair.

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The concepts of myocardial protection developed in adults are directly applicable to the pediatric population, where vulnerability to damage is highest because of preoperative ischemia and cyanosis. These approaches are similar to adult methods, but are rarely employed. The increasing tendency to avoid cardiopulmonary bypass to reduce the inflammatory reaction to extracorporeal circulation has led to coronary artery bypass graft (CABG) without bypass. It is clear that the precursor to regional stunning (that we know globally as the low-output syndrome) is brief occlusion for 10-15 min with normal blood reperfusion. This established technique of damage is applied to patients with coronary artery disease, but there is less damage in them because of collateral flow from stenotic lesions. Methods to protect the regional segment in patients undergoing CABG without bypass must be addressed and included, to avoid stunning of both the endothelium and the myocyte. The method of surgery on the beating heart, which is useful without bypass, is also applicable in patients on extracorporeal circulation. The beating heart with regional ischemia has been used in CABG procedures, since bypass reduces global oxygen demand, and the nonischemic areas remain perfused which potentially limits their injury. A marked advantage of surgery on the beating heart has been achieved during ventricular restoration, where the beating heart is opened and continually perfused as its volume is reduced. This method has been useful both experimentally, and clinically [8-10]. The principle of using the beating heart is not new, as this method has been used during surgical treatment of ventricular arrythmias [ 11 ]. It is also well known, from Kirklin's studies of aortic stenosis, that continuous perfusion of the beating vented heart can cause marked subendocardial ischemia if there is left ventricular hypertrophy [ 12]. The goal in selecting a method of protection is to make the choice after learning how and why the method has been developed, and understanding how to benefit from its advantages, and avoid inappropriate use by recognizing the disadvantages. The choice for protection is precisely similar to the selection of a structural technique for surgical repair of an underlying cardiac lesion. The underlying principle in this dual bilateral program is for each of us to recognize that each effort (mechanical and metabolic) is of equal importance. Failure in either modality is not a surgical problem,

CHAPTER 2

but rather a problem for the patients and the existing cost of caring for those who have delayed recovery despite a technically successful procedure. Improved myocardial protection is not a phase of surgical development, but rather is intrinsic to improved surgical care. The virtual absence of papers at surgical meetings about myocardial protection may indicate that the problem of myocardial protection has not been solved. Despite this, there are reports of patients needing intra-aortic balloons and mechanical assist devices when protection has been inadequate. The search for technical improvement must be accompanied by ongoing learning about cardioprotective methods that avoid completely the need to use machines to correct cardiac performance after the heart has been mechanically restored to its more normal architecture. We should strive to increase our knowledge about protection, as it must become an essential component of the surgical correction of cardiac defects. Protection and technical adequacy cannot be separated, as our deep understanding of how to correct the cardiac lesion must be matched by a recognition of how to avoid damage as we satisfy our dual goals.

References 1 Loop FD, Higgins TL, Panda R, Pearce G, Estafanous FG. Myocardial protection during cardiac operations. 7 Thome Cardiovasc Surg 1992; 104:608-18. 2 Allen BS, Buckberg GD, Fontan F et al. Superiority of controlled surgical reperfusion vs. PTCA in acute coronary occlusion. / Thorac Cardiovasc Surg 1993; 105:864-84. 3 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. / Thorac Cardiovasc Surg 1986; 91:428-35. 4 Allen BS, Rosenkranz ER, Buckberg GD et al. Studies on prolonged regional ischemia. VI. Myocardial infarction with LV power failure: a medical/surgical emergency requiring urgent revascularization with maximal protection of remote muscle. / Thorac Cardiovasc Surg 1989; 98: 691-703. 5 Buckberg GD, Beyersdorf F, Allen B, Robertson JM. Collective review: Integrated myocardial management. Background and initial application. / Card Surg 1995; 10: 68-89. 6 Kronon MT, Allen BS, Halldorsson A et al. Delivery of a nonpotassium modified maintenance solution to enhance myocardial protection in stressed neonatal hearts: a new approach. / Thorac Cardiovasc Surg 2002; 123:119-129.

Duality of cardiac surgery

7 Allen BS, Murcia-Evans D, Hartz RS. Integrated cardioplegia allows complex valve repairs in all patients. Ann ThoracSurg 1996:62: 23-9. 8 Athanasuleas CL, Stanley AWH, Jr, Buckberg GD. Restoration of contractile function in the enlarged left ventricle by exclusion of remodeled akinetic anterior segment: surgical strategy, myocardial protection, and angiographic results. / Card Surg 1998; 13:418-28. 9 Athanasuleas CL, Stanley AWH, Jr, Buckberg GD et al. and the Restore Group. Surgical anterior ventricular endocardial restoration (SAVER) in the dilated remodeled ventricle following anterior myocardial infarction. ] Am Coll Cardiol 2000: 37:1199-209.

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10 Sakamoto Y, Mizuno A, Buckberg GD et al. Restoring the remodeled enlarged left ventricle: experimental benefits of in vivo porcine cardioreduction in the beating open heart. / Cardiac Surg 1998; 13:429-39. 11 Mickleborough LL, Carson S, Ivanov J. Repair of dyskinetic or akinetic left ventricular aneurysm: results obtained with a modified linear closure. / Thorac Cardiovasc Surg 2001; 121:675-682. 12 Sapsford RN, Blackstone EH, Kirklin JW. Coronary perfusion versus cold ischemic arrest during aortic valve surgery. Circulation 1974; 49:1190.

CHAPTER 3

Modification of ischemiareperfusion-induced injury by cardioprotective interventions Ming Zhang, MD, Tamer Sallam, BS,BA, Yan-JunXu, PHD, Naranjan S. Dhalla, PHD, MD (HON), DSC (HON)

Introduction Myocardial ischemia-reperfusion is a phenomenon caused by various clinical procedures such as angioplasty, coronary bypass, and thrombolytic therapy. It is a lethal medical problem and a major economic healthcare concern due to high mortality and morbidity. Multiple factors are involved in ischemiareperfusion injury; occurrence of Ca2+ overload, excessive formation of oxygen-derived free radical, and alterations of enzyme activity are considered to be the major causes of myocardial cell damage and cardiac dysfunction. Ischemia-reperfusion may cause contractile failure, arrhythmias and cell death leading to heart failure or sudden death in patients. Accordingly, it has become vital to develop effective therapeutic strategies to combat the deleterious effects of ischemia-induced myocardial injury. At present, many studies have been conducted to determine the possibility of amplifying the beneficial effects of reperfusion and diminishing the harmful effects of ischemia through pharmacological intervention. This chapter reviews the mechanisms of some of the therapies which are useful in attenuating the ischemia-reperfusioninduced injury in the heart. Ischemia means little or no blood flow to the tissues [ 1 ], resulting in not only a decrease in the supply of oxygen and nutrients to the heart, but also a build up of metabolic wastes locally and thus debilitating the maintenance of an adequate rate of energy production and cellular integrity [2]. Myocardial ischemia can be

18

characterized by rapid accumulation of protons, cessation of oxidative metabolism, cessation of electron transport, and the initiation of the inefficient processes of anaerobic metabolism. Reperfusion injury is a major complication characterized by restoration of flow to a previously ischemic heart [3]. Many factors have been shown to cause ischemic heart disease; major ones include atherosclerosis of the coronary arteries, thrombosis, and coronary artery spasm [4]. Ischemia-reperfusion injury is one of the most common cardiovascular diseases; this injury damages vascular cells and cardiomyocytes [5]. In spite of the variable incidence of ischemic heart disease, it has become one of the most significant medical problems and a major economic healthcare concern for the lethal damage of ischemia-reperfusion injury. It has been reported that almost 45% of all deaths in northern European countries during the past decade were due to cardiovascular disease [6]. In addition, 200 000 Americans under 65 die each year from ischemic heart disease and 25 times that number suffer from symptoms related to the disease [4]. A similar situation exists in Canada, where cardiovascular disease causes more deaths than any other disease, with more than 58% of these deaths attributed to ischemic lesions in 1990 [7]. In economic terms, the direct and indirect cost of heart attack and stroke per year was about $259 billion in the USA [8]. In Canada, cardiovascular disease contributed to 21% of the total healthcare expenditure in 1986, and has became the most expensive disease with direct costs of $5.2 billion

Treatment of ischemia-reperfusion injury and indirect costs of $11.6 billion [4]. Consequently it is crucial to find ways to attenuate the events associated with the irreversible ischemic injury. At present, many studies have been designed to determine the possibility of amplifying the beneficial effects of reperfusion and diminishing the harmful effects of ischemia through pharmacological intervention [9]. Those include: preconditioning, antioxidants, Ca2+ channel blockers, phospholipase A2 inhibitors, Na-H+ exchange inhibitors, P38 MAP (mitogenactivated protein) kinase inhibitors, phosphatase inhibitors, pentoxifylline, 5-HT receptor antagonists, and so on. The aim of this article is to review the pathophysiology of ischemia-reperfusion injury and the mechanisms of pharmacological interventions for this disease.

Preconditioning Myocardial ischemic preconditioning is a phenomenon produced by brief episodes of cardiac ischemia and reperfusion leading to a decrease in the rate of progression of ischemia-induced myocardial injury and the development of resistance to subsequent ischemic episodes [10-12]. The potential therapeutic benefits of this adaptive mechanism have generated much attention in the scientific community, and have revolutionized our understanding of signal transduction and subsequent intracellular events mediating ischemia-reperfusion [13]. Several intracellular signaling pathways which have been implicated in the protective mechanism of ischemic preconditioning include the activation of G proteinlinked phospholipase C-coupled receptors, adenosine receptor, bradykinin receptor, opioid receptor, tyrosine kinase pathways, and protein kinase C (PKC) [12,14-16]. Different mechanisms explain the role of preconditioning in ischemia-reperfusion. Ischemic preconditioning might render protection against ischemia-reperfusion-induced damage to the myocardium by improving sarcoplasmic reticulum function. This is attributed to decreased ryanodine-sensitive sarcoplasmic reticulum Ca2+ release and the regulation of sarcoplasmic reticulum phosphorylation by endogenous Ca2+/calmodulin-dependent protein kinase (CaMK) [17,18]. Some studies have reported that ischemic preconditioning triggers phospholipase D signaling in ischemic myocardium, which appears to

19

be beneficial for the heart because of the production of phosphatidic acid and diacylglycerol as well as subsequent activation of PKC [ 19]. In addition, the adenosine triphosphate (ATP)sensitive potassium channel is a strong candidate for mediation of preconditioning protection. Pharmacological and electrophysiological evidence favorably implicate the involvement of mitoKATp rather than surfaceKATp as the relevant mediator of preconditioning [14]. Opening of mitoKATP has been shown to block apoptosis in cardiac myocytes via PKC-e activation [20]. Preconditioning additionally protects against cell necrosis and possibly against stunning [21]. The mechanism of such protection is still unclear, yet it has been demonstrated that the ATP content of the myocardium is reduced following ischemic preconditioning. However, during prolonged coronary occlusion, the rate of decline in ATP is initially slower in a preconditioned myocardium as compared to a nonpreconditioned one [11]. Thus an alteration in the energy supply-demand relationship may be involved [22]. Preconditioning might further protect against necrosis through its action on tumor necrosis factor alpha (TNF-ct) because it has been shown to reduce myocardial TNF-a production and TNF-a-induced myocardial injury [23]. Preconditioning may also induce protection against other aspects of ischemia/reperfusion injury such as coronary endothelial damage or arrhythmias [13,24]. It has been reported that the incidence of ventricular fibrillation decreases from 90% in control hearts to 20% in preconditioned hearts; also, it has been shown that ischemic preconditioning exerted its protective effect primarily by maintaining the function of the forward mode of the Na-Ca2+ exchanger and limiting the development of intracellular acidosis. This reduces the occurrence of intracellular Ca2+ overload, thus protecting the heart against arrhythmias [25,26]. Other evidence suggests that the antiarrhythmic effects of ischemic preconditioning are mediated through the activation of endothelium bradykinin receptor-1 [16]. It has also been reported that ischemic preconditioning preserved endothelium-dependent coronary dilation significantly [24]. Therefore, the preservation of endothelial function may be one of the mechanisms by which preconditioning reduces the amount of tissue necrosis during reperfusion. In conclusion, the mechanisms modulating ischemic preconditioning include alterations in antioxidant

20

defence [27], stimulation of adenosine Aj receptors, activation of PKC, activation of phospholipase D, induction of heat shock proteins, reduction in TNFa production, attenuation of the development of intracellular acidosis, and prevention of the intracellular Ca2+ overload [18,19,23]. The existing evidence strongly favors preconditioning as an effective intervention of ischemia-reperfusion injury.

Antioxidants Reactive oxygen species, including the superoxide anion (O2~), hydrogen peroxide (H2O2), and the hydroxyl radical (OH), are derivatives of many biologic systems, and in high concentrations are associated with oxidative stress and subsequent cardiovascular tissue injury [11]. The superoxide anion is a key entity in the production of the hydroxyl radical. It has been demonstrated that superoxide radicals and hydrogen peroxide exert their deletions effect on cells through the generation of the highly reactive hydroxyl radicals, and are therefore not directly toxic [9]. One major site of oxygen free radical production and cell injury is endothelial cells. In fact, endothelial cells have been shown to possess a free radical system capable of generating oxygen radicals [28]. Normally oxygen-derived free radicals interact with cellular constituents, including lipids, proteins and nucleic acids. In turn, they can disrupt membrane integrity, ion channels, and enzymatic activities. Such adverse effects of toxic oxygen metabolites were additionally associated with dysfunction of sarcoplasmic reticulum, mitochondria and creatine kinase upon reperfusion of the ischemic myocardium [15]. The view that reactive oxygen species are implicated in ischemia-reperfusion is further substantiated when considering the effects of antioxidants on hearts subjected to ischemia-reperfusion. The antioxidant ability of the cell can be divided into two categories. The first line of cellular defence against oxidative injury is free radical scavenging enzymes including superoxide dismutase, catalase, glutathione peroxidase, and glutathione. The second line antioxidant is the nonenzymatic scavengers such as alpha-tocopherol (vitamin E), beta-carotene, vitamin A, ascorbate, and sulfhydryl-containing compounds [28]. The endogenous antioxidants are depleted by ischemia, predisposing the myocardium to oxidant injury [ 15]. In fact, a direct correlation between the myocardial dysfunc-

CHAPTER 3

tion induced by ischemia-reperfusion and the magnitude of free radical generation by exogenously administered oxidants has been previously demonstrated [17]. This further indicates the major role of antioxidant treatment for ischemia-reperfusion injury. It has been shown that SOD (superoxide dismutase) plus CAT (catalase) treatment prevents changes in sarcoplasmic reticulum protein phosphorylation in the ischemic reperfused heart [17]. Other agents shown to have beneficial effects acting as antioxidants are: N-2 mercaptopropionyl glycine and N-acetylcysteine; melatonin [29]; as well as allopurinol, oxypurinol, and desferrioxamine [15,29-31]. New antioxidant interventions are currently being developed. Recently certain amino acids, such as taurine, have been used for the purpose of maintaining membrane stabilization. In vitro and in vivo studies indicate that taurine has the ability to scavenge HOC1 and thereby prevent ischemia-reperfusion-induced membrane damage as induced by lipid peroxidation [32]. Clearly, anti-free-radical interventions may reduce the severity of reperfusion injury as shown by numerous studies. However, some reports discussing the failure of some antioxidant treatments [33,34] indicate that reperfusion injury is a complex phenomenon and further research is needed to better elucidate this dynamic process.

Ca2+ channel blockers It is well accepted that Ca2+ ions are major regulators of cardiac excitation-contraction coupling. Some of the roles of Ca2+ in cardiac myocyte function include mediating systolic contraction and diastolic relaxation as well as affecting enzymatic activities and mitochondria function. Additionally, Ca2+ is important for maintaining cellular integrity, cell proliferation, cell growth, and the regulation of metabolism. The L-type Ca2+channel is considered the most significant Ca2+channel in the human heart. The small amount of Ca2+ entering the cytosol through this channel triggers the release of additional Ca2+ from the sarcoplasmic reticulum [35]. Reperfusion-induced Ca2+ overload was described three decades ago [36]. Recent studies demonstrate that Ca2+ overload is a major cause of myocardial cell damage and cardiac dysfunction in ischemic heart diseases. The Ca2+ overload evoked by postischemic reperfusion is associated with irreversible injury such as ultrastructure damage, enzyme

Treatment of ischemia-reperfusion injury leakage, membrane damage, reduced capacity of the mitochondria to regenerate ATP, and increased infarct size [36]. The role of Ca2+ in cardiac dysfunction may be further extended to ischemia-induced arrhythmias, especially ventricular tachycardia and ventricular fibrillation which are the major causes of sudden cardiac death. Calcium channel blockers are used in the treatment of ischemic heart disease and these function through reducing the contractility of the myocardium, decreasing the contraction of smooth muscle in the vasculature, and altering the conducting system of the heart [37]. Generally Ca2+ channel blockers can be classified as dihydropyridines and nondihydropyridines. The dihydropyridines act primarily by relaxation of vascular smooth muscle with less effect on cardiac contractility and conduction; nifedipine is the most commonly used representative of dihydropyridines. Nondihydropyridines such as verapamil and diltiazem act primarily on myocardium and cardiac conducting tissue with less effect on vascular smooth muscle. At present, nifedipine, diltiazem and verapamil are the three most clinically used calcium channel blockers [38]. Other Ca2+ channel blockers were also applied in experimental research, such as felodipine, S-2150, lacidipine, anipamil, and benidipine [39-43]. Several mechanisms describe the protective effect of Ca2+ antagonists on the myocardium with ischemiareperfusion injury including: coronary vasodilatation [43-45], an energy-sparing effect which results in a lower rate of ATP depletion, slower loss of adenosine precursors [39,40,46], decreased release of degradative lysosomal proteases [47,48], protection of the sarcolemma [49,50], attenuation of the ischemiareperfusion-induced mobilization of norepinephrine [51], lower endothelial permeability [52], protection of mitochondrial function [53], attenuation of ischemia-induced acidosis [54,55], retardation of the early rise in cytosolic Ca2+ [56], protection of lipid-containing membranes against lipid peroxidation caused by free radicals [41], and antiarrhythmic effects believed to be related to their inhibitory action on the phosphatidylethanolamine (PE) Nmethylation activity [57]. It appears that calcium channel blockers are an effective treatment of ischemiareperfusion injury as indicated by different approaches such as cellular pharmacology, molecular biology, in vitro and in vivo animal pharmacology, clinical pharmacology, and clinical efficacy studies [58].

21

Phospholipase A2 inhibitors The membranes of living cells consist of phospholipids, cholesterol, and proteins. The integrity of the membrane is important for proper cell functioning. Phospholipids, the major constituents of the cellular membrane, provide the principal structural framework of the membrane and therefore undergo a continued turnover process; hence, enabling the cell to synthesize required phospholipids and to regulate the fatty acid composition of the phospholipids. An integral enzyme involved in the hydrolytic part of phospholipid regulation is phospholipase A (PLA), with its two isoforms, namely, phospholipase A t (PLAj) and phospholipase A2 (PLA2) [35]. Of at least three different types of phospholipase A2 (PLA2) in the human heart, the group II PLA2 has been cloned and well studied [59,60]. The regulation of the group II PLA2 activity occurs through multiple entities, such as cytokines (TNF-oc, IL-1, IL-6) and Ca2+ concentration. Phospholipid metabolism is disturbed during myocardial ischemia. Several studies indicate that the degradation of membrane phospholipid is associated with enhanced PLA2 activity stimulated by the Ca2+ overload and increase in cytokines [35]. This activation leads to increased phospholipid catabolism and subsequently the liberation of lysophosphatidylcholine (LPC). LPC has been reported to induce major changes in membrane function. It has been shown to increase the intracellular Na+ concentration by inhibiting myocardial Na-K+ ATPase and increasing the burst of the Na+ influx, in turn producing Ca2+ overload via the Na+-Ca2+ exchanger. It has been additionally reported that LPC might directly increase sarcolemmal permeability to Ca2+ and increase nonselective cation currents for Na+, K+, and Ca2+. All of these effects demonstrate that LPC is an arrhythmogenic agent. In addition, LPC accumulation in cardiac myocytes augments the activity of PLA2 via a positive feedback mechanism [61-64]. In light of the above mentioned results a pharmaceutical agent possessing antiphospholipase activity would render protection against ischemia-reperfusion damage. Manoalide, a phospholipase A2 inhibitor, has been shown to protect the heart from the injury by ischemia-reperfusion and by partially inhibiting the degree of LPC-induced increase in Ca2+ [61]. Mepacrine, another phospholipase inhibitor, while decreasing the level of phospholipid degradation,

22

displayed a negative inotropic effect and appeared to interfere with calcium currents across the sarcolemma [65]. Chlorpromazine and MR-256 (an oligomer of prostaglandin Ej) are two unrelated drugs, both of which were shown to have a protective effect on ischemia-reperfused heart due to their ability to inhibit PLA2 [66]. It has been further reported that coenzyme Q10 could inhibit the effect of PLA2 on inner membranes of myocardial mitochondria or dipalmitoyl phosphatidylcholine, and in turn prevents the development of mitochondrial dysfunction and mitochondria phospholipid hydrolysis by phospholipase [67]. Despite the encouraging results shown by phospholipase inhibitors, their mechanisms of action are still unknown and specific agents need to be developed.

Na+-H+ exchanger inhibitors The sarcolemma Na+/H+ exchanger (NHE) is an electroneutral exchanger that extrudes one proton in exchange for one Na+ under normal conditions [68]. At least five different isoforms of NHE are known to exist. NHE1, the most widely distributed type, is predominant in cardiac tissue. It is thought to mediate a number of physiological functions in various cell types including maintenance of intracellular pH and cell volume. Additionally, it controls cell growth and proliferation by mediating the action of a number of mitogens and growth factors [69,70]. The acidosis induced by a shift to anerobic metabolism during ischemia-reperfusion can activate the NHE. In fact, NHE activity was found to correlate with internal pH; the exchanger is maximally active at low intracellular pH (pH < 6.5) [70]. The intracellular Na+ level is elevated by the activation of NHE and this change leads to Ca2+ overload via the Na-Ca2+ exchanger [71] and subsequent cell injury via necrosis and/or apoptosis and ventricular arrhythmias. In chronic situations, ischemia-reperfusion injury stimulates NHE expression and improves NHE synthesis; finally it induces ventricular remodeling and heart failure [69]. Although not fully understood, the above mechanisms indicate that an inhibitor of NHE may play a key role in protection against ischemia-reperfusion injury. A great deal of research is focused on studying the inhibitor of NHE as a potential treatment of ischemiareperfusion injury [72,73]. Presently, NHE inhibitors are investigated by the use of Na+ nuclear magnetic resonance (NMR). Many inhibitors of NHE have been

CHAPTER 3

used in clinical settings including amiloride and its derivatives (EIPA, DMA, MIBA, HMA), or nonamiloride structure inhibitors, cariporide and HOE 642 [72,74]. These are commonly known as selective NHE1 inhibitors. Since the early 1990s, it has been demonstrated that amiloride and its derivatives reduced Na+ overload in cardiac ischemia-reperfusion injury and consequently influenced Ca2+ accumulation [75-77]. Similarly, cariporide had no effect on the decline in cytosolic pH while preventing the accumulation of intracellular sodium due to ischemiareperfusion. A reduction in infarct size, enzyme release, edema formation, arrhythmias and induction of apoptosis in the ischemic reperfused myocardium were additionally observed [78]. Some NHE inhibitors such as SM-20550 were reported to reduce the Ca2+ and Na+ levels at the end stage of ischemia in guinea pig Langendoff heart. These protective effects might be modulated at the mitochondrial level because HOE 694, another inhibitor of NHE, prevented clumping of Ca2+ aggregates in mitochondria. Clearly, the mitochondria may play a major role in the regulation of both physiological and pathological cell deaths in myocytes [79]. Currently, clinical studies are being carried out which may reveal that NHE inhibitors are an effective intervention for the treatment of ischemia-reperfusion myocardial injury.

P38 MAP kinase inhibitors MAP (mitogen-activated protein) kinases are recognized as regulators of cell growth and proliferation. The MAP kinases are activated upon binding of peptide growth factors to their tyrosine kinase receptors. Three pathways are currently described which ultimately lead to MAP kinase activation. These are adhesion molecules, G protein-coupled receptors, and stress-activated MAP kinase pathways. The stressactivated MAP kinase pathway plays an important role in the response to ischemia-reperfusion in the heart since this phenomenon presents a real pathological stress [80]. The MAP kinases involved in this pathway include c-jun amino-terminal kinase, which phosphorylates the transcription factor c-jun, and P38 MAP kinase. The increase in H2O2 concentration in the heart during ischemia and/or reperfusion could activate P38 MAP kinase [81,82]. Normally mitogenic MAP kinases stimulate protein synthesis and cell proliferation but inhibit apoptosis; however, stressactivated pathways promote apoptosis and cytokine

Treatment of ischemia-reperfusion injury production. P38 MAP kinase appears to be a key factor in the signal transduction cascade of myocardial apoptosis proceeding ischemia and reperfusion [8389]. In addition, P38 MAP kinase has been implied to phosphorylate 72-kDa heat shock protein and 27-kDa heat shock protein, which provide cytoprotection by stabilizing the actin cytoskeleton [90,91 ]. More research is being directed towards the inhibition of the P38 MAP kinase pathway as an intervention in ischemia-reperfusion injury [92,93]. Currently, SB 203580 is the most effective inhibitor of P38 MAP kinase. An important finding from current animal models is that myocardial treatment with SB 203580 significantly decreases the level of cellular apoptosis, and equally significant is the improvement in cardiac function recovery after reperfusion [94,95]. SB 203580 selective blocking of P38 MAP kinase activation and inhibition of the critical component in the signal transduction pathway leading to apoptotic cell death explain these findings. Thus, SB 203580 has the capability to attenuate postischemic myocardial injury and improve heart function recovery. It has been reported that administration of SB 203580 significantly attenuated postischemic myocardial necrotic injury, since the protective effect of SB 203580 against necrotic injury was related to its ability to reduce early apoptosis in the ischemia reperfused heart [93]. Although numerous studies support the notion that P38 MAP kinase inhibition is protective [93,96,97], the benefits of inhibiting this kinase continue to be a subject of controversy [98]. Furthermore, few effective agents have been found that are capable of inhibiting it.

Protein phosphatase inhibitors Protein kinases have been studied for many years because of their important role in the regulation of heart function; however, it has also been demonstrated that protein phosphatases play an equally important role [99]. Protein phosphatases are currently classified into two groups: type 1 (PP1) and 2 phosphatase (PP2); type 2 is further subdivided into PP2A, PP2B, and PP2C. Three major protein phosphatases control cell function and these are PP1, PP2A, and PP2B. They comprise more than 90% of the phosphatase activity in mammalian cells. These phosphatases provide the cell with the ability to rapidly change proteins from their phosphorylated to dephosphorylated form in order to meet different

23

physiological needs such as cell cycle regulation, gene transcription, carbohydrate and lipid metabolism, organization of cytoskeleton, cholesterol and protein biosynthesis [ 100]. It has been postulated that protein dephosphorylation during ischemia could result in damage to the cytoskeletal integrity that leads to cell death. It was believed that the heart can be protected by inhibiting the dephosphorylation rate or by stimulating kinase activity to maintain protein phosphorylation, which could be preserved by ATP utilization under physiological conditions[101,102]. Many phosphatase inhibitors have been widely applied in experimental research and clinical settings. Fostriecin is a highly selective inhibitor for PP2A and is used as an antitumor agent [103]. Although there is no evidence to demonstrate the effectiveness of fostriecin when applied to ischemic heart patients, several studies have suggested the beneficial effects of fostriecin on ischemic heart disease in experimental models [102,104,105]. In animal models this drug has been reported to protect the heart from infarction before or after the onset of ischemia. Weinbrenner et al. [101] have suggested that fostriecin may inhibit dephosphorylation of PKC-specific substrates and thus protect the heart during ischemia. In another study it was reported that fostriecin had similar cardioprotective effects as preconditioning in both rabbit and pig models. This protection might occur via the same effector's mechanism that preserves cytoskeletal phosphorylation and integrity of cell plasma [ 102,106]. Vanadate is another protein phosphate inhibitor. It has been identified to inhibit the dephosphorylation of the aB-crystallin which is translocated to intercalated disks and Z line to stabilize the myofibrils during ischemia in rat [107]. It was also demonstrated that this agent presents some other beneficial effects such as attenuating acidosis and changing glucose utilization in isolated perfused rat heart [ 108]. Other protein phosphatase inhibitors, such as okadaic acid, calyculin A, and cantharidin, have facilitated the study of protein phosphatase function [109,110] and have been shown to protect ischemic rat and rabbit cardiomyocytes [105,111].

Phosphodiesterase inhibitor—pentoxifylline Pentoxifylline, a derivative of theobromine, is a synthetic methylxanthine with a long side chain displacing the methyl group on the carbon position 1 of

24

caffeine. Many experimental and pharmacodynamic studies demonstrate the beneficial effect of pentoxifylline in myocardial vascular disorder [112-118]. In one study, 40 ischemic heart disease patients treated with pentoxifylline 600 mg per day for 25-30 days showed a reduction in glyceryl trinitrate consumption, improved exercise tolerance, improved EGG recording, and reduced tachycardia [119]. The primary pharmacodynamic effects of pentoxifylline are due to increased red blood cell deformability and decreased blood viscosity [119]. Dauber et al. [116] demonstrated that pentoxifylline attenuated the coronary microvascular protein leak and decrement in endothelium-dependent relaxation in the coronary epicedial arteries after ischemia and reperfusion. The increase in neutrophil cyclic AMP induced by pentoxifylline also diminishes superoxide production and adherence of neutrophils to vascular endothelium, as well as a reduction in the response of neutrophil to platelet-activating factor and cytokines such as TNF, interleukin 1 (IL-1) [120-122]. Cytokines are important mediators of cardiovascular diseases. Myocardial ischemia-reperfusion prompts a release of cytokines and other inflammatory mediators that cause coronary vascular injury. The specific target of such mediators appears to be the endothelium and neutrophils. Inflammatory cytokines, such as TNF-a and IL-1, act on neutrophils and adhere to the vascular endothelium inducing the obstruction of the capillary bed and the "no-reflow" phenomenon during reperfusion. Moreover, accumulation of TNF-a and IL-1 within ischemic tissue directly injures the tissue and releases proteolytic enzymes as well as oxygen free radicals, which induce further damage to the endothelium [ 123]. Other studies have demonstrated that TNF-a directly decreases contractile function in isolated hamster trabeculae, dogs, and human subjects [124,125]. This acute negative inotropic effect of TNF-a interferes with Ca2+ homeostasis, consequently disrupting excitationcontraction coupling and desensitizing the p-receptor [126]. In addition, TNF-a induces the production of nitric oxide (NO), hence, desensitizing the myofilament sensitivity to Ca2+, which in turn mediates the late contractile dysfunction [127]. The early contractile depression induced by TNF-a is mediated by sphingosine, an endogenous second messenger [128]. Another mechanism of cardiac depression provoked by TNF-a is the induction of apoptosis in cardiomy-

CHAPTER 3

ocytes, a process that appears to be mediated by sphingosine and nitric oxide [129-131]. The studies indicate that anti-TNF-a therapy may be useful in ischemia-reperfusion injury. Reduction in TNF-a production has been shown to be an important mechanism by which pentoxifylline protects against ischemia-reperfusion heart injury. This has been shown to occur in vitro and/or in vivo. Pentoxifylline decreases TNF-a synthesis via two mechanisms: 1 One of its metabolites can inhibit the lysophosphatidic acid acyltransferase that converts lysophosphatidic acid to phosphatidic acid. This induces a rise in Ca2+ concentration and an increase in the synthesis of TNF-a [132]. 2 As an inhibitor of phosphodiesterase, pentoxifylline induces prolonged cyclic AMP activity resulting in activation of protein kinase A, which serves to block nuclear factor KB inhibition of TNF-a mRNA transcription [133]. This indicates that the phosphodiesterase inhibitor blocks TNF-a gene transcription and consequently protein production [ 134]. Pentoxifylline was also reported to decrease myeloperoxidase (MPO), an index of tissue leukocyte accumulation in ischemic myocardium. This demonstrates that pentoxifylline modification significantly reduced leukocyte adhesion [112,135]. In addition, pentoxifylline is an effective hydroxyl radical scavenger, preventing endothelial injury by reactive oxygen species [114]. Presently, pentoxifylline, with limited side effects and favorable activity in hemorheologic properties, has received attention for its beneficial effect in the ischemic heart disease. Some investigators postulate that it aided the effectiveness by reducing Ca2+ overload, but this mechanism still needs to be developed through future research. Pentoxifylline has gained widespread interest and is widely considered as an effective intervention for ischemia-reperfusion although the dosage and time of treatment remains a subject of debate.

5-HT receptor antagonists Serotonin (5-HT) is stored in platelets and released during platelet aggregation. It is present in large quantities within the heart and is able to stimulate it directly via specific receptors. The receptors are classified as 5-HTj, 5-HT2, 5-HT3, and 5-HT4 [136]. It has been reported that 5-HT plays a role as a mediator of

Treatment of ischemia- reperfusion injury inflammation, since neutrophil uptake of 5-HT results in release of a vasoconstrictive substance. 5-HT similarly affects the function of other leukocytes such as macrophages. The effects of 5-HT suggest a potential therapeutic value on the process of reperfusion injury after experimental ischemia [137]. In addition, 5-HT has been found to provoke contraction of isolated coronary arteries in various species; it may be a major component in eliciting artery vasospasm and thus contribute to arrhythmias indirectly. The findings suggest that 5-HT may play a pathologic role in a variety of low blood flow conditions. It was believed that 5-HT is released during certain types of myocardial ischemia, particularly when thrombosis persists. The role of 5-HT is to amplify the occlusive event via activation of the 5-HT2 receptor. 5-HT is also implicated in platelet-vessel wall interactions inducing vascular smooth muscle cell proliferation, vasospasms, and arterial thrombosis. Therefore, 5-HT receptor antagonists may offer possible treatments for ischemic heart disease [ 138]. Previous studies were able to show the contractile effect of serotonin or 5-HT2 receptor agonists on isolated rat intramyocardial coronary artery, while 5-HT1A or 5-HT3 receptor agonists showed no contraction [139]. This suggests that the 5-HTj receptor mediates vasodilatation [140], while the 5-HT2 receptor mediates vasoconstriction. In the ischemic reperfused heart there is marked impairment of endothelium-dependent relaxation of the coronary arteries [141]. The vascoconstriction of 5-HT2 occurs due to a defect in the counterregulation of vasorelaxation by normal endothelial cells. Since 5-HT2 receptors play a functional role in platelet aggregation, thrombus formation, and the impairment of endothelin-dependent relaxation of arteries [142], many 5-HT2 receptor antagonists have been studied as intervention for ischemia-reperfusion injury; these agents include MDL28, 133 A, LY53857, DV-7028, ICS 205-930, cinanserin, mianserin, ketanserin, and yohimbine [143-146]. Undoubtedly, in vivo studies of 5-HT2 receptor antagonists exhibit inhibition of 5-HT-induced platelet aggregation, decreased lysis time, and delayed reocclusion. In vitro studies report that 5-HT2 receptor antagonists increased the time to contracture in isolated globally ischemic rat heart [147]. It was further suggested that 5-HT might be implicated in the genesis and determination of severity of ventricular arrhythmias induced

25

by acute myocardial ischemia, especially via 5-HT2 receptors. Hence, 5-HT2 receptor antagonists may be useful therapeutic agents for these arrhythmias. The mechanism of 5-HT2-mediated effects may occur through activation of phospholipase C (PLC) and accumulation of inositol phosphates causing the release of Ca2+ from intracellular pools [148], yet the exact mechanism of 5-HT2 receptor antagonists that attenuate ischemic injury is still unknown.

Conclusions Ischemic heart disease is one of the most significant problems facing clinicians now and in recent years. Therefore the need to understand the mechanisms underlying ischemia-reperfusion injury and the development of effective treatments against it has grown to be equally important. As summarized in Figures 3.1 and 3.2, the causes of ischemia-reperfusion injury include: Ca2+ overload for inducing contractile failure and arrhythmias; production of cytokines (TNF-a, IL-1) for inducing apoptosis and myocyte dysfunction; formation of oxygen-derived free radicals for disturbing membrane integrity, ion channel and enzyme function; and for inducing inflammation due to neutrophil accumulation. In this review we have discussed some of the interventions in ischemia-reperfusion heart injury, focusing on general aspects (see Tables 3.1 and 3.2 for a summary). Pharmacological approaches to protect the heart from ischemia-reperfusion injury are currently present, but they still need to be well established from future research. The multiple deleterious effects of ischemiareperfusion injury remain a major challenge in preventing this type of dysfunction. Therefore at present researchers have devoted their efforts towards finding a high-quality agent to protect the heart, or test the effect of a combination of drugs that have proven beneficial for ischemia-reperfusion injury.

Acknowledgments The work reported in this article was supported by a grant from the Canadian Institutes of Health Research (CIHR Group in Experimental Cardiology). N.S.D. held the CIHR/Pharmaceutical Research and Development Chair in Cardiovascular Research supported by Merck Frosst Canada.

Figure 3.2 Causes of ischemia-reperfusion injury.

27

Treatment of ischemia-reperfusion injury

Table 3.1 Effects of antioxidants, Ca2+ channel blockers, Na+-H+ exchanger inhibitors, and phospholipase A2 inhibitors on ischemia-reperfusion induced heart injury. Class

Drugs

Target

Effect

Reference

Antioxidants

Superoxide dismutase

Free radicals

Decrease oxidative

[15,28,29]

Catalase

metabolism

Glutathione Vitamin E Vitamin A N-acetylcysteine 2+

Ca channel blockers

L-type Ca2+ channel

Verapamil Diltiazem

+

Na -H exchanger inhibitors

[36]

protect energy-rich

Nifidipine

+

Block Ca2+ influx, phosphate reserve

+

Amiloride

+

Na -H exchanger

Reduce Na+ overload

[72, 74, 79]

Reduce phospholipid

[61,65]

Cariporide SM-20550 Phospholipase A2 inhibitors

Phospholipase A2

Mepacrine Manoalide

degradation, maintain membrane stabilization

Table 3.2 Effects of MAP kinase inhibitor, phosphodiesterase inhibitor, 5-HT2 receptor antagonists, and protein phosphatase inhibitors on ischemia-reperfusion induced heart injury. Class MAP kinase inhibitor

Drugs SB-203580

Target 38

P MAP kinase

Effect

Reference

Reduce myocardial apoptosis,

[94, 95]

improve cardiac function Phosphodiesterase

Pentoxifylline

TNF-a

inhibitor

Decrease the production

[114, 120, 122]

of TNF-a, reduce the endothelium-neutrophil adhesion

5-HT2 receptor antagonists

MDL28

5-HT2 receptor

Inhibit platelet aggregation

[143-146]

Maintain the phosphorylated

[101,107]

133A

LY53857 DV-7028 ICS 205-930 Cinanserin Miancerin Ketanserin Yohimbine Protein phosphatase

Fostriecin

inhibitors

Vanadate

Protein phosphatase

state of some cytoskeletal protein or protein kinase

28

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68 Avkiran M. Sodium-hydrogen exchange in myocardial ischemia and reperfusion: a critical determinant of injury? EXS 1996; 76:299-311. 69 Avkiran M, Snabaitis AK. Regulation of cardiac sarcolemmal Na+/H+ exchanger activity: potential pathophysiological significance of endogenous mediators and oxidant stress. / Thromb Thrombolysis 1999; 8:25-32. 70 Fliegel L, Wang H. Regulation of the Na+/H+ exchanger in the mammalian myocardium. / Mol Cell Cardiol 1997; 29:1991-9. 71 Ramasamy R, Schaefer S. Inhibition of Na+-H+ exchanger protects diabetic and nondiabetic hearts from ischemic injury: insight into altered susceptibility of diabetic hearts to ischemic injury. / Mol Cell Cardiol 1999; 31: 785-97. 72 Karmazyn M. The role of the myocardial sodiumhydrogen exchanger in mediating ischemic and reperfusion injury. From amiloride to cariporide. Ann NY AcadSci 1999; 874:326-34. 73 Avkiran M, Haworth RS. Regulation of cardiac sarcolemmal Na+/H+ exchanger activity by endogenous ligands. Relevance to ischemia. Ann NY Acad Sti 1999; 874:335-45. 74 Scholz W, Albus U, Counillon L et al. Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. CardiovascRes 1995; 29:260-8. 75 Pike MM, Luo CS, Clark MD et al. NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na+-H+ exchange. AmJPhysiol 1993; 265: H2017-26. 76 Navon G, Werrmann JG, Maron R, Cohen SM. 31P NMR and triple quantum filtered 23Na NMR studies of the effects of inhibition of Na+/H+ exchange on intracellular sodium and pH in working and ischemic hearts. Magn Reson Med 1994; 32:556-64. 77 Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. CircRes 1991; 68:1250-8. 78 Hartmann M, Decking UK. Blocking Na+-H+ exchange by cariporide reduces Na+-overload in ischemia and is cardioprotective. JMol Cell Cardiol 1999; 31:1985-95. 79 Hotta Y, Ishikawa N, Ohashi N, Matsui K. Effects of SM-20550, a selective Na+-H+ exchange inhibitor, on the ion transport of myocardial mitochondria. Mol Cell Biochem 2001; 219:83-90. 80 Katz AM. Proliferative signaling: regulation of gene expression, protein synthesis. In: Cell Growth and Proliferation, Apoptosis, 3rd edn. 2001: pp 312-68. 81 Wei S, Rothstein EC, Fliegel L, Dell'Italia LJ, Lucchesi PA. Differential MAP kinase activation and Na+/H+ exchanger phosphorylation by H2O2 in rat cardiac myocytes. Am J Physiol Cell Physiol 2001; 281: C154250. 82 Clerk A, Fuller SJ, Michael A, Sugden PH. Stimulation of "stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. JBiol Chem 1998; 273:7228 -34.

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97 Rakhit RD, Kabir AN, Mockridge JW, Saurin A, Marber MS. Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury. Biochem Biophys Res Commun 2001; 286:995-1002. 98 Schulz R, Belosjorow S, Gres P et al. p38 MAP kinase is a mediator of ischemic preconditioning in pigs. Cardiovasc Res 2002; 55:690-700. 99 Opie LH. Receptors and Signal Transduction, 3rd edn. New York: Lippincott-Raven Publishers, 1998:173-209. 100 Oliver CJ, Shenolikar S. Physiologic importance of protein phosphatase inhibitors. Front Biosci 1998; 3: D961-72. 101 Weinbrenner C, Baines CP, Liu GS et al. Fostriecin, an inhibitor of protein phosphatase 2A, limits myocardial infarct size even when administered after onset of ischemia. Circulation 1998; 98:899-905. 102 Armstrong SC, Kao R, Gao W et al. Comparison of in vitro preconditioning responses of isolated pig and rabbit cardiomyocytes: effects of a protein phosphatase inhibitor, fostriecin. / Mol Cell Cardiol 1997; 29: 3009-24. 103 Walsh AH, Cheng A, Honkanen RE. Fostriecin, an antitumor antibiotic with inhibitory activity against serine/threonine protein phosphatases types 1 (PP1) and 2A (PP2A), is highly selective for PP2A. FEBS Lett 1997; 416:230-4. 104 Armstrong SC, Gao W, Lane JR, Ganote CE. Protein phosphatase inhibitors calyculin A and fostriecin protect rabbit cardiomyocytes in late ischemia. / Mol Cell Cardiol 1998; 30:61-73. 105 Armstrong SC, Hoover DB, Delacey MH, Ganote CE. Translocation of PKC, protein phosphatase inhibition and preconditioning of rabbit cardiomyocytes. / Mol Cell Cardiol 1996; 28:1479-92. 106 Armstrong SC, Ganote CE. Effects of 2,3-butanedione monoxime (BDM) on contracture and injury of isolated rat myocytes following metabolic inhibition and ischemia. JMol Cell Cardiol 1991; 23:1001-14. 107 Golenhofen N, Ness W, Koob R et al. Ischemia-induced phosphorylation and translocation of stress protein alpha B-crystallin to Z lines of myocardium. Am J Physiol 1998; 274: HI 457-64. 108 Geraldes CF, Castro MM, Sherry AD, Ramasamy R. Influence of vanadate on glycolysis, intracellular sodium, and pH in perfused rat hearts. Mol Cell Biochem 1997; 170: 53-63. 109 Knapp J, Boknik P, Huke S et al. Contractility and inhibition of protein phosphatases by cantharidin. GeneralPharmacol 1998; 31: 729-33. 110 De Windt LJ, Lim HW, Taigen T et al. Calcineurinmediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo: an apoptosis-independent model of dilated heart failure. Circ Res 2000; 86: 255-63. 111 Armstrong SC, Ganote CE. Effects of the protein phosphatase inhibitors okadaic acid and calyculin A on metabolically inhibited and ischaemic isolated myocytes. JMol Cell Cardiol 1992; 24: 869-84.

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112 Gale SC, Hokama JY, Ritter LS et al. Pentoxifylline reduces coronary leukocyte accumulation early in reperfusion after cold ischemia. Ann Thorac Surg 2001; 71:1305-11. 113 Ulus AT, Aksoyek A, Katircioglu SF, Gokce P, Koc B. Preservation of myocardial functions by pentoxyphylline cardioplegia during and after cardiopulmonary bypass. Panminerva Med 2000; 42:253-6. 114 Horton JW, White DJ. Free radical scavengers prevent intestinal ischemia-reperfusion-mediated cardiac dysfunction. / Surg Res 1993; 55:282-9. 115 Lechleitner P, Genser N, Mair J et al. Pentoxifylline influences acute-phase response in acute myocardial infarction. Clin Invest 1992; 70: 755. 116 Dauber IM, Lesnefsky EJ, Ashmore RC et al. Coronary vascular injury due to ischemia-reperfusion is reduced by pentoxifylline. / Pharmacol Exp Ther 1992; 260: 1250-6. 117 Barnett JC, Touchon RC. Therapy of ischemic cardiomyopathy with pentoxifylline. Angiology 1990; 41: 1048-52. 118 Insel J, Halle AA, Mirvis DM. Efficacy of pentoxifylline in patients with stable angina pectoris. Angiology 1988; 39:514-9. 119 Ward A, Clissold SP. Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 1987; 34:50-97. 120 Hou X, Baudry N, Lenoble M, Vicaut E. Leukocyte adherence in an ischemic muscle perfused by a collateral circulation. / Cardiovasc Pharmacol 1995; 25 (Suppl 2): SI19-23. 121 Bessler H, Gilgal R, Djaldetti M, Zahavi I. Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells. JLeukocBiol 1986; 40: 747-54. 122 Semmler J, Wachtel H, Endres S. The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int J Immunopharmacol 1993; 15:409-13. 123 Dhote-Burger P, Vuilleminot A, Lecompte T et al. Neutrophil degranulation related to the reperfusion of ischemic human heart during cardiopulmonary bypass. / Cardiovasc Pharmacol 1995; 25 (Suppl 2): S124-29. 124 Finkel MS, Oddis CV, Jacob TD et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 387-9. 125 Cain BS, Meldrum DR, Dinarello CA et al. Adenosine reduces cardiac TNF-alpha production and human myocardial injury following ischemia-reperfusion. JSurg Res 1998; 76:117-23. 126 Meldrum DR, Dinarello CA, Shames BD et al. Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production. Potential ultimate effector mechanism of preconditioning. Circulation 1998; 98:11214-18. 127 Goldhaber JI, Kim KH, Natterson PD et al. Effects of TNF-alpha on [Ca2+]; and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol 1996; 271: H1449-55.

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139 Deptuch TW, Kurenko-Deptuch M, Witanowska A etal. Influence of selective 5-HT agonists and myocardial preconditioning on ischaemia/reperfusion induced changes in isolated heart of the rat. Inflamm Res 1999; 48 (Suppll):S96-S97. 140 Frishman WH, Huberfeld S, Okin S et al. Serotonin and serotonin antagonism in cardiovascular and noncardiovascular disease. / Clin Pharmacol 1995; 35: 541-72. 141 Perrault LP, Nickner C, Desjardins N et al. Improved preservation of coronary endothelial function with Celsior compared with blood and crystalloid solutions in heart transplantation. / Heart Lung Transplant 2001; 1994;20:549-58. 142 Hsieh CP, Sakai K, Bruns GC, Dage RC. Effects of MDL 28,133A, a 5-HT2 receptor antagonist, on platelet aggregation and coronary thrombosis in dogs. / Cardiovasc Pharmacol 1994; 24: 761-72. 143 McAuliffe SJ, Snow HM, Cox B, Smith CC, Noble MI. Interaction between the effects of 5-hydroxytryptamine and epinephrine on the growth of platelet thrombi in the coronary artery of the anesthetized dog. Br J Pharmacol 1993; 109:405-10. 144 Morishima Y, Tanaka T, Watanabe K et al. Prevention by DV-7028, a selective 5-HT2 receptor antagonist, of the formation of coronary thrombi in dogs. Cardiovasc Res 1991; 25: 727-30. 145 Bush LR, Campbell WB, Kern K et al. The effects of a2adrenergic and serotonergic receptor antagonists on cyclic blood flow alterations in stenosed canine coronary arteries. CircRes 1984; 55:642-52. 146 Coker SJ, Dean HG, Kane KA, Parratt JR. The effects of ICS 205-930, a 5-HT antagonist, on arrhythmias and catecholamine release during canine myocardial ischaemia and reperfusion. Eur J Pharmacol 1986; 127: 211-18. 147 Grover GJ, Sargent CA, Dzwonczyk S et al. Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts. / Cardiovasc Pharmacol 1993; 22: 664-72. 148 el Mahdy SA. 5-Hydroxytryptamine (serotonin) enhances ventricular arrhythmias induced by acute coronary artery ligation in rats. Res Commun Chem PatholPharmacol 1990; 68: 383-6.

CHAPTER 4

Anesthetic preconditioning: a new horizon in myocardial protection Nader D. Nader, MD, PHD, FCCP

Introduction Ischemic heart disease and myocardial infarction are major causes of morbidity and mortality in developed countries. According to statistics released by the American Heart Association at least one in every five deaths is caused by heart attacks while an estimated 12.6 million people are currently living with some form of coronary disease. In recent years, early reperfusion of the ischemic myocardium has become the mainstay of optimal therapeutic management to limit ventricular injury and infarct expansion, thereby improving patient survival. It has become clear that reperfusion promotes effective tissue repair and decreases ventricular remodeling even under circumstances where reperfusion is effected at too late a time to limit myocardial necrosis. One of the striking differences between reperfused and nonreperfused myocardial infarctions is that the early intense inflammatory reaction, which ensues immediately upon reperfusion, has been demonstrated to potentially extend myocardial injury. Reperfusion itself poses a threat to the ischemic myocardium by increasing the generation of oxidants that trigger signal transduction pathways eventually leading to apoptosis, otherwise known as ischemiareperfusion injury (IRI) [ 1 ]. IRI, which is a significant source of morbidity, is potentially preventable with the use of antioxidants or calcium antagonists [2]. IRI is generally characterized by a series of events starting with reperfusion arrhythmias, microvascular damage, decreased myocardial systolic and diastolic function, and eventually ending with cell death [ 3 ]. Brief periods of myocardial ischemia and subsequent reperfusions are almost inevitable during

cardiac surgery. The incidence of ischemic insult and reperfusion is more common in coronary revascularization procedures; however, it is also seen in valvular and even congenital cardiac surgery. The terms "stunned" and "hibernating myocardium" refer to abnormalities in the systolic and diastolic function of the heart following reperfusion. In both situations myocardial contractility and relaxation are deteriorated while the cardiac myocytes are still viable. In hibernating myocardium, however, a programmed cell death (apoptosis) pattern has been described. Myocardial ischemia results in utilization of adenosine triphosphate (ATP) stores secondary to the paralysis of aerobic metabolism and oxidative phosphorylation. Immediate effects of this change include reduced lactate uptake and the loss of sarcoplasmic reticulum and mitochondrial membrane integrity. Myocardial ischemia results in clinical symptoms ranging from angina during exertion to acute massive myocardial infarction leading to cardiogenic shock and/or lethal arrhythmias. Hypotheses have been evolving around the pathophysiology of myocardial ischemia-reperfusion injury. This chapter aims to review the current theories describing the mechanisms of myocardial injury associated with ischemiareperfusion of the heart. It will also review novel findings in the role of various anesthetic agents that demonstrate potential in being utilized for myocardial protection. Although the use of these agents for myocardial protection is in its infancy, the widespread utilization of anesthetics during cardiac surgery makes them potential candidates for cardioprotective purposes in the future. The term "anesthetic preconditioning" is commonly used to note the similarity of anesthetic action to the mechanism of ischemic

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CHAPTER 4

Figure 4.1 Alteration of ion exchange during myocardial ischemia-reperfusion.

preconditioning (IPC). Laboratory and clinical studies have shown that single or multiple brief episodes of ischemia are not only nondeleterious but also appear to protect the myocardium against subsequent ischemic episodes (e.g. stunning, infarction, and malignant ventricular dysrhythmias). The timeframe of myocardial protection following IPC is bimodal with an early peak within 1-2 h and a late peak appearing in 24 h and lasting 3 days. Although this phenomenon is first described in the heart, IPC is not organ-specific and is a fundamental endogenous protective mechanism against ischemic injury in a variety of tissues.

Cell biology of cardiac myocyte during ischemia-reperfusion injury The pathophysiology of IRI has been extensively studied over the past few years. A simplified diagram depicting the cascade of the events during myocardial ischemia-reperfusion is shown in Figure 4.1. In brief, following utilization of cellular stores of ATP, translocation of calcium ions is greatly disturbed. Inability of cardiac myocytes to internalize and reuptake excess cytoplasmic Ca2+ leads to deposition of this ion into the mitochondria. The sarcoplasmic reticulum is the major organelle to eliminate the excess of Ca2+

from the sarcolemma. Although the influx of this ion is necessary for the contractile function of the cardiac myocyte, an active reuptake and decline of cytoplasmic Ca2+ is required for effective relaxation of cardiac myocyte and its subsequent contraction. Central to myocytic calcium homeostasis is the role of mitochondrial adenosine triphosphate-sensitive potassium channels (KATP). Opening of these channels is crucial for the protective effects of IPC. As is shown in Figure 4.1, adenosine is the main ligand that controls the opening and closure of these channels. KATp channels act as metabolic sensors, and its activation leads to shortening of the action potential in the cardiac myocyte by limiting the rate of Ca2+ influx [4,5 ]. Oral hypoglycemic agents, especially glybenclamide, are the specific antagonists of these channels and neutralize the protective effects of IPC. This may be considered of clinical importance for diabetic patients receiving oral hypoglycemic drugs. These drugs need to be investigated for their potential detrimental effect in patients undergoing coronary revascularization procedures. Volatile anesthetics have been shown to protect the ischemic rabbit myocardium from infarction [6]. Despite several potential targets of volatile anesthetics, KATp channels have been hypothesized to be one of the major target proteins involved in cardioprotective effects of volatile anesthetics. Their effects

35

Anesthetic preconditioning

on the myocardium mimic the mechanism described for IPC, which is otherwise known as "anesthetic preconditioning". However, whether volatile anesthetics are able to open the KATP channel independently or they just potentiate the effects of other agonists is still controversial. A recent study on isolated guinea pig cardiac myocyte by Kwok et al. has demonstrated that the effects of isoflurane are additive to a specific agonist of the KATP channel, 2,4-dinitrophenol (DNP), and are reversed after the volatile agent is washed out of the perfusate [7]. These investigators also demonstrated that halothane either inhibits or has no specific effects on the 2,4-DNP on KATP channels. We have performed a series of experiments on isolated myocytes from the rat heart. The isolated cells were loaded with fura-2 and paced at a frequency of 1 or 2 Hz in a pacing chamber. The rate of changes in the light absorbency A340 (intracellular calcium) to A380 (extracellular calcium) ratio were measured and graphed as a function of time (Figure 4.2, lower panel). We concurrently measured changes in the voltage (index of length) over time (6V/8T) (Figure 4.2, upper panel). Our results indicate that there is a tight coupling between myocyte shortening and calcium transients. During reperfusion subsequent to a 30-min period of ischemia, there is a hypercontractile

state in the myocyte. Additionally, there is 20% increase in amplitude of calcium influx during reperfusion. The addition of halothane to the perfusate uncouples calcium transients from the myocyte shortening. Exposure of the myocyte to halothane also diminishes the extent of calcium transients, indicating an inherent inhibitory effect of halothane on voltagedependent calcium channels.

Inflammatory response to myocardial ischemia An inflammatory response is an important component of the acute coronary syndromes. However, its origin and mechanism remain unclear. Inflammation plays an important role in mediating cardiac remodeling following an ischemic event. The intracellular excess of Ca2+ results in activation of protein kinase C, mitogen-activated protein kinases (MIP kinases), and protein tyrosine kinases, and subsequent activation of downstream inflammatory cascade following ischemiareperfusion. It is evident that myocardial stunning and infarction following an ischemic event involves an inflammatory component along with an electrical imbalance across the cell membrane. The inflammatory component of this process will be discussed in

Figure 4.2 Rat cardiac myocytes were isolated and loaded with fura-2. Changes in voltage and A340/380 were plotted over time while the cells were paced in a pacing chamber perfused with media culture solution vaporized with halothane.

36

detail below. Chronic inflammation is also implicated in the pathogensis of atheromatous plaque and development of atherosclerosis and resultant ischemic heart diseases. However, the focus of this review is to identify local and systemic responses following an acute ischemic event and how they contribute to the pathophysiology of myocardial function. Cytokine response Cytokines modulate immunologic processes, inflammation, proliferative responses, and apoptosis. Recent studies have focused on the role of proinflammatory cytokines in cardiovascular diseases. Proinflammatory cytokines, such as interleukin 6 (IL-6), IL-lp and tumor necrosis factor alpha (TNF-a) play important roles in acute coronary syndrome by regulating inflammation, cellular adhesion, and the production of growth factors and various vasoactive substances. Reperfusion after myocardial infarction and transient myocardial ischemia induces the generation of proinflammatory cytokines, which in part play a role in producing myocardial injury during IRI [8-11]. Expression of proinflammatory cytokines in the isolated heart model of myocardial ischemia is further evidence for the myocardial source of these inflammatory mediators [12]; however, a role for cardiac resident mast cells cannot be ruled out [13,14]. It has also been suggested that the IRI-induced release of proinflammatory cytokines is involved in neutrophil chemotaxis to the site of inflammation [15,16]. TNFoc and IL-6 are major stimulating factors for CXC chemokine (IL-8) production from macrophages [ 15]. IL-6 is an acute reactant cytokine with very early expression following reperfusion of the infracted myocardium [17]. Serum levels of IL-6 are elevated after myocardial infarction (MI), and the myocardium is the major site of IL-6 production during myocardial ischemia [18]. IL-6 delays the apoptosis process in neutrophils, resulting in a larger population of neutrophils with greater capacity for oxidant production [19]. IL-6 is also the primary stimulus for intercellular adhesion molecule 1 (ICAM-1) induction, and enhances neutrophil-endothelium and neutrophilmonocyte adhesion and interactions [15]. IL-6 also has a regulatory role in the generation of other cytokines such as IL-8. The effects of IL-6 on neutrophils are postulated to play a role in the mechanisms whereby IL-6 contributes to multiple organ dysfunction [20].

CHAPTER 4

Both mRNA and protein levels of TNF-a and IL-6 are increased within 15-30 min of left anterior descending artery (LAD) occlusion in the heart homogenates, and these elevated levels are generally sustained for 3 h [ 17]. These studies indicate that during early reperfusion, mRNA levels for IL-6 and transforming growth factor betaj (TGF-pj) are significantly reduced compared with permanent LAD occlusion. In both groups, cytokine mRNA levels all returned to baseline levels at 24 h, while IL-lp, TNF-a and TGFPj mRNA levels again rose significantly at 7 days only in animals with permanent LAD occlusion. However, the exact role of these cytokines in mediation of the injury is not clear [21]. Neutralization of local TNFa release from cardiac myocytes after ischemia by specific antibody improves myocardial recovery during reperfusion [22,23], although we have not been able to reproduce these results in isolated rabbit hearts. By contrast, our data indicate that administration of recombinant TNF-a to the isolated heart during reperfusion following 15 and 50 min of ischemia improves both contractile function and myocardial relaxation. This functional improvement, however, is not associated with decreases in myocytic damage as examined by the release of myoglobin and troponin I into the perfusate solutions. This finding indicates that postischemic autocrine and paracrine TNFa activity plays an important role in myocardial function. In a murine model of myocardial IRI, the extent of reperfusion-induced apoptosis is modulated by the inflammatory process, during which locally produced TNF-a plays a significant role in the development of tissue injury. Subsequently, this proinflammatory reaction is followed by endogenous production of the anti-inflammatory cytokine IL-10, which serves as a physiological counterbalance to the effects of TNF-a [24]. There is also evidence that exogenous administration of IL-10 reduces cellular injury following IRI in the myocardium, as evident by increases in tissue inhibitor of metalloproteinases (TIMP)-l mRNA expression [24,25]. This protective effect is also due to an inhibitory effect of IL-10 on generation of TNF-a. We postulate that the duration of ischemia is a major determinant of the pattern of cytokine expression that may lead to activation of protective versus injurious cytokines. Exposure of isolated human peripheral mononuclear cells to halothane, enflurane, or sevoflurane demonstrates suppressive effects of

37

Anesthetic preconditioning

Figure 4.3 Blood samples were obtained from both a coronary sinus catheter and an indwelling arterial catheter for patients undergoing CABG surgery. IL-6 was measured in plasma samples using an ELISA technique.

IL-1 (3 and TNF-a release [26]. The anti-inflammatory effect of these volatile anesthetics may also be beneficial in limiting the extent of IRI after percutaneous transluminal coronary angioplasty (PTCA) and/or coronary artery bypass. Ultimately, by identifying the exact mechanisms of signaling that lead to the activation of proinflammatory cytokines, we will be able to modify these responses to maximize the level of cardiac protection. Several anesthetic agents decrease the extent of inflammatory cytokine response to myocardial IRI. We have previously assessed the effects of sevofiuranevaporized cardioplegia solution on the local generation and release of TNF-a and IL-6 into the coronary sinus blood during aortic cross-clamping in patients undergoing coronary artery bypass surgery. Our results indicate that the concentrations of both IL-6 and IL-8 significantly increase following the release of aortic cross-clamp when compared to their baseline levels in the coronary sinus blood. The concentra-

I Figure 4.4 Western blotting performed on heart homogenates prepared after an in vivo ischemia (10 min) and subsequent reperfusion for 4 h. This demonstrates an increase in local expression of this cytokine 4 h after IRI that is blunted by isoflurane. Recombinant rabbit TNF-a was used for the positive control (lane 1).

tions of these cytokines partly declined by the fourth hour after termination of cardiopulmonary bypass. Vaporizing cardioplegia solutions with sevoflurane blunts the initial IL-6 and IL-8 response locally (Figure 4.3). TNF-a levels were not detectable in either group of patients. Using a rabbit model of myocardial IRI we have demonstrated that the concentration of TNF-a increases after 4 h in the tissue homogenates obtained from the heart following 15 min occlusion of the LAD. Exposure of these animals to isoflurane attenuates the TNF-a band on the Western blotting, while propofol (an intravenous anesthetic) accentuates the tissue concentration of this cytokine (Figure 4.4). Interestingly, blocking TNF-a does not improve the myocardial contraction or relaxation following ischemia-reperfusion of global anoxia-reoxygenation in isolated hearts. Troponin T and myoglobin release from the isolated hearts are also not affected by blocking TNF-a during reperfusion.

38

Propofol is an intravenous anesthetic that is often used in cardiac surgery due to its favorable pharmacokinetic effects of rapid awakening, low incidence of nausea, and ease of titration control [27]. Furthermore, propofol may prove beneficial in reducing IRI due to its structure, similar to vitamin E, which gives it free radical scavenging properties [28,29], and also calcium channel blocking properties [30,31]. Despite this, conflicting studies on its ability to reduce IRI has made propofol a well-studied but controversial topic over the past few years. Some clinical and experimental studies find that in normal hearts, propofol has cardiodepressive effects such as decreasing myocardial contractility and relaxation, whereas other studies, involving ischemic hearts, report a cardioprotective function, or no effect of reducing IRI. For example, studies involving ischemic rat hearts, which underwent global ischemia for 25 min or 1 h with immediate reperfusion of 30 min or 1 h, respectively, suggest that propofol, in high doses, facilitates the recovery of myocardial contractility, decreases the release of lactate dehydrogenase (LDH) and histological injury, and attenuates the increase of left ventricular enddiastolic pressure during ischemia and reperfusion [28,32]. On the other hand, a recent study by De Hert etal. found a load-dependent decrease in dP/dT(max) which was preserved in patients anesthetized with sevoflurane [33]. Ketamine, another intravenous anesthetic in clinical use, has been reported to inhibit the production of TNF-a following endotoxin stimulation in a dosedependent manner [34]. Ketamine also significantly improved arterial oxygen tension (Pao2), metabolic acidosis and hypoglycemia, and attenuated endotoxininduced hepatic injury in a dose-dependent fashion. In addition, ketamine treatment significantly improved lipopolysaccharide-induced lethality in carrageenan-sensitized mice [35]. The majority of anti-inflammatory effects of ketamine are mediated via its action on neutrophils.

Neutrophilic inflammatory response to myocardial ischemia Inflammatory cells are recruited to the area of the injury if the ischemic event leads to necrosis of cardiac tissue. This recruitment is part of a physiologic repair mechanism in action to promote ventricular remodeling and adaptation of the injured myocardium to the altered geometry of the heart. Since the cardiac

CHAPTER 4

myocyte is a well-differentiated omnipotent cell, its repair mechanism involves fibrosis and replacement of cardiac tissue with fibroblasts and scar formation. Neutrophils are the predominant phagocytes in the early stages of myocardial ischemia-reperfusion response and are also implicated in the development of tissue damage. Neutrophils are quickly recruited to the site of myocardial infarction following experimental occlusion of coronary arteries in animal models [16]. This neutrophilic infiltration is evident by increases in myeloperoxidase activity measured in the heart homogenates of these animals. Mechanisms by which neutrophils are attracted to the myocardium in ischemia/reperfusion are not fully defined. Lipopolysaccharide-induced CXC chemokine (LIX), cytokine-induced neutrophil chemoattractant (KG), and macrophage inflammatory protein-2 (MIP-2) are rodent chemokines with potent neutrophilchemotactic activity. In humans, IL-8, which is an analog of the rodent MIP-2, seems to be a major chemotactic factor that promotes neutrophil recruitment. IL-8 is produced by various other types of cells following inflammatory stimuli and exerts a variety of functions on leukocytes [36]. Furthermore, complement activation and release of C5a play some role in neutrophil activation and migration to the site of myocardial injury. LIX is highly regulated in the cardiac myocytes following an ischemic event and its regulation is mediated through a redox stress and activation of nuclear factor kappa B (NFKB) [37]. Upon reperfusion, neutrophils accumulate and produce an inflammatory response in the myocardium that is responsible in part for the extension of tissue injury associated with reperfusion [24,38]. Neutrophil activation occurs in two phases following IRI [39]. The early phase is a result of complement activation (release of C5a), and it is abolished in a C6-deficient animal model [40]. Activation of neutrophils at this phase results in further generation of IL-8. Myocardial ischemia and reperfusion result in release of chemoattractants in response to locally produced endothelin 1 proteins [41]. Local generation of complementrelated chemotactic factors is presumed to mediate the sequence of events leading to the infiltration of neutrophils at inflammatory sites. It has been shown that patients with acute myocardial infarction have a transient but significant rise in serum IL-8 concentration within 24 h after the onset of symptoms, whereas IL-8 is not detected in any of the samples from patients

39

Anesthetic preconditioning

Figure 4.5 Flow cytometry of peripheral blood cells performed on samples obtained from the coronary sinus (pre and post CPB) and a peripheral artery (4th post CPB) from left to right. The blood cells were stained with antiCDI 3-cy5, antiCD11 bPE, and antiCD18-FITC. CD13+ cells were gated and counted to a total number of 5000 cells.

with angina pectoris or normal controls [42]. The transient nature of the plasma IL-8 elevation is probably due to a high affinity of this cytokine for the red blood cells [43]. Similar findings have been reported in a canine model of myocardial ischemia with mRNA upregulation of IL-8 and evidence for its presence in the inflammatory infiltrate near the border between necrotic and viable myocardium [44]. IL-8 initiates neutrophil recruitment by increasing the expression of (3-integrins. The effect of TNF-oc on adherence is significantly inhibited by monoclonal antibody against ICAM-1, indicating a regulatory role for this cytokine in expression of ICAM-1 following myocardial ischemia [45]. The leukocyte-adhesion molecule family GDI I/ CD 18 ((32 integrins) is critical to the function of neutrophils and monocytes in inflammation and injury [46]. These interactions are exaggerated during IRI by triggering the expression of E-selectin mRNA in the reperfused organ [47]. Our clinical studies indicate that the CD lib/CD 18 ratio dramatically increases following cardiopulmonary bypass, suggesting activation of neutrophils during cardiopulmonary bypass (Figure 4.5). In vivo activation of neutrophils is initiated by the adherence of these cells to the proteins expressed on the surface of vascular endothelium. "Tethering" of these adhesion molecules to the endothelium stimulates neutrophilic oxygen "burst" and generation of reactive oxygen species [48]. Activation of neutrophils occurs in response to complement activation secondary to cardiopulmonary bypass (CPB) and release of IL-8 from the myocardial origin due to

ischemia and reperfusion. In our laboratory measurement of IL-8 in the blood draining from the coronary sinus has demonstrated significant rises of this chemokine. The CD lib/CD 18 ratios parallel the rises of IL-8 concentrations, implying the importance of ischemia-reperfusion in initiating the inflammatory cascade leading to neutrophilic activation. However, the use of CPB also results in upregulation of (3integrins on the surface of neutrophils through the activation of complement (alternate pathway). While sevoflurane-vaporized cardioplegia does not affect the alternate pathway—activation of complement due to CPB—it significantly decreases IL-8 generation and the classic pathway of complement as quantified by measurement of C4b component of the complement system. Therefore, we hypothesize that the main antiinflammatory effects of sevoflurane are mediated through its inhibitory role in myocardial IRI. Furthermore, concurrent perfusion of isolated hearts with neutrophils and platelet activating factor (PAF), a phospholipid mediator of inflammation, results in detrimental mechanical function and conduction blocks. Specific antagonists of PAF and eicosanoids such as leuktrienes can effectively block the negative inotropic and arrhythmogenic effects of neutrophils [49]. Regardless of the source of stimulation, activated leukocytes are attracted to the ischemic myocardium secondary to upregulation of ICAM-1 in the ischemic tissue and will result in neutrophilinduced injury to the myocardium at risk. Neutrophils activated in this manner generate PAF, and the effects of their activation are prevented by blockade of

40

PAF receptors. Thus, during reperfusion of ischemic myocardium, PAF generated by activated neutrophils is most likely a cause of arrhythmias [50]. In summary, damage to the heart due to IRI is a source of morbidity and mortality during revascularization procedures. Volatile anesthetics reduce postischemic adhesion of neutrophil in the coronary system, and decrease adhesion to cultured human endothelial cells [51].

The role of oxidants as neutrophilic mediators of ischemia-reperfusion injury Oxidative metabolism and generation of reactive oxygen species (ROS) are also increased in the presence of oxygen excess during the reperfusion phase. In myocardial IRI, neutrophils and the ischemic myocytes are "primed" for free radical production [52]. With reperfusion and reintroduction of molecular oxygen there is a burst of oxygen radical production resulting in extensive tissue destruction. Limitation of infarct size in anesthetized dogs following occlusion and reperfusion of the left circumflex coronary artery by ibuprofen has been associated with marked suppression of leukocyte accumulation within the ischemic myocardium [53]. The potential sources of ROS during myocardial IRI include the mitochondrial electron transport system [54], prostaglandinbiosynthesis [55], activated neutrophils that infiltrate ischemic and reperfused myocardium, and the enzymatic pathway involving xanthine oxidase which is localized within the vascular endotheliuni in many animal species [56]. The oxidase form of this enzyme is generated upon activation of Ca2+proteases [57]. CI-959, a cell-activation inhibitor that prevents the formation of ROS by inflammatory cells, significantly reduces the myocardial infarct size without causing thinning of the resultant scar [58]. A protective effect of superoxide dismutase against myocardial IRI further signifies the role of neutrophil mediated myocardial damage [59]. A recent study by Zilberstein et al. has demonstrated that administration of ketamine inhibits superoxide generation by peripheral neutrophils following cardiopulmonary bypass. Furthermore, inclusion of ketamine in the anesthesia induction results in inhibition of superoxide generation by neutrophils following chemical and bacterial stimulation. This inhibition lasts up to 7 days following cardiopulmonary bypass [60].

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Although there is a general agreement about the injurious nature of oxidant excess in tissues, mitochondrial generation of these reactive species is necessary for full protection of IPC and volatile anesthetics. A recent study has demonstrated that the beneficial effects of isoflurane are eliminated by antioxidant pretreatment. These antioxidants do not have any direct effect on myocardial function during IRI. Oxidative metabolism is also regulated by KATP channels located on the surface of mitochondria. Opening of these channels enhances the oxidative metabolism and subsequent changes of the redox state of the mitochondria. On the other hand, cytoplasmic concentrations of ROS adversely affect the enzymatic function and membrane integrity through carbonylation and peroxidation of protein and lipid molecules. Furthermore, ROS alter gene expression and deterioration of transcription machinery through their effects on DNA molecules.

Conclusions Anesthetic agents are a hydrophobic class of chemicals with high affinity to the lipid membrane of living cells. This particular characteristic of anesthetics makes them potentially active on cellular ion exchange and several membrane-related functions of mammalian cells. Myocardial ischemia and reperfusion involves multiple steps in the process of cellular injury, ranging from reversible electrical imbalance to activation of the inflammatory cascade leading to cell death. Various anesthetic agents offer protective effects at both electrical and inflammatory stages of IRI. Inclusion of these agents in myocardial protection strategies will potentially provide a novel venue to preserve the myocardial function and minimize cellular damage to the heart during cardiac surgery.

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37 Chandrasekar B, Smith JB, Freeman GL. Ischemiareperfusion of rat myocardium activates nuclear factor-kappa B and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation 2001; 103:2296 -302. 38 Bohle RM, Pich S, Klein HH. Modulation of the inflammatory response in experimental myocardial infarction. EurHeart J1991; 12 (Suppl. D): 28-31. 39 Ivey CL, Williams FM, Collins PD, Jose PJ, Williams TJ. Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8 [comment]./C/mInvest 1995; 95: 2720-8. 40 Kilgore KS, Park JL, Tanhehco EJ et al. Attenuation of interleukin-8 expression in C6-deficient rabbits after myocardial ischemia/reperfusion. / Mol Cell Cardiol 1998; 30: 75-85. 41 Hofman FM, Chen P, Jeyaseelan R et al. Endothelin-1 induces production of the neutrophil chemotactic factor interleukin-8 by human brain-derived endothelial cells. Blood 1998; 92:3064-72. 42 Abe Y, Kawakami M, Kuroki M et al. Transient rise in serum interleukin-8 concentration during acute myocardial infarction. BrHeartJ1993; 70:132^4. 43 de Winter RJ, Manten A, de Jong YP et al. Interleukin 8 released after acute myocardial infarction is mainly bound to erythrocytes. Heart 1997; 78:598-602. 44 Kukielka GL, Hawkins HK, Michael L et al. Regulation of intercellular adhesion molecule-1 (ICAM-1) in ischemic and reperfused canine myocardium. / Clin Invest 1993; 92:1504-16. 45 Ikeda U, Ikeda M, Kano S, Shimada K. Neutrophil adherence to rat cardiac myocyte by proinflammatory cytokines. / CardiovascPharmacol 1994; 23: 647-52. 46 Dana N, Fathallah DM, Arnaout MA. Expression of a soluble and functional form of the human beta 2 integrin GDI Ib/CDlS.ProcNatlAcadSciUSA 1991; 88:3106-10. 47 Billups KL, Palladino MA, Hinton BT, Sherley JL. Expression of E-selectin mRNA during ischemia/reperfusion injury. ]Lab Clin Med 1995; 125:626-33. 48 Walzog B, Jeblonski F, Zakrzewicz A, Gaehtgens P. Beta2 integrins (GDII/CD 18) promote apoptosis of human neutrophils.FASEB/1997; 11:1177-86.

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49 Alloatti G, Montrucchio G, Emanuelli G, Camussi G. Platelet-activating factor (PAF) induces platelet/neutrophil cooperation during myocardial reperfusion. JMol Cell Cardiol 1992; 24:163-71. 50 Hoffman BF, Feinmark SJ, Guo SD. Electrophysiologic effects of interactions between activated canine neutrophils and cardiac myocytes. / Cardiovasc Electrophysiol 1997; 8:679-87. 51 Kowalski C, Zahler S, Becker BF et al. Halothane, isoflurane, and sevoflurane reduce postischemic adhesion of neutrophils in the coronary system. Anesthesiology 1997; 86:188-95. 52 Hammond B, Kontos HA, Hess ML. Oxygen radicals in the adult respiratory distress syndrome, in myocardial ischemia and reperfusion injury, and in cerebral vascular damage. Can JPhysiol Pharmacol 1985; 63:173-87. 53 Werns SW, Shea MJ, Lucchesi BR. Free radicals in ischemic myocardial injury. / Free Radic Biol Medl985; 1:103-10. 54 Otani H, Tanaka H, Inone T et al. In vitro study on contribution of oxidative metabolism of isolated rabbit heart mitochondria to myocardial reperfusion injury. Circ Res 1984;55:168-75. 55 Egan RW, Gale PH, Kuehl FA Jr. Reduction of hydroperoxides in the prostaglandin biosynthetic pathway by a microsomal peroxidase. / Biol Chem 1979; 254: 3295302. 56 Jarasch E, Bruder G, Heid H. Significance of xanthine oxidase in capillary endothelial cells. Acta Physiol Scand 1986; 548: 39-46. 57 Parks D, Granger D. Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand 1986; 548:87-99. 58 Burke SE, Wright CD, Potoczak RE et al Reduction of canine myocardial infarct size by CI-959, an inhibitor of inflammatory cell activation. / Cardiovasc Pharmacol 1992; 20:619-29. 59 Alloatti G, Montrucchio G, Camussi G. Role of plateletactivating factor (PAF) in oxygen radical-induced cardiac dysfunction. J Pharmacol Exp Ther 1994; 269: 766-71. 60 Zilberstein G, Levy R, Rachinsky M et al. Ketamine attenuates neutrophil activation after cardiopulmonary bypass. Anesth Analg 2002; 95:531-6.

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Myocardial protection during acute myocardial infarction and angioplasty Alexandre C. Ferreira, MD, FACC & Eduardo deMarchena, MD, FACC

Survival of ischemic myocardium requires timely reperfusion. It has been demonstrated that reperfusion has a harmful and injurious component, which in experimental models appears to be mediated by reperfusion-induced augmentation of the inflammatory response and generation of reactive oxygen free radicals [ 1 ]. Myocardial protection, during myocardial infarct or percutaneous coronary intervention, is achieved by strategies which attempt to either decrease oxygen requirements by the ischemic myocardium, make myocytes more resistant to ischemia, and/or decrease reperfusion injury.

The timing and mechanism of reperfusion Critically well-timed coronary reperfusion as treatment for acute myocardial infarction (AMI) reduces myocardial infarct size, enhances recovery of left ventricular function, and improves short and long-term survival. There is still concern that at the time of reperfusion a further injury occurs to the myocardium. At least in theory, if reperfusion injury could be prevented or eliminated, the outcome for patients with myocardial infarction may improve. The general notion of reperfusion injury is closely connected to the concept that oxygen radicals generated at the time of reperfusion cause cell death and necrosis [2]. At least four expressions of myocardial reperfusion injury have been defined:

1 Reperfusion arrhythmias. 2 Postischemic contractile dysfunction or myocardial stunning. 3 Coronary vascular and microvascular reperfusion injury. 4 Precipitation of necrosis in reversibly injured cells. The speed and completeness of reperfusion depends on the type of strategy used for reperfusion, primary angioplasty, or thrombolytic therapy. At least in the elderly, patients with extensive infarct and heart failure, there is superiority of a mechanical reperfusion over thrombolitic agents. There may be several explanations for the smaller myocardial infarct size after primary angioplasty. First, a higher rate of open infarct-related vessels after angioplasty may result in more effective myocardial salvage. Thrombolytic agents will achieve reperfusion at best in 60% of patients. Clinical trials of angioplasty in AMI have been found to achieve reperfusion in over 90% of patients. A second explanation of the better results after angioplasty is that reperfusion is faster or more complete with angioplasty. Further, aggressive anticoagulation can lead to hemorrhagic conversion of infarct, a phenomenon that reflects severe microvascular injury with extravasation of erythrocytes [3]. Thrombolytic agents may also have a proinflammatory effect. An extensive neutrophil aggregation caused by thrombolytic therapy may promote myocardial injury. A higher reocclusion rate due to a procoagulant activity and a depletion of the reservoir of plasminogen in serum reduces clot lysability and

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therefore the efficacy of these agents. Left ventricular dysfunction, which has also been described after treatment of AMI, varies with the reperfusion strategy. In one animal model, the induction of a systemic lytic state resulted in immediate echocardiographic and early histologic alterations characteristic of reperfusion injury and was associated with impaired functional recovery of the myocardium. Such effects are not observed with direct recanalization of thrombotic occlusions by mechanical interventions [4]. Regardless of the mechanism of reperfusion, further improvement is feasible if myocardial cells are made more resistant to ischemia, oxygen requirement is reduced and reperfusion injury is avoided.

Making myocytes more resistant to ischemic injury Ischemic preconditioning Experimental studies indicate that brief, transient episodes of ischemia render the heart very resistant to infarction from a subsequent sustained ischemic insult, an effect termed "ischemic preconditioning." Transient and repetitive occlusion of a coronary artery in the catheterization laboratory is associated with progressively less intense chest discomfort and a lesser degree of electrocardiographic abnormalities. It has been demonstrated that preconditioning myocardium before prolonged occlusion with brief ischemic episodes affords substantial protection to the cells by delaying lethal injury, thereby limiting infarct size [5]. The mechanism of ischemic preconditioning is not totally understood. Some oral hypoglycemic agents appear to block the ischemic preconditioning response in diabetics. This effect may be due to blockade of potassium channels. Adenosine receptors and adrenoreceptors may also play a pivotal role in this process. Animal studies have suggested that stimulation of adenosine receptors can be a critical event in ischemic preconditioning. Human studies have shown that exogenous adenosine administration can limit signs of ischemia with repetitive coronary occlusion, and pretreatment with agents that block adenosine receptors, either selectively or nonselectively, can also limit ST-segment depression with repetitive coronary occlusion. Adrenoreceptors are ubiquitous to all mammalian species. There are clinical and animal data to suggest

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that they play an important role in mediating ischemic preconditioning. During cycles of myocardial ischemia, cardiomyocytes have to depend exclusively on anerobic glycolysis for energy production. Stimulation of alphaj-adrenoreceptors increases glucose transport inside the cardiomyocytes and enhances glycogenolysis by activating phosphorylase kinase. It also causes an increase in the rate of glycolysis by activating the enzyme phosphofructokinase. Stimulation of alphajreceptors also inhibits apoptosis by increasing the levels of the antiapoptotic protein Bcl-2. Interestingly, myocardial ischemia produces an increase in the expression of alphaj-adrenoreceptors in cardiomyocytes. The levels of the alphaj-agonist, norepinephrine also increases several fold. During ischemic states, upregulation of alphaj-adrenoreceptors and an increase in norepinephrine release could be a powerful adaptive mechanism that drives ischemic preconditioning [6]. One human model of ischemic preconditioning is repetitive occlusion of a coronary artery during angioplasty, in which pain and ST-segment depression are lower after the initial balloon occlusion of the artery [7]. Clinical data, although limited, suggest that episodes of angina within 24 h of an infarct, improve clinical outcome and decrease infarct size. This effect is present even in the absence of collaterals, indicating the presence of a cellular protective mechanism [8]. Glucose insulin potassium Several metabolic mechanisms have been implicated for the beneficial effects of glucose insulin potassium (GIK) in AMI. GIK decreases both circulating levels of free fatty acids (FFA) and myocardial FFA uptake. Increased FFA levels are toxic to ischemic myocardium and are associated with increased membrane damage, arrhythmias, and decreased cardiac function. Another possible beneficial effect of GIK is the stimulation of myocardial K+ reuptake by insulin's stimulation of Na+,K+-ATPase and the provision of glucose for glycolytic ATP production. The significance of the relatively small increase in ischemic glycolytic ATP production that results from increased provision of glycolytic substrate has been questioned. Experimental data also show that a high glucose substrate increases myocyte resistance to the toxic effects of the increase in cell calcium concentration that occurs during hypoxia [9].

Myocardial protection during AMI and angioplasty Since first introduced by Sodi-Pallares et al. [10], the usage of GIK in AMI is controversial and clinical trials have yielded mixed results. A recent metaanalysis of all randomized clinical trials where GIK was initiated relatively early, discarding those in which GIK was started too late to be useful or in inadequate doses, suggested that GIK was highly likely to reduce AMI mortality [11]. The ECLA (Estudios Cardiologicos Latinoamerica) trials demonstrated AMI mortality reduction by GIK in the thrombolytic era. The ECLA Collaborative Group were able to show a dramatic reduction in death rate from AMI, from 11.5% in the control group to 6.7% in patients treated with GIK. This is the largest reduction of mortality by any intervention that has been tried [12]. Other clinical trials have not confirmed those findings, and the use of GIK in AMI remains controversial.

Adenosine tri phosphate-potassium channel agonist The concept of ischemic preconditioning appears to be closely linked to the ATP-K channel. The adenosine triphosphate-dependent potassium channel was shown to be vital to this cardioprotective mechanism in numerous animal models. As we previously indicated in this chapter, sulfonylurea drugs block this potassium channel and may therefore attenuate this potentially beneficial mechanism of cardioprotection, which could contribute to the adverse clinical outcomes of diabetic patients treated with sulfonylureas after acute coronary syndromes. Both the adaptation to balloon inflations during angioplasty, which was also previously discussed, and the contractile recovery after ischemia can be blocked by glyburide [13]. Patients with noninsulin-dependent diabetes mellitus experience a higher cardiovascular mortality rate than patients with insulin-dependent diabetes mellitus. It appears that K(ATP) channel inhibition with oral sulfonylureas prevents myocardial preconditioning and may explain the increased cardiovascular death in patients with noninsulin-dependent diabetes mellitus. The relationship between the K(ATP) channels and human myocardial preconditioning is an interesting one. In experimental models treatment with a selective mitochondrial K(ATP) channel opener for 5 min, followed by a 10-min washout, protects both viability and function of human myocardium against ischemia/reperfusion [ 14,15].

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Nicorandil, a drug with both nitrate-like and ATPsensitive potassium-channel (K + ATP) activating properties, has been available in Europe for the treatment of refractory angina and may have a myocardial protective effect. Nicorandil, as an antianginal drug, significantly improved the results of exercise tolerance tests in patients with stable effort angina pectoris. The drug also improved the results of exercise tolerance tests relative to placebo in early randomized, double-blind, placebo-controlled trials. In randomized, double-blind comparative studies in patients with angina pectoris, nicorandil has demonstrated equivalent efficacy, as measured by exercise tolerance testing, to isosorbide di- and mononitrate, betablockers and calcium blockers [16]. The IONA study was conducted to see whether these antianginal effects would translate into reductions in clinical events in stable angina patients. The trial involved 5126 patients with stable angina and one or more of the following risk factors: decreased left ventricular (LV) systolic function, LV hypertrophy, diabetes mellitus, and hypertension. The patients were randomized to nicorandil 20 mg twice daily or placebo in addition to standard antianginal therapy. Mean follow-up was 1.6 years. The primary composite endpoint of coronary heart disease (CHD) death, nonfatal MI, or unplanned hospital admission for cardiac chest pain was significantly reduced by 17% in the nicorandil group. The secondary endpoint of CHD death or nonfatal MI was not significantly different between the groups [17]. Studies in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have shown that the administration of nicorandil reduces STsegment elevation during ischemia, thus demonstrating its cardioprotective effects. The effects of nicorandil on various aspects of myocardial recovery from ischemic damage caused by AMI have been investigated in the short term. Regional LV wall motion, a marker of myocardial function, was significantly improved in nicorandil recipients relative to control. In summary, nicorandil has demonstrated potential cardioprotective effects when used as part of an intervention strategy directly after AMI in high-risk patients. Further large-scale longer-term studies of nicorandil in this latter indication are awaited with interest.

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Hypothermia Hypothermia may render the myocardium less susceptible to ischemia. A large amount of experimental and clinical data suggests that moderate hypothermia suppresses the generation of oxygen free radicals and the inflammatory response that compounds injury after ischemia. There is also some indication that it may reduce reperfusion injury after successful recanalization, both in the brain and in the heart. Surface cooling, with cold air blankets and alcohol rub down, while effective in reducing core temperature, is usually imprecise and followed by unstable temperatures over the course of maintenance. Surface cooling also causes naturally uncontrolled shivering. Patients need to receive paralytic drugs and sedation to hamper the shivering. Ventilatory support is also frequently necessary to address the suppression of respiration from paralytic drugs. A new internal cooling device is now undergoing clinical trials for myocardial protection in patients undergoing AMI. The COOL MI trial will randomize 40 MI patients presenting less than 6 h from symptom onset. The trial will incorporate a new technology to achieve and maintain hypothermia, called the SetPoint (Radiant trademark) Endovascular Temperature Management System. The new system uses a catheter inserted into the inferior vena cava to achieve and maintain temperatures in the range of 32-33°C. With the new device, core temperatures can be reduced as surface warmth is maintained, so that the patient can be both awake and comfortable during cooling. Results are not yet available [ 18].

Fatty acid oxidation inhibitors Normally the heart obtains its major source of energy from the oxidation of fatty acids. This process requires large amounts of oxygen, and during ischemia the supply of oxygen is diminished. Under these circumstances, glucose provides a more efficient source of energy. During myocardial ischemia, at a time of decreased oxygen supply, there is a significant increase in fatty acid levels. Agents belonging to a new class, the fatty acid oxidase inhibitor drugs, called fatty acid oxidation inhibitors (pFOX), are under clinical investigation. The pFOX inhibitors increase the efficiency of oxygen use during ischemic stress by shifting the metabolism to a more efficient fuel source, glucose, instead of fatty acids. This metabolic change allows for an increase in

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ATP production per mole of oxygen consumed. At the same time it reduces the rise in lactic acid and acidosis, and maintains myocardial function under conditions of reduced myocardial oxygen supply. Ranolazine, a pFOX inhibitor, reduces cellular acetyl-CoA content via inhibition of fatty acid betaoxidation and activates pyruvate dehydrogenase. The possible benefit of ranolazine was evaluated in the CARISA trial. This was a phase III, multinational, randomized, double-blind, placebo-controlled, parallelgroup trial designed to evaluate the safety and efficacy of ranolazine for the treatment of chronic angina. CARISA randomized 823 patients with stable angina to either a 12-week course of two different doses of ranolazine (570 mg/bid or 1000 mg/bid) or placebo. Ranolazine produced a modest increase in exercise time in patients with chronic angina. Unlike betablockers, the drug has no effect on heart rate or contractility. There was a small dose-related prolongation of the QT interval [19]. Ranolazine may be effective in reducing myocardial infarct size. In the rat model of left anterior descending coronary artery occlusion and reperfusion, rats subjected to ranolazine bolus injection plus infusion prior to left anterior descending coronary artery occlusion had a significant reduction in myocardial infarct size of approximately 33% compared to saline control (P< 0.05). In addition, infusion of ranolazine significantly attenuated the release of cardiac troponin T into the plasma [20]. It is still unclear whether ranolazine causes a reduction of infarct size and cardiac troponin T release in humans.

Reducing oxygen requirements A reduction in oxygen requirement by the heart may be achieved by drugs such as ACE inhibitors or betablockers, or by mechanical devices. Several mechanical approaches have been developed as adjuncts to high-risk coronary angioplasty to improve patient tolerance of coronary balloon occlusion and maintain hemodynamic stability in the event of complications. These percutaneous techniques include intra-aortic balloon counterpulsation, coronary sinus retroperfusion, and cardiopulmonary bypass.

Angiotensin blockers Infarct size maybe reduced by the use of AT(1) receptor blockers. Patients under treatment with AT(1)

Myocardial protection during AMI and angioplasty receptor blockers for indications such as hypertension treatment or prevention of ventricular remodeling after myocardial infarction may have improved prognosis after suffering a second AMI. Pretreatment with AT( 1) receptor blockers may protect the myocardium against ischemic injury during elective interventions with the risk of regional ischemia, such as percutaneous transluminal coronary angioplasty or coronary artery bypass grafting [21]. The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. Although at least two angiotensin II receptor subtypes, the AT(1) and the AT(2) receptor, have been identified, the cardiovascular effects of angiotensin II have been attributed largely to activation of AT( 1) receptors. In the animal model, the density of AT( 1) receptors is higher than that of AT(2) receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. In animal studies, AT(1) receptor blockade increases coronary blood flow during ischemia and during reperfusion, reduces the incidence of ischemia-related arrhythmias, limits infarct size, improves functional and metabolic recovery after myocardial ischemia, and attenuates ventricular remodeling postmyocardial infarction. The potential mechanisms responsible for the cardioprotection by AT(1) receptor blockade remain to be elucidated in detail, but appear to involve AT(2) receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Experimental evidence for the beneficial effects on heart failure of chronic treatment with ACE inhibitors accumulated from early 1980 in experimental models of LV dysfunction secondary to AMI. These studies demonstrated an improvement in hemodynamics, LV remodeling, and mortality with ACE inhibitor treatment. The effect of ACE inhibitors during the acute phase of AMI was less clear, although there was evidence of protection from ischemic damage, possibly mediated by an increase in collateral coronary blood flow [22]. Likewise, patients under treatment with AT( 1) receptor blockers for indications such as hypertension and ventricular dilatation after myocardial infarction are likely to have improved prognosis when suffering an AMI [23]. Beta-adrenergic blockers Beta-blockers appear to be beneficial in reducing

47

mortality after myocardial infarction. This benefit may be due to their negative chronotropic and inotropic effects, leading to reduction of arterial blood pressure, reduction of myocardial oxygen demand, and arrhythmogenesis. Further, beta-blockers also improve epicardial to endocardial flow ratios and myocardial energy efficiency. Early treatment with an intravenous beta-blocker is recommended for most patients with an acute infarct, as it appears to reduce infarct size. This recommendation is based on several randomized clinical trials conducted in the 1970s and early 1980s. The benefits of early beta-blocker treatment are greater in older than in younger patients and in patients with larger infarcts. Although most of the clinic data derived from studies conducted in the prereperfusion era, the results remain applicable today. Overall, mortality rates were reduced by 25-30% within the first year in these trials. Although beta-blocker use reduces infarct size in spontaneously occurring nonreperfused infarcts, it may not affect infarct size in patients treated with reperfusion therapy. The role of beta-blockers in non-Q wave infarction is less clear. More recently, the second Thrombolysis in Myocardial Infarction (TIMI) trial indicated that beta-blockers reduce recurrent ischemic events even in patients receiving a thrombolytic agent [24]. A recent observational study also suggested that beta-blocker use concurrent with percutaneous coronary intervention (PCI) decreased the risk of creatine kinase (CK)-MB elevation [25]. Treatment with a beta-blocker should be started within 24 h of a myocardial infarction. The size of the infarct can be reduced by intravenous metoprolol or atenolol followed by oral beta-blockers. This regimen also reduces the incidence of reinfarction, ventricular fibrillation, cardiac rupture, and intracranial hemorrhage in hospital. Treatment should be continued for at least 2 or 3 years and for longer if well tolerated [26,27]. The beneficial effects of beta-blockers seem to be a class effect. However those with partial agonist activity do not show a beneficial effect on mortality, and their use cannot be recommended.

Intra-aortic balloon pump The concept of the intra-aortic balloon pump (IABP) is an interesting one. The inflation during diastole improves coronary blood flow and during systole allows ventricular emptying at lower resistance.

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IABP is usually indicated in cardiogenic shock, but it is also frequently placed during myocardial infarction, refractory unstable angina, and prophylactic for high-risk angioplasty [28]. For patients who remain hemodynamically unstable, IABP offers the angioplasty operator the chance to have a less complicated angioplasty procedure with a higher technical success [29]. Cardiogenic shock mortality in the setting of AMI in the absence of IABP and aggressive revascularization is over 85%. Nonrandomized clinical trials in which aggressive hemodynamic support and revascularization were performed revealed improved outcome. In the SHOCK trial, the beneficial effect of early revascularization on 6- and 12-month survival was observed in the context of most patients receiving IABP. IABP may be used to prevent reocclusion after successful angioplasty. Patients with an acute anterior infarct who had successful angioplasty of their infarctrelated artery were randomized to either 24 h of counterpulsation after angioplasty or conventional therapy. The reocclusion rate was 2.4% compared to 17.7% in the conventional group [30]. It is difficult to establish the benefit of IABP for prophylatic use for high-risk angioplasty. IABP is usually used when a critical amount of myocardium is about to be made ischemic during angioplasty. The use of perfusion balloons and stents has decreased the necessity for mechanical support during angioplasty [31].

Cardiopulmonary bypass support Cardiopulmonary bypass support (CPS) is frequently used in the catheterization laboratory during a hemodynamic collapse complicating an angioplasty procedure or providing stand-by circulatory support for high-risk procedures. The use of large femoral cannulas which can be percutaneously placed make this technique safe and easy to apply by most interventionists. This technique allows hemodynamic stability to be maintained during high-risk interventional procedures regardless of intrinsic cardiac function. This form of support also permits transport of the patient to the operating room in a stable condition after an unsuccessful angioplasty. A National Registry of 14 centers performing elective CPS-supported angioplasty was created. Suggested indications were ejection fraction less than

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25% or a target vessel supplying more than half the myocardium, or both. The data from 105 patients undergoing supported angioplasty were entered into the Registry. Twenty patients were considered not to be bypass surgery candidates, and 30 patients had dilatation of their only patent coronary vessel. Seventeen patients had stenosis of the left main coronary artery and 15 underwent dilatation of that vessel. Chest pain and electrocardiographic changes occurred uncommonly despite prolonged balloon inflations. The angioplasty success rate was 95% for the 105 patients. Morbidity was frequent (41 patients), in most cases due to arterial, venous or nerve injury associated with cannula insertion or removal, or both [32]. Because of many drawbacks associated with prophylactic CPS, standby CPS is now the preferred method. The patient's outcome is significantly improved when CPS is initiated within 10 min of cardiac arrest. Improvement in angioplasty technique and availability of stents have greatly decreased the need for CPS.

Coronary retroperf usion Synchronized coronary sinus retroperfusion produces pulsatile blood flow via the cardiac veins to the coronary bed distal to a stenosis. This perfusion technique limits the development of ischemic chest pain and myocardial dysfunction in patients undergoing prolonged balloon inflations. This technique was inspired in the abandoned Beck II surgical procedure for coronary disease (performed in the 1950s), which entailed arterial grafting to the coronary sinus to perfuse the myocardium from the venous end of its circulation. In 1984, Mohl etal. [33] first reported intermittent catheter occlusion of the coronary sinus to protect myocardium during experimental coronary occlusion. In 1976, coronary sinus retroperfusion was used in animals and since then the technique has been applied in humans. Weiner et al. [34] treated patients with unstable angina, and several workers reported use during angioplasty in 1990. During angioplasty, it appears to reduce wall motion abnormalities during balloon inflation. In one study of 28 patients undergoing left anterior descending artery (LAD) angioplasty assisted by retrograde coronary venous perfusion, the incidence of angina was reduced by 50% [35]. Coronary retroperfusion provides regional myocardial support mainly during LAD angioplasty.

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Myocardial protection during AMI and angioplasty The major disadvantage of this technique is that it does not provide systemic support. Transient atrial fibrillation and coronary sinus staining have been reported.

Reducing reperfusion injury Antiplatelet llb-llla inhibitors The glycoprotein Ilb-IIIa receptor inhibitors effectively block the final common pathway of platelet aggregation. Clinical trials have demonstrated mortality benefit in patients with unstable angina undergoing angioplasty, decrease in enzymes elevation during elective angioplasty, and improved myocardial perfusion during acute infarct. The EPIC trial was the first large-scale study to test the hypothesis that glycoprotein receptor inhibitors, in this case abciximab, could reduce angioplasty procedural complications in a high-risk population. EPIC conclusively demonstrated that glycoprotein Ilb-IIIa receptor inhibitors can prevent acute ischemic events in the highest risk subset of patients with unstable angina (UA) under-going PTCA [36]. Since then, many clinical trials have confirmed the benefit of IlbIIIa inhibitors in angioplasty of patients with stable and unstable angina, and for the medical treatment of acute coronary syndromes. In the 1990s, Gibson and colleagues [37] introduced the concept of myocardial perfusion blush score, which takes into consideration both epicardial and microvascular flow. The usage of Ilb-IIIa inhibitors became very attractive as it improves myocardial and microvascular perfusion during acute myocardial infarction angioplasty and lytic therapy. Combining fibrinolytic therapy and angioplasty with antiplatelet therapy appears to improve tissue perfusion and therefore decrease myocardial infarct size. This approach is presently undergoing clinical investigation.

The sodium-hydrogen exchanger The sodium-hydrogen exchanger (NHE) acts to extrude hydrogen from cells, protecting them from acidosis. There are six known isoforms of the exchanger. Cardiac myocytes mostly express NHE-1. The activity of NHE is determined by intracellular pH, but it also responds to extracellular stimuli such as thrombin and angiotensin II.

During ischemia, the NHE mechanism removes hydrogen from within the cell, and exchanges it for sodium. Because the NHE mechanism becomes inactive in the setting of ischemia, intracellular sodium builds. An increase in intracellular sodium stimulates calcium influx through the NHE mechanism, leading to lethal calcium overload. The mechanism is active between ischemia and reperfusion and may contribute to reperfusion injury [38]. The use of NHE inhibitors is presently being investigated with two agents, cariporide and eniporide. The NHE inhibitors appeared, in preclinical studies, to limit the extent of myocardial infarction when administered prior to coronary occlusion. It is not yet clear if these agents are beneficial if given after coronary occlusion but before reperfusion. Two clinical trials to date, ESCAMI and GUARDIAN, using eniporide and cariporide, respectively, failed to demonstrate a significant benefit of NHE inhibitors in AMI patients undergoing reperfusion therapy. It is possible the ineffectiveness of these agents in the clinical trials could have been due to the inability of the drug to achieve the site of action due to the presence of an occluded vessel. The ideal setting for NHE inhibitors would be prior to ischemia. The drug may be of benefit in certain circumstances where one can give it before ischemia onset, such as prior to coronary artery bypass grafting (CABG) or in patients with unstable angina, prior to myocardial infarction. In the GUARDIAN trial, a subgroup of patients receiving the highest dose of cariporide prior to CABG appeared to derive ischemic injury protection [39]. In summary, further carefully designed clinical trials are required, in which the dose and timing of drug treatment are rationally chosen, to prove if NHE inhibitors are beneficial as cardioprotective agents.

Magnesium Magnesium may protect ischemic myocardium from reperfusion injury. Studies in different animal models of coronary occlusion and reperfusion have demonstrated that magnesium administration before or at the time of restoration of perfusion reduces infarct size; the benefit is markedly reduced or lost if magnesium administration is delayed after reperfusion. The mechanism of the beneficial effect of magnesium has not yet been elucidated. It has been hypothesized that supplemental magnesium would

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have an antiarrhythmic effect, reducing peri-infarct arrhythmias. It may also decrease peri-infarct heart failure and mortality independent of the decrease in arrhythmia. Magnesium also has an antiplatelet effect, which may help to prevent arterial reocclusion, and vasodilatory effect, which may decrease afterload and prevent spasm. Magnesium is also functional as an inorganic calcium channel blocker and it can inhibit efflux of calcium from the cardiac sarcoplasmic reticulum [40]. In humans, a direct myocardial protective effect of magnesium at the time of reperfusion has been advocated to explain the beneficial effect of intravenous magnesium. Two meta-analyses, including seven small randomized trials, and the second Leicester Intravenous Magnesium Intervention Trial (LIMIT2) demonstrated a protective effect of magnesium. The benefit of magnesium remains controversial, as in the fourth International Study of Infarct Survival (ISIS-4) there was no benefit of intravenous magnesium. Some workers have attributed this lack of benefit to the fact that magnesium therapy was started relatively late and this would have hampered the high magnesium serum concentration to be achieved at the onset of reperfusion in most patients randomized to magnesium infusion. Therefore the controversy about the role of magnesium in AMI is far from being settled. According to experimental data, magnesium might protect the myocardium from reperfusion injury and reduce infarct size only if it is administered at the initiation of or before reperfusion [41-43].

Adenosine Adenosine has well-known vascular smooth-muscle relaxing effects and has antiadrenergic and negative chronotropic and dromotropic properties. Adenosine is a cardioprotective agent, which has been used during cardiac surgery. Adenosine exhibits a broad spectrum of effects against neutrophilmediated events and can therefore intervene in the ischemia and reperfusion response, a capacity that may offer therapeutic benefits. Adenosine may also trigger a hibernation effect that may be cardioprotective. The cardioprotective effect of adenosine was investigated in the setting of AMI and reperfusion. Adenosine is a promising agent for reduction of infarct in patients undergoing reperfusion therapy. It may limit infarct size, replenish phosphate stores,

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reduce platelet aggregation, mediate preconditioning, and inhibit free radical formation [44]. In the AMISTAD I trial, 236 patients treated with adenosine had a 33% reduction in infarct size, but this was only apparent in patients with anterior MI [45]. No benefit was seen in patients with inferior MI and this group also showed an increase in bradycardia and hypotension with adenosine treatment. The AMISTAD II trial enrolled only patients with anterior ML The study randomized 2118 such patients within 6 h of symptom onset to two doses of adenosine. The primary endpoint of death/new heart failure/rehospitalization for heart failure at 6 months showed a trend towards benefit with the pooled adenosine groups, but this was not statistically significant. The higher dose showed better results than the lower dose, but this still did not reach statistical significance. The secondary endpoint of infarct size also showed a trend towards benefit with adenosine, which was statistically significant in the high-dose group.

Leukocyte receptor monoclonal antibody Reperfusion injury is usually associated with inflammation and migration of macrophages into the infarcted area. The integrin receptor CD 11/CD 18 plays a key role in the migration of macrophages through the endothelium into the infarcted area. Monoclonal antibodies against GDI 1/CD18 have been developed and clinical trials are under way to assess their benefit in reducing infarct size [46]. The HALT-MI trial was designed to assess the effect of the monoclonal antibody to CD 11/CD 18 (Hu23F26, Leukarrest) on infarct size in AMI patients undergoing primary angioplasty [47]. Hu23F26 is a humanized monoclonal antibody that binds to and blocks an integrin receptor necessary for the migration of macrophages across endothelium. It was felt that the treatment with Hu23F26 at the time of angioplasty would limit reperfusion injury-associated inflammation and thus reduce infarct size. This small trial failed to demonstrate any significant reduction in infarct size as measured by SPECT imaging. There was a trend toward a beneficial effect on both mortality rate and congestive heart failure, but the trial was not powered to detect an effect on clinical end points. Other trials with other CD 11/CD 18 inhibitors are needed and are ongoing.

Myocardial protection during AMI and angioplasty

Complement inhibitors The complement system has been implicated in reperfusion injury during AMI. Animal data suggested that a monoclonal antibody (MAb) to the complement component C5a reduces reperfusion injury. In vitro the MAb reduces C5a-stimulated neutrophil aggregation, chemotaxis, degranulation, and superoxide generation. At least in the pig model, inhibition of C5a limits neutrophil-mediated impairment of endothelium-dependent relaxation after cardiopulmonary bypass and cardioplegic reperfusion. It has no effect on short-term myocardial functional preservation [48]. In one animal study of occlusion/reperfusion using 13 control pigs and nine pigs pretreated with this MAb, infarct area was significantly reduced. The authors concluded that myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, decreases infarct size in pigs [49]. This data suggests an important role of the alternative complement pathway and C5a in the propagation of ischemic cardiac damage during reperfusion. It appears that adhesion of the white cell to vascular endothelium maybe an important element of the pathogenesis of myocardial infarction. Because C5a induces tissue injury by activating polymorphonuclear leukocytes, it is possible that inhibition of C5a activity would also reduce infarct size and reperfusion injury in humans.

Summary Myocardial protection during acute myocardial infarction and angioplasty can be achieved with pharmacotherapy and mechanical devices. Rapid catheter-based reperfusion, the use of beta-blockers to decrease oxygen requirements, ACE-inhibitors to promote better healing, and antiplatelet Ilb-IIIa inhibitors for better tissue perfusion, remain the most appropriate strategy, as many other approaches continue to be developed to resolve this complex problem.

References 1 Hansen PR. Myocardial reperfusion injury: experimental evidence and clinical relevance. Eur Heart } 1995; 16: 734-40. 2 Kloner RA. Does reperfusion injury exist in humans? JAm Coll Cardiol 1993; 21:537-45.

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3 Nash IS. Improving outcomes of percutaneous intervention. Am Heart 11999; 137:979-982. 4 Beranek ST. Why primary angioplasty is less offensive to the myocardium compared with thrombolysis for acute myocardial infarction. Am Heart J 2000; 140: 5-6. 5 Nakagawa Y. Effect of angina pectoris on myocardial protection in patients with reperfused anterior wall myocardial infarction: retrospective clinical evidence of "preconditioning". / Am Coll Cardiol 1995; 25: 107683. 6 Sawi S. Protecting the myocardium from ischemic injury. A critical role for alphaj-adrenoreceptors? Chest 2001; 119:1242-1249. 7 Heidland VE. Preconditioning during PTCA. Am Heart} 2000; 140: 813-20. 8 Ottani F. Prodromal angina limits infarct size. A role for ischemic preconditioning. Circulation 1995; 91:291—7. 9 Apstein CS, Taegtmeyer H. Glucose-insulin-potassium in acute myocardial infarction: the time has come for a large, prospective trial. Circulation 1997; 96:1074-7. 10 Sodi-Pallares D, Testelli MR, Fishleder BL et al Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction: a preliminary clinical report. Am J Cardiol 1962; 9:166-81. 11 Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation 1997; 96:1152-6. 12 Diaz R, Paolasso EC, Piegas LS et al. on behalf of the ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Metabolic modulation of acute myocardial infarction: the ECLA Glucose-Insulin-Potassium Pilot Trial. Circulation 1998; 98:2227-34. 13 McGuire DK. Diabetes and ischemic heart disease. Am Heart J1999; 138 (5 Part 1): S366-75. 14 Pomerantz BJ. Selective mitochondrial KATp channel opening controls human myocardial preconditioning, too much of a good thing? Surgery 2000; 128: 368-73. 15 Spedding M. Medicines interacting with mitochondria: anti-ischemic effects of trimetazidine. Therapie 1999; 54: 627-3. 16 Markham A. Nicorandil: an updated review of its use in ischemic heart disease with emphasis on its cardioprotective effects. Drugs 2000; 60:955-74. 17 Lesnefsky EJ. The IONA study: preparing the myocardium for ischemia? Lancet 2002; 359 (9314): 1262-3. 18 COOL AID. Pilot Study suggests hypothermia may limit ischemic damage. Heart Wire News 2001; February 20. 19 Pepine CJ. A. controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group. Am J Cardiol 1999; 84:46-50. 20 Zacharowski K. Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat. Eur J Pharmacol 2001; 418: 105-10. 21 Zuanetti G, Latini R, Maggioni AP et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with

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acute myocardial infarction: data from the GISSI-3 Study. Circulation 1997; 96:4239-4245. Roberts R, Rogers WJ, Mueller HS et al. Immediate vs. deferred |3-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of Thrombolysis Myocardial Infarction (TIMI) II-B study. Circulation 1991; 83:422-37. Mehta R, Eagle KA. Secondary prevention in acute myocardial infarct. BrMedJ 1998; 316: 838-42. ISIS-1 (First International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction. Lancet 1986; ii (8498): 57-66. Ellis SG, Brener SJ, Lincoff AL et al. p-Blockers before percutaneous coronary intervention do not attenuate postprocedural creatine kinase isoenzyme rise. Circulation 2001; 104:2685. The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI): a randomised placebocontrolled international trial. Eur Heart } 1985; 6: 199-226. Hjalmarson A, Elmfeldt D, Herlitz J et al. Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet 1981; ii (8251): 823-7. Flaherty JT, Becker LC, Weiss JL et al. Results of a randomized prospective trial of intra-aortic balloon counterpulsation and intravenous nitroglycerin in patients with acute myocardial infarction. / Am Coll Cardiol 1985; 6:434-46. Hochman JS. The SHOCK Trial Study Group: Should we Emergently Revascularize Occluded Coronaries for Cardiogenic Shocfc. An international randomized trial of emergency PTCA/CABG—trial design. Am Heart] 1999; 137:313-21. Field JM. The reperfusion era strategies for establishing or maintaining coronary patency. Cardiol Clin 2002; 20: 137-157. O'Rourke MF, Norris RM, Campbell TJ et al Randomized controlled trial of intra-aortic balloon counterpulsation in early myocardial infarction with acute heart failure. Am ] Cardiol 1981; 47:815-20. Vogel RA. Initial report of the National Registry of Elective Cardiopulmonary Bypass Supported Coronary Angioplasty. ] Am Coll Cardiol 1990; 15:23-9. Mohl W, Glogar DH, Mayr H et al. Reduction of infarct size induced by pressure-controlled intermittent coronary sinus occlusion. Am J Cardiol 1984; 53:923—8. Weiner BH, Gore JM, Benotti JR et al. Preliminary experience with synchronized coronary sinus retroperfusion in humans. Circulation 1986; 74: 381-8. Kar S. Reduction of PTCA induced ischemia with retroperfusion. J Am Coll Cardiol 1990; 15:250.

36 EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein Ilb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330:956-66. 37 Gibson CM, Cannon CP, Daley WL et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996; 93:879-88. 38 Yellon DM, Baxter GF. Sodium-hydrogen exchange in myocardial reperfusion injury. Lancet 2000; 356: 5223. 39 Avkiran M, Marber MS. Na(+)/H(+) exchange inhibitors for cardioprotective therapy. J Am Coll Cardiol 2002; 39: 747-753. 40 Christensen CW, Rieder MA, Silverstein EL, Gencheff NE. Magnesium sulfate reduces myocardial infarct size when administered before but not after coronary reperfusion: a canine model. Circulation 1995; 92: 2617-21. 41 ISIS-4. A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulfate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669-85. 42 Woods KL, Fletcher S, Roffe C, Haider Y. Intravenous magnesium sulfate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1992; 339:1553-8. 43 The MAGIC Steering Committee. Rationale and design of the magnesium in coronaries (MAGIC) study: a clinical trial to reevaluate the efficacy of early administration of magnesium in acute myocardial infarction. Am Heart J 2000; 139(1 Parti): 10-14. 44 Mahaffey KW, Puma JA, Barbagelata NA et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarct. JAm Coll Cardiol 1999; 34:1711-20. 45 Mentzer RM Jr. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann Surg 1999; 229:643-9. 46 Curtis WE, Gillinov AM, Wilson 1C et al. Inhibition of neutrophil adhesion reduces myocardial infarct size. Ann Thorac Surg 1993; 56: 1069-72; discussion 10723. 47 Faxon DP. The effect of blockade of the CD 11 /CD 18 integrin receptor on infarct size: the results of the HALT-MI study. JAm Coll Cardiol 2002; 40:1199-1204. 48 Amsterdam EA, Stahl GL, Pan HL et al. Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs. Am J Physiol 1995; 268 (!Part2):H448-57. 49 Tofukuji M, Stahl G, Agah A et al. Anti C5a monoclonal antibody reduces cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction. / Thorac Cardiovasc Surg 1998; 116:1060-8.

CHAPTER 6

Intermittent aortic cross-clamping for myocardial protection Fabio Biscegli Jatene, MD,PHD, Paulo M. Pego-Fernandes, MD, PHD, &Alexandre Ciappina Hueb, MD

Introduction One of the main causes of morbidity and mortality in heart surgery is inadequate myocardial protection, leading to intraoperative myocardial damage. There are a number of myocardial protective techniques that have been used throughout the evolution of heart surgery. Bigelow and Shumway made the first references to myocardial protection in the early 1950s, based on the evidence that hypothermia reduced significantly myocardial metabolism [ 1,2]. In the early days of heart surgery, the most frequently employed technique was to have the heart perfused and beating empty while normothermic despite technical disadvantages. Up to 1975, this technique was considered to provide the best myocardial protection and gathered many advocates [3], Technical difficulties during surgery and studies showed that myocardial protection was not ideal [4,5]. The technique was therefore almost completely abandoned. Despite theoretical criticisms of intermittent aortic cross-clamping at core temperatures of 32°C, the simplicity of the technique and positive clinical outcomes led a number of surgeons to use this technique. To perform the anastomosis, the aorta is intermittently cross-clamped when the core temperature reaches 31-32°C, with opening of the clamp and subsequent reperfusion of one anastomosis after the other. This technique is based on the concept that myocardial oxygen consumption reduces during hypothermia and that the effects of ischemia that lasts less than 20 min are quickly reversed with blood reperfusion. For each 3-4 min of clamping, reperfusion is

allowed for 1 min. As reported by Flameng [6], despite the fact that clinical outcomes are an imprecise index to assess myocardial protection, good clinical outcomes are the most important criteria to assess whether protection was adequate. One of the issues concerning the technique of intermittent aortic cross-clamping is that repetition of ischemic episodes, which are individually reversible, could lead to cumulative damage and consequent necrosis [7]. Reimer et al. [8] showed experimentally that intermittent reperfusion prevents cumulative metabolic deficits and myocardial ischemia with cell death. The first episode of ischemia reduces the consumption of high-energy phosphates during the following episodes. A number of other studies [9-11] showed that brief episodes of ischemia do not cause irreversible cell damage and do not lead to build up of metabolic, structural, and functional deficits. Conversely, it was documented that brief periods of ischemia increase the heart tolerance, instead of making it more vulnerable to consecutive episodes of ischemia. This ischemia-tolerance induction was named ischemic preconditioning [12]. Ischemic preconditioning was described by Murry et al. [12], who demonstrated in animal experiments that the heart, subjected to intermittent reversible ischemia with periods of reperfusion, demonstrates myocardial resistance to infarction after a prolonged ischemic period, which would otherwise lead to irreversible damage. In addition to protection against infarction, ischemic preconditioning can prevent reperfusion arrhythmia, contractile dysfunction, and

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ischemic contracture [13-15]. Moreover, it can improve the metabolic status of myocytes through limitation of acidosis [13] and preservation of myocardial high-energy phosphates [16]. This mechanism of endogenous protection was demonstrated in all studied animal species [17], and some authors also suggested its existence in humans [ 18-24].

Pathophysiology of intermittent aortic cross-clamping During the initial episode of intermittent aorticclamping, endogenous substances are formed or secreted, starting the mechanisms of myocardial protection; the same substances, or others, may subsequently maintain protection during the following episode of ischemia. Adenosine, acetylcholine, catecholamines, angiotensin II, bradykinin, and opioids are involved in intermittent cross-clamping, but their quantitative contribution and effective participation at the beginning or as a mediator varies from species to species [25]. Adenosine is released during the process of ischemiareperfusion from the receptor of Al adenosine, which is coupled to G-protein, through secondary messengers leading to translocation of cytosol proteinkinase C to the membrane and causing phosphorylation of a nonidentified protein that mediates protection [26]. Such protein may be the adenosine triphosphatedependent potassium channel (KATp) that is activated during the intermittent aortic-clamping process, leading to reduction of action potential duration and calcium influx, and consequent loss of contractile function and energy-saving effect. There is evidence that adenosine may protect the heart against ischemia reperfusion injury [17,27]. Yao and Gross [27] suggested that endogenous adenosine released during the ischemic episode was an important trigger or mediator of intermittent clamping. They also suggested that multiple complex mechanisms should be involved in the production of this kind of endogenous heart protective phenomenon.

Operative technique Once extracorporeal circulation (ECC) is established with aortic and single bicaval cannulation, systemic cooling to 32°C is induced after which intermittent aortic cross-clamping is applied. In order to avoid

CHAPTER 6

excessive manipulation of the aorta, the Department of Bioengineering of Institute do Cora9ao constructed an aortic clamp with longer serrated tips so it could be placed at one point on the aorta, promoting opening and closing of the clamp without having to reposition it for each procedure. During each period of aortic clamping, an anastomosis was constructed between the graft and the coronary artery to be revascularized. For each 3-4 min of clamping, 1 min of reperfusion was allowed. The procedure was used both for the distal and proximal anastomoses. If the anastomosis could not be performed within 10 min, the procedure was interrupted; the aortic clamp was opened with a reperfusion period of 3-4 min. Then the aorta was reclamped to conclude the anastomosis. During the performance of the last anastomosis, the patient was rewarmed. By the end of the last anastomosis, the aorta was declamped, normal temperature and hemodynamics became stable, and disconnection of the ECC followed. One of the advantages of the use of intermittent aortic cross-clamping is the moment-by-moment functional assessment of the myocardium. In addition, it is easier to position and accommodate the grafts and to manage the surgery. The disadvantages are frequent aortic manipulation because of the various clamping procedures and the limited time for performance of the anastomosis. The aortic clamp with longer serrated tips allows the clamp to remain in place and partially occluded, avoiding excessive manipulation (Figure 6.1).

Comments There are few randomized studies comparing the efficacy of intermittent aortic cross-clamping with the use of cardioplegic solutions [28-32] and none of them concluded which method was the best. Jatene et al. [33-35] have used intermittent clamping since 1969 with excellent clinical outcomes. Data collected from myocardial revascularization with intermittent aortic-clamping in populations from 500 to 5880 subjects showed that mortality ranged from 0.2 to 2.1% [31,36]. The use of an intra-aortic balloon pump in the studies varied from 0.2 to 1% [33,35]. The incidence of perioperative myocardial infarction ranged from 2 to 4.1%. Flameng [6] who used this technique reported his experience with 3529 patients pretreated with lidoflazine. The results showed an overall

Intermittent aortic cross-clamping for myocardial protection

55

example, were similar to those of other studies of patients subjected to myocardial revascularization, regardless of the technique used. In a prospective randomized study we compared the intermittent clamping technique with the St Thomas cardioplegic solution and analyzed 163 patients subjected to elective myocardial revascularization with preserved ventricular function and subjected to no other procedures. Patients were randomized in two groups: (i) the intermittent aortic cross-clamping (IACC) group, 93 patients, 86% males, mean age 57.7 years; and (ii) the crystalloid cardioplegia (CC) group, 70 patients, 80% male, mean age 56.7. The period analyzed comprised the surgery undertaken up to the 61st postoperative month. The surgical technique employed was similar in both groups. After sternotomy, extracorporeal circulation was established. Patients were then subjected to moderate hypothermia at 32°C. In the IACC group when the temperature was reached, the aorta was cross-clamped and maintained until the end of the anastomosis. Intracavity air was then aspirated and the aortic clamp was released. In the CC group, cardioplegia was started at the aortic root after aortic clamping. Cardioplegia was then repeated every 20 Figure 6.1 Use of aortic clamp with longer serrated tips. min until the anastomoses were constructed. The clinical variables analyzed were: (i) electromortality of 1.2% from cardiac problems, but when cardiographic findings; (ii) enzyme abnormalities analyzing the elective cases, mortality from myo- (CK-MB); (iii) postoperative low cardiac output; (iv) cardial causes was 0.4%. The use of an intra-aortic length of stay in the ICU; and (v) late clinical evolution balloon was present in 0.6% and left ventricular assist- (Table 6.1). In the IACC group, 82.8% of the patients were ance devices were used in 0.2%. Kirklin et al. [36] analyzed 5880 patients operated asymptomatic in the period between 30 and 61 on with intermittent aortic-clamping and found an months (±37.1 months). There were five deaths, one expected 10-year survival rate of 80%, the same sur- from cardiac disease, during the 22nd month. In the vival expected for the general population with similar CC group, 77.1% of the patients were asymptomatic demographic characteristics; mortality by the end of between 31 and 61 months (±38.9 months). There the first year was 1.6%. Other data, such as the correla- was one sudden death probably caused by coronary tion with the use of the internal thoracic artery, for failure. Statistical analysis did not show statistically

Table 6.1 Clinical variables in groups IACC and CC.

Group IACC

Group CC

Ischemic abnormality in the ECG*

7 (7.5)

9(12.8)

CK-MB increase*

14(15)

5(7.1)

Abnormal ECG and CK-MB*

2(2.1)

1(1.4)

Low cardiac output*

2(2.1)

6 (8.5)

Length of stay in the ICU (days)

2-5 (±2.3)

2-5 (±2.3)

Results given show frequency with percentage in parentheses.

56

significant differences between the studied variables in the groups. In a study conducted by Gerola et al. [29], comparing blood normothermic cardioplegic solution enriched with aspartate and intermittent aorticclamping in a group of 60 randomized patients undergoing myocardial revascularization, it was observed that both groups behaved in the same way when hemodynamic variables and intrahospital mortality were examined. Advances in diagnostic methods have allowed the detection of minor myocardial episodes, which have little or no hemodynamic repercussion. The development of radioisotopes and the dosage of myocardialspecific enzymes have enabled a better comparison of the various methods used to provide myocardial protection during surgery in humans. Among the markers of myocardial damage, troponin I, CK-MB, intramyocardial ATP content, and lactate are highlighted. A recent study was carried out with myocardial damage markers in patients subjected to intermittent aortic cross-clamping by Pego-Fernandes et al. [37]. The authors evaluated 18 patients subjected to myocardial revascularization with intermittent aortic cross-clamping. The criteria for inclusion were: (i) preoperative ejection fraction higher than 30%; (ii) no reoperation; (iii) at least two coronary arteries damaged; (iv) extracorporeal circulation (ECC) provided; (v) no operative unstable angina present; (vi) patient not to be in an acute myocardial infarction; and (7) no other corrections of valvulopathies or left ventricular aneurysms. After the establishment of ECC, a catheter was introduced into the coronary sinus for collection of blood samples. Following systemic cooling to 32°C, aortic-clamping was initiated. Between each aorticclamping, one anastomosis was connected between the graft and the coronary artery to be revascularized. For each 3-4 min of clamping, there was 1 min of reperfusion. The same procedure was followed for both distal and proximal anastomoses. The blood samples were collected directly from the coronary sinus. The samples were collected at three stages: at the beginning of ECC under normothermic conditions (moment 1); immediately after the first anastomosis was made at 32°C (moment 2); and at the end of ECC, again under normothermic conditions (moment 3). The blood samples were used for dosages of troponin I, lactate, CK-MB, and adenosine. No

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Figure 6.2 Graphic representation of the mean evolution of values for lactate, troponin, CK-MB, and adenosine, at the three moments of dosage.

patient presented signs of intraoperative myocardial infarction. The mean values of troponin I at moment 3 were 152.55% higher than those for moment 2. Upon comparing the medians of troponin I at moments 2 and 3, the authors concluded that there was a significant increase (P< 0.001) (Figure 6.2). For lactate, there was a statistically significant increase at moment 2 compared to moment 1 (P< 0.001). Moment 2 was similar to moment 3 (P = 0.098). Moment 3 had a statistically significant difference from moment 1 (P = 0.002), despite the tendency to restore to initial values. For CK-MB, there was a progressive increase in dosage values at the three moments: moment 2 was greater than moment 1 (P < 0.001), and moment 3 was greater than moment 2 (P < 0.001). There was an increase in adenosine at moment 2 compared to moment 1, which was statistically significant (P < 0.001). At moment 3, there was a decrease in adenosine, but not enough to restore moment 1 levels [38,39]. Researchers [17,24,37,39] studied the difference between the dosage in the artery and the coronary sinus of lactate, inorganic phosphate, and potassium levels, after the opening of aortic-clamping in a group of 72 randomized patients who underwent myocardial revascularization surgery. Three techniques of myocardial protection were used: (i) intermittent aortic cross-clamping at 34°C; (ii) intermittent aortic crossclamping at 25°C; or (iii) continuous aortic-clamping associated with the use of St Thomas cardioplegic solution. Cumulative enzymatic release was small and there were no marked structural changes in the mitochondria, presenting no difference among the three techniques. The study's purpose was to compare

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9 Heyndrickx GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. / Clin Invest 1975; 56: findings were observed for the dosage of lactate, 978-85. inorganic phosphate, and potassium, and reflected the 10 Henrichs KJ, Matsuoka H, Schaper J. Influence of action of the ischemic preconditioning mechanism. repetitive coronary occlusions on myocardial adenine nucleosides, high energy phosphates and ultrastructure. One author, upon reviewing data years after, pointed BasicRes Cardiol 1987; 82:557-65. out a decrease in the clearing of inorganic phosphates 11 Lange R, Ware J, Kloner RA. Absence of a cumulative after subsequent intervals of ischemia, as a result of the deterioration of regional function during three repeated 5 increase of ischemia tolerance [32]. of 15 minute coronary occlusions. Circulation 1984; 69: Pego-Fernandes et al. [37] demonstrated a similar 400-8. 12 Murry CE, Jennings RB, Reimer KA. Preconditioning behavior for the release of CK-MB, troponin I and with ischemia: a delay of lethal cell injury in ischemic lactate in the coronary sinus of the control group, and myocardium. Circulation 1986; 74:1124-36. the group submitted to preconditioning, leading us to 13 Asimakis GK, Inners-McBride K, Medellin G, Conti VR. the conclusion that intermittent aortic cross-clamping Ischemic preconditioning attenuates acidosis and postisas employed by us and most surgeons may be conchemic dysfunction in isolated rat heart. Am J Physiol 1992; 263 (3 Part 2): H887-94. sidered an effective preconditioning modality. 14 Shiki K, Hearse DJ. Preconditioning of ischemic In conclusion, the intraoperative damage from myocardium: reperfusion-induced arrhythmias. Am J inadequate myocardial protection has decreased proPhysiol 1987; 253 (6 Part 2): H1470-6. gressively. Intermittent cross-clamping is a simple, 15 Cohen MV, Liu GS, Downey JM. Preconditioning causes improved wall motion as well as smaller infarcts after safe, and efficient operative technique that provides transient coronary occlusion in rabbits. Circulation 1991; excellent clinical results. 84:341-9. 16 Murry CE, Richard VJ, Reimer KA, Jennings RB. Ischemic preconditioning slows energy metabolism and References delays ultrastructural damage during a sustained ischemic episode. CircRes 1990; 66:913-31. 1 Reissman KR, Van Citters RL. Oxygen consumption and 17 Downey JM, Liu GS, Thornton JD. Adenosine and the mechanical efficiency of the hypothermic heart. / Appl anti-infarct effects of preconditioning. Cardiovasc Res PhyszoZ 1956; 9:427-32. 1993; 27: 3-8. 2 Lee 1C. Effect of hypothermia on myocardial metabolism. AmJPhysiol 1965; 208:1253-8. 18 Tomai F, Crea F, Gaspardone A et al. Ischemic pre3 Buckberg GD, Olinger GN, Mulder DG, Maloney JV Jr. conditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel Depressed postoperative cardiac performance: prevenblocker. Circulation 1994; 90: 700-5. tion by adequate myocardial protection during car19 Patel DJ, Purcell HJ, Fox KM. Cardioprotection by opendiopulmonary bypass. / Thorac Cardiovasc Surg 1975; 70: ing of the KATP channel in unstable angina: is this a 974-94. clinical manifestation of myocardial preconditioning? 4 Follette D, Fey K, Mulder D, Maloney JV Jr, Buckberg Results of a randomized study with nicorandil. Eur Heart GD. Prolonged safe aortic clamping by combining membrane stabilization, multidose cardioplegia and appropri} 1999; 20: 51-7. ate pH reperfusion. / Thorac Cardiovasc Surg 1977; 74: 20 Ikonomidis JS, Tumiati LC, Weisel RD, Mickle DAG, Li RK. Preconditioning human ventricular cardiomyocytes 682-94. 5 Miyamoto ATM, Robinson L, Matloff JM, Norman JR. with brief periods of simulated ischaemia. Cardiovasc Res 1994; 28:1285-91. Perioperative infarction: effects of cardiopulmonary bypass on collateral circulation in an acute canine model. 21 Alkhulaifi AM. Preconditioning the human heart. Ann R Circulation 1978; 58 (Suppl 1): 1147-55. Coll Surg Engl 1997; 79:49-54. 6 Flameng W. Intermittent ischemia. Semin Thorac 22 Szmagala P, Morawski W, Krejca M, Gburek T, Bochenek Cardiovasc Surg 1993; 5:107-13. A. Evaluation of perioperative myocardial tissue damage in ischemically preconditioned human heart during 7 Whalen DA Jr, Hamilton DG, Ganote CE, Jennings RB. aorto coronary bypass surgery. / Cardiovasc Surg 1998; Effect of a transient period of ischemia on myocardial 39: 791-5. cells: I—effects on cell volume regulation. Am } Pathol 23 Alkhulaifi AM, Yellon DM, Pugsley WB. Preconditioning 1974;74:381-97. the human heart during aorto-coronary bypass surgery. 8 Reimer KA, Murry CE, Yamasawa I, Hill ML, Jennings RB. Four brief periods of myocardial ischemia cause no Eur JCardiothorac Surg 1994; 8:270-6. cumulative ATP loss or necrosis. Am ] Physiol 1986; 251 24 Jenkins DP, Pugsley WB, Alkhulaifi AM et al. Ischaemic preconditioning reduces troponin T release in patients (6Part2):H1306-15. techniques. There was a larger difference between the arterial and coronary sinus dosages in the first reperfusion period than in the following periods. These

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27

28

29

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undergoing coronary artery bypass surgery. Heart 1997; 77:314-18. Downey JM, Cohen MV. Signal transduction in ischemic preconditioning. ZKardiol 1995; 84 (Suppl4): 77-86. Chagas ACP, Galvao TFG, Ferreiro CR, Luz PL. Precondicionamento isquemico: um mecanismo protetor eficaz do coracao em risco de necrose. Rev Soc Cardiol Estado Sao Paulo 1998; 8: 314-28. Yao Z, Gross GJ. A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs: efficacy, time course, and role of KATP channels. Circulation 1994; 89:1229-36. Jatene FB, Ferreira HP, Ramires JA et al. Estudo comparative da cardioplegia e do clampeamento intermitente da aorta em cirurgia de revascularizacao do miocardio. ArqBras Cardiol 1990; 54:105-9. Gerola LR, Oliveira SA, Moreira LF et al. Blood cardioplegia with warm reperfusion versus intermittent aortic crossclamping in myocardial revascularization: randomized controlled trial. / Thorac Cardiovasc Surg 1993; 106: 491-6. Pepper JR, Lockey E, Cankovic-Darracott S, Braimbridge MV. Cardioplegia versus intermittent ischaemic arrest in coronary bypass surgery. Thorax 1982; 37:887-92. Flameng W, Van der Vusse GJ, De Meyere R et al. Intermittent aortic cross-clamping versus St Thomas' Hospital cardioplegia in extensive aorta-coronary bypass grafting: a randomized clinical study. / Thorac Cardiovasc Surg 1984; 88:164-73.

32 Anderson JR, Hossein-Nia M, Kallis P et al. Comparison of two strategies of myocardial management during coronary artery operations. Ann Thorac Surg 1994; 58: 768-73. 33 Jatene AD, Paulista PP, Souza LC. Tratamento cinirgico da insuficiencia coronariana com ponte de safena: aspectos tecnicos. Arq Bras Cardiol 1970; 23:85-90. 34 Jatene AD, Sousa JEMR, Paulista PP et al Le pontage aorto-coronarie de viene saphene: a propos de 671 cas. Cower 1972; 3:607-18. 35 Jatene AD. Late results of aorto coronary saphenous vein by-pass grafts. / Cardiovasc Surg (Torino) 1975; (special issue): 91-4. 36 Kirklin JW, Naftel CD, Blackstone EH, Pohost GM. Summary of a consensus concerning death and ischemic events after coronary artery bypass grafting. Circulation 1989; 79 (6 Part 2): 181-91. 37 Pego-Fernades PM, Jatene F, Kwasnicka K etal Ischemic preconditioning in myocardial revascularization with intermittent aortic cross-clamping. / Card Surg 2000; 15: 333-8. 38 Pego-Fernades PM, Jatene F, Coelho FF et al. Evolucao hemodinamica da revasculariza9ao do miocardio com dois metodos de protecao miocardica. Rev Bras Cir Cardiovasc 2000; 15:212-18. 39 Pego-Fernades, Jatene F, Gentil AF et al. Influence of ischemic preconditioning in myocardial protection in patients undergoing myocardial revascularization with intermittent crossclamping of the aorta. Analysis of ions and blood gases. Arq Bras Cardiol 2001; 77:318-23.

CHAPTER 7

Intermittent warm blood cardioplegia: the biochemical background Ganghong Tian, MD, PHD, TomasA. Salerno, MD, & Roxanne Deslauriers, PHD

Introduction Cardioplegia has been used to protect the heart during cardiac surgery for several decades [ 1,2]. Its protective effects result mainly from the inhibition of myocardial electromechanical activity by the induction of rapid diastolic arrest and lowering of heart temperature, leading to a significant decrease in myocardial oxygen consumption [1,2]. Even when arrested, the oxygen consumption of the heart is not zero [3]. Ischemic injury will occur if infusion of cardioplegic solution is interrupted. However, a quiescent bloodless field is sometimes essential for surgeons to perform delicate surgical procedures. Thus, repetitive short periods of interruption of cardioplegic infusion are inevitable during certain types of cardiac surgery. This chapter focuses on the effects of intermittent warm blood cardioplegia (IWBC) on myocardial energy metabolism.

Use of magnetic resonance spectroscopy and imaging for studies of cardioplegia It is well known that myocardial energy metabolism as manifest in the levels of ATP, phosphocreatine (PCr), and intracellular pH (pHi) is closely related to cellular homeostasis [4-8]. Hearse et al. showed that myocardial contracture occurred when the level of myocardial ATP dropped below 12 (j,mol/g dry wt [9,10]. Moreover, according to Gebhard and others, reversible myocardial ischemic injury can be defined

in terms of myocardial energy metabolism as < 40% decrease in ATP and < 80% decreases in PCr [10-13]. It has also been demonstrated that the decrease in pHi is almost linearly related to the severity of myocardial injury. In mild ischemic injury, a small decrease in pHi accelerates glycolysis, whereas in a severe ischemic injury a large drop in pHi inhibits glycolysis [14,15]. Conceivably, tissue pH is also an important and reliable metabolic indicator of ischemic injury. The high-energy phosphates and pHi of the heart can be monitored using phosphorus-31 (31P) magnetic resonance (MR) spectroscopy. Because the energy used in MR spectroscopy and imaging is very low and many MR-sensitive nuclei, such as 1H,31P and 23 Na, are ubiquitous, MR spectroscopy and imaging are noninvasive and nondestructive [16,17]. Consequently, 31P MR spectroscopy and *H imaging are ideal techniques for serial studies on a single heart because the heart can serve as its own control. The changes in myocardial high-energy phosphates, enzyme kinetics, ionic gradients, and pHi can be followed quantitatively and repetitively using 31P MR spectroscopy throughout an experiment without any need to take tissue samples, while physiological parameters, such as cardiac contractile function, myocardial oxygen consumption, and coronary flow, can be continuously monitored [18,19]. With the advent of new techniques in 31P MR spectroscopy, myocardial high-energy phosphates and pHi can be measured at different depths across the left ventricular wall. Using localized 31P MR spectroscopy, it was found that the

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PCr content and the PCr/ATP ratio are lower in the subendocardium than in the subepicardium whereas the ATP content is constant throughout the ventricular wall [20,21]. Localized 31P spectroscopy also showed that ischemic changes induced by occlusion of the left anterior descending artery (LAD) in a beating heart are different across the ventricular wall [20-24]. The application of 31P MR spectroscopy to studies of cardioplegia has led to fundamental new information on myocardial energy metabolism, force generation, ischemia, and reperfusion injury. Contrast-enhanced MR perfusion imaging has recently been developed for noninvasive assessment of myocardial perfusion [25-27]. It uses fast gradientecho imaging sequences to follow the changes in signal intensity after a bolus injection of a contrast agent. The degree of signal change is related to blood flow and can be used to calculate regional myocardial perfusion. Contrast-enhanced MR imaging offers high spatial resolution and is excellent for detecting small regions of perfusion deficit. For example, the field of view of a heart image obtained from an isolated heart usually covers an area of 150 x 150 mm2 with a resolution of 128x128, resulting in a pixel size of 1.17x1.17 mm2. This pixel size is much smaller than that achievable using conventional techniques. The pixel size for radioactive microspheres, for example, may range from 5 x 5 mm2 to 10 x 10 mm2. In addition, MR perfusion imaging can follow dynamic changes of contrast agent during its first pass, which provides information about the hemodynamics of the coronary circulation. This cannot be obtained using radioactive microspheres. Using an intravascular contrast agent (gadolinium diethylenetriamine pentaacetic acidPolylysine, Gd-DTPA-Polylysine) in the isolated pig heart, we showed that when Gd-DTPA-Polylysine is injected during antegrade cardioplegia, changes in MR signal intensity peaked within seconds and returned to the baseline level at a similar rate [28]. However, with Gd-DTPA-Polylysine administered into the coronary sinus during retrograde cardioplegia at the same "coronary flow" as antegrade cardioplegia, it took much longer for the MR signal intensity to reach a maximum. The mean transit time of the contrast agent measured during retrograde cardioplegia was significantly longer than that obtained during antegrade cardioplegia [28]. This suggests that the actual myocardial blood flow of retrograde cardioplegia is significantly lower than that of antegrade cardioplegia,

CHAPTER 7

even though the delivery rate of cardioplegia is similar for both cardioplegic techniques. Both Tl- and T2*-weighted MR imaging methods have been used for the assessment of myocardial perfusion in vivo and ex vivo. We found that Tl- and T2*weighted imaging techniques emphasize different aspects of tissue perfusion, which maybe related to the differences in their mechanisms of image generation [29,30]. Tl-weighted images may reflect mainly exchange/diffusion processes while T2*-weighted images may be more dependent on vascular flushing [29,30]. The combination of MR contrast agents with MR imaging has provided a unique method for the evaluation of myocardial perfusion and injury. Information obtained using MR contrast agents has significantly helped in the understanding of myocardial physiology and pathology. Based on their distribution, MR contrast agents can be divided into three types: intravascular (confined exclusively within vascular compartment), extracellular (moving freely out of the vascular compartment into the interstitial space), and all compartment types (diffuse freely to all compartments and have the largest distribution volume) [31]. Because each type of contrast agent has its own confined distribution space, use of various types of agents consecutively in one subject may help distinguish nutritional flow from total vascular flow. Finally, when MR perfusion imaging and MR spectroscopy are used together, heart metabolism, pHi and ionic gradients across the cell membrane as well as tissue perfusion can be assessed simultaneously.

Effect of intermittent cardioplegia on myocardial energy metabolism Continuous normothermic antegrade blood cardioplegia (CNABC) has emerged as an alternative method of myocardial protection. In theory, this method may be optimal for myocardial protection during cardiac surgery because it aims to avoid myocardial ischemia and subsequent reperfusion injury [32]. Practically, continuous infusion of warm blood cardioplegia may result in inadequate visualization of the operative field and make intracardiac manipulations difficult in some circumstances [33]. Surgical precision may require the interruption of delivery of cardioplegia for short intervals. As a result, IWBC may be more feasible clinically than CNABC. One consideration with this technique, however, is

61

Intermittent warm blood cardioplegia

interval, the differences in Pi at the end of the sk ischemic intervals were not statistically significant (Table 7.1). Our results suggest that IWBC with the pattern of cardioplegia infusion and interruption described above does not result in cumulative loss of PCr or increase in Pi. The intracellular pH of the heart was obtained indirectly by measuring the difference in chemical shifts of the Pi and PCr peaks. During control perfusion and reperfusion, pHi was 7.22 ± 0.02 and 7.20 ± 0.03 pH units, respectively (Table 7.1). A 10-min interruption of warm blood cardioplegia resulted in an average decrease in pHi by 0.12 pH units (Table 7.1). Subsequent interruptions of cardioplegia did not cause any further decrease in pHi. This also suggests that IWBC does not cause cumulative myocardial injury. Moreover, we found that the recovery of contractile function of the hearts subjected to IWBC was similar to that of hearts subjected to CNABC. The results of our study demonstrate that IWBC with 10 min of ischemic interruption results in mild ischemic changes, which are not cumulative. This suggests that warm blood cardioplegia can be safely interrupted for surgical precision provided interruption is not longer than 10 min. Other investigators have also reported longer safe ischemic intervals. According to the levels of myocardial high-energy phosphates, reversible myocardial injury can be arbitrarily divided into three phases: latency, survival time, and revival time [1]. During the first period of ischemia, there are essentially no changes in the levels of ATP, PCr, or Pi. Oxidative phosphorylation is still the major energy source for maintenance of function and structure of the myocytes by using oxygen remaining in the myocardium in the form of oxymyoglobin, oxyhemoglobin, and physically dissolved oxygen. Myocardial oxygen consumption in a normal

Image Not Available

Figure 7.1 Time course of myocardial ATP, phosphocreatine (PCr), and inorganic phosphate (Pi) from pig hearts during control perfusion, intermittent warm blood cardioplegia, and reperfusion. Data are presented as means ± standard errors of means. Reprinted from Deslauriers R, Tian G, Kupriyanov V, Lareau S & Salerno TA. Basic research on myocardial protection: a magnetic resonance approach. In: Salerno TA (ed.) Warm Heart Surgery. © 1995, by permission of Hodder Arnold.

that interruption of cardioplegia, particularly under normothermic conditions, may cause cumulative ischemic damage, leading to impaired recovery of heart function following cardiac surgery. To determine the effect on myocardial energy metabolism of IWBC and to determine whether ischemic changes induced by IWBC are cumulative, we subjected isolated pig hearts to six 5-min periods of warm blood cardioplegia, which were interrupted by six 10-min ischemic episodes. It was found that a 10-min ischemic interval resulted in a decrease of approximately 50% in the level of PCr with a corresponding increase in inorganic phosphate (Pi) (Figure 7.1) [34]. There were no significant differences between PCr values measured at the end of the six ischemic intervals (Table 7.1). Moreover, although Pi levels increased significantly during each ischemic

Table 7.1 Effect of intermittent warm blood cardioplegia on intracellular pH, PCr, and Pi. End of each interruption Precardioplegia

1

2

3

4

5

6

Reperfusion

pHi

7.22

7.10

7.13

7.12

7.10

7.10

7.10

7.20

PCr*

230

128

122

115

118

119

119

265

70

131

136

144

141

143

147

80

Pi*

pHi, intracellular pH; PCr, phosphocreatine; Pi, inorganic phosphate. * Intensity relative to ATP levels measured precardioplegia.

62 beating heart is approximately 10 ml/min/100 g tissue. The total oxygen reserve in the myocardium at the beginning of ischemia is about 1-2 ml/100 g tissue. The latency period initiated by stopping coronary flow in a beating heart therefore lasts only 5-20 s. This period will be significantly prolonged in an arrested heart because oxygen consumption is significantly reduced. As a result, the latency period in a heart subjected to IWBC may be as long as 1-2 min. During this period, myocardial energy metabolism, structure, and function remain essentially unchanged. During the second phase of ischemia (survival time), PCr is used to replenish ATP stores in the cytoplasm, which leads to a decrease in the PCr level, accompanied by a rise in Pi. This period ends when the PCr level decreases to 40% of its normal value and lasts about 1-3 min in a beating heart. In arrested hearts, it lasts more than 10 min due to cessation of energy consumption for electromechanical activity. As found in our study, it took 10 min for PCr to decrease to 50% of its normal level. This suggests that ischemic injury resulting from a 10-min interruption of warm blood cardioplegia still falls within the survival phase of reversible injury. As a result, we believe that IWBC with 10 min of ischemic intervals is safe for surgical precision as well as myocardial protection. One important consequence of myocardial ischemia is generation of protons derived from anaerobic glycolysis and from other metabolic cycles, leading to a decrease in tissue pH [16]. As discussed above, the severity of ischemic injury is related to the extent of decrease in pHi [15]. Accumulation of protons causes influx of sodium and calcium via Na+-H+ and Na+'Ca^ exchange [35-37]. Moreover, a fall in pHi inhibits the activity of phosphofructokinase, which in turn decreases energy production during ischemia [16]. It is generally accepted that pHi below 6.2 represents severe ischemia [38]. In our study, a 10-min interruption of warm blood cardioplegia resulted in a decrease in pHi only by 0.12 unit (from its control value of 7.22-7.10) and subsequent interruption did not cause any further decrease in pHi (Table 7.1). The pHi at the end of each ischemic interval remained within the normal physiological range. This further suggests that interruption of warm blood cardioplegia for 10 min results in mild alteration in myocardial energy homeostasis. It is well known that reperfusion is not always fully beneficial although it is an absolute prerequisite for

CHAPTER 7

survival of the ischemic myocardium [39,40]. The severity of reperfusion injury is closely related to the degree of sodium and calcium overload. Dysfunction of the Na+-K+ pump is one of the important mechanisms responsible for overload of these cations. Under physiological conditions, the free energy of ATP hydrolysis (AGATP) is normally about 15-20 kilojoules per mole greater than the energy required to drive the Na + -K + pump [41]. The decreases in ATP and pHi observed during a 10-min interruption of warm blood cardioplegia were not significant (Figure 7.1 & Table 7.1). Therefore, the pump kinetics are not expected to be limited during IWBC. As a result, intracellular sodium and calcium would not increase significantly during IWBC with a similar ischemic interval. This suggests that IWBC should not result in significant reperfusion injury. This was supported by comparable recovery of contractile function in the hearts preserved with either IWBC or CNABC (Figure 7.2).

Heterogeneous ischemic changes during intermittent warm blood cardioplegia As mentioned above, the decreases in PCr, ATP, and pHi observed during 10 min of interruption of warm cardioplegia are within the survival phase of reversible ischemic injury. In the above study, however, myocardial ATP, PCr, Pi, and pHi were measured from the whole hearts and were averages of these parameters over different regions of the heart and various layers of the ventricular wall. It has been shown that myocardial ischemic injury induced by occlusion of a coronary artery, lowering of perfusion pressure, or an increase in heart work in a beating heart may be more severe in the subendocardium than in the subepicardium [20-22]. The heterogeneity of ischemic injury is attributed to a decrease in blood flow to the inner layer of the ventricular wall and higher workload or muscle tension in this region relative to those in the outer layer of the heart [20-22]. Under arrest conditions, the variations in mechanical work and muscle tension between different layers of the myocardium may be abolished or minimized. The transmural heterogeneity of ischemic changes in an arrested heart may therefore differ from that observed under beating conditions. To determine whether ischemic changes induced by interruption of warm blood

63

Intermittent warm blood cardioplegia

Image Not Available

Figure 7.2 Comparison of rate-pressure product (RPP) and +dp/dt measured during reperfusion in pig hearts subjected to either continuous or intermittent warm blood cardioplegia. Reprinted from Deslauriers R, Tian G, Kupriyanov V, Lareau S & Salerno TA. Basic research on myocardial protection: a magnetic resonance approach. In: Salerno TA (ed.) Warm Heart Surgery. © 1995, by permission of Hodder Arnold.

cardioplegia are homogenous across the ventricular wall, we repeated the above study using localized 31P MR spectroscopy. A surface coil was positioned over the anterior wall of the left ventricular wall and signals were recorded from four separate layers across the ventricular wall. Representative localized 31P MR spectra obtained across the left ventricular wall during warm blood cardioplegia and interruption of cardioplegia are shown in the top and bottom panels of Figure 7.3, respectively. The spectra in the top panel were obtained during infusion of cardioplegia and show prominent peaks from ATP and PCr without evident elevation of Pi peak in all layers of the heart wall. The spectra in the

bottom panel of Figure 7.4 were acquired at the end of the ischemic interval and show a more prominent decrease in PCr and increase in Pi in the outer layers than in the inner layers of the myocardium. Because the signal intensity of phosphorus spectra is highly dependent on the distance from the MR coil to the region of myocardium where MR signals are acquired, it is difficult to compare the absolute levels of compounds between various layers of the ventricular wall. For this reason, the ratio of Pi/PCr was used as measurement of ischemic injury. This ratio was significantly higher in the subepicardium (Pi/PCr = 1.27) than in the subendocardium (0.45), suggesting that the ischemic changes induced by the interruption

64

Figure 7.3 Transmural 31P MR spectra acquired from the anterior wall of the left ventricle during warm blood cardioplegia (a) and at the end of ischemic interval (b). Reprinted from Journal of Thoracic and Cardiovascular Surgery, Vol. 109, Tian G, Xiang B, Butler KW eta/. A 3 1 P nuclear magnetic resonance study of intermittent warm blood cardioplegia, pp. 1155-1163. © 1995, with permission from Elsevier.

of warm blood cardioplegia were more severe in the Subepicardium than in the subendocardium. Because the localized 31P MR spectroscopy used in this study may cause unidirectional signal overlap between the adjacent layers of myocardium, the spectra supposed to be from the inner layer of the ventricular wall may actually contain some MR signals from the outer layer of the ventricular wall. Therefore, it is possible that the real difference in the ratio of Pi/PCr between the subendocardium and the Subepicardium may be larger than that shown in Figure 7.3. Nevertheless, the ratio returned to normal level rapidly in all layers of the ventricular wall upon infusion of warm blood cardioplegia.

CHAPTER 7

The severity of ischemic injury is dependent on the balance between the energy requirement (determined by basal metabolism and mechanical work) and blood supply. When the heart is arrested, electromechanical activity ceases and basal metabolism and blood supply then become the main factors in influencing myocardial survival. Studies from various laboratories have shown that blood supply between the inner and outer layers of the ventricular wall is highly dependent on heart rate [42,43]. Blood flow to all layers of the myocardium is almost uniform when heart rate is around 100 bpm [42]. As heart rate increases, the ratio of blood flow to the subendo/subepicardium decreases and reaches 0.5 when the heart rate is about 200 bpm, indicating that the subendocardium receives approximately half of the blood flow delivered to the Subepicardium under strenuous working conditions. When the heart is arrested, the ratio of blood flow to the subendo/subepicardium is about 1.5, suggesting that the subendocardium receives as much as 50% more blood flow relative to the Subepicardium when heart muscle is completely relaxed [42]. This heart rate-dependent property of blood flow is related to the compression force upon the subendocardium generated by myocardial contraction. By measuring the transmural distribution of blood flow and energy metabolites (ATP, PCr, and Pi), Bache and associates found that an increase in heart rate from 200 to 240 bpm resulted in a significant decrease in blood flow to the subendocardium with the depletion of PCr and appearance of Pi in this region [44]. These results indicate that blood distribution across the ventricular wall is highly dependent on the heart rate or mechanical work of the heart. When the heart is arrested, blood flow favors the subendocardium. We believe that this is the reason for more prominent ischemic changes observed in the Subepicardium than in the subendocardium when blood cardioplegia is interrupted. The above studies indicate that cardioplegia provides preferential protection to the subendocardium relative to the Subepicardium due to higher blood flow delivered to the region. Ischemic injury induced by the interruption of warm blood cardioplegia is therefore unlikely to be more prominent in the subendocardium than in the Subepicardium in the normal heart. It has been shown that the coronary blood distribution is also affected by perfusion pressure [21 ]. A study from Ugurbil's laboratory suggested that lowering the perfusion pressure decreased the ratio of blood

Intermittent warm blood cardioplegia

65

Figure 7.4 Time courses of phosphocreatine (PCr) and inorganic phosphate (Pi) measured during warm blood cardioplegia at different perfusion pressures.

flow to the subendocardium relative to the subepicardium [21]. In hearts with severe coronary disease, myocardial blood flow to the inner layer of the ventricular wall may already be impaired. Under these conditions, warm blood cardioplegia may compro-

mise myocardial protection in the subendocardial region if perfusion pressure is not sufficiently high. Therefore, the minimum perfusion pressure or flow rate of warm blood cardioplegia necessary to avoid regional ischemic injury remains to be defined.

66

CHAPTER 7

Figure 7.5 Representative contrast-enhanced MR images obtained from a pig heart during antegrade warm blood cardioplegia at perfusion pressures of 24, 17, and 7 mmHg. Perfusion deficits became apparent only when the heart was perfused at 7 mmHg perfusion pressure.

Minimum perfusion pressure of warm blood cardioplegia to sustain normal myocardial energy metabolism To determine the minimum perfusion pressure of warm blood cardioplegia required to maintain normal myocardial energy levels, we monitored ATP, PCr, and Pi in the region normally served by the LAD using a 1.0-cm-diameter MR surface coil positioned over the anterior wall of the left ventricle in isolated pig hearts. The hearts were perfused using a mixture of blood and K-H solution in 1 : 1 ratio. Perfusion pressure was gradually decreased until the appearance of apparent ischemic changes. Each perfusion pressure was used for 20 min to ensure that its ability to sustain myocardial energy metabolism was properly assessed. As shown in Figure 7.4, no decrease in PCr or increase in Pi was observed during 20 min of IWBC at either 24 or 17 mmHg perfusion pressure. This suggests that the blood flow at 17 mmHg perfusion pressure is sufficiently high to sustain normal myocardial energy metabolism. Ischemic changes (decrease in PCr with increase in Pi) were observed only when the perfusion pressure was lowered to 7 mmHg, which is considerably lower than that used during cardiac surgery (70-90 mmHg) (Figure 7.4). The results indicate that IWBC is very effective in terms of oxygen delivery to

the myocytes. The perfusion pressure of IWBC does not need to be in the range of physiological arterial pressure to ensure adequate myocardial protection. To determine whether antegrade warm blood cardioplegia at a relatively low perfusion pressure provides homogenous perfusion, MR contrast agent was injected into the aorta during the period of cardioplegia. Its distribution was assessed using MR imaging. As shown in Figure 7.5, warm blood cardioplegia at perfusion pressures of 25 mmHg and 15 mmHg provided homogenous perfusion across the myocardium. When perfusion pressure decreased to 7 mmHg, perfusion deficits were observed in the subendocardial regions (Figure 7.5). The results demonstrate that warm blood cardioplegia at physiological pressure should not result in regional ischemic injury. It should be mentioned that this study was performed in young healthy pigs with normal coronary systems. The relation between cardioplegia pressure and myocardial perfusion in the hearts with severe coronary disease may differ from that observed in our studies. Significant coronary stenosis and occlusion compromise the delivery of cardioplegia to the jeopardized myocardium. Under these conditions, the use of IWBC may result in regional ischemic injury if adjacent normal arteries cannot deliver sufficient blood to the jeopardized myocardium. To determine whether the coronary artery system in the pig had significant

67

Intermittent warm blood cardioplegia

Figure 7.6 Representative MR images obtained during antegrade warm blood cardioplegia with contrast agent delivered into the left circumflex artery (LCX, left panel), the left anterior descending artery (LAD, middle panel), and the right coronary artery (RCA, right panel).

provides sufficient blood flow to sustain normal myocardial energy metabolism in myocardium distal to a coronary occlusion [45].

Summary

Figure 7.7 Outflow rates measured at the venting arteries during antegrade warm blood cardioplegia. LAD, left anterior descending artery; RCA, right coronary artery; LCX, left circumflex artery.

collateral circulation, areas of the myocardium supported by each of three major coronary arteries were defined using contrast-enhanced MR imaging. We found no significant overlap among the regions served by the three coronary arteries (Figure 7.6). This suggests there was no significant arterial collateral circulation between the coronary arteries. We also found that effluents collected from the two nonused coronary arteries were insignificant when warm blood cardioplegia was conducted through a single coronary artery (Figure 7.7). This also demonstrates that normal hearts have no significant arterial collateral circulation. As a result, regional ischemic injury may occur in the heart with severe coronary stenosis if IWBC is the only technique used for myocardial protection. In this situation, retrograde cardioplegia or simultaneous antegrade/retrograde cardioplegia (SARC) may have to be instituted periodically to prevent regional ischemic injury. Using localized 31P MR spectroscopy and MR imaging, we have recently found that SARC

Intermittent antegrade warm blood cardioplegia is a useful technique for myocardial protection during cardiac surgery. The ischemic interval should be shorter than 10 min to prevent severe and cumulative ischemic injury. In contrast to the changes that occur in the beating heart, the ischemic changes resulting from repetitive interruption of warm blood cardioplegia are more prominent in the subepicardium than in the subendocardium. A perfusion pressure significantly lower than physiological arterial perfusion pressure is able to sustain normal myocardial energy metabolism.

References 1 Gabhard MM, Bretschneider HJ, Schnabel PA. Cardioplegia principles and problems. In: Sperelakis N, eds. Physiology and Pathophysiology of the Heart, 2nd edn. Boston: Kluwer Academic, 1989:655-69. 2 Takahashi A, Chambers DJ, Braimbridge MV et al. Cardioplegia: relation of myocardial protection to infusion volume and duration. Eur J Cardiothorac Surg 1989; 3:130-4. 3 Preusse CH, Winter J, Schulte HD et al. Energy demand of cardioplegically perfused human hearts. / Cardiovasc Surg 1985; 26:558-63. 4 Allen D, Orchard C. The role of intracellular calcium, pH and ATP in myocardial failure during hypoxia. In: Yamada K, Katz AM, Toyama I, eds. Cardiac Function

68

5

6

7

8

9

10 11

12

13

14

15

16

17

18

19

20

CHAPTER 7

Under Ischemia and Hypoxia. Nagoya: University of Nagoya Press, 1986:303-16. Kammermeier H, Schmidt P, Jungling E. Free energy change of ATP hydroxlysis: a causal factor of early hypoxic failure of the myocardium? / Mol Cell Cardiol 1982; 14:267-77. Opie LH. ATP synthesis and breakdown: adenosine and response to ischemia. In: Opie LH, ed. The Heart: physiology and metabolism. New York: Raven Press, 1991: 247-74. Kentish JC, Allen DG. Is force production in the myocardium directly dependent upon the free energy change of ATP hydrolysis. / Mol Cell Cardiol 1986; 18: 879-82. Veech RL, Lawson JWR, Cornell NM et al. Cytosolic phosphorylation potential. / Biol Chem 1979; 254: 6538-47. Hearse DJ, Braimbridge MV, Jynge P, eds. Protection of the Ischemic Myocardium. Cardioplegia. New York: Raven Press, 1981. Hearse DJ. Ischemia, reperfusion, and the determinants of tissue injury. Cardiovasc Drugs Ther 1990; 4:767-76. Kubler W, Spieckermann PG. Regulation of glycolysis in the ischemic and the anoxic myocardium. / Mol Cell Cardiol 1970; 1:352-77. Kubler W, Katz A. Mechanism of early pump failure of the ischemic heart: possible role of adenosine triphosphate depletion and inorganic phosphate accumulation. Am J Cardiol 1977; 40:467-71. Bretschneider HJ, Gebhard MM, Preusse CJ. Reviewing the pros and cons of myocardial preservation within cardiac surgery. In: Longmore DB, ed. Towards Safer Cardiac Surgery. Boston: GK Hall Medical Publishers, 1981:21-53. Tantillo MB, Khuri SF. Myocardial tissue pH in the assessment of the extent of myocardial ischemia and adequacy of myocardial protection. In: Piper HM, Preusse CJ, eds. Ischemia-Reperfusion in Cardiac Surgery. London: Kluwer Academic, 1993: 335-52. Dennis SC, Gevers W, Opie LH. Proton in ischemia: where do they come from; where do they go to? JMol Cell Cardiol 1991; 23:1077-86. Ingwall JS. Phosphorus nuclear magnetic resonance spectroscopy of cardiac and skeletal muscle. Am J Physiol 1982; 242: H729-44. Gillies RJ. Nuclear magnetic resonance and its applications to physiological problems. Ann Rev Physiol 1992; 54: 733-48. Brunotte F, Peiffert B, Escanye JM et al. Nuclear magnetic resonance spectroscopy of excised human hearts. Br Heart} 1992; 68:272-5. Koretsky AP. Application of localized in vivo NMR to whole organ physiology in the animal. Annu Rev Physiol 1992; 54: 799-826. Path G, Robitaille PM, Merkle H et al. Correlation between transmural high energy phosphate levels and myocardial blood flow in the presence of graded coronary stenosis. CircRes 1990; 67:660-73.

21 Fukunamki M, Yellon DM, Kudoh Y et al. Spatial and temporal characteristics of the transmural distribution of collateral flow and energy metabolism during regional myocardial ischemia in the dog. Can J Cardiol 1987; 3:94-103. 22 Bache RJ, McHale PA, Greenfield JC. Transmural myocardial perfusion during restricted coronary inflow in the awake dog. Am J Physiol 1977; 232: H645-51. 23 Gelpi RJ, Cingolani HH, Mosca SHAM et al. Myocardial blood flow distribution across the left ventricular wall. III. Mechanical factors. Arch Int Physiol Biochim 1982; 70:377-83. 24 Bottomley PA, Weiss RG. Noninvasive localized MR quantification of creatine kinase metabolites in normal and infarcted canine myocardium. Radiology 2001; 219: 411-18. 25 Saeed M, Wendland MF, Higgins CB. The developing role of magnetic resonance contrast media in the detection of ischemic heart disease. Proc Soc Exp Biol Med 1995; 208:238-54. 26 Wilke N, Kroll K, Merkle H et al. Regional myocardial blood volume and flow: first-pass MR imaging with polylysine-Gd-DTPA. Magn Reson Med 1995; 5:227-37. 27 Simor T, Chu WJ, Johnson L et al. In vivo MRI visualization of acute myocardial ischemia and reperfusion in ferrets by the persistent action of the contrast agent Gd (BME-DTPA). Circulation 1995; 92:3549-59. 28 Tian G, Shen J, Su S et al. How effective is retrograde cardioplegia? A perfusion imaging perspective. In: Proceedings of the International Society for Magnetic Resonance in Medicine, vol 2, p 678, abstract. 29 Su S, Shen J, Tian G et al A re-evaluation of Tl - and T2*weighted imaging methods for myocardial perfusion. Proceedings of the International Society for Magnetic Resonance in Medicine, vol 2, p 684, abstract. 30 Tian G, Shen J, Dai G et al. An interleaved Tl—T2* imaging sequence for assessing myocardial injury. / Cardiovasc Magn Reson 1999; 1:145-51. 31 Nelson KL, Runge VM. Principles of MR contrast. In: Runge VM, ed. Contrast-enhanced Clinical Magnetic Resonance Imaging. Lexington: The University Press of Kentucky, 1997:1-13. 32 Matsuura H, Lazar HL, Yang X et al. Warm versus cold blood cardioplegia: is there a difference? / Thorac Cardiovasc Surg 1993; 105:45-51. 33 Buckberg GD. Myocardial protection: an overview. Semin Thorac Cardiovasc Surg 1993; 5:98-106. 34 Tian G, Xiang B, Butler KW et al. A 31P nuclear magnetic resonance study of intermittent warm blood cardioplegia. JThorac Cardiovasc Surg 1995; 109:1155-63. 35 Philipson KD. Cardiac sodium-calcium exchange research, new directions. Trends Cardiovasc Med 1992; 2:12-14. 36 Haigney MCP, Miyata H, Lakatta EG et al. Dependence of hypoxic cellular calcium loading on Na+-Ca2+ exchange. CircRes 1992; 71:547-57. 37 Fliegel L, Wang H. Regulation of the Na+/H+ exchanger in the mammalian myocardium. JMol Cell Cardiol 1997; 29:1991-9.

Intermittent warm blood cardioplegia

38 Garlick PB, Radda GK, Leeley PJ. Studies of acidosis in the ischemic heart by phosphorus nuclear magnetic resonance. BiochemJ 1979; 184:547-54. 39 Hearse DJ, Bolli R. Reperfusion-induced injury, manifestations, mechanisms, and clinical relevance. Trends CardiovascMed 1991; 1:233-40. 40 Hearse DJ. Reperfusion injury, progress and problems. Cardiovasc Drugs Ther 1991; 5:313-16. 41 Chapman JB. Thermodynamics and kinetics of electrogenie pumps. In: Blaustein MP, Leiberman M, eds. Electrogenic Transport. New York: Raven Press, 1984:17-32. 42 Spaan JAE, ed. Coronary Blood Flow. London: Kluwer Academic, 1991:1-36.

69 43 Rouleau J, Boerboom LE, Surjadhana A et al. The role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs. CircRes 1979; 45: 804-15. 44 Bache RJ, Zhang J, Path G et al. High energy phosphate responses to tachycardia and inotropic stimulation in left ventricular hypertrophy. Am J Physiol 1994; 266: H1959-70. 45 Tian G, Xiang Dai G et al. Simultaneous antegrade/ retrograde cardioplegia protects myocardium distal to a coronary occlusion: a study in isolated pig hearts. Magn ResonMed200l; 46: 773-80.

CHAPTER 8

Warm heart surgery Hassan Tehrani, MB, BCH, Atiq Rehman, MD, Pierluca Lombardi, MD, Mohan Thanikachalam, MD, & Tomas Salerno, MD

to the elimination of electromechanical activity. The addition of hypothermia decreases oxygen requireThe historical background of warm heart surgery fol- ments by over 50%, but this has to be regarded in the lows the typical cyclical nature of medical progress. context of an overall decrease in oxygen requirements Although originally proposed by Gott in 1957 [ 1 ], the from only 10% to 5% of normal by adding hypothermia concept of warm heart surgery came as a natural step to cardioplegia-induced electromechanical arrest. Durin the evolution of myocardial protection. ing the administration of continuous normothermic The combination of hypothermia introduced by cardioplegia, oxygen and substrate delivery for metaBigelow et al. [2] and potassium cardioplegic arrest bolism is at approximately 30-50% of normal levels. introduced by Melrose et al. [3] became the most This allows for a considerable safety margin, with an common method of myocardial protection during abundance of oxygen and substrate to accommodate the 1960s and 1970s. Later, blood was added to car- the metabolic needs of the myocardium [8]. dioplegia solution to supply the myocardium with The rationale for continuous as opposed to interoxygen, nutrients, and buffers. mittent warm cardioplegia administration is to avoid Studies by Buckberg et al. [4] clarified the patho- periods of normothermic ischemia. Despite continuphysiology of myocardial ischemia and reperfusion ous cardioplegia perfusion, near perfect visualization injury. As a consequence of these findings, Rosenkranz can still be achieved for construction of anastomoses, and colleagues [5] introduced the concept of sub- thereby preventing a period of normothermic ischemia. strate-enhanced warm cardioplegia induction. Teoh However, animal and clinical studies demonstrate and colleagues [6] in Toronto followed this with the that warm blood cardioplegia infusion can be safely proposal of the so-called terminal "hot shot" before interrupted for periods of less than 10-12 min withremoving the aortic cross-clamp. In 1989, Salerno's out clinical or metabolic sequelae [9]. group [7] introduced normothermic blood cardioHypothermia appears to have several detrimental plegia, considering the addition of hypothermia no cellular and subcellular effects, such as impaired longer necessary. A new era in myocardial preserva- mitochondrial and cell volume control, membrane tion had begun. stability, and sarcoplasmic reticulum calcium handling. These effects lead to a depletion of myocardial energy supplies and a delay in the metabolic and Anatomic and physiologic basis functional recovery of the heart [ 10]. The guiding rule for myocardial protection during Conversely, continuous normothermic cardioplegia cardiac surgery should be the maintenance of a balance has several potential disadvantages including systemic in the myocardial energy supply/demand equation. hyperkalemia, hyperglycemia, and hemodilution The arrested, normothermic heart requires 90% due to the increased volume of cardioplegia delivery. less oxygen than does the normal working heart due Altering the blood-crystalloid ratio (2 : 1 and 4 : 1 )

Introduction

70

Warm heart surgery

71

and using modified cardioplegia delivery systems have been observed to reduce the cardioplegic load and hemodilution. Furthermore, normothermia and hemodilution lead to systemic vasodilatation necessitating vasoconstrictor agents to maintain adequate perfusion pressures, with an increased risk of vasospasm of native arteries and bypass grafts.

Results of clinical trials Since the introduction of warm continuous blood cardioplegia as a means of myocardial protection, there

have been multiple trials published on this subject in the literature. These studies have compared warm or tepid blood cardioplegia with cold blood or crystalloid cardioplegia delivered either continuously or intermittently, and either in antegrade or retrograde fashion. The largest trials (each involving more than 1000 patients) have been the Warm Heart Investigators Trial and the Emory Study. The results of these two trials and other trials are summarized in Table 8.1. The Warm Heart Investigators [12] enrolled over 1700 patients at three centers. This was a prospective randomized trial of 37°C cardioplegia with systemic

Table 8.1 Review of trials on warm continuous blood cardioplegia in myocardial protection. Adapted from Caputo eta/. [11]. Study

Subject

Methodology

Warm Heart

CAWBC/IAWBCvs.

Three-center prospective

No difference in

Better myocardial

Investigators

IACBC

randomized study.

morbidity or mortality.

protection in warm group

[13]

Martin eta/.

CRWBC vs. IACCC

[14]

Finding

Conclusion

Morbidity and mortality

T Low cardiac output in

comparison

IACBC group

Prospective randomized

No difference in

Equivalent myocardial

study. Morbidity and

infarction or mortality

protection. Higher stroke

mortality comparison

rate. Higher stroke rate

rate in warm group

in warm group (3.1 %

vs. 1 .0%) Pelletiereta/.

IAWBC vs. IACBC.

Prospective randomized

Similar morbidity and

Better myocardial

[15]

Clinical and myocardial

study. CK-MB and

mortality. CK-MB and

protection in warm group

metabolic evaluation

troponin-T release

troponin-T lower in

comparison

IAWBC

Rousou eta/.

Clinical and metabolic

Clinical and metabolic

No differences

[16]

changes for CRWBC

comparison

Brief periods of warm cardioplegia interruption are well tolerated

with varying periods of ischemic interruptions Fremeseta/.

CAWBC/IAWBC vs.

Late follow-up from one

Nonfatal perioperative

No difference between

[18]

IACBC

of centers in Warm

cardiac events are

warm and cold groups

Heart Investigators trial

associated with reduced late survival

Bouchart eta/.

CAWBC vs. IACCC vs.

Prospective randomized

CK-MB lowest in

Warm cardioplegia

[19]

IACCC with terminal

study. Functional and

CAWBC

provides best myocardial

'hotshot' in

metabolic evaluation

protection in

hypertrophied hearts

following isolated aortic

hypertrophied hearts

valve surgery Jacqueteta/.

IAWBC vs. IACCC/IRCCC

[20]

Prospective randomized

No difference in

Better myocardial

study. Functional and

myocardial infarction,

protection in warm group,

metabolic evaluation

morbidity or mortality

but no difference in clinical

rate

outcomes

CAWBC, continuous antegrade warm blood cardioplegia; CK-MB, isoenzyme of creatine kinase; CRWBC, continuous retrograde warm blood cardioplegia; IAWBC, intermittent antegrade warm blood cardioplegia; IACBC, intermittent antegrade cold blood cardioplegia; IACCC, intermittent antegrade cold crystalloid cardioplegia; IRCCC, intermittent retrograde cold crystalloid cardioplegia.

72

normothermia versus hypothermic coronary bypass surgery. Blood cardioplegia was administered either as antegrade continuous or intermittent (CAWBC or IAWBC) in the warm group and intermittent antegrade in the cold group (IACBC). The results showed a nonsignificant decrease in mortality rates (1.4% vs. 2.5%, P < 0.12) in favor of warm cardioplegia. There was no difference in the nonfatal Q-wave myocardial infarction (MI) rate, but enzymatic infarction rates by serial creatine kinase-myoglobin (CK-MB) fraction measurements were lower in the warm group (12.3% vs. 17.3%, P < 0.001). The incidence of postoperative low cardiac output syndrome was lower in the warm group (6.1% vs. 9.3%; P<0.01). In a follow-up study, Fremes et al. [18] examined late outcomes of patients previously enrolled at one of the centers in the Warm Heart Investigators trial. They hypothesized that: (i) nonfatal perioperative cardiac events are associated with reduced survival; and (ii) because nonfatal perioperative cardiac events and mortality rates were decreased in the warm cardioplegia arm (though not significant statistically), this would reach significance at late follow-up. They confirmed that late survival was significantly reduced in those patients who suffered perioperative nonfatal MI, but that there was no difference in late survival between the warm and cold cardioplegia groups. Martin et al. [14] enrolled 1000 patients in a prospective randomized trial of continuous retrograde warm blood cardioplegia (CRWBC) versus intermittent antegrade cold crystalloid cardioplegia (IACCC). There was no difference in MI or mortality rates between the groups. Strikingly there was a higher incidence of total neurologic events (4.5% vs. 1.4%; P< 0.005) and strokes (3.1% vs. 1.0%; P< 0.02) in the warm group. Pelletier et al. [15] randomized 200 patients undergoing coronary artery surgery to either receive IAWBC or IACBC. Mortality and myocardial infarction rates were similar in the two groups. Release of the isoenzyme of creatine kinase (CK-MB) and troponin T were significantly lower in the IAWBC group. In a study examining the effects of varying lengths of interrupting warm retrograde cardioplegia administration, Rousous et al. [16] compared clinical outcomes, MI, use of intra-aortic balloon pump, mortality, and length of stay. They concluded that temporarily interrupting cardioplegia administration was not deleterious with respect to outcomes.

CHAPTER 8

Concerns regarding interrupting warm cardioplegia administration have been echoed by Menasche [17], who cautions that "it is virtually impossible to predict in a given patient, the time point beyond which myocardial metabolism is going to shift toward anaerobic patterns." Bouchart et al. [19] studied patients undergoing surgery for isolated aortic stenosis. They compared three strategies of myocardial protection in this group of patients with hypertrophied myocardium. Patients were randomized to receive CAWBC, IACCC, or IACCC with a terminal "hotshot." There was no difference found among the groups in terms of morbidity, mortality, or length of stay in hospital. Postoperative CK-MB release was lower in those patients receiving CAWBC, though this did not translate into a lower rate of MI.

Conclusion The ability of cardiac muscle to tolerate ischemia is finite. Kirklin et al. have shown that the severity of ischemia is directly proportional to the cross-clamp time. Using hypothermia in addition to cardioplegia administration was seen as yet another way of increasing the level of myocardial protection during this critical period. The addition of blood to cardioplegia was seen as a way of providing oxygen, nutrients, and buffering capacity. However, there exists a delicate balance between the beneficial and deleterious effects of hypothermia on jeopardized myocardium. The use of hypothermia has been shown to be counterproductive at temperatures lower than 15°C due to the leftward shift of the oxyhemoglobin curve, leading to a decrease in oxygen unloading and to impaired utilization of oxygen by the myocardium. Thus, hypothermic blood cardioplegia leads to cold, ischemic and anaerobic arrest. To prepare the heart for this insult, Buckberg and colleagues supplemented cold arrest with warm induction and the terminal hot shot. This method of sandwiched cold cardioplegia proved to be a better strategy for myocardial protection, especially in ischemic injured hearts [5]. In the light of Buckberg's findings that warm blood cardioplegia added a measure of protection when placed at the beginning and the end of cross-clamp duration so as to protect the heart from the intervening cold-ischemic-anaerobic arrest, the question remained as to why not eliminate ischemia altogether

Warm heart surgery by giving continuous warm blood cardioplegia? Given the deleterious effect of hypothermia and the very minimal additive benefit to myocardial protection, why cool the heart so aggressively? Since its introduction in the late 1980s, the use of warm blood cardioplegia as a means of myocardial protection has stimulated much debate in the cardiac surgery community. As in the aforementioned studies, the safety record of warm heart surgery is comparable to that of cold cardioplegia, and from a metabolic standpoint it clearly provides superior myocardial protection, and is of greater benefit to high-risk patients who may have metabolically compromised hearts. The latter benefit is attained by avoiding the further ischemic insult that occurs with traditional hypothermic arrest. One concern initially raised with the introduction of warm heart surgery was the apparent increased incidence of stroke. The findings from the 1994 warm heart trial at Emory University, showing an increased rate of perioperative strokes in patients undergoing warm heart surgery, received much attention, and led to a backlash against the use of this form of myocardial protection. Although the exact etiology of the significantly higher neurological event and stroke rate in that study still remains unknown, the proposed theories for this have included maintenance of systemic perfusion above 37°C and hyperglycemic crystalloid cardioplegia exacerbating intraoperative neurologic injury. Since then, multiple other studies have countered this finding. It is generally accepted that allowing the systemic temperature to drift to 32-34°C during warm heart surgery allows for cerebral protection and avoids the need to use significant quantities of vasoconstrictors due to normothermic-induced vasodilatation. Thus warm blood cardioplegia not only protects but also more likely prevents ischemia to the heart while additionally protecting the brain. In addition, there are concerns regarding possible failure of the pump oxygenator during warm heart surgery as the heart is not as protected due to the lack of hypothermia. However, pump failure is currently extremely rare and, as mentioned before, temporary interruptions of warm cardioplegia are not deleterious. Warm heart surgery has proven in the last decade to be a safe method of myocardial protection. As the practice of cardiac surgery includes a greater number of high-risk patients, alternative techniques such as

73

warm heart surgery should continue to remain in the armamentarium of cardiac surgeons.

References 1 GottVL,GonzalezJL,PanethMetal. Cardiacretroperrusion with induced asystole systole for open surgery upon the aortic valve or coronary arteries. Proc Soc Exp Biol Med 1957; 94:689-92. 2 Bigelow WG, Lind WK, Greenwood WF. Hypothermia: its possible role in cardiac surgery. An investigation of factors governing survival hi dogs at low body temperatures. Ann Surg 1950; 132: 849-66. 3 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Elective cardiac arrest. Lancet 1955; ii: 21-2. 4 Buckberg GD, Brazier JR, Nelson RL et al. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart. / Thorac Cardiovasc Surg 1977; 73: 87-94. 5 Rosenkranz ER, Vinten-Johansen J, Buckberg GD et al Benefits of normothermic induction of blood cardioplegia in energy-depleted hearts with maintenance of arrest with multidose blood cardioplegia infusions. / Thorac Cardiovasc Surg 1982; 84:667-77. 6 Teoh KH, Christakis GT, Weisel RD. Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia (hot shot). / Thorac Cardiovasc Surg 1986;91:888-95. 7 Lichtenstein SVEL, Dalati H, Panos A, Slutsky AS. Long cross clamp time with warm heart surgery [letter]. Lancet 1989; i: 1443. 8 Bernhard WF, Schwarz HF, Malick NP. Selective hypothermia cardiac arrest in normothermic animals. Ann Surg 1961; 153:43-51. 9 Deslauriers R, Butler KW, Haas N et al. The effect of intermittent cold and continuous warm blood cardioplegia on isolated pig hearts: P NMR and functional studies. In: Proceedings of the llth Annual Meeting of the Society of Magnetic Resonance in Medicine, Berlin, August 8—14, 1992. 10 Panos A, Ashe K, El-Dalati H etal. Clinical comparison of continuous warm (37°C) versus continuous cold (10°C) blood cardioplegia in CABG surgery. Clin Invest Med 1989;12(5Suppl):C55. 11 Caputo M, Bryan AJ, Calafiore AM et al. Intermittent antegrade hyperkalaemic warm blood cardioplegia supplemented with magnesium prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery. Eur } Cardiothorac Surg 1998; 14: 596-601. 12 Salerno TA, Houck IP, Barozzo CA et al. Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection. Ann Thorac Surg 1991; 51:245-7. 13 The Warm Heart Investigator. Randomised trial of normothermic versus hypothermic coronary bypass surgery. Lancet 1994; 343:559-63.

74

14 Martin TD, Graver JM, Gott JP et al. Prospective, randomized trial of warm blood cardioplegia: myocardial benefit and neurologic threat. Ann Thorac Surg 1994; 57: 298-304. 15 Pelletier LC, Carrier M, Leclerc Y et al. Intermittent anterograde warm versus cold blood cardioplegia: a prospective, randomized study. Ann Thorac Surg, 1994; 58:41-8. 16 Rousous JA, Engelman RM, Flack JE et al. Does interruption of normothermic cardioplegia have adverse effect on myocardium? A retrospective and prospective clinical evaluation. Cardiovasc Surg 1995; 3: 587-93. 17 Menache P. Blood cardioplegia: do we still need to dilute? Ann Thorac Surg 1996; 62:957-60.

CHAPTER 8

18 Fremes SE, Tamariz MG, Abramov D et al. Late results of the warm heart trial: the influence of nonfatal cardiac events on late survival. Circulation 2000: 102 (sill): 339-45. 19 Bouchart F, Bessou JP, Tabley A et al. How to protect hypertrophied myocardium? A prospective clinical trial of three preservation techniques. IntJArtif Organs 1997; 20:440-6. 20 Jacquet LM, Noirhomme PH, Van Dyck MJ et al. Randomized trial of intermittent antegrade warm blood versus cold crystalloid cardioplegia. Ann Thorac Surg 1999; 67:471-7.

CHAPTER 9

Intermittent antegrade warm blood cardioplegia Antonio Maria Calafiore, MD, Giuseppe Vitolla, MD, & Angela lacd, MD

During the last decade warm heart surgery, reported by Salerno et al. [1,2], was accepted as a feasible and safe technique for myocardial protection. This concept has had a striking impact on modern cardiac surgery. It was possible to maintain the heart in diastolic arrest without cooling. The basic concept had already been known for many years. The oxygen consumption of a heart arrested by potassium-enriched normothermic blood is 90% less than baseline value [3] and only a slight reduction in oxygen consumption is achieved by lowering the temperature to 11°C. Salerno et al. [1] underlined that continuous perfusion of warm blood was needed by the retrograde route, by means of coronary sinus cannulation, ensuring continuous normothermic perfusion during the aortic cross-clamping period. In our institution a different approach to warm blood cardioplegia with two characteristics was standardized: the delivery route is exclusively antegrade, and cardioplegic flow is discontinued for 85-90% of the aortic cross-clamping period, and only KC1 is added to blood.

clarify that there are two venous systems in the heart: the greater and the lesser systems. The lesser cardiac system is composed of the small thebesian veins, which are venous or sinusoidal connections to the cardiac chambers. These drain primarily the septum, the conus of the right ventricle, and the lateral walls of the atria. Seventy percent of venous return is drained by the coronary sinus; the remainder is drained through the lesser system. Therefore, if more thebesian veins and an arteriovenous shunt exist there is less nutrient flow to the capillaries. Real nutritional flow may be reduced further in hearts with coronary artery disease. Possible detrimental effects of retrograde perfusion may be enhanced by continuous warm blood cardioplegia. The potential benefits of the retrograde route exist in acute coronary occlusion when even a low amount of nutrient flow may be useful in maintaining cellular viability. However, many other techniques are effective in this situation (cold, warm, noncardioplegia).

Warm blood cardioplegia The antegrade method of cardioplegia delivery In 1898 Pratt [4] theorized the retrograde coronary route to deliver oxygenated blood to myocardium; later Lillehi et al. [5] reported the first clinical use and Menasche [6] reproposed this route of cardioplegia delivery. However, the fundamental question remains, "can retroperfusion of the coronary sinus provide enough flow for the whole heart?" Many studies on the anatomy of coronary veins

Bigelow et al. [7] demonstrated the essential role of hypothermia in preserving the heart and whole body during open-heart procedures. This is still valid even if hypothermia has some detrimental effects [8]. There is metabolic evidence that the sodium-potassium, ATPase and calcium ATPase enzyme systems of the sarcoplasmic reticulum are inactivated by hypothermia. All ATPase-dependent reactions are impaired, with a negative influence on membrane stability, energy production, enzyme function, aerobic glucose

75

76

utilization, ATP generation and utilization, cyclic adenosine monophosphate production, and osmotic homeostasis. Moreover, cold blood fails to deliver normal amounts of oxygen to the tissues; with hypoxia, lactate acidosis accumulates from glucose utilization via the Embden-Meyerhoff pathway. Intracellular and extracellular pH falls further impairing a variety of pH-dependent enzymatic processes. The availability of warm blood cardioplegia represents a radical change in arrested heart management, and surgical teams have adopted the warm techniques routine for their clinical use whereas other teams are more cautious. We began our experience with the warm technique in 1991, and demonstrated the superiority of warm over cold protection, which we had used previously, as shown by lower morbidity and mortality rates [9,10].

Intermittent delivery of warm cardioplegia The fundamental principle of warm heart surgery (90% reduction of O2 consumption at 37°C if the heart is arrested) has led us to change only the temperature of the blood cardioplegic solution. The maximum ischemic interval allowed during surgery was not known on a scientific basis, but we think that 15 min of normothermic ischemia allows construction of the distal anastomoses without reinfusion of cardioplegia. In our experience, "intermittent" means that the ischemic time is 85-90% of total aortic crossclamping time. Continuous antegrade delivery of

CHAPTER 9

warm cardioplegia is difficult to manage during surgery, mainly in mitral valve operations. The physiologic antegrade route ensures homogenous distribution of cardioplegic flow and reinfusion over 15 min, allows complete reperfusion of the heart, replenishes the energy stores, and prepares the heart for another period of ischemia. During ischemic periods, not anoxic intervals, the surgical field is without blood and the operation becomes easier and quicker. Clinical experience shows that repeated short periods of controlled ischemia, even for aortic cross-clamping time exceeding 2 h, allows excellent cardiac recovery because the ischemic periods are not cumulative.

Surgical technique and delivery protocol Cannulation of the heart is via the ascending aorta and a single double stage right atrial cannula (two separate cannulas in mitral valve surgery). An aortic needle is used for cardioplegic infusion and/or venting when necessary. Blood is taken directly from the oxygenator by means of quarter-inch tubing and a roller pump, then is infused into the aortic root. The tubing is connected to a syringe pump that delivers potassium at a concentration of 2 mEq/mL. The circuit is shown in Figure 9.1 and the delivery protocol is shown in Table 9.1. After the first infusion of cardioplegia (600 mL in 2 min), reinfusions are administered after construction of each distal anastomosis or after 15 min of ischemia. The duration of each reperfusion may be prolonged, if necessary for contingent reasons

Figure 9.1 The circuit for the administration of intermittent antegrade warm blood cardioplegia (see text).

Intermittent antegrade warm blood cardioplegia

77

Table 9.1 Delivery protocol. From Flow rate

Calafiore eta/. [9], with permission from Society of Thoracic Surgeons.

1st dose 2nd dose 3rd dose 4th dose 5th dose 6th dose

Roller pump

Syringe pump

Duration

(mllmin)

(1 ml/2 mEq)

(min)

300 200 200 200 200 200

push 2 ml then 150 60 60 40 40 40

2

by reducing the syringe pump flow rate. The body temperature is actively maintained at 37°C, which is the same temperature as the cardioplegic solution.

Metabolic studies Preservation of myocardial function during global ischemia for aortic cross-clamping represents a major concern during open-heart surgery. In fact, termination of ischemia by the resumption of coronary flow, while necessary for myocardial recovery, can result in paradoxical extension of the ischemic damage, the so-called ischemia-reperfusion injury. Biochemical evidence suggests that this injury is partly mediated by the oxygen-derived free radicals which are maximally produced at the onset of myocardial reperfusion [11]. A salient biochemical feature of free radical injury is represented by oxidation of biomembranes at cellular and subcellular levels. This reaction exists in a selfexpanding chain, ultimately resulting in loss of membrane integrity and cellular necrosis. The level of this oxidative stress is strictly dependent on the preceding ischemic period.

Free radical production during open-heart surgery Cavarocchi et al. [12] first reported evidence of free radicals production during cardiopulmonary bypass in humans. Marked and sustained coronary sinus release of reduced and oxidized glutathione (expression of increased oxidative stress) has recently been reported during reperfusion in patients subjected to long-lasting hypothermic cardiac arrest during coronary surgery. Several studies in animal models have shown that adding free radical enzymatic and nonenzymatic scavengers to the cardioplegic solution

2 2 2 2 2

[K+] (mEqIL) 18-20 10 10 6.7 6.7 6.7

could reduce myocardial oxidative damage. Moreover, an increased level of lipid peroxides has recently been demonstrated at the end of prolonged ischemic periods in the human myocardium protected by cold crystalloid cardioplegia [13,14]. This increased oxidative stress is associated with the depletion of glutathione and activation of cellular antioxidant enzymes. There is a significant positive correlation between tissue lipid peroxide levels and the duration of the ischemic period, confirming the existence of a crucial relationship between severity of ischemia and free radical production during reperfusion.

Effect of warm blood cardioplegia on free radical generation The essential role of myocardial protection consists of lowering the tissue energy requirements during cardioplegic arrest. In other words, the marked reduction of coronary perfusion due to aortic cross-clamping must not be followed by myocardial damage. For many years hypothermia was considered to be one of the most important means to obtain this result [15,16]. Hypothermia slows myocardial metabolism, thereby reducing ischemia-reperfusion free radical generation. Various authors have shown myocardial free radical production after prolonged hypothermic cardioplegic arrest [14-17]. However, normothermic cardioplegia has been shown to offer good metabolic and clinical results [1]. We compared the effects of intermittent antegrade warm blood cardioplegia and intermittent antegrade cold blood cardioplegia on the myocardial metabolism, and free radicals generated during reperfusion after cardioplegic arrest, in 30 patients undergoing mitral valve replacement [10] (Table 9.2). The levels of fluorescent lipoperoxidation products, reduced and oxidized glutathione, and

78

Patients (n)

Age (yr) Sex (M/F) NYHA class (II/III/IV) CPBtime(min) Aortic clamping time (min)

CHAPTER 9

IAWBC

IACBC

15

15

P

Table 9.2 Clinical data of patients included in the metabolic study. From Calafiore eta/. [9], with permission from

0.27

63 ±2.8

69 ±4.7

8/7

9/6

8/6/1 76.4 ±9.6 56.5 ±8.7

8/5/2 83 ±18.6 62.5±16

Society of Thoracic Surgeons.

0.23 0.21

Data shown are mean ± standard deviation of the mean. IAWBC, intermittent antegrade warm blood cardioplegia; IACBC, intermittent antegrade cold blood cardioplegia; NYHA, New York Heart Association; CPB, cardiopulmonary bypass.

IAWBC

Table 9.3 Metabolic data:

(nmol/dl)

IACBC (nmol/dl)

P

-24.8 ±4.5

-161 + 19

<0.0001

-3.2 + 1.3 -1.9 ±0.4

-23.9 ±3.3 -16.3 ±2.8

<0.0001

-0.41 ±0.3 -12.2±1.8

-4.35 ±0.5 <0.0001 CPK -41.5 + 4.3 <0.0001

+0.4 ±0.1 427 + 35

-0.9 ±0.2 521 ±34

arterial-coronary sinus differences in plasma levels.

GSH sinus concentration Throughout reperfusion (nmol/dl) GSSG sinus concentration Throughout reperfusion (nmol/dl) After cross-clamp off (URF/ml)

<0.0001 FPL

Ascorbic acid After cross-clamp off (nmol/dl) Cross-clamp off (U/L) Lactate Throughout reperfusion (nmol/dl) Elastase cross-clamp off (ng/dl)

<0.0001 <0.0001

CPK, creatinine phosphokinase; FLP, fluorescent lipoperoxidation products.

ascorbic acid were used as an index of myocardial oxidative stress. The values of these parameters were measured with lactate, creatinine phosphokinase, and in blood samples withdrawn from radial artery and coronary sinus before and after aortic cross-clamping. It is evident (Table 9.3) that the oxidative stress was completely prevented in the hearts protected by intermittent antegrade warm cardioplegia; in fact there are no significant differences in these values in comparison with baseline. However, in hearts protected with intermittent antegrade cold blood cardioplegia, the reinfusion of oxygenated blood seems to shift the oxidation-reduction state of cells toward oxidation with free radical generation and finally myocardial damage. In conclusion, metabolic studies seem to demonstrate that hypothermia is not a necessary component of the cardioplegic solution. It appears that normothermia in an arrested heart is the most

favorable condition for myocardial protection during open-heart surgery.

Clinical results Coronary artery bypass grafting Since 1991 over 4000 myocardial revascularization procedures have been performed using intermittent antegrade warm blood cardioplegia. This method of myocardial protection has become routine in our institution. In 1995 we published our results in patients who had undergone coronary revascularization with warm blood cardioplegia in comparison with cold cardioplegia [9]. The preoperative and postoperative data are reported in Tables 9.4 and 9.5, respectively. In this study we found that the warm group had less mortality and morbidity in comparison with the cold group. The incidence of perioperative

Intermittent antegrade warm blood cardioplegia

79

Table 9.4 Preoperative demographic data of patients who underwent coronary artery bypass graft. From

Group A

Group B

IAWBC

IACBC

P

Calafiore eta/. [9], with permission from

Age (yr)

59.4 ±10.0

59.9 ±7.8

NS

Society of Thoracic Surgeons.

Sex F (no.)

28

23

NS

Body surface area (m2)

1.79±0.16

1.79 + 0.16

NS

Unstable angina (no.) Urgent/elective (no.)

115

103

NS

86/164

71/179

NS

One-vessel disease (no.)

23

20

NS

Two-vessel disease (no.)

94

109

NS

Three-vessel disease (no.)

133

121

NS

Main left stenosis (no.)

16

10

NS

Redo rate (no.) LVEF (%) mean

16

10

NS

51 ±20

54112

<0.0025

LVEF < 35% (no.)

53

28

<0.005

LVEF, left ventricle ejection fraction; NS, not significant. Table 9.5 Clinical data of patients who IAWBC

underwent CABG. From Calafiore eta/.

IACBC

P

[9], with permission from Society of

CPB time (min)

67.2121.3

76.3127.5

<0.0005

Thoracic Surgeons.

Ao. cl.time (min)

45.2116.3

44.8115.2

NS

Ischemictime (% Ao. cl. time)

87.8129.8

87.6130.7

NS

Grafts/patients (no.)

2.910.5

3.010.5

NS

Spontaneous rhythm Circulatory assistance

248

103

5

IABP

-

<0.0005 <0.025

4

<0.05

Low output syndrome

1

20

<0.0005

Lidocaine infusion

5

18

<0.01

Deaths Poor LV

2

9

<0.05

0/53

2/28

<0.05

PMI

3

7

NS

CK-MB peaks Absolute value

38138

51130

<0.0005

% total CK

8.214.1

<0.0005

CVA

6.112.9 4

7

NS

Awaking time (h) ICU stay (h)

2.711.5 2817

3.912.8 43110

<0.0005 <0.0005

Postoperative inhospital stay (d)

8.2 + 5.0

9.819.5

<0.0005

Ao. cl. time, aortic clamping time; CVA, cerebrovascular accident; IABP, intra aortic balloon pump; ICU, intensive care unit; PMI, post myocardial infarction. Poor LV (EF < 30%).

myocardial infarction was also lower in the warm group.

Valve surgery In valve surgery the technique of cardioplegia delivery is slightly different. In fact, even if the first dose is delivered in the same way via the aortic root, it may be necessary to inject the cardioplegia directly in to

the coronary ostia. In any case, the second dose of cardioplegia has to be infused in the left coronary ostium while sutures are being placed on the ring. We published our results in patients who underwent aortic and mitral valve surgery with intermittent warm cardioplegia in comparison with a cold cardioplegia in 1996 [18]. The characteristics and results of these patients are reported in Tables 9.6 and 9.7. In

80

CHAPTER 9

Table 9.6 Demographic and clinical data

P

IAWBC

IACBC

Patients (no.)

50

50

Age (yr)

63.9 ±10.9

60.2+11.9

NS

M/F

34/16

37/13

NS

LVEF (%)

57.4 ±17.6

59.9+14.4

NS

LVEF < 35%

10

4

NS

CPBtime(min)

63.2+15.6

82.8 + 21.1

<0.0005

Ao. cl.time(min)

47.9+12.9

56.5115.9

<0.0025

Circulatory assistance

0

5

<0.025

IABP

0

0

-

Low output syndrome

0

8

<0.005

Lidocaine infusion

2

8

CVA

2

2

<0.05 -

of patients who underwent aortic valve surgery. From Calafiore eta/. [9].

Ventricular arrythmia

1

1

<0.05

Deaths

0

4

<0.05

ICU stay (h)

24±10

41±15

<0.0005

Postoperative inhospital stay (d)

9.0 + 3.4

11.2±4.9

<0.01

IAWBC

IACBC

P

Table 9.7 Demographic and clinical data surgery. From Calafiore eta/. [9].

Patients (no.)

50

50

Age (yr)

57.1 + 11.0

57.1 ±10.4

M/F

21/29

24/26

NS

LVEF (%)

58.1 ±7.8

63.1 ±8.7

<0.0025

LVEF < 35%

6

3

NS

CPBtime(min)

76.1+27.0

87.0 + 21.0

<0.05

NS

Ao. cl.time(min)

59.7 ±20.1

59.0 ±16.5

NS

Circulatory assistance

0

6

<0.025

IABP

0

0

-

Low output syndrome

1

8

<0.025

Lidocaine infusion

3

5

NS

CVA

1

0

NS

Ventricular arrhythmia

1

2

NS

Deaths

2

2

NS

ICU stay (h)

28 + 9

40±13

<0.0005

Postoperative inhospital stay (d)

9.3 ±2.8

10.9±3.3

<0.01

both types of surgery there was significantly lower mortality, postoperative morbidity, ICU and inhospital stay in the warm group. Since 1991 over 600 aortic valve replacements and 500 mitral repairs and replacements were performed using this method of myocardial protection.

Comment Intermittent antegrade warm blood cardioplegia (IAWBC) is not only recognized as an alternative, but

of patients who underwent mitral valve

also as a safe technique for myocardial protection currently available. This method is similar to other cardioplegic techniques except for the temperature of the solution delivered. Surgeons using this technique do not need to change their strategy for the operation because IAWBC allows us to have a bloodless operative field. Despite previous studies demonstrating the influence of temperature on cerebral perfusion and metabolism [19], Engelman et al. recently reported that hypothermia might be detrimental to cerebral

Intermittent antegrade warm blood cardioplegia

81

9 Calafiore AM, Teodori G, Mezzetti A et al. Intermittent antegrade warm blood cardioplegia. Ann Thorac Surg 1995; 59: 398-402. undergoing hypothermic or normothermic cardio10 Mezzetti A, Calafiore AM, Lapenna D et al. Intermittent pulmonary bypass, and could not document any effect antegrade warm blood cardioplegia reduces oxidative of the temperature at cardiopulmonary bypass on the stress and improves metabolism in the ischemic reperfused human myocardium. / Thorac Cardiovasc Surg prevalence of perioperative stroke [21]. However, 1995,1995:109: 787-95. Jacquet et al. [22] demonstrated the evidence that 11 McCord IM. Oxygen-derived free radicals in postisIAWBC results in less myocardial cell damage in a ranchemic tissue injury. NEngJMed 1985; 312:159-63. domized trial. The same authors demonstrated that 12 Cavarocchi NC, England MD, Schaff HV et al. Oxygen impaired right ventricular filling is always associated free radical generation during cardiopulmonary bypass: correlation with complement activation. Circulation with cold cardioplegia, which seemed better preserved 1986; 74:130-3. by IAWBC [23]. 13 Mezzetti A, Lapenna D, Pierdomenico SD et al. Finally, experimental, metabolic and clinical studMyocardial antioxidant defenses during cardiopulies have shown that IAWBC is a safe and effective monary bypass. / Card Surg 1993; 8:167-71. technique providing superior results in comparison 14 Lapenna D, Mezzetti A, De Gioia S et al. Blood cardioplegia reduces oxidant burden in the ischemic reperfused to intermittent antegrade cold blood cardioplegia. human myocardium. Ann ThoracSurg, 1994; 57:1522-5. Therefore, the technique of IAWBC has found a place 15 Roe BB, Hotchinson JC, Fishman NH, Ullyot DJ, Smith as a myocardial protective strategy in surgery. D. Myocardial protection with cold ischemic cardioplegia. J Thorac Cardiovasc Surg 1977; 73:366-70. 16 Earner HB, Laks H, Codd JE et al. Cold blood as the References vehicle for hypothermic potassium cardioplegia. Ann ThoracSurg 1979; 28: 509-21. 1 Salerno TA, Houck JP, Barrozo CA et al. Retrograde 17 Ferrari R, Alfieri O, Curello S et al. Occurrence of oxidcontinuous warm blood cardioplegia: a new concept in ative stress during reperfusion of the human heart. myocardial protection. Awn ThoracSurg 1991; 51:245-74. 2 Lichtenstein SV, Ashe KA, El Dalati H et al. Warm heart Circulation 1990; 81:201-11. 18 Calafiore AM, Teodori G, Bosco G et al. Intermittent surgery. / Thorac Cardiovasc Surg 1991; 101:269-74. antegrade warm blood cardioplegia in aortic valve 3 Buckberg GD, Brazier JR, Nelson RL et al. Studies on the replacement. / Card Surg 1996; 11: 348-54. effect of hypothermia on regional myocardial blood flow 19 O'Dwyer C, Prough DS, lonston WE. Determinants and metabolism during cardiopulmonary bypass. / Thorac of cerebral perfusion during cardiopulmonary bypass. Cardiovasc Surg 1977; 73:87-94. / Cardiothorac VascAnesth 1996; 10:54-65. 4 Pratt FH. The nutrition of the heart through the vessels of 20 Engelman RM, Fleet AB, Rousou IA et al. Influence of Thebesius and the coronary veins. Am J Physiol 1898; 1: cardiopulmonary bypass perfusion temperature on neu86-103. rologic and hematologic function after coronary artery 5 Lillehi CW, Dewall RA, Gott VL et al. The direct vision bypass grafting. Ann ThoracSurg 1999; 67:1547-56. correlation of calcine aortic stenosis by means of pump 21 Gaudino M, Martinelli L, Di Leila G et al. Superior extenoxygenator and retrograde coronary sinus perfusion. sion of intraoperative brain damage in case of normothDis Chest 1956; 30:123-32. ermic systemic perfusion during coronary artery bypass 6 Menasche P, Kural S, Fauchet M et al. Retrograde coronary sinus perfusion: a safe alternative for ensuring operations. / Thorac Cardiovasc Surg 1999; 118:432-7. cardioplegic delivery in aortic valve surgery. Ann Thorac 22 lacquet LM, Noirhomme PH, Van Dick MJ et al. Randomized trial of intermittent antegrade warm blood Surg 1982; 34:647-58. versus cold crystalloid cardioplegia. Ann Thorac Surg 7 Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia: its possible role in cardiac surgery. Ann Surg 1950; 132: 1999;67:471-7. 849-66. 23 lacquet LM, Honore P, Beale R. et al. Cardiac function 8 Kaijser L, Hansson E, Schmidt W et al. Myocardial energy after intermittent antegrade warm blood cardioplegia: contribution of the double indicator dilution technique. depletion during profound hypothermic cardioplegia for Intensive Care Med 2000; 26:686-92. cardiac operation. / Thorac Cardiovasc Surg 1985; 90: 900-86. function [20]. Gaudino et al. found that the pre-

valence of neurologic events was similar in patients

CHAPTER 10

Antegrade, retrograde, or both? Frank G. Scholl, MD & Davis C. Drinkwater, MD

Introduction The achievement of a technically perfect operation performed under bloodless conditions in a still operative field resulting in minimal myocardial injury and dysfunction while yielding the best long-term benefit is the goal of any myocardial protective strategy. The techniques used should be integrated into the conduct of the operation, allowing the smooth seamless performance of the technical aspects of the case while achieving optimal preservation of myocardial function. In addition, myocardial protective strategies must be aimed toward minimizing reperfusion injury upon resolution of the coronary occlusion and release of the aortic cross-clamp. Operative strategies must also allow for resuscitation of acutely ischemic myocardium should the need arise. The attributes of an ideal cardioprotective strategy are outlined in Table 10.1. While the ideas for cardiac surgery and myocardial protection utilizing cardiac arrest and hypothermia date back to the 1950s [1,2], current techniques utilizing warm and cold blood cardioplegia given via the antegrade and retrograde routes have evolved as a result of experimental work and the clinical application of it over the past 30 years. As evidenced by the

Table 10.1 Attributes of an ideal myocardial protection strategy. Still, dry operative field Homogenous delivery of cardioplegia Reduction of the utilization of high energy phosphates Decreased anerobic metabolism Buffering of acidosis Replenishment of energy stores

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myriad of articles in the current literature regarding techniques and types of cardioplegia and its delivery, it is likely that in the majority of patients with adequate myocardial reserve the type of cardioplegia solution, its temperature, and its delivery route may have a minimal impact on patient survival. However, the highrisk patient with proximal coronary artery stenoses and poor left ventricular function may suffer should the cardioplegia and delivery techniques used prove ineffective in providing adequate metabolite and energy supply to prevent myocardial damage during and following aortic cross-clamping. Analyzing the benefits and limitations of the various cardioplegia delivery techniques has allowed us to develop a combined approach to the problem of myocardial protection in these high-risk patients.

Antegrade delivery The ability to deliver cardioplegia in antegrade fashion via the aortic root or with direct coronary cannulation provides a route of delivery which mimics the natural path of blood flow through the coronary circulation. The technique is simple in its use, requiring only a suitable cannula and a way to secure it in the aortic wall. In the case of direct coronary cannulation this is even simpler, only requiring a traumatic right-angled cannula held firmly against the coronary ostium. Antegrade delivery of cardioplegia ensures that the cardioplegia reaches all of the myocardium the native coronary circulation can supply. Herein lie both the strengths and weaknesses of the technique. It is obviously beneficial to provide the myocardium with oxygenated blood which parallels the nonarrested state as closely as possible to help maintain cellular metabolism and carry away waste products. However, in patients with significant coronary artery obstructive

Antegrade, retrograde, or both? disease there maybe a nonuniform distribution of cardioplegia. Coronary obstruction and stenoses, which cause myocardial ischemia in the perfused working normal state, also prevent cardioplegia from reaching these areas when it is provided in an antegrade fashion. Thus the administration of antegrade cardioplegia via the aortic root, or even via the coronary ostia by direct cannulation with an open root, may not provide adequate perfusion of arrested myocardium [3]. This is of particular concern in patients with high-grade left main and/or right coronary artery lesions in which large areas of myocardium may be left unprotected. An additional concern with the administration of antegrade cardioplegia is noted in patients with aortic regurgitation. In these patients even mild amounts of aortic valve insufficiency may lead to poor antegrade coronary perfusion and ventricular distention. This combination of factors can result in severe myocardial dysfunction upon weaning from cardiopulmonary bypass. Inadequate delivery of cardioplegia to the coronaries may produce ischemic areas of myocardium and myocardial necrosis, while distention of the left ventricle causes overstretching of myocardial fibers (increased wall tension and decreased coronary perfusion) and later inefficient contractility. Direct coronary perfusion is a potential way around the problem of aortic insufficiency. The coronary ostia are cannulated usually with a soft tip right-angled cannula and the tip is held firmly against the ostia while cardioplegia is administered. While this allows accurate and reliable delivery to the coronary circulation, the technique has significant shortcomings. It requires cessation of the technical aspects of the operation to manually give cardioplegia, thus interrupting the smooth flow of the procedure. The technique also requires "downtime" to give the dose of cardioplegia and thus increases aortic cross-clamp time and the overall length of the operation. Additionally, there exists potential for injury to the coronary ostia from the cannula tip, leading to acute coronary artery dissection or embolization of debris down the artery, and late ostial stenoses [4]. In patients with an ostial left main or ostial right coronary lesion, injury may be more likely to occur and the technique should probably be avoided in these patients or certainly limited to the use of a cannula with a flat-tipped soft contact surface. Several strategies of antegrade delivery have been proposed in attempts to circumvent the nonhomoge-

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nous distribution of cardioplegia. The aorta itself, vein grafts, and distal native coronaries at the site of planned anastomosis have all been used as routes of delivery for antegrade cardioplegia. However, these techniques still run the risk of delayed protection in areas served by a stenotic coronary artery that is revascularized late in the cross-clamp period, such as by internal mammary artery grafting [5,6]. Patients undergoing aortic valve replacement for aortic stenosis should be able to tolerate induction of arrest with antegrade cardioplegia down the aortic root provided the degree of associated aortic insufficiency is mild. However, patients with a large amount of aortic insufficiency associated with aortic stenosis or patients undergoing aortic valve replacement for primary aortic regurgitation are unlikely to benefit from solely antegrade delivery via the aortic root as previously mentioned. Thus, in these patients the aortic root may be opened immediately after aortic cross-clamping and cardioplegia infused directly down the coronary ostia, or alternative methods of delivery can be used. An additional concern with the use of antegrade cardioplegia delivery via the aortic root arises in patients requiring mitral valve procedures. Placement of retractors for adequate visualization of the mitral apparatus required to carry out the procedure will distort the aortic valve and render it incompetent. This leads to the inability to give additional antegrade doses of cardioplegia via the aortic root due to low pressure in the root. It also will lead to filling of the left ventricle and obstruction of the operative field. The aortic root may be opened to give direct ostial antegrade cardioplegia; however, this will disrupt the smooth flow of the operation and has the additional dangers of ostial cannulation.

Retrograde delivery The delivery of cardioplegia via the coronary sinus was described as early as 1957 [7]. The advantages of a retrograde delivery route include the potential for a more homogenous delivery of cardioplegia in the presence of proximal coronary artery stenosis or occlusion [8], thus avoiding the problem of "islands" of poorly protected myocardium, which can be seen with antegrade delivery. This method of delivery in conjunction with initial doses of antegrade cardioplegia has been shown to be as safe and effective as antegrade cardioplegia alone in a prospective randomized trial [9].

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The mechanism of myocardial protection due to retrograde cardioplegia is similar to that of antegrade cardioplegia, in that both techniques can provide nutritive (i.e. capillary bed) flow and myocardial cooling. However, the two routes differ in their distribution. Retrograde flow via the coronary sinus distributes to subendocardial muscle whether coronary arterial stenoses are present or not, and has preferential distribution in the left ventricle, with decreased flow to the right ventricle and septum. Despite this decreased flow to the right side of the heart, retrograde delivery does provide effective cooling of the right ventricle and septum [ 10]. The use of retrograde cardioplegia during coronary revascularization allows arterial grafts to be de-aired in a retrograde fashion after completion of the distal anastomosis. The retrograde technique is also useful in reoperative surgery to help flush out old vein grafts and prevent distal migration of atheroemboli. An additional advantage of retrograde cardioplegia is the ability to give cardioplegia while performing key technical components of an operation. Aortic [11] and mitral valve operations are ideally suited to the use of retrograde cardioplegia. The placement of a suction catheter near the coronary ostia allows delivery of cardioplegia while debridement of the aortic valve is carried out, valve sutures are placed, or the valve is being sized, it can also be given while the aorta is being closed to help de-air the aortic root. During mitral valve operations retrograde cardioplegia may be given without the need to reposition the retractors, as the myocardial protection is no longer dependent on a competent aortic valve as it would be in the case of antegrade delivery, thus allowing an uninterrupted progression of the operation. The use of a left internal mammary artery is the standard of care in modern coronary revascularization and it is often anastomosed to the left anterior descending coronary artery. Additionally, the use of the right and/or both internal mammary arteries is becoming more frequent as the goal of all arterial revascularization is realized. Myocardium distal to the site of internal mammary artery anastomosis cannot be adequately protected in the presence of proximal native coronary disease when antegrade cardioplegic techniques are used alone. The delivery of retrograde cardioplegia can protect what is usually a significant area of myocardium. The benefits of a warm dose of low potassium cardioplegia at the end of the aortic cross-clamp

CHAPTER 10

period have been shown in experimental studies [12], although clinical results are controversial [13,14]. We routinely use a warm dose of low potassium retrograde cardioplegia prior to the removal of the aortic cross-clamp. Various techniques have been described to achieve adequate delivery, including right atrial delivery with clamping of the pulmonary artery and passive flow into the coronary sinus [15] which has been largely abandoned, direct cannulation of the coronary sinus ostia with or without a pursestring, and trans-atrial "blind" cannulation via a stab wound in the right atrial free wall [16]. When used by itself the retrograde technique has a prolonged time to arrest when compared to antegrade delivery [17]. Other disadvantages include possible direct injury of the coronary sinus by the catheter, stylet, or balloon. Myocardial injury with subsequent hemorrhage and edema if cardioplegia is delivered at pressures higher than 45-50 mmHg has been shown [18]. Retrograde delivery can be a technically more cumbersome technique depending on how it is instituted. In the case of right atrial delivery, the large volumes required and ineffectiveness of the technique in the presence of an atrial septal defect are disadvantages. We have described a simplified method of direct transatrial coronary sinus cannulation for retrograde delivery, which can eliminate these disadvantages when used correctly [ 16]. We have used this technique since 1988. A further disadvantage of retrograde delivery alone is the possibility of inadequate protection of the right ventricle. This may be exacerbated if the tip of the delivery catheter is placed deep into the coronary sinus proximal to the ostium of the posterior interventricular vein. It has been proposed that the technique of right atrial isolation and delivery can avoid this problem; however, this technique depends on distention of the right ventricle, which may produce postoperative dysfunction [19]. Placing a pursestring within the ostium of the coronary sinus and directly cannulating the ostium may avoid the problem. This technique has the disadvantage of requiring bicaval cannulation and isolation of the right atrium, but we feel it likely affords better distribution of retrograde cardioplegia to the right ventricle, and we use this technique for procedures with potentially long cross-clamp times where it may be imprudent or inconvenient to give repeated doses of antegrade cardioplegia as in the Ross operation. It is important that the pursestring be

Antegrade, retrograde, or both? placed within the coronary sinus ostium and not around it if atrioventricular (AV) conduction problems are to be avoided.

Combined use of antegrade and retrograde cardioplegia The benefits of both antegrade and retrograde delivery can be maximized and the risks minimized when the techniques are combined in an integrated system of myocardial protection. Since 1988 we have used this technique exclusively for our myocardial protection strategy in both acquired and selective congenital lesions of the adult and pediatric age groups [16,20]. Our strategy affords us the advantages of rapid arrest and myocardial cooling with antegrade cardioplegia via the aortic root, with the improvement in homogenous delivery of the retrograde technique. The two methods are usually used sequentially, to avoid myocardial hemorrhage and edema when given simultaneously. This may be a theoretical concern, as a recent randomized study has shown improvement in functional recovery and oxygen utilization with simultaneous antegrade and retrograde delivery when compared to continuous retrograde alone [21]. Although this technique may eventually prove safe and gain wide

Figure 10.1 Intraoperative diagram of integrated cardioplegia/ cardiopulmonary bypass system. Cardioplegia delivery, antegrade or retrograde, can be selected with simple inline switches. Continuous delivery pressures are measured. The passive aortic root vent is integrated into the system and selected with switches. Arrows indicate the direction of blood flow.

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acceptance, we currently limit it to patients with highgrade proximal left main and right coronary lesions whose right-sided grafts have been completed. We can then use retrograde delivery supplemented by simultaneous antegrade delivery down the right grafts directly or via the aortic root to enhance right-sided protection. Our current technique consists of standard aortic and single venous cannulation for cardiopulmonary bypass (except in patients undergoing intracardiac procedures). The aortic cannula includes a side port for passive root venting. A coronary sinus cannula with a passively inflating balloon is placed via a mattress suture in the lateral wall of the right atrium after placement of the venous cannula, except in patients in whom the right heart is opened where a catheter with a manually inflating balloon is placed via the coronary sinus and a pursestring is placed within the ostium of the sinus itself (this technique will avoid injury to the AV node). Figure 10.1 shows the setup of our integrated cardioplegia delivery and cardiopulmonary bypass system. We use the identical setup for adult and pediatric patients including transplantation; the delivery cannula and tubing are changed according to patient size. For standard coronary revascularization patients are systemically cooled to 29°C, for more

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complex procedures a goal of 26°C or lower may be used. In adult patients the initial dose of cold antegrade blood cardioplegia solution diluted at a ratio of 4 : 1 (blood : cardioplegia) is given at rates of 300 ml/min or at a maximum pressure of 70 mmHg for 2 min, followed by a dose of retrograde cardioplegia at 200 ml/min or a maximum pressure of 35 mmHg for 2 min. It is essential that pressure be monitored continuously in both the antegrade and retrograde cannulas to assure proper administration of cardioplegia. A low retrograde pressure identifies an improperly positioned cannula, and a low antegrade pressure may indicate aortic valve incompetence. The maintenance doses are then given approximately every 15-20 min via the retrograde cannula. We have adapted a goal of all arterial grafting for our coronary revascularizations whenever possible. Due to the absence of valves in the radial artery conduits the patency of distal anastomoses can be assessed by direct visualization of the effluent exiting the proximal aspect of these grafts during retrograde cardioplegia administration. Patients are individually selected for standard revascularization using cardioplegic arrest or for off pump coronary artery bypass (OPCAB) on a case-by-case basis. Our policy is to perform the proximal anastomosis of a graft immediately following the distal anastomosis. In the event a patient has an occluded right coronary artery and high-grade proximal left-sided lesions we will graft the right-sided vessels first and give antegrade cardioplegia via the aortic root down newly completed radial artery grafts to augment right heart protection. After completing the last anastomosis just prior to unclamping the aorta we give a dose of 300 ml of warm retrograde cardioplegia; this is followed by warm whole blood until the cross-clamp is removed. In certain higher risk patients the final dose of warm cardioplegia will be enhanced with the hydrophilic basic amino acids glutamate and aspartate. We use either 37°C antegrade or retrograde delivery and give 300 ml as a final dose prior to switching to whole blood. Patients who have suffered an acute myocardial infarction undergoing emergent revascularization, and patients undergoing procedures with relatively long cross-clamp periods such as a Ross procedure or a double switch for congenitally corrected transposition of the great vessels, are most likely to receive enhanced cardioplegia. Glutamate- and aspartateenhanced leukocyte-depleted controlled reperfusion

CHAPTER 10

Table 10.2 Components of enhanced reperfusate. Normal saline

500ml

Tromethamine

200 ml 0.3 mol/l

CPD

50ml

KCI

30 mmol/l

Monosodium glutamate/aspartate

250 ml 0.46 mol/l

is also given in an antegrade fashion to all of our heart transplant recipients prior to removal of the aortic cross-clamp. Table 10.2 shows the components of the enhanced cardioplegia. This solution is mixed with oxygenated whole blood at a 4 : 1 ratio prior to infusion and is delivered in a controlled fashion at a pressure of 50 mmHg or less antegrade or 30 mmHg or less retrograde.

Conclusions We have used the described integrated approach to myocardial protection since 1988, albeit with modification of the technique to suit the development of newer operations, such as all arterial coronary grafting and the Ross procedure. The results of our experience from 1997 to the present in consecutive patients undergoing coronary artery bypass grafting using cardiopulmonary bypass, alone or in combination with valvular procedures, along with our consecutive series of patients undergoing Ross and Ross/Konno procedures are summarized in Table 10.3. These Table 10.3 Results with antegrade and retrograde integrated cardioplegia strategy: 1997-2001.

CABG alone Combined CABG/valve

Patients

Early mortality

(no.)

(%)

843

2.5

147

5.4

CABG/AVR

83

CABG/MVR

22

CABG/AVR/MVR Combined CABG/MVR Ross and Ross/Konno procedure

5

37 72

4.1

1062

3.0

(adult and pediatric) Total patients*

* Deaths due to low cardiac output: 2.4%. CABG, coronary artery bypass graft; AVR, aortic valve replacement; MVR, mitral valve replacement.

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Antegrade, retrograde, or both? techniques have led themselves to a broad variety of both adult and congenital cardiac operations with satisfying results. Our clinical results are contingent upon homogenous distribution of cardioplegia to the potentially ischemic myocardium and this integrated approach with its basis in careful experimental and clinical evaluation appears to have achieved this goal in most patients.

11

12

13

References 1 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Elective cardiac arrest. Lancet 1955; ii: 21. 2 Bigelow W, Lindsay W, Greenwood W. Hypothermia: its possible role in cardiac surgery. Ann Surg 1950; 132:849. 3 Hilton CJ, Teubl W, Acker M et al. Inadequate cardioplegic protection with obstructed coronary arteries. Ann Thome Surg 1979; 28:323-34. 4 Midell AI, DeBoer A, Bermudez G. Postperfusion coronary ostial stenosis: incidence and significance. / Thorac Cardiovasc Surg 1976; 72:80-5. 5 Menasche P, Piwnica A. Cardioplegia by way of the coronary sinus for valvular and coronary surgery. / Am Coll Cardiol 1991; 18:628-36. 6 Buckberg GD, Beyersdorf F, Kato NS. Technical considerations and logic of antegrade and retrograde blood cardioplegic delivery. Semin Thorac Cardiovasc Surg 1993;5:125-33. 7 Gott V, Gonzalez J, Paneth M et al. Retrograde perfusion of the coronary sinus for direct vision aortic surgery. Surg Gynecol Obstet 1957; 104:319-28. 8 Gundry SR, Kirsh MM. A comparison of retrograde cardioplegia versus antegrade cardioplegia in the presence of coronary artery obstruction. Ann Thorac Surg 1984; 38: 124-7. 9 Diehl JT, Eichhorn EJ, Konstam MA et al. Efficacy of retrograde coronary sinus cardioplegia in patients undergoing myocardial revascularization: a prospective randomized trial. Ann Thorac Surg 1988; 45: 595-602. 10 Partington MT, Acar C, Buckberg GD, lulia PL. Studies of retrograde cardioplegia. II. Advantages of antegrade/ retrograde cardioplegia to optimize distribution in

14

15

16

17

18

19

20

21

jeopardized myocardium. / Thorac Cardiovasc Surg 1989; 97:613-22. Menasche P, Kural S, Fauchet M et al. Retrograde coronary sinus perfusion: a safe alternative for ensuring cardioplegic delivery in aortic valve surgery. Ann Thorac Surg 1982; 34:647-58. Lazar HL, Buckberg GD, Manganaro AJ et al. Reversal of ischemic damage with amino acid substrate enhancement during reperfusion. Surgery 1980; 88: 702—9. Teoh KH, Christakis GT, Weisel RD et al. Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia. / Thorac Cardiovasc Surg 1986; 91: 888-95. Edwards R, Treasure T, Hossein-Nia M et al. A controlled trial of substrate-enhanced, warm reperfusion ("hot shot") versus simple reperfusion. Ann Thorac Surg 2000; 69:551-5. Fabiani IN, Deloche A, Swanson J, Carpentier A. Retrograde cardioplegia through the right atrium. Ann Thorac Surg 1986; 41:101-2. Drinkwater DC, Laks H, Buckberg GD. A new simplified method of optimizing cardioplegic delivery without right heart isolation. Antegrade/retrograde blood cardioplegia. / Thorac Cardiovasc Surg 1990; 100: 56-63; discussion 63-4. Fiore AC, Naunheim KS, Kaiser GC et al. Coronary sinus versus aortic root perfusion with blood cardioplegia in elective myocardial revascularization. Ann Thorac Surg 1989; 47:684-8. Hammond GL, Davies AL, Austen WG. Retrograde coronary sinus perfusion: a method of myocardial protection in the dog during left coronary artery occlusion. Ann Surg 1967; 166: 39-47. Salter DR, Goldstein IP, Abd-Elfattah A et al. Ventricular function after atrial cardioplegia. Circulation 1987; 76 (5Part2):V129-40. Drinkwater DC Jr, Cushen CK, Laks H, Buckberg GD. The use of combined antegrade-retrograde infusion of blood cardioplegic solution in pediatric patients undergoing heart operations. / Thorac Cardiovasc Surg 1992; 104:1349-55. Jasinski M, Wos S, Kadziola Z et al. Comparison of retrograde vs simultaneous ante/retrograde cold blood cardioplegia. / Cardiovasc Surg (Torino) 2000; 41 (1): 11-6.

CHAPTER 11

Miniplegia: biological basis, surgical techniques, and clinical results Giuseppe D'Ancona, MD, Hratch Karamanoukian, MD, Luigi Martinelli, MD, Michael O. Sigler, MD, d- TomasA. Salerno, MD

Introduction Different researchers have substantiated the superiority of blood versus crystalloid cardioplegia in the late 1970s and early 1980s. Feindel et al. [1] first showed the superiority of blood cardioplegia in reducing irreversible myocardial injury in a canine model of global myocardial ischemia. In a later prospective randomized study, Fremes et al. [2] demonstrated that blood cardioplegia enhanced aerobic metabolism during aortic cross-clamping, increased myocardial oxygen consumption, reduced anaerobic lactate production, and preserved high-energy phosphate stores. Blood cardioplegia also improved both diastolic and systolic function following surgery [2]. Studies by Follete et al. also suggested that blood constituted the best vehicle for cardioplegia delivery after myocardial ischemic injury [ 3 ]. The advantages offered by blood cardioplegia were attributed to its oxygen- and nutrients-carrying, osmotic and buffering natural capacities. The original formula of blood cardioplegia included 4 parts of blood and 1 part of crystalloid solution. This dilution was necessary in part to prevent hyperviscosity and red cells' rouleau formation at low perfusion temperatures. Secondly, hemodilution and the addition of biochemical substrates in the crystalloid solution could actively ease the protective and restorative capacity of the final cardioplegic formulation. Finally, moderate hemodilution would decrease the concentration of inflammatory chemical and cellular mediators that

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are inevitably stimulated by cardiopulmonary bypass and result in myocardial ischemic insult. In the early 1990s Menasche et al. suggested that undiluted blood cardioplegia could retain the same functions of blood cardioplegia, avoiding the possible disadvantages of hemodilution [4,5]. Menasche simplified the blood cardioplegia formula by using a minimal amount of crystalloid additives including potassium and magnesium. This new miniplegia formulation would, in theory, maximize the endogenous protective and nutritious properties of blood, eliminating the necessity for added buffers, calcium-chelating agents, and metabolic substrates. In this chapter we will summarize the biochemical basis of miniplegia and will focus on its clinical application, as originally described by Menasche et al. We will then summarize the limited existing research studies that compare diluted cardioplegia versus miniplegia, attempting to define the pros and cons of these two techniques.

Miniplegia: rheologic and biologic issues Blood hyperviscosity and red blood cell aggregation have been demonstrated when the blood temperature is lowered [6]. As a result, the risk of capillary occlusion and consequent tissue underperfusion triplicates from 37°C to 10°C [7j. For this reason, cardioplegia dilution should be advocated when maintaining a

Miniplegia perfusate temperature around 4-10°C. However, the introduction and popularization of warm heart surgery [8] has led to the concept of miniplegia and minimal cardioplegia dilution. As demonstrated both in vitro [9] and in vivo [10], if blood cardioplegia is perfused in the 30-37°C range (tepid and warm cardioplegia) increased blood viscosity is improbable [9] and coronary vascular resistance is unchanged [10]. For temperatures below 27°C viscosity sharply increases for increasing hematocrit levels [9]. From a rheologic standpoint it seems to be unnecessary to lower the perfusate hematocrit level when warm cardioplegia is used, at least in the absence of pathologic prothrombotic states, such as polycythemia. As a consequence, in the clinical setting, warm cardioplegia can be safely used by maintaining the perfusate hematocrit level at a value of 25%. Apart from the above-mentioned rheologic issues, the addition of crystalloid solution to the blood cardioplegia formulation was viewed as a vehicle to provide the myocardium with arresting (potassium), calcium-chelating (citrate-phosphate-dextrose, CPD), buffering (tris-hydroxymethyl aminomethane, THAM), and nutritious (aspartate, glutamate, glucose) agents. The usefulness of providing most of these additives has been re-evaluated with the introduction of miniplegia. The addition of arresting agents such as potassium is mandatory to achieve adequate mechanical myocardial arrest. In the original miniplegia formulation of Menasche, potassium was added to the cardioplegic blood to reach a concentration of 16 mEq/L. Furthermore, to enhance cardiac arrest and antagonize calcium ions at the sarcolemmal and intracellular level, an adjunct of 3 mmol/L of magnesium was recommended. The desired quantity of potassium and magnesium is easily mixed in a 20-ml ampoule and is injected to achieve cardiac arrest within 1 min of aortic cross-clamping. CPD is added in order to reduce the concentration of ionized calcium in the cardioplegic solution and, as a consequence, to decrease the chances of myocardial calcium overload at the time of arrest and during reperfusion. However, animal studies have demonstrated that warm perfusates may prevent postischemic intracellular calcium overload [11]. Continuous warm blood cardioplegia may maintain adequate myocardial aerobic metabolism and support energy for normal functioning of the calcium pumps. Furthermore, the

89

dilutional effect of the crystalloid pump prime, which per se reduces cardioplegia ionized calcium concentration, and the supplementation with magnesium, which antagonizes the remaining calcium ions, has been shown to ease postischemic myocardial recovery and reduce enzyme leakage [ 12]. On the basis of these considerations, the calcium paradox may be prevented by adding magnesium to the warm blood perfusate without including pharmacologic chelating agents (CPD). As with chelating agents, pharmacologic buffers (THAM) are omitted in the original miniplegia formulation. Continuous warm cardioplegia maintains aerobic metabolism and prevents the accumulation of intramyocardial lactates. In this condition, any external buffering agent is unnecessary and actually may result in the creation of a deleterious alkalotic status that indirectly will cause intracellular calcium overload. Furthermore, as demonstrated in animal studies, both THAM and bicarbonate do not seem to improve the natural buffering capacity of blood cardioplegia [13,14]. Aspartate and glutamate seem to ease the production of ATP in anaerobic conditions and, for this reason, they should be added in cardioplegic vehicles with low oxygen tension (i.e. crystalloid cardioplegia). In the setting of continuous/intermittent warm blood perfusion, where aerobic conditions are maintained, free fatty acids and glucose are the main nutrients for myocardial metabolism. Although some benefits from aspartate and glutamate utilization have been shown in experimental studies [15,16] with cold blood cardioplegia, the use of amino acids in the clinical setting remains controversial [ 17,18]. However, adoption of a miniplegia formula does not preclude the utilization of amino acids that can be concentrated in a small volume of fluid.

Miniplegia: perfusion technique Menasche et al. [4] described a simplified method for miniplegia delivery. Blood for cardioplegia is withdrawn directly from the oxygenator via a standard perfusion tubing (2.5 inches (7.5 cm)) that passes through a separate roller pump allowing delivery of cardioplegia at a controlled flow rate (Figure 11.1). The limb of the tubing distal to the roller pump goes to the aortic root and incorporates a three-way stopcock used for the delivery of the miniplegia solution into the oxygenated blood. The cardioplegia solution consists

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CHAPTER 11

Figure 11.1 The miniplegia circuit. Reprinted from [20], with permission from Society of Thoracic Surgeons.

of 20 ml ampoules containing potassium chloride (16 mEq per ampoule) and magnesium chloride (6 mEq per ampoule) in distilled water. After aortic cross-clamping, normothermic blood perfusion is begun into the aortic root at a rate of 300 ml/min. Meantime, a 20-ml ampoule of cardioplegia is manually injected over a 30-s period via the stopcock. Once the heart is arrested, blood is perfused in a retrograde fashion via the coronary sinus at a rate of 150200 mL/min. An electrically driven syringe is connected to the stopcock, allowing for the continuous delivery of retrograde cardioplegia during the remaining cross-clamp time. The syringe is filled with 3 ampoules (60 ml) of cardioplegia and the infusion rate is empirically set at 45 ml/h (36 mEq KCl/h). When recurrence of electromechanical activity is noticed, the flow rate is temporarily increased (up to 60 ml/h). If stable asystole has been achieved, the syringe infusion rate is transiently dropped (down to 30 ml/h). So, for a 1-h period of aortic occlusion, the average volume of infused crystalloid solution will be 65 ml (20 ml for induction and 45 ml for replenishment) for a total KC1 load of 52 mEq (16 mEq for induction and 36 mEq for replenishment). To maintain the desired composition of the blood cardioplegic solution (25 mmol/L KC1 concentration for induction and 9 mmol/L for maintenance), Le Houerou et al. [19] calculated normograms for the infusion rate of the KCL syringe. At any given cardioplegia roller pump output, the KC1 syringe infusion rate can be calculated using the following formula:

q = 60[Q(p-k)]/K-p where q is the estimated infusion rate of the KC1 syringe expressed in ml/h, 60 the conversion factor from ml/min to ml/h, Q the oxygenated blood output from the cardioplegia pump in ml/min, p the desired concentration of KC1 in the blood cardioplegia (high = 25 mmol/L, low = 9 mmol/L), k the patient's serum potassium level expressed in mmol/L, and K the concentration of potassium in the syringe KC1 solution. Furthermore, the same authors [19] proposed the use of two separate syringes, one containing KC1 and the other magnesium sulfate (12 mmol at 10%) and CPD (30 ml). The magnesium syringe infusion rate is obtained with the following formula: <j = 0.48xQ where Q represents the oxygenated blood output from the cardioplegia pump and 0.48 represents the factor that allowed the authors to achieve a magnesium concentration of 3.5 mmol/L in the blood cardioplegia and to deliver a CPD concentration equivalent to the Fremes' solution [19]. More recently, Calafiore et al. [20] proposed an alternative miniplegia delivery protocol with exclusive use of intermittent (every 15 min) antegrade warm blood cardioplegia. As summarized in Table 11.1, the total amount of delivered potassium is around 37mEq/h[20].

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Miniplegia

Miniplegia: clinical and experimental studies Although the theoretical bases of miniplegia are clear, its advantages in the clinical setting remain poorly investigated and the number of prospective randomized studies comparing standard versus minimally diluted cardioplegic solutions are limited. In a prospective study including 50 patients, Menasche et al. [5] demonstrated that the use of miniplegia reduces the incidence of perioperative systemic vasodilatation and the need for vasopressors infusion and volume loading. However, no differences in terms of perioperative myocardial injury, recovery, and function and no differences in terms of mortality and morbidity rates were reported between the highly and minimally diluted cardioplegia groups [5]. The authors concluded that routine use of the miniplegia technique should be advocated to prevent peripheral vasodilatation occurring with warm heart operations, to simplify the formulation of cardioplegia, to enhance control on potassium perfusion rate, and to reduce operative economic burdens. In a more recent retrospective study, Calafiore et al. [20] analyzed perioperative results in a cohort of 500 patients operated upon using either intermittent antegrade warm blood miniplegic solution or intermittent antegrade cold (10°C) blood diluted solution (half blood and half crystalloid solution). As summarized in Table 11.1, the cardioplegia infusion protocol in the miniplegia group slightly differed from that proposed by Menasche. Perioperative mortality rate was significantly lower in the warm blood miniplegia group (0.8% vs. 3.6%, P < 0.05). Furthermore, the occurrence of perioperative lowoutput syndrome, use of the intra aortic balloon pump (IABP) or ventricular assistance, CK-MB release, ICU and postoperative inhospital length of stay, were all

significantly lower in the warm blood miniplegia group [20]. Although these findings are encouraging, it remains difficult to determine whether the differences in the two groups' outcomes were the result of either the cardioplegic perfusion temperature (warm vs. cold) or the cardioplegic dilution level (miniplegia vs. diluted). In an animal study, Velez et al. tested the differences between miniplegia and highly diluted cardioplegia delivered in a continuous retrograde tepid (30°C) modality during surgical reperfusion of evolving myocardial infarction [21]. No differences between the two groups were noticed in terms of CK-MB activity, myocardial infarction size, and systolic shortening. Although a trend for a greater tissue (heart, lung, liver, skeletal muscle) edema was reported in the diluted cardioplegia group, significant differences were noticed only at the duodenal and renal level. At the coronary endothelial level, the minicardioplegia group had greater adherence of unstimulated neutrophils in both the ischemic and nonischemic areas, suggesting damage to the coronary artery endothelium [21]. Furthermore, coronary artery maximum relaxation responses to acetylcholine and sodium nitroprusside were impaired in the minicardioplegia group. The greater endothelial dysfunction in the miniplegia group may be related to the higher concentration of neutrophils present in the solution. The interaction between neutrophils and ischemia will determine endothelial injury, which manifests as abnormal response to vasodilating agents and increased adherence of unstimulated neutrophils. Although there were no large-scale acute differences between the two cardioplegia groups, the long-term effects of the endothelial dysfunction present in the minicardioplegia group were not investigated in that study. In reality, this condition could predispose to

Table 11.1 Intermittent antegrade warm blood minicardioplegia protocol as proposed by Calafiore eta/. [20].

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coronary thrombosis and enhance extension of myoReferences cardial infarcted areas. 1 Feindel CM, Tait GA, Wilson G. Multidose blood versus Yeatman et al. [22] investigated the effects of crystalloid cardioplegia. Comparison by quantitative magnesium supplementation during intermittent assessment of irreversible myocardial injury. / Thorac antegrade warm minicardioplegia delivery. In this proCardiovasc Surg 1984; 87:585-95. spective randomized study, 400 elective and emergent 2 Fremes SE, Christakis GT, Weisel RD et al. A clinical trial CABG patients were treated with either magnesium of blood and crystalloid cardioplegia. / Thorac Cardiovasc Surg 1984; 88: 726-41. enriched or magnesium depleted cardioplegia. Per3 Follette DM, Fey K, Buckberg GD et al. Reducing fusion protocols and dilution levels of the miniplegia postischemic damage by temporary modification of solution followed the above-mentioned Calafiore's reperfusate calcium, potassium, pH, and osmolarity. indications [20] (Table 11.1). Analysis of 178 patients / Thorac Cardiovasc Surg 1981; 82:221-38. undergoing urgent CABG for unstable symptoms 4 Menasche P, Touchot B, Pradier F et al. Simplified method for delivering normothermic blood cardioplegia. demonstrated significantly lower requirement for Ann Thorac Surg 1993; 55:177-8. internal defibrillation and temporary epicardial pac5 Menasche P, Fleury JP, Veyssie L et al. Limitation of ing in the magnesium enriched cardioplegia group. vasodilation associated with warm heart operation by a Furthermore, there was a nearly two-fold lower mini-cardioplegia delivery technique. Ann Thorac Surg incidence of new postoperative atrial fibrillation in 1993; 56:1148-53. 6 O'Neill MJ, Francalancia N, Wolf PD et al. Resistance the same group. Moreover, postoperative plasma differences between blood and crystalloid cardioplegic Mg2+ levels were consistently lower in patients who solutions with myocardial cooling. / Surg Res 1981; 30: developed new postoperative atrial fibrillation com354-60. pared with those who did not [22]. 7 Sakai A, Miya J, Sohara Y et al. Role of red blood cells

Conclusion In summary, in the context of warm or tepid blood cardioplegia, the minicardioplegia technique may present some advantages over the 4 : 1 cardioplegia formulation, including limitation of fluid overload and systemic vasodilatation [5], enhanced control of potassium infusion, improved practicality, and improved cost-effectiveness. Furthermore, improved perioperative outcomes seem to result with intermittent antegrade warm blood miniplegia compared to intermittent antegrade cold diluted blood solutions [20]. Moreover, the addition of magnesium in the cardioplegia formulation reduces the rate of perioperative cardiac arrhythmias [22]. However, recent experimental studies suggest that miniplegia use may cause endothelial injury, which manifests as an abnormal response to vasodilating agents and increased adherence of unstimulated neutrophils. Although initial clinical results with miniplegia are encouraging, further prospective randomized studies on larger cohorts of patients are needed in order to better define the pros and cons of this technique.

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in the coronary microcirculation during cold blood cardioplegia. Cardiovasc Res 1988; 22:62-6. Salerno TA, Houck JP, Barrozo CA et al. Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection. Ann Thorac Surg 1991; 51:245-7. Rand PW, Lacombe E, Hunt HE et al. Viscosity of normal human blood under normothermic and hypothermic conditions. / ApplPhysiol 1964; 19:117-22. Hayashida N, Weisel RD, Shirai T et al. Tepid antegrade and retrograde cardioplegia. Ann Thorac Surg 1995; 59: 723-9. Liu X, Engelman RM, Rousou JA et al. Normothermic cardioplegia prevents intracellular calcium accumulation during cardioplegic arrest and reperfusion. Circulation 1994; 57:177-82. Takemoto N, Kuroda H, Hamasaki T et al. Effect of magnesium and calcium on myocardial protection by cardioplegic solutions. Ann Thorac Surg 1994; 57: 17782. Neethling WML, van de Heever JJ, Cooper S et al. Interstitial pH during myocardial preservation: assessment of five methods of myocardial preservation. Ann Thorac Surg 1993; 55:420-6. Warner KG, Josa M, Butler MD. Regional changes in myocardial acid production during ischemic arrest: a comparison of sanguineous and asanguineous cardioplegia. Ann Thorac Surg 1988; 45: 75-81. Rosenkranz ER, Okamoto F, Buckberg GD et al. Safety of prolonged aortic clamping with blood cardioplegia. II. Glutamate enrichment in energy-depleted hearts. / Thorac Cardiovasc Surg 1984; 88:402-10. Lazar HL, Buckberg GD, Mangarano AM et al. Myocardial energy replenishment and reversal of ischemic

Miniplegia

damage by substrate enhancement of secondary blood cardioplegia with amino acids during reperfusion. / Thome Cardiovasc Surg 1980; 80: 350-9. 17 Wallace AW, Ratcliffe MB, Nose PS et al Effect of induction and reperfusion with warm substrate-enriched cardioplegia on ventricular function. Ann Thorac Surg 2000 October; 70:1301-7. 18 Edwards R, Treasure T, Hossein-Nia M et al. A controlled trial of substrate-enhanced, warm reperfusion ("hot shot") versus simple reperfusion. Ann Thorac Surg 2000; 69:551-5. 19 Le Houerou D, Singh Al, Romano M et al. Minimal hemodilution and optimal potassium use during

93 normothermic aerobic arrest. Ann Thorac Surg 1992; 54: 815-16. 20 Calafiore AM, Teodori G, Mezzetti A et al. Intermittent antegrade warm blood cardioplegia. Ann Thorac Surg 1995; 59:398-402. 21 Velez DA, Morris CD, Budde JM et al All-blood (miniplegia) versus dilute cardioplegia in experimental surgical revascularization of evolving infarction. Circulation 2001; 104:1296-302. 22 Yeatman M, Caputo M, Naravan P et al. Magnesiumsupplemented warm blood cardioplegia in patients undergoing coronary artery revascularization. Ann Thorac Surg 2002; 73:112-18.

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Substrate enhancement in cardioplegia ShafieFazel, MD, Marc P. Pelletier, MD, d* Bernard S. Goldman, MD

Introduction Cardioplegic arrest is the most common method for intraoperative myocardial protection. Traditionally, arrest has been achieved with high potassium solutions. Optimal protection entails delivering cardioplegia in the right vehicle, at the right temperature, and via the most effective route. The University of Toronto has a rich history in investigating cardioplegic delivery. Years of investigation, mostly in Dr R.D. Weisel's laboratory, have revealed that the best cardioplegic vehicle is blood, that the optimal temperature for cardioplegia is tepid, and that the most effective delivery route is a combination of antegrade and retrograde routes. The next step in myocardial protection, now that it can be delivered to all cardiomyocytes, is to modify the solution to target various intracellular events that are triggered by the ischemia-reperfusion cardioplegic arrest event. Ischemia-reperfusion causes metabolic derangement, triggers ischemic preconditioning, predisposes to myocardial stunning, induces an inflammatory reaction, precipitates endothelial dysfunction, and enhances reactive oxygen speciesmediated myocardial damage (Figure 12.1) [1]. Our discussion of cardioplegia additive solutions therefore will address the aforementioned six end products of ischemia-reperfusion injury. In the domain of ischemia-reperfusion, cardioplegic arrest, postinfarction reperfusion, and coronary angioplasty represent different perspectives on the same injurious pathway. In the following chapter, therefore, we have made an effort to bring the cardiologist's perspective to bear

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on a purely surgical problem. We have much to learn from the cardiology data, and the cardiologists have much to extract from the data uncovered by various surgical research groups. Each section begins by introductory remarks to help with understanding of the various investigations reported therein. Each cardioplegia additive subsection begins by highlighting the evidence from animal experiments before discussing limited human trials, and concludes, if applicable, with presenting the results of randomized clinical trials. While we have made every effort to make the following an exhaustive discussion of cardioplegic additives, it is inevitable that the important work of many investigators has gone unmentioned. We apologize to those investigators in advance.

Figure 12.1 The effects of an ischemia-reperfusion event such as cardioplegic arrest.

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Figure 12.2 Myocardial metabolism. Under aerobic conditions, the cardiomyocyte is able to use fatty acids, lactate, glucose, and amino acids to run the electron transport chain, and generate ATP by oxidative phosphorylation. Under anaerobic conditions, however, pyruvate dehydrogenase (PDH) is inactive, and the Kreb's cycle is shut down. Energy requirements of the cell are derived from glycolysis, which leads to the conversion of pyruvate to lactate. Under such conditions, the cellular ATP and high-energy phosphates are depleted.

Myocardial metabolism A synopsis of the key points of myocardial metabolism is presented below to serve as background to the various cardioplegia-enhancement techniques aimed at alleviating the metabolic derangements induced by the ischemia-reperfusion insult of cardioplegic arrest. Glucose enters the cardiomyocyte where it undergoes glycolysis to pyruvic acid. Pyruvate dehydrogenase (PDH) then converts pyruvic acid to acetyl-CoA under aerobic conditions. Acetyl-CoA, in turn, is transported into the mitochondria, with the help of L-carnitine, where acetyl-CoA enters the Kreb's cycle. The Kreb's cycle, or the citric acid cycle, oxidizes acetyl-CoA to yield NADH, FADH2, GTP, water, and carbon dioxide. This oxidization process yields electrons to the electron transport chain, where the transfer of the electron allows the activation of hydrogen ion pumps. The increasing H+ concentration within the inner mitochondrial membrane drives the ATPase to produce ATP. Key intermediates in the Kreb's cycle include cc-ketoglutarate and oxaloacetate. These two intermediates allow the entry of amino acids glutamate and aspartate into the Kreb's cycle. Fatty acids may also participate in oxidative phos-

phorylation by being converted to acetyl-CoA (Figure 12.2). Under anaerobic condtions, pyruvate is converted to lactic acid by lactate dehydrogenase and back to glucose through the Cori cycle, which involves the liver. Principles of substrate enhancement of cardioplegic solutions center around restoring aerobic metabolism efficiently after the onset of reperfusion, and restoring drained supplies of various intermediates that allow resumption of oxidative metabolism.

Insulin Infusion of a glucose-insulin-potassium (GIK) solution was first shown to limit infarct size and increase survival in 1965 by Sodi-Pollares [2]. Results from a trial by the British Medical Research Council, however, dampened initial enthusiasm for GIK therapy by showing that GIK infusion after a myocardial infarction did not affect patient outcome [3]. More recently a significant amount of laboratory data attests to the benefit of GIK in ameliorating the ischemiareperfusion injury caused by cardioplegic arrest, especially in the era of warm heart surgery. The concern with cold cardiopulmonary bypass and cardioplegia was that during hypothermia, the enzymatic machinery

96 activated by GIK infusion would be inactive because of the low temperature [4]. The benefits of providing GIK to ischemic myocardium has been well worked out in several animal models. The results of these investigations are detailed below. During ischemia the principal cellular fuel is glucose. By providing GIK, ATP levels derived from glycolysis are maintained. Insulin also activates pyruvate dehydrogenase, and promotes the cardiomyocyte to switch back to aerobic metabolism upon reperfusion. In addition, the presence of insulin ensures repletion of the Kreb cycle intermediates. GIK solution also helps to reverse insulin resistance after cardiopulmonary bypass. In addition, there is evidence to suggest that insulin helps nitric oxide production by the endothelium, and thus prevents endothelial dysfunction associated with reperfusion injury [5,6]. Following the positive laboratory results, Lazar and colleagues undertook investigations [7,8] to study the possible benefits of GIK infusion in cardiac surgery. GIK was started in a randomized fashion upon anesthetic induction and continued for 12 h postoperatively in 30 patients. The authors reported that the GIK patients had higher cardiac indices, a decreased need for inotropic support, faster extubation, and shorter intensive care and hospital stays [7,8]. These results were also seen in diabetic patients undergoing coronary artery bypass grafting (CABG) who received GIK solution [9]. The results from the University of Toronto [ 10] in a large trial, enrolling a total of 1127 patients, did not support Lazar's findings. In this Insulin Cardioplegia Trial, patients who received 10 IU/L of insulin cardioplegia were shown, in a randomized double blind prospective manner, to have the same clinical outcome as those patients who were not randomized to the insulin arm. Specifically, mortality, myocardial infarction, and postoperative low-output syndrome were similar between the two groups [10]. The major difference between these two studies was that Lazar's group began insulin administration at induction and continued the infusion up to 12 h postoperatively, whereas we only supplied insulin in the cardioplegia line. It may be that prolonged GIK infusion is required to duplicate the promising results that were obtained in the laboratory.

Glutamate-aspartate Early work by Sanborn and associates [11] in rabbits

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suggested that the amino acids glutamate and aspartate might be used by the anoxic cardiomyocyte in the Kreb's cycle to generate ATP. Interestingly, in a porcine model of myocardial infarction followed by reperfusion, Engelman etal. [12] were able to demonstrate a significant reduction in infarct size if a solution of aspartate and glutamate was administered immediately before reperfusion. In a canine model, Rosenkranz et al. [13] demonstrated that following global ischemia, hearts that were arrested with aspartate-enriched glutamate cardioplegia demonstrated more complete functional recovery than the control group. The work of Svedjeholm [14] and colleagues in CABG patients demonstrated that glutamate is lost during ischemia, and that upon replenishment it is incorporated into the myocardium. Glutamate administration also increased myocardial lactate uptake and led to better myocardial performance in this study. Teoh et al. [15] from the University of Toronto, reported on a randomized trial of CABG patients in which a terminal "hot-shot" enriched with glutamate and aspartate was used. In the study patients, terminal warm blood cardioplegia accelerated myocardial metabolic recovery, preserved highenergy phosphates, improved the metabolic response to postoperative hemodynamic stresses, and reduced left atrial pressures. A study by Edwards et al. [16], however, did not support these earlier findings. As such, the role of glutamate-aspartate enrichment of cardioplegia solution remains unproven.

L-carnitine Fatty acids are activated on the outer mitochondrial membrane and oxidized in the matrix. Long-chain acyl CoA molecules do not readily traverse the inner mitochondrial membrane, and require a special transport mechanism. Carnitine [17], a lysine derivative, carries activated long-chain fatty acids across the inner mitochondrial membrane, where (3-oxidation takes place. It has also been shown to stimulate the oxidation of fatty acids, and suppress the development of damage caused by reactive oxygen species [18]. Kobayashi etal. [ 19] in a canine model of left anterior descending (LAD) ligation followed by reperfusion, showed that carnitine levels fell in ischemic myocardium and longchain acyl CoA accumulated in the cytosol. If the dogs were treated with exogenous carnitine, however, these changes were reversed. Furthermore, ATP levels were

Substrate enhancement in cardioplegia increased and postischemic ventricular fibrillation was decreased in the carnitine group. Paulson and colleagues [20] also demonstrated significantly improved recovery of cardiac output following global ischemia and reperfusion with L-propionylcarnitine. In isolated rat heart model of ischemia-reperfusion, L-propionylcarnitine protected against washout of high-energy phosphates [21]. Nakagawa et al. [22] demonstrated that exogenous carnitine is incorporated into the cellular energy metabolism pathway and preserves myocardial ATP levels. In 18 patients with coronary artery disease, administration of L-carnitine induced lactate and free fatty acid extraction [23]. In a model of cardioplegic arrest of isolated rat hearts, finally, Tatlican et al. [24] demonstrated improved myocardial function after arrest with L-carnitine-enhanced cardioplegia. At our current state of knowledge, these findings are not robust enough to mandate a human clinical trial.

Histidine-tryptophan-ketoglutarate Bretschneider popularized histidine-tryptophanketoglutarate (HTK) crystalloid cardioplegia in the 1970s [25]. Histidine acts as a buffer, ketoglutarate improves high-energy production during reperfusion, and tryptophan stabilizes cell membranes. With the adoption of blood cardioplegia, the HTK solution is becoming more or less abandoned. The evidence regarding the HTK cardioplegia solution is therefore only examined briefly. Kober et al. [26,27] compared the HTK cardioplegia with the University of Wisconsin, St Thomas' Hospital, and National Institute of Health cardioplegia solution. The HTK solution in these investigations demonstrated better myocardial protection with improved postcardioplegic arrest ventricular function in a working rat heart model. In a human trial Sakata and associates [28] demonstrated that in 46 patients undergoing mitral valve surgery, HTK cardioplegia resulted in increased spontaneous defibrillation and decreased requirement for pacing when compared to cold blood cardioplegia. It is of note, however, that in this study creatine kinase (CK) leakage tended to be less in the cold blood cardioplegia group. The study by Careaga et al. [29] also demonstrated the decreased incidence of postoperative arrhythmias and low-output syndrome. The crystalloid HTK solution, however, is not in routine use.

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Coenzyme Q10 Coenzyme Q10 (CoQIO), also known as ubiquinone, is part of the oxidative machinery of the mitochondria. Electrons in the iron-sulfur clusters of NADHQ reductase are shuttled to CoQIO, reducing it to ubiquinol. The electrons then flow from ubiquinol to cytochrome c, a proton pump in the respiratory chain. CoQIO is therefore directly involved in energy transduction and aerobic ATP production, and couples the respiratory chain to oxidative phosphorylation [30]. It is also a powerful antioxidant [31]. As such, CoQIO may serve as a therapeutic agent to reduce myocardial ischemia-reperfusion injury [32]. Sugawara et al. [33] demonstrated that ischemia leads to decreased CoQIO levels. Subsequent studies showed that high-energy phosphate stores were better preserved [34], ATP content was higher [35], and aortic flow was improved when dog hearts were protected with CoQIO supplementation. Atar and associates [36] further demonstrated that myocardial stunning was attenuated by CoQIO administration. Hano and colleagues [37] found that CoQIO improved functional recovery during reperfusion by enhancing recovery of high-energy phosphates and preventing calcium overload. The work of Yokoyama et al. [38] on isolated perfused rat hearts documented the direct antioxidant effects of CoQIO, which lead in turn to better preservation of endothelium-dependent vasorelaxation when compared with the control group. Investigations by Crestanello etal. have confirmed the above findings as well [39,40]. Sunamori et al. [41] in a clinical trial demonstrated that patients who were administered CoQIO 2 h prior to CABG surgery had lower creatine kinase-myoglobin (CK-MB) levels and higher stroke work indices postoperatively. Patients receiving CoQIO supplementation also had a lesser incidence of low cardiac output [42]. Chello et al. [43] documented decreased incidence of ventricular arrhythmia in patients treated with CoQIO 7 days before elective CABG. Interestingly, as later confirmed by Zhou and associates [44], the degree of lipid peroxidation seemed also to be reduced in the CoQIO-treated patients. Results reported by Taggart et al. [45], however, stand in contrast with the above results. In a randomized trial of CoQIO administration 12 h preoperatively versus placebo, they found higher troponin T leakage in the treatment group, and no evidence for myocardial protection.

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Figure 12.3 Ischemic preconditioning. Ischemia or binding of the transmembrane receptor for adenosine leads to the activation of phospholipase C (PLC) through interaction with a G protein (G). This, in turn, leads to production of diacyl glycerol (DAG) that activates protein kinase C (PKC). Activation of PKC allows the opening of mitochondriol K-ATPase and results in the classic, or immediate preconditioning of the cardiomyocyte. PKC activation also results, through activation of transcription factors, in new gene transcription and protein synthesis. The new gene expression enhances ischemic tolerance in delayed preconditioning.

Ischemic preconditioning Murry and colleagues first described the phenomenon of preconditioning [46]. In a canine model of 40 min of ischemia, the dogs that had been subjected to serial 5-min episodes of ischemia followed by reperfusion for 5 minutes, had a substantially smaller infarct size. Much work has ensued ever since to elucidate the mechanism of ischemic preconditioning. The following discussion will only address classic or immediate preconditioning, and not delayed preconditioning that becomes evident after 24—96 h [47]. Although the triggers and mediators of preconditioning are unclear, the three players identified thus far are adenosine, KATP channels, and the epsilon isoform of protein kinase C (PKC) kinase (Figure 12.3) [48-50]. Adenosine is released into the extracellular fluid very early during ischemia. In a rabbit model, Liu et al. [51] showed that adenosine, which is released, acted through the Al receptor to induce preconditioning. In a canine model, Grover and associates showed that stimulation of the Al adenosine receptor led to the activation of KATP channels, and that by inhibition of the KATP channels using glyburide, they could block preconditioning. Furthermore, adenosine stimulation of Al receptor also leads to PKC activation [52], which most likely mediates the late response after a brief episode of ischemia. Ultimately, these changes lead to slower energy metabolism, thus allowing longer periods of ischemia before irreversible myocardial injury [53].

The results of a study published by Juggi et al. [54] are interesting. This group showed that preconditioning, when combined with hypothermia or hypothermic cardioplegia, offered no significant additional protection for global ischemia of isolated rat hearts [54]. KATP channel openers Diazoxide has been shown to be a relatively specific opener of mitochondrial KATP channels, and to induce preconditioning [55-57]. However, more recently diazoxide has also been shown to open sarcolemmal KATP channels [58]. In an ischemiareperfusion injury model of human atrial trabeculae, KATP channel opening by diazoxide protected viability and function of the myocytes [59]. In an isolated rabbit heart model of myocardial infarction, preischemic diazoxide treatment reduced the area of myocardial infarction significantly. The KATP channel blocker 5-hydroxydecanoate blocked this effect [60]. Wang and associates [61] extended these observations by noting that PKC translocated to the mitochondria of Langendorff-perfused rat hearts upon treatment with diazoxide. Furthermore, treatment of rats with phorbol 12-myristate 13-acetate, which downregulates PKC activation, abolished the noted cardioprotection in the presence of diazoxide. Diazoxide treatment before ischemia-reperfusion injury stabilized mitochondrial membrane potential and decreased apoptosis by preventing mitochondrial damage and cytochrome closs [62]. Finally, in a porcine model of LAD ligation, followed by global ischemia under

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Substrate enhancement in cardioplegia cardioplegic arrest, followed by reperfusion, Wakiyama et al. [63] demonstrated smaller infarct area in diazoxide-treated hearts. Apoptosis, as estimated by TUNEL staining, was also significantly decreased in the border-zone of the diazoxide hearts. In spite of these encouraging laboratory results, diazoxide enhancement of cardioplegic solutions has not been investigated in humans. Because the safety profile of diazoxide is well established, such trials would be relatively easy to conduct. Perhaps diazoxide therapy should first be investigated in diabetic patients who are on sulfonylurea drugs because these drugs have been shown to block the mitochondrial KATP channels and preclude preconditioning.

Nicorandil Nicorandil is another KTP channel opener. Sugimoto and associates first used it as a pretreatment of guinea pig papillary muscle preparation in a cardioplegic ischemia model [64]. The investigators reported significant negative inotropic phenomenon associated with nicorandil use. Mechanical function, however, was better preserved in this cohort. Isolated rat hearts demonstrated an improvement in myocardial protection in a cardioplegic global ischemia model when pretreated with nicorandil. This effect was abolished by pretreatment with the sulfonylurea glibenclamide [65]. As with diazoxide, it also limits the area of infarction in a rabbit model of LAD ligation [66-68]. In a human trial with a total of 40 patients, nicorandil enhancement of the cardioplegic solution resulted in significantly lower serum CK levels. Troponin T levels tended to also be lower, and the cardiac output tended to be higher in this cohort [69]. Hayashi et al. confirmed these results by showing lower CK-MB levels and decreased exogenous catecholamine requirements in 35 patients who received nicorandil therapy when compared with the 35 patients who did not [70]. Thus, although randomized clinical trials are lacking, the initial experience with nicorandil is positive. Its negative inotropic effects, however, may be both a limiting and a confounding factor in the application of this substrate to cardioplegic arrest. Recent evidence suggests that KATP opening leads to inhibition of the Na-H exchange channel [71], which in turn may aid cardioprotection. The evidence for myocardial protection with Na-H exchange inhibition will be covered in the section "Myocardial stunning" below.

Adenosine Considerable evidence indicates that adenosine is a cardioprotective agent. In numerous species, adenosine has been shown to decrease myocardial stunning [72-74]. It enhances the myocardial phosphorylation potential and thereby improves myocardial energetics in the stunned heart [75]. It has also been shown to decrease oxygen-derived free radical production by neutrophils [76]. In 1995, Lee and associates reported the first trial of adenosine in cardiac surgery [77]. A total of 14 patients with ejection fractions of about 30% and triple-vessel disease were assigned to either receive adenosine prior to the institution of cardiopulmonary bypass or not. The patients who received adenosine had a better cardiac index immediately and 40 h postoperatively. They also had lower CK levels, indicating better myocardial protection. In a phase 1 dose-ranging trial, Fremes et al. [78] from our center at the University of Toronto reported that adenosine in doses greater than or equal to 50 |J,inol/L resulted in hypotension and increased phenylephrine use, but that it was otherwise safe. In a phase 2 trial, this same group concluded that there was no evidence of any consistent treatment benefit with adenosine cardioplegia dosages of up to 100 |iimol/L [79]. In a parallel series of studies, Mentzer and colleagues [80,81] studied higher doses of adenosine up to 2 mmol/L without adverse hypotensive episodes. Presumably, using warm blood cardioplegia in Fremes' study resulted in higher predisposition to hypotension. In the higher adenosine groups, Mentzer reported less incidence of the composite outcome of high-dose dopamine use, epinephrine use, intra-aortic balloon counterpulsation, myocardial infarction, or death. Warm cardioplegia, however, has been associated with a lower incidence of postoperative low-output syndrome [82]. It remains unclear therefore whether cold and high-dose adenosine-enhanced cardioplegia would provide better myocardial protection when compared with warm cardioplegia alone.

Excitation-contraction coupling The depolarization of the sarcolemmal membrane leads to an inward calcium current at the sarcolemmal cisternae, T tubular network, and the sarcoplasmic reticulum. The bulk of the cytosolic calcium is derived from the passage through the L (long-lasting) calcium channel. The L-type calcium channels open at a membrane potential of -30 to -20 mV and remain open

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Figure 12.4 Calcium channels and normal cytosolic calcium homeostasis. Modified from Guyton eta/. [83].

through much of the action potential. The troponincalcium complex then uncovers tropomyosin-covered active actin sites. The energized myosin heads can now engage actin and sweep the actin filament along. The myosin heads, following de-energization in this process, "recock" and are ready for another cycle of interaction with actin. Myosin-ATPase mediates this action. The cytosolic calcium is then pumped across the sarcolemmal and sarcoplasmic membranes by the action of the calcium-ATPase channels. Thus, diastolic extrusion of cytosolic calcium is an energy-dependent process. Catecholamine stimulation of the cardiomyocyte activates a stimulatory G protein, which in turn increases the intracellular c-AMP concentration through the activation of adenyl cyclase. Increased c-AMP levels lead to calcium channel activation, induced by phosphorylation-related conformation change, and to increased activity of c-AMP-dependent protein kinase, which leads to phosphorylation of phospholamban. Calcium channel activation leads to a positive chronotropic effect at the SA node, positive dromotropic effect at the AV node, positive inotropic

effect by increasing myosin-actin interaction, and postive lusitropic effect by enhancing sarcoplasmic reticulum calcium uptake at the end of the action potential (Figure 12.4) [83].

Myocardial stunning Heyndrickx and colleagues [84] demonstrated in a canine model in 1975 that coronary occlusion of 5-15 min, which does not induce myocardial cell death, resulted in decreased contractile function of the affected area for up to 24 h after reperfusion. Braunwald and Kloner [85] termed this phenomenon "myocardial stunning" in 1982. The essential attribute of the dysfunctional myocardium is the decoupling of the excitation-contraction process [49,50]. Much investigational work has been performed to elucidate the exact mechanism of myocardial stunning. Thus far oxygen-derived free radicals and disruption in calcium homeostasis have been implicated in the pathogenesis of myocardial stunning (Figure 12.5) [86]. The role of oxygen free radicals will be discussed in the section "Reactive oxygen species."

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Figure 12.5 Myocardial stunning. Increased reactive oxygen species and cytosolic calcium decrease the sensitivity of the contractile proteins to intracellular calcium perhaps through degradation of myofibrils and troponin I by the activated calpain I.

Disruption of calcium homeostasis in myocardial stunning Marban and colleagues [87] demonstrated an increase in cytosolic calcium levels in ferret hearts during 15 min of ischemia. The calcium levels returned to normal levels upon reperfusion. Przyklenk and Kloner [88] studied the effect of verapamil treatment on stunning in a canine model of transient myocardial ischemia. They found that pretreatment with verapamil essentially ablated the phenomenon of postischemic stunning as segment shortening was restored to 115 + 8% of normal after 3 h of reflow, thus arguing for a pivotal role of L-type calcium channels in mediating stunning. Krause and associates also documented the decreased activity of the sarcoplasmic reticulum Ca-ATPase [89]. More recently, Valdivia and associates [90], studying the effect of transient ischemia of 10 min in a pig model, showed that both the rate of sarcoplasmic reticulum calcium uptake and release via the ryanodine receptor calcium-release channels was decreased in stunned myocardium. Additionally, the intracellular acidosis caused by ischemia activates the Na+-H+ exchanger, which promotes transport of a hydrogen ion in exchange for a sodium ion. In turn, the rising intracellular Na+ concentration leads to increased levels of intracellular calcium by activating the Na+-Ca2+ exchanger [91,92]. The increased cytosolic calcium (Figure 12.6) levels in turn have been shown to decrease the responsiveness of the cardiac myofilaments to intracellular calcium [93-95]. It

appears that activation of the calcium-dependent protease Calpain I leads to the proteolysis of the myofibrils and troponin I [96,97]. Interestingly, troponin I degradation and stunning could be prevented by a low calcium reperfusion buffer in the intact heart [97].

L-type calcium channel blockade in cardioplegia Several laboratories were involved in investigating the effects of various L-type calcium channel blockers (CCBs) in providing superior myocardial protection in the early 1980s. These investigations were spurred by the previous findings that necrotic myocytes had exceptionally high cytosolic calcium levels. The role of calcium in myocardial stunning was not well described at the time. These early animal studies demonstrated a consistent superiority of CCBs in the return of left ventricular function postcardioplegic arrest with no evidence of decreased myocardial necrosis on microscopic examination of pathologic slides [98-104]. Interestingly, metabolic studies did not reveal better preservation of high-energy phosphates in these experiments. In retrospect, these findings are consistent with decreased levels of myocardial stunning. The success of the initial laboratory findings provided an impetus to various clinical investigators to take CCBs to human trials. Clark and associates [99] first reported a decrease in the use of intra-aortic balloon pump counterpulsation in high-risk patients with poor ventricular function who underwent cardioplegic

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Figure 12.6 The role of various ion channels in ischemic injury. Intracellular acidosis leads to an increase in intracellular sodium by activating the Na+-H+ antiport and inhibiting the Na+-K+ ATPase. The Na+-Ca2+ channel, in turn, leads to the exchange of extracellular calcium for intracellular sodium. Ischemia also inhibits the sarcoplasmic reticulum Ca2+-ATPase, which is responsible for the uptake of cytosolic calcium into the sarcoplasmic reticulum during diastole.

arrest at the time of operation with nifidepineenhanced cardioplegic solution when compared with similar patients who did not receive nifedipine. In later studies the authors documented better cardiac indices, stroke volume, and left ventricular work index in nifedipine cardioplegic patients. More importantly, low cardiac output death declined from 11% in the regular cardioplegic group to 4% in the nifedipine cardioplegic group [105,106]. Flameng and colleagues [107], in a randomized study of 48 patients undergoing bypass or valve operations, documented a decrease in left ventricular stroke work index in the nifedipine group immediately after bypass. After admission of the patients to the intensive care unit, however, the incidence of low cardiac output tended to be lower in the nifedipine group. Presumably the negative inotropic effects of CCB, followed by an attenuating effect of CCB on myocardial stunning, cause the particular sequence of events. These results have been confirmed in a double-blind, placebocontrolled, randomized clinical study conducted by Trubel and associates [108]. Diltiazem cardioplegia was studied at the University of Toronto by Christakis and colleagues [109] in a prospective, randomized trial. Whereas diltiazem cardioplegic patients had higher postoperative cardiac indices and lower CKMB levels, placebo patients had higher left ventricular stroke work indices and shorter periods of electromechanical arrest. The authors concluded that diltiazem cardioplegia should be used with caution in patients

with ventricular dysfunction because of its negative inotropic effects. In a single blind randomized study, Earner and associates [110] showed higher cardiac indices, higher stroke work indices, and lower CKMB peak levels in diltiazem cardioplegia patients in comparison with placebo patients. These effects were shown to be dose dependent. Lastly, verapamil cardioplegia has also been shown to decrease release of CK-MBisoenzyme[lll]. The totality of this experience indicates a similar action of the three major classes of L-type CCBs. While the decreased release of CK-MB in some of the studies in the patients treated with CCBs indicates a lower myocyte necrosis rate induced by cardioplegic arrest, the improved postcardioplegia systolic function of the left ventricle in the CCB-treated patients would argue for a lesser degree of myocardial stunning. As highlighted in some of the above studies, important confounding and clinically significant variables are the negative chronotropic, dromotropic, and inotropic effects of the CCB. Currently, CCB-enhanced cardioplegia is not used at our center. The dose of this medication may also be of paramount importance in balancing the risks and benefits of calcium channel blockade. Alternatively, should a CCB with an extremely short half-life become available, the use of this particular CCB only during cardioplegiac arrest, and its clearance immediately after removal of the aortic cross-clamp, could allow for myocardial stunning blockade without the negative inotropic effects.

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Substrate enhancement in cardioplegia Na+-H+ exchanger inhibitors As described above, intracellular acidosis ultimately results in the activation of the Na+-H+ exchanger (NHEI), which in turn results in increased concentrations of cytosolic calcium (Figure 12.6). This effect is particularly pronounced upon reperfusion of ischemic cardiomyocytes when extracellular lactic acid is washed out [112]. Inhibitors of the NHEI have therefore been studied in various settings as cardiomyocyte protect ants [113]. Studies of isolated rat hearts subjected to regional ischemia and reperfusion in the presence or absence of amiloride, amiloride derivate, or cariporide (HOE694) delineated several benefits in inhibition of the NHEI [113-115]. Specifically, the investigators demonstrated decreased incidence of reperfusion arrythmias, decreased release of lactate dehydrogenase (LDH) and CK, and increased levels of glycogen and high-energy phosphates [113-115]. Mochizuki et al. [116] further demonstrated that NHEI administration was best done during ischemia. Moffat and colleagues [117] confirmed that NHEI-treated isolated rat hearts regained more contractile function than the control group when treated prior to reperfusion. Hendrikx et al. [118] extended these observations to a rabbit model. In a porcine model of ischemia-reperfusion, Sack and colleagues [119] demonstrated decreased ultrastructural changes and necrosis in the heart of the pigs treated with NHEI prior to the onset of ischemia. In addition, NHEI also seemed to protect against neutrophil-induced reperfusion injury [120]. Interestingly, the work of Gumina and associates [121,122] demonstrated that not only is NHEI administration efficacious just before revascularization of an occluded LAD, but that the protection afforded by NHEI administration was greater than that afforded by ischemic preconditioning in a canine model of myocardial infarction. Experience with NHEI-enhanced cardioplegia, however, is surprisingly small and limited to isolated rodent heart models. Myers et al. [123] first demonstrated better systolic and diastolic functional recovery after cardiplegic arrest and profound hypothermic (4°C) storage for 12 h if the cardioplegia solution contained cariporide. Other investigators have also shown, under different cardioplegic arrest protocols and temperatures, improved recovery of ventricular function [124-126]. The positive results from various animal models served as impetus to a major, multicentred, ran-

domized, double-blind, placebo-controlled trial by the GUARD during Ischemia Against Necrosis (GUARDIAN) investigators [127,128]. More than 11 000 patients with unstable angina (UA), non-STelevation myocardial infarction (NSTEMI), or undergoing percutaneous or surgical revascularization were randomized to receive cariporide or placebo. Drug therapy was initiated as soon as possible after admission in patients with UA/NSTEMI and between 15 min and 2 h before revascularization. No significant survival benefit of cariporide could be demonstrated across a wide range of clinical situations. In the highdose cariporide CABG group, however, there was a significant relative risk reduction of c. 25% (P = 0.03) in the incidence of nonfatal myocardial infarctions. Two years after the publication of this trial, cariporide is still not used as a cardioplegic additive. With the c. 25% relative and c. 5% absolute risk reduction in nonfatal MI rate in the CABG group, the number needed to treat to prevent one nonfatal MI would be 25. We postulate that cariporide would have an even greater impact on the incidence of postoperative low output syndrome. Perhaps its use should be adopted and its role as a pure cardioplegia additive should be evalutated.

The inflammatory reaction Cardioplegic arrest of the heart, akin to ischemiareperfusion, stimulates a cascade of inflammatory reactions [129]. These involve complement activation, neutrophil interaction with selectins and intercellular adhesion molecules (ICAMs), leading to their activation in the inflammatory milieu of a reperfused heart. There is subsequent plugging of capillaries, release of oxygen free radicals, and vasospasm of the myocardial beds correlated with elevated levels of endothelin. This leads to myocardial damage by apoptosis, decreased blood flow, "no reflow" phenomenon, and myocardial stunning. Thus intense investigation has ensued in search of a method to abrogate this inflammatory cascade of events during cardioplegic arrest of the heart. The systemic inflammatory response to cardiopulmonary bypass will not be discussed in this chapter.

Complement cascade In the setting of ischemia-reperfusion injury and

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Figure 12.7 Neutrophil-endothelium interaction. Expression of selectins by the endothelial cells after ischemic injury leads to the rolling of the neutrophils (PMN) over endothelial cells by selectin ligand-selectin interaction. Expression of integrins by damaged endothelium allows firm adhesion of PMN to the endothelium through their intercellular adhesion molecule (ICAM)-integrin interaction. Chemoattractants such as complement fragments C3a and C5a, and interleukin 8 (IL-8) promote the diapedesis of the PMN into the tissue.

cardiopulmonary bypass, the complement cascade is activated, leading to the generation of complement fragments. While membrane attack complexes induce direct cell injury, C3a and C5a fragments act as chemoattractants and inflammatory mediators. The role of complement activation in myocardial infarction has been well established [ 130-132]. Therapeutic alternatives have involved use of the cobra venom factor complement depletion [133], specific antibodies against complement fragments [134], or use of a soluable complement receptor [135,136]. In the arena of cardiac surgery, Tofukuji et al. [137] reported on the use of anti-C5a antibodies in reducing cardioplegia-related injury. Following cardioplegic arrest of pig hearts for 1 h, the investigators found that pretreatment with anti-C5a antibody improved endothelium-dependent relaxation, decreased neutrophilic infiltration, and decreased myeloperoxidase activity (a surrogate marker for neutrophilic activation). However, there was no difference in postarrest left ventricular function. In a porcine infarct followed by cardioplegic arrest, revascularization, and reperfusion model, Riley and associates [138] investigated the role of a recombinant C5a antagonist. They reported a significant reduction of the infarcted area and improved postbypass ventricular function with the use of the C5a antagonist. Although these results suggest a modest benefit to complement inactivation in the setting of cardioplegic arrest, our knowledge is too limited at this point to allow for the design of human clinical trials.

Neutrophil activation The initial event in neutrophil activation is the interaction between the neutrophil and the endothelium through P- and E-selectins on the endothelium that

interact with membrane oligosaccharides on the neutrophil surface. As indicated in a previous section, this leads to rolling of the neutrophil along the endothelium until integrin-ICAM interactions allow sticking of neutrophils followed by transmigration (Figure 12.7). Therefore, the initial investigations in interfering with the mechanism have been focused on blocking selectin-mediated rolling of neutrophils. Using fucoidin, a nontoxic sulfated fucose oligosaccharide that blocks selectins, Miura et al. [139] concluded that selectin blockade resulted in better recovery of left ventricular function, coronary blood flow, and myocardial energy consumption after cold ischemia in an isolated, blood-perfused neonatal lamb heart model. Using a similar model, Nagashima and colleagues [140] demonstrated the efficacy of Pselectin specific monoclonal antibody-enriched cardioplegia solution. Schermerhorn et al. [141] extended these observations, using a synthetic oligosaccharide analog of sialyl-Lewis (x)—natural ligand for selectins —to show that endothelial function was better preserved with selectin blockade. In a canine model, however, selectin blockade made no difference in preload recruitable stroke work or neutrophilic myeloperoxidase activity [ 142]. Therefore, in spite of the sound theoretical basis arguing for a beneficial effect of selectin blockade in cardioplegic arrest, this therapy remains mostly unproven, even in the laboratory setting.

Steroid therapy Although initial laboratory results suggested possible beneficial effects of methylprednisolone on recovery from cardioplegic arrest [143], subsequent studies failed to show a benefit [144-147]. Systemic steroid therapy received a significant amount of attention with regards to fast tracking of cardiac surgery patients. As

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Endothelial dysfunction

through their interaction with the selectins. The ICAM-integrin interaction leads to firm adherence of the neutrophils and their transmigration. Ischemiareperfusion injury also promotes release of endothelin, which is a highly potent vasoconstrictor. Along with platelet aggregation and leukocyte degranulation, endothelin-induced vasoconstriction may lead to significant impairement of microcirculatory flow. This has been termed the no-reflow phenomenon. Attenuating endothelial activation is therefore important in improving intraoperative myocardial protection and postoperative myocardial function.

Endothelium supports cardiovascular function by promoting vasodilatation, and inhibiting platelet aggregation, white blood cell adhesion, and smooth muscle cell proliferation. Chronic dysfunction of the endothelium has been documented in patients with coronary artery disease risk factors. In the acute setting of global ischemia followed by reperfusion, there is strong evidence of acute endothelial dysfunction as well [148]. Under these circumstances, activation of the endothelium by the hypoxic arrest and reperfusion-induced oxygen free radical burst leads to increased vasomotor tone and capillary plugging by white blood cells. Ischemia-reperfusion reduces both basal and stimulated nitric oxide (NO) release, also referred to as the endothelium-derived relaxing factor. This decrease in NO also aids neutrophil adherence to the endothelium. Hypoxia induces endothelial Weibel-Palade bodies to release P-selectin and, through activation of the NF-KB pathway, promotes transcription of E-selectins, ICAMs, IL-8, and IL-1 genes. Neutrophils begin rolling along the endothelium

NO is becoming increasingly recognized as an important mediator of endothelial function. It is produced by nitric oxide synthetase (NOS). The three isoforms of NOS include neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). Under normal circumstances, L-arginine is oxidized in the presence of tetrahydrobiopterin (BH4) to L-citrulline and NO with the concomitant consumption of NADPH. Although the exact redox mechanism by which BH4 participates in the biosynthesis of NO is still not understood, accumulated evidence indicates that an optimal concentration of this compound is of critical importance for normal functioning of eNOS. Suboptimal concentrations of BH4 lead to "uncoupling of NOS" with a resultant decrease in NO synthesis and increased formation of superoxide anions such as peroxynitrite and hydrogen peroxide (Figure 12.8) [149]. Attempts at increasing NO tissue levels have included the use of nitroglycerine, HMG-CoA inhibitors,

a pure cardioplegic additive, however, steroids have not shown any benefit. This is likely because of the timeline of steroid activity. Steroids exert their effects by entering cells and binding to cytosolic steroid receptors, then migrating to the nucleus and enhancing the transcription of certain genes. As such, steroid therapy results in biologic responses hours after steroid administration. The finding that cardioplegia enhancement with steroids does not attenuate myocardial recovery is therefore not surprising.

Figure 12.8 Nitric oxide production. In the presence of tetrahydrobiopterin (BH4), endothelial nitric oxide synthase (eNOS) converts L-arginine to L-citrulline and nitric oxide (NO). Uncoupling of eNOS in the presence of low tissue BH4 levels, leads to the production of the superoxide anion and peroxynitrite (OONO-).

Nitric oxide pathway

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angiotensin-converting enzyme inhibitors, and antioxidants. Several strategies have also been developed to increase cardiac NO production at the time of cardioplegic arrest as detailed below.

Nitric oxide donors As indicated above, the innate endothelial mechanisms to synthesize NO may be disrupted in situations of ischemia and reperfusion. For instance, production of NO from L-arginine under conditions where BH4 is not in abundance may be suppressed in favor of the production of oxygen free radicals. For this reason, some investigators have turned to direct NO donors for myocardial protection. Johnson and associates [150,151], for instance, showed that administration of authentic NO gas or NaNO2 at the onset of reperfusion in a feline model of ischemia-reperfusion decreased infarct size by nearly 75%. This effect was evident at subvasodilatory concentrations of NO. Nakanishi and colleagues [152] used SPM-5185, a cysteine-containing compound that readily releases NO [153], in a canine model of cardioplegia during cardiopulmonary bypass. One hour of cardioplegic arrest was followed by 1 h of reperfusion, after which time the left ventricular systolic performance was measured. This revealed that hearts arrested with SPM-5185-enhanced blood cardioplegia showed complete recovery of systolic performance in comparison with only c. 50% recovery of function in the control group. In other models of ischemia-reperfusion, however, studies have shown deleterious effects of the NO breakdown product, peroxynitrite, on both the endothelium and myocardium [154,155]. This is in contrast to other similar studies [156]. It appears that peroxynitrite's effect on the heart is milieudependent. For instance, peroxynitrite appears to be deleterious in crystalloid cardioplegia while being beneficial in blood cardioplegia [157]. The role of NO donors in cardioplegia therefore requires more elucidation. L-arginine Engelman and associates [158,159] first reported on the use of L-arginine as a cardioplegic additive in a porcine model. They showed that enhancement with L-arginine led to higher myocardial NO levels, along with a reduction in lipid peroxidation, plasma levels of soluble adhesion molecules, myocardial stunning, and arrhythmias. Furthermore, the investigators

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demonstrated better-developed aortic pressures in the L-arginine group following ischemia-reperfusion. Sato et al. [160], in a parallel series of experiments in a canine model of LAD occlusion for 30 min followed by revascularization, concluded that cardioplegic solution supplemented with L-arginine reduced infarct size, preserved postischemic systolic and diastolic regional function, and prevented endothelial dysfunction. L-arginine supplementation also allowed for an increase in coronary blood flow and a faster recovery of myocardial tissue pH [ 161 ]. In a phase I pilot study, Carrier and colleagues documented the safety of L-arginine cardioplegia in 50 patients. Subsequently, Wallace and associates [162] demonstrated that systemic L-arginine infusion reduced postcardiopulmonary bypass coronary vasoconstriction. Finally, in a prospective randomized, double-blind clinical trial involving 200 patients undergoing aortocoronary bypass operations, Carrier and associates recently demonstrated that L-arginine cardioplegia decreased levels of troponin I release (P = 0.03), increased cardiac indices (P = 0.09), and decreased ICU and hospital stays (P = 0.09). It appears therefore that L-arginine supplementation may provide better myocardial protection. Tetrahydrobiopterin As indicated above, tetrahydrobiopterin (BH4) has a major role in the synthesis of NO (Figure 12.8), and inhibiting the production of oxygen free radicals such as peroxynitrite and hydrogen peroxide. It may also play a role in the biosynthesis of catecholamines [163]. There is mounting evidence that in acute ischemia-reperfusion models and chronic endothelial dysfunction models, increased oxidative stress leads to a decline in tissue BH4, thus leading to decreased endothelial NO output as eNOS is "uncoupled." In a variety of rat and pig models of chronic endothelial dysfunction, supplementation of BH4 has been shown to have beneficial effects on endothelial function [164-169]. In humans, the evidence is quite strong as well. Higman et al. [170] showed that saphenous vein rings from smoking patients had increased vasorelaxation when incubated with the calcium ionophore A23187 and BH4 when compared with vein rings that were only treated with A23187. Enhancement of saphenous vein endothelium-dependent relaxation, when incubated with BH4, has been also observed in patients with coronary artery disease [171]. Ueda

Substrate enhancement in cardioplegia and associates [172], demonstrated that BH4 supplementation improved the bioactivity of endotheliumderived NO in smokers. The work of Stroes et al. [173] extended these observations to hypercholesterolemic patients. In patients with coronary artery disease, BH4 prevented acetylcholine-induced vasoconstriction of angiographically normal vessels by the use of coronary flow velocity measurements [ 174]. Despite the heterogeneity of animal models and patient populations studied, BH4 appears to have consistently improved endothelium-dependent vasorelaxation. Although the role of BH4 in intraoperative myocardial protection has not been addressed yet, studies are underway to evaluate its effectiveness in the coronary bypass operation. BH4 may prove to be an important adjunct to bypass operations, especially with the increasing use of arterial conduits.

Endothelin Endothelin 1 (ET-1) is the most widely distributed and studied of the three isoforms of endothelin. ET-1 exerts its effects through ETA and ETB receptors. ET-1 is a potent vasoconstrictor and an important chemoattractant and mitogen when acting through ETA on endothelium, vascular smooth muscle cells, and fibroblasts (Figure 12.9). It is also an inflammatory mediator by activating monocytes, and a vasodilator when acting through ETB receptors on monocytes and endothelial cells, respectively [175,176]. Endothelin has been increasingly implicated in cardiovascular disease processes [177]. Specifically,

Figure 12.9 Role of endothelin 1. Production of endothelin 1 (ET-1) by the endothelial cell results in potent vasoconstriction, and smooth muscle cell growth and division by acting through endothelin receptor A (ETA). ET-1 also acts on the endothelin receptor B (ETB) on endothelial cells to promote production of nitric oxide (NO) and enable vasodilatation. The specific effect of endothelin therefore depends on the relative density of ETA and ETB receptors.

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endothelin appears to play a major deleterious role in both acute and chronic models of myocardial injury. In a study of endothelin levels in 142 patients 3 days after a myocardial infarction, Omland and colleagues [178] reported a strong correlation between ET-1 levels and 1 -year mortality. In a canine ischemia reperfusion model, endothelin levels increased during ischemia and correlated with decreased blood flow on reperfusion [ 179]. Endothelin levels also correlated directly with pulmonary hypertension and vascular resistance, and inversely with cardiac indices in 24 patients with chronic heart failure [180]. In a rat model of chronic heart failure, ETA receptor antagonism greatly improved survival and was associated with improvement of left ventricular function and prevention of ventricular remodeling. In a randomized controlled trial, bosentan inhibition of ETA and ETB receptors led to a decrease in mean blood pressure of essential hypertension patients [181], and an increase coronary artery blood flows [182]. In the setting of cardioplegic arrest and cardiopulmonary bypass, there is increasing evidence that ET-1 levels increase during cardiopulmonary bypass (CPB) and that ET-1 levels are associated with depressed myocardial function and increased vasoconstriction post CPB [183]. Increased ET-1 levels are caused by systemic and cardiomyocyte ET-1 production [184, 185]. In an isolated porcine myocyte system, Dorman et al. demonstrated reduced myocyte-shortening velocity when exposed to ET-1 and associated higher intracellular calcium levels when compared to control

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myocytes. Goldberg and associates, however, recently demonstrated increased contractility when exposing myocardial biopsies of CABG patients to endothelin [ 186]. In isolated blood-perfused neonatal lamb hearts before and after 2 h of 10°C cardioplegic ischemia, Hiramatsu and colleagues examined the effects of the ETA receptor antagonist BE-18257B [187]. At 30 min of reperfusion, the ETA antagonist hearts had significantly greater recovery of LV systolic and diastolic function, coronary blood flow, and Mvo2 when compared with controls. In isolated rat hearts, coronary blood flow was improved with the endothelin converting enzyme inhibitor bosentan following prolonged hypothermic arrest [188]. Also, there was preservation of ATP pool and high-energy phosphates levels [189]. Finally, Maxwell and colleagues [190] showed increased microvascular competence and diminished necrosis with ischemia-reperfusion of isolated rat hearts when treated with endothelin antagonists. Thus, there is ample evidence to suggest that myocardial protection may be enhanced at several levels, from contractility to energy metabolism, in the ischemia-reperfusion that occurs at cardioplegic arrest if the actions of endothelin are counteracted. It is unclear from the literature which endothelin receptor should be blocked or whether dual-receptor antagonism should be employed. It appears that endothelin is cleared in the lungs via binding to the ETB receptor [191,192], and that by blocking both receptors the half-life of endothelin in the systemic circulation maybe prolonged. Reactive oxygen species Reactive oxygen species (ROS) are molecules with unpaired electrons in their outer orbit. They have the potential to directly injure cardiac myocytes and endothelium, and to trigger an inflammatory cascade by inducing the production of cytokines and complement. In addition, a body of evidence is gathering that supports a major role for ROS in inducing myocardial stunning by interfering with calcium homeostasis. Intracellular sources of ROS include the electron transport chain in the mitochondria, amino acid oxidation in microsomes, the cytochrome P450 activity in the endoplasmic reticulum, and the arachidonic acid cascade in the sarcolemma. An important source of extracellular ROS is the oxidative burst

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by the myeloperoxidase machinery of the activated neutrophil. Multiple defence mechanisms exist in the mammalian cells to scavenge or inhibit the activity of ROS. Superoxide dismutase (SOD) catalyzes O 2 dismutation to H2O2. Subsequently, H2O2 is reduced to H2O and O2 by peroxidases such as glutathione peroxidase or catalase. Glutathione peroxidase catalyzes the peroxidation of H2O2 in the presence of glutathione to form H2O and oxidized glutathione, which in turn requires NADPH from the hexose monophosphate shunt to be reduced by glutathione reductase back to glutathione (Figure 12.10). It is important to note at this point that SOD activity is therefore the most proximal arm of the antioxidant apparatus. Other endogenous antioxidants include vitamin E, vitamin C, and vitamin A. Considering that each bolus of cardioplegia is a reperfusion event after an ischemic period, administration of antioxidants at the time of cardioplegia delivery would be ideal. It is based on this theory that much experimental work has been done to assess the efficacy of various antioxidant additives to the cardioplegic solution. By way of an example and a word of caution, the role of SOD and catalase, in the setting of myocardial infarction, is reviewed here. Jolly and associates [193] demonstrated that a combination of SOD and catalase reduced infarct size in a canine model of ischemia and reperfusion. This observation combined with the works of Woo etal. [194] and Chen etal. [195] led to two clinical trials using human recombinant SOD. The recombinant SOD was used in the setting of myocardial infarction in patients undergoing either thrombolysis [196] or balloon angioplasty [197]. There was no significant improvement in left ventricular function in the two trials. These trials are reminders of the difficulty in extrapolating data from a controlled laboratory setting to an uncontrolled clinical setting. As a result, only human studies with antioxidant-enhanced cardioplegia will be presented below. Deferoxamine Superoxide anion and hydrogen peroxide may give rise, through the Haber-Weiss reaction and in the presence of iron or copper, to the cytotoxic hydroxyl radical. Chelation of iron or copper, theoretically, would quench this mechanism of ROS-derived

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Figure 12.10 Reactive oxygen species (ROS). The injurious superoxide anion (O»2> is converted by superoxide dismutase (SOD) to hydrogen peroxide. In the presence of iron, the Haber-Weiss reaction results in the production of the highly cytotoxic hydroxyl radical («OH). Catalase and glutathione peroxidase (GPX) allow hydrogen peroxide to be converted to water. GPX requires the presence of glutathione (GSH). ROS scavengers, such as vitamin E, scavenge hydroxyl radicals and thereby protect the cells against lipid peroxidation.

cytotoxicity. Myers and associates [198] first tested this hypothesis in 1986. In an isolated rabbit heart model of cardioplegic arrest for 2 h followed by reperfusion for 1 h, the investigators found that deferoxamine supplementation prevented ischemia-induced increase in coronary vascular resistance. It failed, however, to provide any benefit to the function of the reperfused left ventricle. In a separate study, however, Menache et al. [199,200] were able to demonstrate significantly improved ventricular systolic function in an isolated rat heart model when deferoxamine was added to the cardioplegic mix. There is evidence to suggest that deferoxamine enhancement also aids postcardioplegia diastolic dysfunction [201]. DeBoer and colleagues demonstrated improved survival in rat hearts subjected to 25 min of normothermic global ischemia followed by deferoxamine-enhanced cardioplegia and reperfusion [202]. Further experimental work has now shown that deferoxamine also decreases myocardial stunning after regional ischemia caused by LAD ligation followed by surgical revascularization [203]. It also decreases endothelial dysfunction

after cardioplegia-reperfusion [204]. Interestingly, the addition of zinc or gallium to the deferoxamine cardioplegia increased the benefits of iron chelation, presumably by causing displacement of iron by the redox-inactive zinc or gallium metal molecules [205]. In a human trial, Ferreira et al. [206] were unable to confirm decreased ROS activity by chemiluminescence technique, but they did detect fewer damaged mitochondria on electron microscopy of biopsies taken from human hearts arrested using deferoxamine cardioplegia. In the only other human study, however, Drossos and associates also documented decreased levels of superoxide anion production in valve patients who underwent supplementation of their cardioplegia with deferoxamine. In spite of the positive experimental and human investigations carried out so far, no prospective, randomized trial has been initiated to examine the role of deferoxamineenhanced cardioplegia. Considering the weight of the evidence outlined above, such a trial should be forthcoming, especially in light of our knowledge of the side effect profile of deferoxamine.

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Allopurinol The evidence for allopurinol enhancement of cardioplegia solution is not as strong as the evidence for deferoxamine enhancement. Allopurinol inhibits the enzyme xanthine oxidase, which catalyzes the conversion of hypoxanthine (derived from adenosine— the breakdown product of ATP) to uric acid. The byproduct of this reaction is ROS production. It is postulated that a significant amount of intracellular ROS activity, especially after ischemia-reperfusion injury, is derived from the action of this enzyme. The inhibition of xanthine oxidase should therefore confer superior myocardial protection. The initial work by Chambers and associates [207] suggested that in an isolated rat heart model allopurinol enhancement of cardioplegia solution conferred benefit only with normothermic ischemic arrest and not under hypothermic conditions. Vinten-Johansen's [208] work confirmed in a canine model that allopurinol addition to cardioplegia enhanced postischemic performance of the left ventricle. During a 12-h preservation study of rabbit hearts, Nishida also concluded that the added combination of allopurinol and catalase to the cardioplegia solution enhanced left ventricular developed pressures and decreased diastolic pressures [209]. The result of two human trials of pretreatment with allopurinol also demonstrated less inotropic usage, better cardiac indices, fewer perioperative myocardial infarctions, and decreased lipid peroxidation [210,211]. The trial conducted by Bical etal. [212] is the only human trial in which allopurinol has been used as a cardioplegic additive. In this trial the authors reported no difference among patients undergoing cold blood cardioplegia with blood reperfusion, crystalloid cardioplegia with crystalloid reperfusion, and crystalloid cardioplegia with allopurinol-enriched blood reperfusion with respect to adenine nucleotides and malondialdehyde (surrogate marker for ROSinduced lipid peroxidation) levels. Improvements of left ventricular function, however, were not documented. It may be that adequate inhibition of xanthine oxidase by allopurinol may require more time than the cardioplegic period. Glutathione Glutathione is an endogenous intracellular antioxidant that is involved in the peroxidation of the H2O2 molecule. The addition of exogenous glutathione to the cardioplegia solution may aid in extracellular

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scavenging of ROS. This concept has been tested as detailed below with some indication that it may be beneficial. The initial dog experiments performed by Standeven et al. [213] suggested that exogenous glutathione was not beneficial. Evidence from a heart transplant preservation solution, however, indicated that addition of glutathione would provide better graft preservation in buffer-perfused rat hearts and heterotopic rabbit heart transplantation [214,215]. Recent evidence from Nakamura and colleagues [216] in a canine model of global normothermic ischemia followed by 60 min of intermittent cold crystalloid caridoplegia showed that glutathione enhancement preserved systolic and diastolic function, preserved endothelial function, and decreased neutrophil adherence. Evidence from glutathione transgenic (overexpressing glutathione) and knockout mice (with no glutathione expression) myocardial infarction models clearly documented the importance of glutathione in preserving ischemic myocardium [217,218]. In the only human trial, glutathione enhancement of crystalloid cardioplegia significantly reduced CK-MB release after cardiac surgery [219]. No other benefit was demonstrated in this limited study. The evidence therefore for the use of glutathione in cardioplegic solution is scant at present. Nitecapone Nitecapone is a catechol-O-methyl transferase inhibitor, and was first used to extend the action of levodopa in Parkinson's patients [220]. It has also been shown to have significant antioxidant activity [221]. In a Langendorff rat heart model of ischemia-reperfusion, it was shown to have some beneficial effects in decreasing myocardial enzyme leakage [222]. Vento and associates [223,224], in a rat heart transplant model, showed decreased levels of lipid peroxidation and myeloperoxidase activity. These observations were extended to a small human trial in which patients undergoing CABG had cardioplegic arrest in the presence of nitecapone [225,226]. The authors noticed a decrease in cardiac neutrophilic accumulation and activation in the nitecapone-enhanced cardioplegia patient group. Although the incidence of ventricular arrythmias was significantly reduced in the nitecapone group, no other clinical benefit was found. In summarizing the work with reactive oxygen species, there is a trend towards preservation of

Substrate enhancement in cardioplegia cardiac function in multiple animal models. In the few human trials, there appears to be limited clinical benefit. Thus, pending data from larger clinical trials, routine use of ROS cannot be advocated for routine use in cardiac surgery.

Conclusion It is becoming increasingly difficult to demonstrate mortality differences between two methods ofcardioplegic arrest. At the University of Toronto we have begun emphasizing the importance of other end points such as postoperative low-output syndrome as an indicator for the degree of protection afforded by one cardioplegia method versus another in clinical trials. The fact, however, remains that our current methods of myocardial protection are very effective, and improving on a good thing is a difficult task. The data presented above highlights several very important points with regards to myocardial protection. First, it is imperative that we understand the exact molecular signaling and pathways that lead to ischemiareperfusion injury to be able to, with surgical accuracy, attenuate it. The surgeon therefore should become a more sophisticated operator. Second, it is becoming increasingly clear that many injurious pathways interact synergistically. For instance, myocardial stunning is caused by reactive oxygen species and disruption of calcium homeostasis. It should follow, then, that effective inhibition of myocardial stunning should combine attenuating reactive oxygen speciesmediated damage and preventing cytosolic calcium overload. By corollary, stimulating ischemic preconditioning and abrogating myocardial stunning may lead to exponential increase in benefits. Third, we should begin shifting our myocardial protection paradigm: it is possible to prepare the myocardium for a limited ischemia-reperfusion injury prior to opening the chest. The experiences with cariporide and allopurinol clearly illustrate this point. Fourth, myocardial reserve far exceeds the body's demands in the same manner as the renal and pulmonary reserves clearly exceed the body's requirements. However, myocardial loss no matter how clinically silent today will translate, as is the case with glomerular or alveolar loss, to significant impediment years later. Therefore even in the absence of 30-day mortality benefits we should continue to refine our myocardial protection methodologies. Molecular biology is an exciting

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domain, and as surgeons it is imperative that we keep up to date with advances that will enable us to perform increasingly better procedures. We hope that this chapter has been successful in shedding light on a few molecular pathways that mediate ischemiareperfusion injury, and on how to effect a change in those pathways.

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Substrate enhancement in cardioplegia

endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta. Diabetes 1999; 48:2437-45. 168 Shinozaki K, Nishio Y, Okamura T et al. Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ #£52000; 87: 566-73. 169 Yu PK, Yu DY, Cringle SJ, Su EN. Tetrahydrobiopterin reverses the impairment of acetylcholine-induced vasodilatation in diabetic ocular microvasculature. JOculPharmacolTher2QOl; 17:123-9. 170 Higman DJ, Strachan AM, Buttery L et al. Smoking impairs the activity of endothelial nitric oxide synthase in saphenous vein. Arteriosder Thromb Vase Biol 1996; 16: 546-52. 171 Verma S, Lovren F, Dumont AS et al. Tetrahydrobiopterin improves endothelial function in human saphenous veins. / Thorac Cardiovasc Surg 2000;120:668-71. 172 Ueda S, Matsuoka H, Miyazaki H et al Tetrahydrobiopterin restores endothelial function in long-term smokers. /Am Coll Cardiol 2000; 35: 71-5. 173 Stroes E, Kastelein J, Cosentino F et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia./C7m Invest 1997; 99:41-6. 174 Maier W, Cosentino F, Lutolf RB et al. Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. / Cardiovasc Pharmacol200Q;35:173-8. 175 Hunley TE, Kon V. Update on endothelins—biology and clinical implications. Pediatr Nephrol 2001; 16: 752-62. 176 Dashwood MR, Tsui JC. Endothelin-1 and atherosclerosis: potential complications associated with endothelinreceptor blockade. Atherosclerosis 2002; 160:297-304. 177 Schiffrin EL, Intengan HD, Thibault G, Touyz RM. Clinical significance of endothelin in cardiovascular disease. CurrOpin Cardiol 1997; 12:354-67. 178 Omland T, Lie RT, Aakvaag A et al. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994; 89:1573-9. 179 Velasco CE, Turner M, Inagami T et al. Reperfusion enhances the local release of endothelin after regional myocardial ischemia. Am Heart J1994; 128:441-51. 180 Kiowski W, Sutsch G, Hunziker P et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995; 346: 732-6. 181 Krum H, Viskoper RJ, Lacourciere Y et al. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators. N Engl J Med 1998; 338: 784-90. 182 Wenzel RR, Fleisch M, Shaw S et al. Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease. Circulation 1998; 98:2235-40. 183 Ergul A, Joffs C, Walker AC, Spinale FG. Potential role of endothelin receptor antagonists in the setting of

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cardiopulmonary bypass: relevance to myocardial performance. Heart Fail Rev 2001; 6:287-94. 184 Dorman BH, Bond BR, Clair M J et al. Temporal synthesis and release of endothelin within the systemic and myocardial circulation during and after cardiopulmonary bypass: relation to postoperative recovery. /Cardiothorac VascAnesth 2000; 14:540-5. 185 Ergul A, Walker CA, Goldberg A et al. ET-1 in the myocardial interstitium: relation to myocyte ECE activity and expression. Am J Physiol Heart Circ Physiol 2000; 278: H2050-6. 186 Goldberg AT, Bond BR, Mukherjee R et al. Endothelin receptor pathway in human left ventricular myocytes: relation to contractility. Ann Thorac Surg 2000; 69: 711-15; discussion 716. 187 Hiramatsu T, Forbess J, Miura T et al. Effects of endothelin-1 and endothelin-A receptor antagonist on recovery after hypothermic cardioplegic ischemia in neonatal lamb hearts. Circulation 1995:92: II400-4. 188 Goodwin AT, Amrani M, Gray CC et al. Inhibition of endogenous endothelin during cardioplegia improves low coronary reflow following prolonged hypothermic arrest. Eur J Cardiothorac Surg 1997; 11:981-7. 189 limuro M, Kaneko M, Matsumoto Y et al. Effects of an endothelin receptor antagonist TAK-044 on myocardial energy metabolism in ischemia/reperfused rat hearts. J Cardiovasc Pharmacol 2000; 35:403-9. 190 Maxwell L, Harrison WR, Gavin JB. Endothelin antagonists diminish postischemic microvascular incompetence and necrosis in the heart. Microvasc Res 2000; 59: 204-12. 191 Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation 1996; 94:1578-84. 192 Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. / Appl Physiol 1996; 81: 1510-15. 193 Jolly SR, Kane WJ, Bailie MB et al. Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase. Circ Res 1984; 54:277-85. 194 Woo YJ, Zhang JC, Vijayasarathy C et al. Recombinant adenovirus-mediated cardiac gene transfer of superoxide dismutase and catalase attenuates postischemic contractile dysfunction. Circulation 1998; 98:11255-60; discussion II260—1. 195 Chen Z, Siu B, Ho YS et al. Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. /Mo/ Cell Cardiol 1998; 30: 22819. 196 Murohara Y, Yui Y, Hattori R, Kawai C. Effects of superoxide dismutase on reperfusion arrhythmias and left ventricular function in patients undergoing thrombolysis for anterior wall acute myocardial infarction. Am J Cardiol 1991; 67: 765-7. 197 Flaherty JT, Pitt B, Gruber JW et al. Recombinant human superoxide dismutase (h-SOD) fails to improve

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recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction. Circulation 1994; 89:1982-91. Myers CL, Weiss SJ, Kirsh MM et al. Effects of supplementing hypothermic crystalloid cardioplegic solution with catalase, superoxide dismutase, allopurinol, or deferoxamine on functional recovery of globally ischemic and reperfused isolated hearts. / Thome CardiovascSurg 1986; 91:281-9. Menasche P, Grousset C, Gauduel Y et al. Prevention of hydroxyl radical formation: a critical concept for improving cardioplegia. Protective effects of deferoxamine. Circulation 1987; 76: V180-5. Menasche P, Grousset C, Mouas C, Piwnica A. A promising approach for improving the recovery of heart transplants. Prevention of free radical injury through iron chelation by deferoxamine. / Thorac Cardiovasc Surg 1990; 100:13-21. Nicholson SC, Squier M, Ferguson DJ et al. Effect of desferrioxamine cardioplegia on ischemia-reperfusion injury in isolated rat heart. Ann Thorac Surg 1997; 63: 1003-11. DeBoer DA, Clark RE. Iron chelation in myocardial preservation after ischemia-reperfusion injury: the importance of pretreatment and toxicity. Ann Thorac Surg 1992; 53:412-18. Illes RW> Silverman NA, Krukenkamp IB et al Amelioration of postischemic stunning by deferoxamineblood cardioplegia. Circulation 1989:80: III30-5. Sellke FW, Shafique T, Ely DL, Weintraub RM. Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation 1993:88:11395-400. Karck M, Tanaka S, Berenshtein E et al. The push-andpull mechanism to scavenge redox-active transition metals: a novel concept in myocardial protection. / Thorac Cardiovasc Surg 2001; 121:1169-78. Ferreira R, Burgos M, Milei J et al. Effect of supplementing cardioplegic solution with deferoxamine on reperfused human myocardium. / Thorac Cardiovasc Surg 1990; 100: 708-14. Chambers DJ, Braimbridge MV, Hearse DJ. Free radicals and cardioplegia: allopurinol and oxypurinol reduce myocardial injury following ischemic arrest. Ann Thorac Surg 1987; 44:291-7. Vinten-Johansen J, Chiantella V, Faust KB et al. Myocardial protection with blood cardioplegia in ischemically injured hearts: reduction of reoxygenation injury with allopurinol. Ann Thorac Surg 1988; 45: 319-26. Nishida K. The effect of supplementing hypothermic crystalloid cardioplegia with catalase plus allopurinol in the isolated rabbit heart. Surg Today 1993; 23: 404. Coghlan JG, Flitter WD, Glutton SM et al Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting. / Thorac Cardiovasc Surg 1994; 107:248-56.

211 Sisto T, Paajanen H, Metsa-Ketela T et al. Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg 1995; 59:1519-23. 212 Bical O, Gerhardt MF, Paumier D et al. Comparison of different types of cardioplegia and reperfusion on myocardial metabolism and free radical activity. Circulation 1991: 84: III375-9. 213 Standeven JW, Jellinek M, Menz LJ et al. Cold-blood potassium cardioplegia: evaluation of glutathione and postischemic cardioplegia. / Thorac Cardiovasc Surg 1979; 78:893-907. 214 Menasche P, Termignon JL, Pradier F et al. Experimental evaluation of Celsior, a new heart preservation solution. EurJ Cardiothorac Surg 1994; 8:207-13. 215 Pietri S, Culcasi M, Albat B et al. Direct assessment of the antioxidant effects of a new heart preservation solution, Celsior. A hemodynamic and electron spin resonance study. Transplantation 1994; 58: 739-42. 216 Nakamura M, Thourani VH, Ronson RS et al. Glutathione reverses endothelial damage from peroxynitrite, the byproduct of nitric oxide degradation, in crystalloid cardioplegia. Circulation 2000:102: III332-8. 217 Yoshida T, Watanabe M, Engelman DT et al Transgenic mice overexpressing glutathione peroxidase are resistant to myocardial ischemia reperfusion injury. / Mol CellCardiol 1996; 28:1759-67. 218 Yoshida T, Maulik N, Engelman RM et al. Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation 1997; 96: 11216-20. 219 Amano J, Sunamori M, Okamura T, Suzuki A. Effect of glutathione pretreatment on hypothermic ischemic cardioplegia. Jpn ]Surg 1982; 12: 87-92. 220 Kaakkola S, Gordin A, Mannisto PT. General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. Gen Pharmacol 1994; 25: 813-24. 221 Suzuki YJ, Tsuchiya M, Safadi A et al. Antioxidant properties of nitecapone (OR-462). Free Radic Biol Med 1992; 13: 517-25. 222 Valenza M, Serbinova E, Packer L et al. Nitecapone protects the Langendorff perfused heart against ischemiareperfusion injury. Biochem Mol Biol Int 1993; 29:443-9. 223 Vento AE, Ramo OJ, Nemlander AT et al. Nitecapone is of benefit to functional performance in experimental heart transplantation. ResExp Med 1997; 197:137-46. 224 Vento AE, Ramo OJ, Nemlander AT et al. Nitecapone inhibits myeloperoxidase in vitro and enhances functional performance after 8 h of ischemia in experimental heart transplantation. Res Exp Med (Berl) 1999; 198: 299-306. 225 Vento AE, Aittomaki J, Verkkala KA et al. Nitecapone as an additive to crystalloid cardioplegia in patients who had coronary artery bypass grafting. Ann Thorac Surg 1999; 68:413-20. 226 Pesonen EJ, Vento AE, Ramo J et al. Nitecapone reduces cardiac neutrophil accumulation in clinical open heart surgery. Anesthesiology 1999; 91: 355-61.

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Is there a place for on-pump, beating heart coronary artery bypass grafting surgery? The pros and cons Simon Fortier, MD, Roland G. Demaria, MD, PHD, FETCS, e^ Louis R Perrault, MD, PHD, FRCSC, FAGS

Background Coronary artery bypass grafting was first conceived of and experimented on by Alexis Carrel at the beginning of the previous century [1]. Sabiston in 1962 performed the first aortocoronary venous bypass graft in humans [2] and Kolesov the first left internal mammary artery (IMA) to left anterior descending (LAD) graft in 1966 [3]. All these operations were performed on the beating heart. At the end of the 1960s, Favaloro and the Cleveland Clinic team opened the era of modern coronary artery bypass surgery [4]. All these pioneers were confronted with the issue of blood intrusion at the anastomotic site. Different techniques such as compression, irrigation of the area, or external clampage with poor stabilization were used. Rapidly, cardiopulmonary bypass (CPB) without and eventually with cardioplegic arrest was used almost universally in coronary artery bypass surgery to obtain an optimal bloodless and motionless operative field. The majority of coronary operations were soon performed with this technique, and beating heart coronary revascularization was abandoned except in selected situations. Because CPB entails a risk of systemic inflammatory response and various complications in some patients, and probably because of economical reasons, some surgical teams were involved in the revival of beating heart coronary surgery. Recently, minimally invasive coronary artery bypass

grafting has been the subject of several studies, with emphasis usually put on the switch from conventional median sternotomy to minithoracotomy [5,6] or to the port-access approach [7]. The invasiveness of coronary artery operations is determined more by myocardial ischemia incurred during the crossclamping period and the inflammatory response to CPB than by the site and type of incision. Ideally, these two issues are addressed by off-pump surgery, but this strategy, which is far from new [8], raises the very concerns that led to the development of CPB. An intermediary option is to continue to use CPB but to eliminate the ischemic component of invasiveness by avoiding aortic cross-clamping and keeping the heart beating throughout the operation.

Principles of myocardial protection In the new millennium, despite new minimally invasive techniques, the basic principles of myocardial protection have remained the same. Maintenance of the balance between myocardial oxygen demand and supply, modification and control of reperfusion, and improvement of endogenous bioprotection are the three basic concepts that need to be respected [9].

Ischemia and reperfusion The heart represents only 0.5% of total body weight but has an oxygen consumption (MVo2) of 7% [10].

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The three determinants of MVb2 are the heart rate, the stroke work, and the inotropic state. The lowest MVo2 during open heart surgery is obtained during total electromechanical quiescence and the maximum MVo2 occurs during weaning of cardiopulmonary bypass run, when the heart recovers from the oxygen debt contracted during the aortic cross-clamping period [11,12]. In an experimental study, the heart's total oxygen requirements were reduced by approximately 70% when the external work of the heart was eliminated by emptying the heart with CPB and ventricular decompression and controlling the heart rate to 100 beats per minute [13]. Myocytes have little glycolytic reserve and poorly adapt to anerobia. Ischemia can be global as with cardioplegic arrest or regional with temporary vessel occlusion. Ionic shifts and intracellular calcium accumulation follow. Aortic cross-clamping during CPB and the resulting myocardial ischemia has the potential to cause severe damage to the myocytes and endothelium of coronary arteries, which is compounded with restoration of blood flow, the so-called reperfusion injury [ 10]. During coronary reperfusion, blood-borne cells (such as neutrophils) and the endothelium are activated, with generation and release of oxygen radicals. The ionic shifts are exaggerated and interstitial and intracellular water accumulate, resulting in swelling and disruption of membrane integrity. Hypercontracture of myofibrils is probably one of the major causes of cell death following reperfusion [14]. Evidence of reperfusion injury is present at autopsy in 25% of cases succumbing to heart surgery and is associated with long periods of aortic cross-clamping [15].

Cardiac arrest and cardioplegia The first description of induction of cardiac arrest goes back to 1955 by Melrose who used a hyperkalemic blood cardioplegia solution. Unfortunately it was abandoned because of cardiac injury secondary to the excessively high potassium concentration [16]. In the following years, improvements in cardioplegic techniques were introduced to reduce cardiac energy requirements. Intermittent aortic cross-clamping with ventricular fibrillation was nearly abandoned because of the greatly increased cardiac energy requirements during fibrillation. However, some groups still use this technique with good results [17,18]. Repeated brief episodes of ischemia induced by intermittent aortic cross-clamping may be a form of preconditioning. This may protect the heart from a longer period of

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ischemia by mechanisms that are still incompletely determined [19]. Numerous randomized studies have demonstrated the superiority of sanguineous cardioplegia solutions over crystalloid cardioplegia in reducing morbidity [20-25] and mortality [26]. However, continuous normothermia blood cardioplegia, which is expected to keep the heart in an aerobic and normothermic environment, may not completely prevent some degree of postoperative stunning or myocardial dysfunction [27,28]. This can be explained by myocardial edema formation which decreases left ventricular function. Organized myocardial contraction, lost with cardiac arrest, appears to be the major factor for optimal myocardial lymphatic drainage [29]. Occurrence of myocardial edema can also be explained by the prolonged time available for myocardial microvascular fluid filtration associated with the diastolic state [28,30]. Beating heart surgery, avoiding this diastolic and arrested state, can prevent myocardial edema formation. Even with reduced contractility such as under beta-blockade, keeping the heart beating is associated with less myocardial edema and a better postoperative function [31]. The optimal composition of cardioplegia solutions and temperature are still a matter of debate. Data are confusing due to lack of clear definitions about primary end points and the different techniques [32]. However, by avoiding cold cardioplegia, which leads to myocardial hypothermia, recovery is faster [33]. Delivery of cardioplegia through the antegrade route may be reduced with severe coronary stenosis and retrograde cardioplegia may underprotect the right ventricle and septum, increasing the risk of myocardial injury during surgery. Combination of the two delivery techniques may be optimal but does not completely eliminate the risk of myocardial injury.

Effects of beating heart surgery performed with cardiopulmonary bypass The detrimental effects of aortic cross-clamping are probably inconsequential in the vast majority of patients with sufficient cardiac reserve but may precipitate hemodynamic failure in patients with marginal left ventricular function. Theoretically, the ideal solution to this problem is myocardial revascularization without extracorporeal circulation. However, this approach raises some concerns. Clinical outcomes for

On-pump beating CABG surgery low-risk patients are excellent [34-37], but controversial in high-risk groups [38]. In fact, no significant change in mortality and morbidity has been observed. Neurologic events are not eliminated with off-pump coronary bypass. Good patency rates at discharge are documented [39], although the long-term graft patency and clinical results of this approach are still unknown [40]. One study, with a mean follow-up of 3 months, demonstrated a poor patency for grafts anastomosed to vessels other than the left anterior descending artery [41]. Currently available data do not conclusively establish the superiority of the beating heart technique over any other method of myocardial protection; in fact, excellent clinical results have been reported in high-risk patients with the use of different strategies of cardioplegic arrest [42,43]. Nevertheless, low ejection fraction, evolving myocardial ischemia, and advanced age are all factors for an increased morbidity and mortality after coronary artery bypass grafting [44], and this alone provides a sound rationale for the investigation of alternative surgical approaches in high-risk patients. For this reason, on-pump, beating-heart bypass may constitute, in selected patients, an interesting trade-off. In an attempt to find an alternative surgical approach, a nonrandomized prospective study was conducted with 43 consecutive patients with poor left ventricular function (median ejection fraction of 26%), evolving myocardial ischemia or acute myocardial infarction, old age (mean of 79.5 years), and comorbid conditions [45,46]. These patients were operated for myocardial revascularization with CPB on the beating heart. Clinical outcomes (morbidity and mortality), markers of myocardial ischemia (troponin Ic), systemic inflammation (interleukins 6, 10 and elastase) and the adaptation to stress (heat shock protein (HSP) 70 mRNA from the right atrium) were analyzed. This group was compared to a control group operated with conventional CPB and normothermic blood cardioplegia. In the on-pump beating heart group, there was one cardiac-related death (2.3%) and one myocardial infarction (2.3%). There was no stroke or differences in inotrope or intra-aortic balloon pump requirements, time to extubation, and alveolar-arterial gradients. Myocardial injury was minimal with a twofold decrease in postoperative troponin Ic levels compared to controls. There was no significant difference in the peak levels of inflammatory mediators. Finally, a threefold increase in beating heart group of HSP 70 levels suggested better

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adaptation to stress than controls, as a rise in HSP 70 has been associated with an increased tolerance to ischemia [19,47]. Other groups have reported similar results. Sweeney et al. [48] using biventricular assist devices during coronary revascularization in a similar patient population reported one cardiac-related death (2.3%), with improvement in cardiac function in all survivors at follow-up (averaging 8.9 months). Krejca and his team studied cardiac troponin T release during myocardial revascularization in three randomized groups: CPB and intermittent cross-clamping, CPB with beating heart, and beating heart without CPB [49]. However, this was in a low-risk population. Nevertheless, troponin T levels were significantly higher in the group with intermittent cross-clamping when compared to the other groups. Troponin T levels were significantly higher in the beating heart group with CPB compared to the beating heart group without CPB at 48 h and 72 h, suggesting low myocardial injury when aortic cross-clamping is avoided. Maintenance of the heart in a beating state throughout the operation seems to cause less damage than aortic cross-clamping, even when blood cardioplegia is used in a continuous fashion. This conclusion is based on two specific findings: a lower release of troponin I, a highly cardiac specific marker of tissue damage [50], and a threefold increase in the postoperative myocardial content of mRNA coding for HSP 70 compared with the preoperative value (Table 13.1). Not surprisingly, troponin I levels were lower without the use of aortic cross-clamping. In fact, although oxygen demand is minimal with sanguineous cardioplegia, sustained aerobiosis is deficient. Distribution is not always uniform and continuous, leading to anerobic metabolism in some parts of the myocardium. In CPB without aortic cross-clamping, global ischemic damage to myocytes is avoided, explaining these results. Increases in the postoperative myocardial content of mRNA coding for HSP 70 reflect the preserved ability of the beating heart to display an appropriate adaptive response to ischemic stress. The arrested heart may lose this capacity, as demonstrated by the fact that levels of HSP 70 mRNA at the end of crossclamping were unchanged from baseline in patients undergoing conventional warm cardioplegic arrest in our study. This observation is consistent with that of McGrath and coworkers [51], who failed to document any change in myocardial levels of HSP 72 in patients protected with cardioplegia when undergoing various

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Table 13.1 Comparison of markers of inflammation and ischemia for three different techniques of surgical myocardial revascularization. Markers Inflammation

Ischemia

Technique

IL-6

IL-10

Elastase

Troponin Ic

Troponin T

HSP-70

1-CPB: cardioplegic arrest 2-CPB: beating heart

T T T

T T <->

T T

TT T T

TT T T

o

1-2<0.05

3-OPCAB P value References

<-»

1-2 NS

1-2 NS

1-2 NS

1-2<0.05

1-3<0.05

1-3 NS

1-3<0.05

1-3<0.05

2-3 NS

[45,68]

[45,68]

1-3<0.05 [45,74]

[45,68]

[49,73]

T X

[45]

CPB, cardiopulmonary bypass; OPCAB, off-pump coronary artery bypass; HSP, heat shock protein; NS, not significant. T, increase; <->, no change; x, not applicable.

open heart operations. Several experimental studies have documented a close relationship between increased myocardial levels of HSPs and attenuation of stunning. Plumier and coauthors [52] and Marber and colleagues [53] have shown improved recovery after ischemia in mice overexpressing the gene for HSP. As ischemia seems to prevent the expression of HSPs [54], our study documents, at the molecular level, the effectiveness of the beating heart technique in ensuring adequate prevention against myocardial injury, thereby making this technique a major component of any minimally invasive procedure. The benefits of ventricular decompression should not be overlooked. Indeed, with reduction of the ventricular wall tension, the resistance to flow through stenotic coronary arteries may be decreased. Blood flow can therefore increase in ischemic regions [55]. The size of acute infarct can actually be decreased experimentally with ventricular decompression [56]. Especially in impaired ventricles, left ventricular wall tension reduction with augmented coronary flow is probably beneficial. On-pump beating heart coronary artery bypass surgery may also be used as a learning step for trainees in beating heart revascularization. With the hemodynamic stability afforded by CPB, the anastomosis on a beating heart can be easily performed [57].

Adverse effects A systemic inflammatory syndrome is triggered by CPB. Excellent reviews have been published about this

subject [58,59]. This inflammatory response results from the contact of cellular and humoral blood components with the extracorporeal circuit, even when heparin-coated. Leukocyte and endothelial activation secondary to ischemia and reperfusion and endotoxemia are also implicated. At the cellular and molecular level, numerous pathways and mediators have been identified in this inflammatory response. Activation of the complement, of the intrinsic (material contact) and extrinsic (surgical wound and trauma and tissue factor) coagulation pathways, and of fibrinolysis, as well as platelets, endothelial cells, and neutrophils, are all involved in producing organ failure and postoperative complications following CPB. Clinically, this is manifested by bleeding and coagulopathy, pulmonary dysfunction and prolonged intubation times, stroke and neurologic/neuropsychologic deficiencies, renal failure, and gastrointestinal complications. Neurologic injury, initially thought to result from pump-generated embolism, now appears to be related mostly to atheroembolism from manipulation of the aorta [60]. This can explain in part why strokes still happen with off-pump beating heart surgery [38,60]. Of the inflammatory mediators released during CPB, elastase, interleukin (IL) 6, and IL-10 were selected as sensitive markers of neutrophil activation, proinflammatory cytokine production, and antiinflammatory cytokine production, respectively [61, 62]. Measurements of markers for systemic inflammation are not significantly different between the beating

On-pump beating CABG surgery heart technique and the warm blood cardioplegic approach (Table 13.1) [47]. The ischemic and reperfused heart is a major source of inflammatory mediators, in particular of neutrophil chemotactic factors and cytokines [63,64]. Perhaps the specific production of cytokines by the myocardium was not captured in our study because of the timing and site of blood samples, since release of inflammatory mediators by myocardium occurs early after aortic declamping [65,66], while our samples were taken 4 h after bypass from the peripheral blood. However, regardless of their source, inflammatory mediators are released in response to CPB, but there is no conclusive evidence that this translates into clinically relevant postoperative adverse events. Whether the magnitude of the response may be mitigated by the use of heparincoated circuits, as suggested by some studies [67], cannot be determined from these data. Another concern about beating heart surgery is the risk of temporary occlusion of target vessels and associated regional ischemia. Some studies have demonstrated regional wall contractility abnormalities [68], although this was not associated with the elevation of biochemical markers of myocardial injury. Snaring of coronary arteries seems to cause less myocardial injury than global ischemia induced by cardioplegia [69]. However, endothelial denudation and vascular injury may occur due to the hemostatic devices used in off-pump coronary artery bypass (OPCAB), especially shunts and intravascular coronary occludens [ 70 -72 ].

Conclusions In selected high-risk patients who may poorly tolerate cardioplegic arrest and in situations where an OPCAB intervention is not technically feasible, myocardial revascularization on the pump-supported, decompressed, noncross-clamped heart maybe an acceptable alternative. The conjunction of the two techniques, in addition to the better understanding of the consequences of coronary artery manipulation at the level of the vascular wall, associated with the surgeon's training and experience, will lead to continued improvement in the long-term results of this revived aspect of cardiac surgical revascularization. Studies of late graft patency and randomized studies are needed to establish the proper place of OPCAB in the field of modern myocardial revascularization.

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In conclusion, we do not believe that the on-pump, beating heart technique is a panacea, but it may be a transitional step to "off-pump" coronary artery bypass grafting and a useful tool in the surgical armamentarium in contemporary myocardial revascularization.

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17 Akins CW, 1987. Early and late results following emergency isolated myocardial revascularization during hypothermic fibrillatory arrest. Updated in 1994 by Gary W. Akins,MD. Ann ThoracSurg 1994; 58:1205-6. 18 Okamura Y, Sugita Y, Mochizuki Y et al. [Indication and result of hypothermic fibrillatory arrest in coronary artery bypass grafting.] Nippon Kyobu Geka Gakkai Zasshil996; 44:623-8. 19 Knowlton AA. The role of heat shock proteins in the heart. JMol Cell Cardiol 1995; 27:121-31. 20 Flack JE 3rd, Cook JR, May SJ et al. Does cardioplegia type affect outcome and survival in patients with advanced left ventricular dysfunction? Results from the CABG Patch Trial. Circulation 2000; 102 (19 Suppl 3): III84-9. 21 Gasior Z, Krejca M, Szmagala P et al. Long-term left ventricular systolic function assessment following CABG. A prospective, randomised study. Blood versus crystalloid cardioplegia. / Cardiovasc Surg (Torino) 2000; 41:695-702. 22 Fremes SE, Tamariz MG, Abramov D et al. Late results of the Warm Heart Trial: the influence of nonfatal cardiac events on late survival. Circulation 2000; 102 (19 Suppl 3): 111339-45. 23 Elwatidy AM, Fadalah MA, Bukhari EA et al Antegrade crystalloid cardioplegia vs antegrade/retrograde cold and tepid blood cardioplegia in CABG. Ann Thorac Surg 1999; 68:447-53. 24 Jacquet LM, Noirhomme PH, Van Dyck MJ et al. Randomized trial of intermittent antegrade warm blood versus cold crystalloid cardioplegia. Ann Thorac Surg 1999;67:471-7. 25 Hendrikx M, Jiang H, Gutermann H et al. Release of cardiac troponin I in antegrade crystalloid versus cold blood cardioplegia. / Thorac Cardiovasc Surg 1999; 118:452-9. 26 Christakis GT, Fremes SE, Weisel RD et al. Reducing the risk of urgent revascularization for unstable angina: a randomized clinical trial. / Vase Surg 1986; 3:764-72. 27 Misare BD, Krukenkamp BD, Lazer ZP et al Recovery of postischemic contractile function is depressed by antegrade warm continuous blood cardioplegia. / Thorac Cardiovasc Surg 1993; 105: 37-44. 28 Mehlhorn U, Allen SJ, Adams DL et al Normothermic continuous antegrade blood cardioplegia does not prevent myocardial edema and cardiac dysfunction. Circulation 1995; 92:1940-6. 29 Mehlhorn U, Davis KL, Burke EJ et al. Impact of cardiopulmonary bypass and cardioplegic arrest on myocardial lymphatic function. Am J Physiol 1995; 268: H178-83. 30 Laine GA, Granger HJ. Microvascular, interstitial, and lymphatic interactions in the normal heart. Am J Physiol 1985; 249: H834-42. 31 Mehlhorn U, Allen SJ, Adams DL et al. Cardiac surgical conditions induced by |3-blockade: effect on myocardial fluid balance. Ann ThoracSurg 1996; 62:143-50. 32 Menasche P. Warm cardioplegia or aerobic cardioplegia? Let's call a spade a spade. Ann Thorac Surg 1994; 58:5-6. 33 Rosenkranz ER, Buckberg GD, Laks H et al Warm induction of cardioplegia with glutamate-enriched blood

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in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intra-aortic balloon support. J Thorac Cardiovasc Surg 1983; 86:507-18. Benetti FJ, Naselli G, Wood M et al. Direct myocardial revascularization without extracorporeal circulation. Experience 700 Patients Chest 1991; 100:312-16. Pfister AJ, Zaki MS, Garcia JM et al Coronary artery bypass without cardiopulmonary bypass. Ann Thorac Surg 1992; 54:1085 -92. Moshkowitz Y, Lucky A, Mohr R. Coronary artery bypass without cardiopulmonary bypass. Analysis of shortterm and mid-term outcome in 220 patients. / Thorac Cardiovasc Surg 1995; 110:979-87. Buffolo E, de Andrade JCS, Branco JNR et al Coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg 1996; 61:63-6. Yokoyama T, Baumgartner FJ, Gheissari A et al Offpump versus on-pump coronary bypass in high-risk subgroups. Ann Thorac Surg 2000; 70:1546-50. Puskas JD, Thourani VH, Marshall JJ et al Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive off-pump coronary bypass patients. Ann Thorac Surg 2001; 71:1477-83. Gundry SR, Razzouk Al Bailey LL. Coronary artery bypass with and without the heart—lung machine: a casematched 6 year follow-up [abstract]. Circulation 1996; 94 (Suppl 1): 52. Omeroglu SN, Kirali K, Guler M et al. Midterm angiographic assessment of coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg 2000; 70: 844-9. Diet! CA, Berkheimer MD, Woods EL et al Efficacy and cost-effectiveness of preoperative IABP in patients with ejection fraction of 0.25 or less. Ann Thorac Surg 1996; 62: 401-9. Chan RKM, Raman J, Lee KJ et al Prediction of outcome after revascularization in patients with poor left ventricular function. Awn Thorac Surg 1996; 61:1428-34. Rao V, Ivanov J, Weisel RD et al Predictors of low cardiac output syndrome after coronary artery bypass. / Thorac Cardiovasc Surg 1996; 112: 38-51. Perrault LP, Menasche P, Peynet J et al. On-pump, beatingheart coronary artery operations in high-risk patients: an acceptable trade-off? Ann Thorac Surg 1997; 64: 136873. Bel A, Menasche P, Paris B et al La chirurgie coronaire a coeur battant sous circulation extracorporelle chez les patients ii haut risque. Un compromis acceptable? Arch Mai Cceur 1998; 91:849-53. Williams RS. Heat shock proteins and ischemic injury to the myocardium. Circulation 1997; 96:4138-40. Sweeney MS, Frazier OH. Device-supported myocardial revascularization: safe help for sick hearts. Ann Thorac Surg 1992; 54:1065-70. Krejca M, Skiba J, Szmagala P et al. Cardiac troponin T release during coronary surgery using intermittent cross-clamp with fibrillation, on-pump and off-pump beating heart. Eur } Cardiothorac Surg 1999; 16: 33741.

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50 Adams JE, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 1993; 88: 750-63. 51 McGrath LB, Locke M, Cane M et al. Heat shock protein (HSP 72) expression in patients undergoing cardiac operations. / Thome Cardiovasc Surg 1995; 109: 370-6. 52 Plumier JCL, Ross BM, Currie RW et al. Transgenic mice expressing the human heat shock protein 70 have improved postischemic myocardial recovery. / Clin Invest 1995;95:1854-60. 53 Marber MS, Mestril R, Chi SH et al. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. / Clin Invest 1995; 95:1446-56. 54 Plumier JCL, Robertson HA, Currie RW. Differential accumulation of mRNA for immediate early genes and heat shock genes in heart after ischaemic injury. JMol Cell Cardiol 1996; 28:1251-60. 55 Smalling RW, Cassidy DB, Barrett R et al. Improved regional myocardial blood flow, left ventricular unloading, and infarct salvage using an axial-flow, transvalvular left ventricular assist device. A comparison with intraaortic balloon counterpulsation and reperfusion alone in a canine infarction model. Circulation 1992; 85: 11529. 56 Lachterman BS, Felli P, Smalling RW. Improved infarct salvage by left ventricular unloading with the hemopump immediately prior to and during reperfusion after a 2hour coronary occlusion [abstract]. J Am Coll Cardiol 1991;17(Suppl2A):134. 57 Ricci M, Karamanoukian HL, D'Ancona G et al. Survey of resident training in beating heart operations. Ann Thorac Surg 2000; 70:479-82. 58 Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest 1997; 112:676-92. 59 Asimakopoulos G. Mechanisms of the systemic inflammatory response. Perfusion 1999; 14:269-77. 60 Blauth CI. Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg 1995; 59:1300-3. 61 Faymonville ME, Pincemail J, Duchateau J et al. Myeloperoxidase and elastase as markers of leukocyte activation during cardiopulmonary bypass in humans. / Thorac Cardiovasc Surg 1991; 102: 309-17.

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62 Steinberg JB, Kapelanski DP, Olson JD et al Cytokine and complement levels in patients undergoing cardio pulmonary bypass. / Thorac Cardiovasc Surg 1993; 106: 1008-16. 63 Elgebaly SA, Hashmi ES, Houser SL et al. Cardiac-derived neutrophil chemotactic factors. Detection in coronary sinus effluents of patients undergoing myocardial revascularization. / Thorac Cardiovasc Surg 1992; 103:952-9. 64 Wan S, DeSmet JM, Barvais L et al. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. / Thorac Cardiovasc Surg 1996; 112:806-11. 65 Wan S, Marchant A, DeSmet J et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. / Thorac Cardiovasc Surg 1996; 111: 469-77. 66 Weerwind PW, Maessen JG, van Tits LJH et al. Influence of Duraflo II heparin-treated extracorporeal circuits on the systemic inflammatory response in patients having coronary bypass. / Thorac Cardiovasc Surg 1995; 110: 1633-41. 67 Lotto AA, Caputo M, Ascione R et al. Evaluation of myocardial metabolism and function during beating heart coronary surgery. Eur J Cardiothor Surg 1999; 16 (Suppll): SI 12-16. 68 Czerny M, Baumer H, Kilo J et al. Inflammatory response and myocardial injury following coronary artery bypass grafting with or without cardiopulmonary bypass. Eur J Cardiothor Surg2000; 17: 737-42. 69 Hangler HB, Pfaller K, Antretter H et al. Coronary endothelial injury after local occlusion on the human beating heart. Ann Thorac Surg 2001; 71:122-7. 70 Perrault LP, Menasche P, Wassef M et al. Endothelial effects of hemostatic devices for continuous cardioplegia or minimally invasive operations. Ann Thorac Surg 1996; 62:1158-63. 71 Demaria RG, Fortier S, Carrier M et al. Early multifocal stenosis after coronary artery snaring during off pump coronary artery bypass in a patient with diabetes. / Thor Cardiovasc Surg 2001; 122:1044-45. 72 Menasche P, Haydar S, Peynet J et al. A potential mechanism of vasodilation after warm heart surgery. The temperature-dependent release of cytokines. / Thorac Cardiovasc Surg 1994; 107: 293-9.

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Myocardial protection in beating heart coronary artery surgery VinodH. Thourani, MD 6^ John D. Puskas, MD,MSC

Introduction Although coronary artery bypass graft surgery (CABG) was first performed without the use of extracorporeal circulation in the late 1960s [1,2], this technique was largely abandoned after the use of cardiopulmonary bypass (CPB) and cardioplegic arrest became routine. However, increased awareness that blood contact with the CPB circuit produces a well-documented diffuse inflammatory response affecting multiple organ systems has led to the resurgence of off-pump coronary artery bypass grafting (OPCAB). Specific deleterious effects of the inflammatory response following CPB have been documented in the heart, lungs, central nervous system, kidneys, and gastrointestinal tract, and increase with increased duration of CPB [3,4]. With presently available instrumentation, off-pump CABG via sternotomy can now be performed for lesions in virtually any coronary artery with a high degree of patient safety and surgeon comfort. Recent reports have documented improved outcomes, excellent short-term angiographic patency, and lower costs with OPCAB [5,6]. Techniques of myocardial protection specific to OPCAB are essential to optimize outcomes with this procedure. The goals of myocardial protection during offpump coronary surgery are not only to avoid iatrogenic surgical injury induced by manipulation of the heart, but also to prevent reperfusion injury upon resolution of the coronary occlusion. Furthermore, basic tenets of myocardial protection including maintaining a balance in myocardial oxygen delivery/ consumption, reducing ventricular distention, and preventing postoperative ventricular arrhythmias should be maintained. Well-orchestrated and methodical

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protection of the heart should remain the cornerstone of coronary artery surgery, whether performed onor off-pump. The resurgence of off-pump coronary artery surgery has led cardiac surgeons to re-evaluate the role of myocardial protection for these patients. This chapter outlines the current strategy and practice of myocardial protection for cardiac surgeons performing off-pump coronary artery bypass grafting.

Myocardial injury in off-pump coronary artery bypass grafting Concern for myocardial protection during OPCAB stems from the knowledge that the brief periods of ischemia necessary to visualize the target vessels during construction of distal anastomoses produce some degree of myocardial injury that may not only affect the individual target areas, but also cause cumulative global dysfunction after sequential occlusions imposed during multivessel bypass grafting. Even brief periods of ischemia during simulated OPCAB in animals are associated with measurable contractile dysfunction, endothelial injury in the target coronary artery, myocardial edema, and the genesis of apoptosis that may contribute to postrevascularization pathology [7-11]. Reperfusion of ischemic myocardium in the absence of cardioprotective strategies applied during either ischemia or reperfusion results in additional vascular endothelial dysfunction, contractile dysfunction, and myocardial infarction over and above that observed during the ischemic period [7-11]. Furthermore, myocardial stunning, even after a transient period of ischemia, may render the ventricle more susceptible to arrhythmias [12]. In humans, Bonatti et al. [10] have shown that subclinical myocardial injury is a

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OPCAB myocardial protection common event in OPCAB when measured by the sensitive myocardial marker protein cTnl. In addition, Imasakaeffl/. [13] and others [14] have demonstrated contractile dysfunction in regional wall motion induced by intraoperative myocardial ischemia utilizing sophisticated transesophageal echocardiography (TEE) technology. Although the period of target vessel occlusion imposed during OPCAB may be confined to approximately 5-15 min, the notion that multiple grafts may impose cumulative ischemic injury on sequential target areas raises concern. The knowledge that the target vessel(s) is not reperfused adequately until the proximal anastomoses are completed for all vessels heightens concern about extended myocardial ischemic intervals during OPCAB. Strategies to protect the myocardium from ischemic and reperfusion injuries may improve both acute and longer-term outcomes after OPCAB procedures.

Overview of myocardial protection The most important contributors to myocardial protection during OPCAB are gentle cardiac manipulation, which maintains stable hemodynamics, and appropriate graft sequencing, which limits cumulative ischemia. In addition, the OPCAB cardioprotective armamentarium includes systemic intravenous pharmacologic agents, ischemic preconditioning, coronary shunting, preload and afterload reduction using axial pumps, intra-aortic balloon counterpulsation, and perfusion-assisted direct coronary artery bypass (PADCAB) with or without intracoronary pharmacologic agents.

Systemic intravenous pharmacologic agents Myocardial protection during OPCAB has taken many forms during the evolution and refinement of techniques for OPCAB. Early on, prior to the development of sophisticated mechanical stabilizing devices, intermittent, pharmacologic arrest with bolus doses of adenosine, or profound bradycardia induced by short-acting beta-blockers, enjoyed a brief period of clinical interest. Other pharmacologic agents tried as myocardial protectants included nucleoside transport inhibitors, selective Na+-H+ exchange inhibitors, ATP-dependent potassium-channel opening agents, and adenosine derivatives including acadesine. Among

the various benefits touted for these pharmacologic interventions was myocardial protection due to reduced myocardial oxygen consumption with subsequent reduction in the metabolic substrates responsible for myocardial ischemia-reperfusion injury [15]. Due to the limited effectiveness and significant negative hemodynamic effects of these agents, they are not routinely used as clinical myocardial protective agents and have largely been abandoned with the advent of third generation mechanical stabilizers.

Ischemic preconditioning Ischemic preconditioning also enjoyed a brief popularity as a cardioprotective strategy during off-pump coronary grafting. The theoretical benefit of brief occlusion and reperfusion preceding the longer occlusion necessary to construct a coronary anastomosis was supported by abundant laboratory evidence demonstrating improved protection in the subtended myocardium [7-9,16,17]. In the human heart undergoing cardiopulmonary bypass, ischemic preconditioning has been shown to be associated with beneficial metabolic effects including a reduced rate of high-energy phosphate catabolism and deleterious metabolite accumulation during prolonged periods of ischemia, the additive result of which enhances postischemic myocardial function [18]. Since in humans, ischemic preconditioning has not been universally shown to attenuate myocardial contractile dysfunction or "stunning" [19], the clinical utility of this technique in OPCAB has been questioned. It is plausible that patients with severe coronary stenoses have undergone endogenous ischemic preconditioning during their disease process. Although ischemic preconditioning seemed appropriate and acceptable for single-vessel bypass via small thoracotomy, as the number of bypass grafts performed during OPCAB increased, the enthusiasm of surgeons to perform repeated episodes of ischemic preconditioning for each coronary artery has diminished. While presently a small minority of OPCAB surgeons perform surgical ischemic preconditioning, a chemical preconditioning mimetic agent is conceivable. Pharmacologically, ischemic preconditioning has been mimicked with adenosine, norepinephrine, bradykinin, nitric oxide, and endothelin receptor agonists [20-24]. Furthermore, protein kinase C and ATP-sensitive potassium channel-mediated mechanisms have been suggested as likely end effectors which

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lead to myocardial protection [25,26]. Although the exact mechanisms, dosing, timing, and duration of these mimetics remains unclear, these agents may become important clinical adjuncts for myocardial protection during off-pump coronary artery bypass grafting in the future. Intracoronary shunts Myocardial ischemia during OPCAB may be reduced by the use of intracoronary or aortocoronary shunts [27-30]. Intracoronary shunts have been demonstrated to cause loss of vascular endothelial cells in and around the anastomotic site, and for this reason are used sparingly by the authors. However, particularly in the case of a large right coronary artery where risk of bradyarrhythmias and heart failure during coronary occlusion is quite real, an intracoronary shunt may be useful. Also, if an important collateralizing artery must be occluded prior to restoration of alternative flow during OPCAB, an intracoronary shunt may prevent sudden cardiac collapse due to critical ischemia. Intracoronary shunts rely on passive flow through a fixed lumen and do not bridge the native coronary stenosis for which bypass is necessary. Although flow through an intracoronary shunt must be considered to be significantly less than optimal coronary flow, even this small amount of flow may help maintain hemodynamic stability function during the time required to construct a distal anastomosis. Similarly, aortocoronary shunts may provide direct flow into the coronary artery distal to the anastomotic site during construction of distal anastomoses. Aortocoronary shunts, like intracoronary shunts, constitute an obstacle at the anastomotic site around which the surgeon must maneuver in order to construct the sutured anastomosis. While aortocoronary shunts provide flow directly distal to the anastomosis, bypassing the proximal native coronary stenosis, they include a fixed stenosis within the length of the shunt itself and are dependent on systemic arterial pressure for passive flow.

Hemodynamic changes during heart manipulation During off-pump coronary artery bypass, optimizing coronary perfusion pressure throughout the procedure is vitally important. Ensuring an adequate coronary perfusion pressure begins with maintenance of adequate stable systemic hemodynamics. During the

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performance of distal anastomoses, hemodynamic instability may be caused by two categories of events, namely, regional myocardial ischemia and its sequela and mechanical disturbances of cardiac function due to cardiac displacement/stabilization. Of these, mechanical disturbances are more common and more often problematic. While regional ischemia may cause regional myocardial dysfunction, bradycardia or other arrhythmias, compression of the right or left ventricle by stabilizing devices, or manipulations of the heart leading to partial obstruction of the superior and inferior vena cava or pulmonary artery or veins are common. The techniques for manipulating the heart and exposing posterior and lateral vessels have evolved and improved dramatically over the last 3-5 years. Previous studies have reported that vertical displacement of the heart is associated with hemodynamic instability hallmarked by reduced cardiac output and hypotension [31-33]. Although not used in our practice, right heart circulatory support has been reported in off-pump coronary artery patients to alleviate acute hemodynamic compromise during distal anastomosis [33,34]. While the need for inotrope administration to maintain blood pressure was common in our early experience, the requirement for pharmacologic support has been markedly reduced by refinements in surgical techniques. It is now very infrequent that the authors encounter significant hemodynamic instability during multivessel OPCAB. Simple, inexpensive techniques have been developed and implemented to facilitate the performance of multivessel off-pump coronary artery bypass grafting. It is important to open the pericardium widely and to divide the pericardium from the diaphragm bilaterally down towards (but not into) the phrenic nerves on both sides. The right pleural cavity is opened widely whenever an obtuse marginal coronary artery graft is anticipated. The diaphragmatic muscle slips, which insert on the right side of the xiphoid, are scrupulously divided and the right sternal border is elevated, creating space for the apex of the heart to rotate under the right sternal border and into the right pleural cavity. Simply placing two folded towels under the right limb of the sternal retractor can facilitate this. Traction sutures are used liberally. The most useful traction suture is a deep pericardial suture placed approximately two-thirds of the way between the inferior vena cava and the left inferior pulmonary

OPCAB myocardial protection vein at the point where the pericardium reflects over the posterior aspect of the left atrium. This suture, retracted toward the patient's feet, elevates the base of the heart toward the ceiling and tilts the apex vertically. This is especially useful when approaching the posterior descending coronary artery (PDA) and posterior left ventricular (PLV) branches of the right coronary artery. It may also be useful when approaching the posterolateral obtuse marginal (PLOM) coronary arteries. However, when approaching the left anterior descending (LAD), diagonal coronary arteries, ramus intermedius, or anterior marginals, this traction suture must be retracted toward the patient's head, thereby rotating the heart into the right pleural cavity and avoiding compression of the right ventricle and inflow/outflow tracts. With careful application of these techniques, the majority of hearts can be rotated so that the apex passes under the right sternal border and the lateral wall is well visualized. A variety of cotton slings has been described and may aid in gently displacing the heart into the right pleural cavity, especially when cardiomegaly is present. In addition to effective cardiac manipulation, rotation and tilting of the operating table are vital adjuncts to proper cardiac positioning during OPCAB. Vigorous tilting of the bed toward the patient's right will aid in displacement of the heart into the right pleural cavity. Similarly, impaired inflow to the right side of the heart, which may accompany vigorous rotation, can be ameliorated by steep Trendelenburg position. It is vital to recognize that excellent hemodynarnics may be maintained if the heart is slowly and gently manipulated, rotated, or displaced. The heart may not, however, be compressed against the right sternal border or right pericardium. Thus, no traction is placed on the right pericardium during maneuvers to expose the left-sided vessels. A clear understanding and gentle application of these principles will allow the careful surgeon to maintain remarkably stable hemodynamics while performing multivessel OPCAB. Several manufacturers have recently introduced suction-based devices to provide gentle traction on the apex of the heart to assist with cardiac repositioning/displacement during OPCAB. These devices do, indeed, provide exposure of the lateral and inferior/posterior walls of the heart without cardiac compression and will have a role in facilitating broader adoption of multivessel OPCAB. Preoperative insertion of an intra-aortic balloon pump in initially unstable patients may provide an

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additional measure of hemodynamic stability, allowing OPCAB to be performed in very high-risk patients [35].

Off-pump coronary artery bypass graft sequence and distal anastomosis construction With the advent of more sophisticated mechanical stabilization devices, surgeons are more able to perform complex multivessel OPCAB cases. We believe that certain practical considerations during the creation of proximal and distal anastomoses are essential to effective myocardial protection during OPCAB. Perhaps the simplest and most important is the choice of graft sequence or order during multivessel OPCAB. As a general rule, it is important to graft the collateralized vessel(s) first, reperfuse these by performing proximal anastomoses or releasing clamps on the internal mammary artery pedicles, and then to graft the collateralizing vessels. By this approach, vital coronary flow provided by collateralizing vessels is not interrupted prior to restoration of flow to the collateralized vessels via the newly constructed coronary grafts. Though the tendency among many OPCAB surgeons to perform left internal mammary artery grafting (LIMA) to the LAD first is based on the principle of restoring flow to the anterior wall and septum of the left ventricle, this approach is clearly ill advised if the LAD is the collateralizing vessel for the majority of the rest of the heart. The right coronary artery, particularly when large and dominant, can pose significant risks for the OPCAB surgeon. If its degree of stenosis is relatively minor (60-80%), residual flow within the right coronary artery may be high; therefore acute occlusion of the vessel for construction of a distal OPCAB anastomosis may be poorly tolerated and may lead to bradyarrhythmias. This situation may be best avoided by the use of epicardial pacer wires to eliminate bradycardia and by the use of an intracoronary shunt if a prolonged period of target vessel occlusion is expected. Construction of proximal anastomoses first allows the surgeon to immediately reperfuse each coronary artery upon completion of the distal anastomosis. However, this approach makes estimation of optimal graft length somewhat more difficult. Similarly, performance of the LIMA-LAD anastomosis first may

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require that the IMA pedicle be left somewhat longer than it otherwise might be, perhaps increasing the risk of kinking or redundant folding of the IMA pedicle. Thus, the preferred sequence is outlined in the following six rules: 1 Graft completely occluded, collateralized vessels first. There will be little decrement in myocardial perfusion during construction of this distal anastomosis. Once this graft has been constructed and reperfused, the collateralizing vessel may be more safely occluded and grafted. 2 Be flexible with the timing of the LIMA-LAD anastomosis. It should be done first when the LAD is collateralized and in most cases of tight left main stenosis. However, LIMA-LAD grafting should be performed last if the LAD is the least diseased, collateralizing vessel. To occlude the lightly diseased, collateralizing LAD first is to critically limit total myocardial blood flow during construction of the LAD-LIMA anastomosis, since the collateralized vessel(s) will be effectively occluded simultaneously. 3 Be flexible with the timing of proximal anastomoses. Aorto-saphenous or aorto-radial anastomoses may be done first or early in the case after the distal anastomosis of critical collateralized target(s). The collateralized vessels are then reperfused via the grafts before the collateralizing coronary artery is occluded and grafted. This limits global ischemia and dysfunction. In most routine cases, however, the proximal aorto-saphenous anastomoses may be constructed after all distals have been completed, allowing graft length to be most easily estimated. 4 Be aware that occlusion of the large right coronary artery (RCA) may result in bradycardia. Epicardial pacing should be immediately available, as well as a selection of appropriately sized intracoronary or aortocoronary shunts. Reperfusion of an adjacent or collateralizing coronary graft(s) either by completion of the proximal anastomosis or via perfusion-assisted techniques (see below) prior to occlusion of the RCA may reduce the likelihood of untoward events. 5 Hearts with ischemic mitral regurgitation may be stabilized by early grafting and reperfusion of the culprit vessel(s) causing papillary muscle dysfunction. 6 Above all, customize the graft sequence for each individual case, considering coronary anatomy, patterns of collateralization, myocardial contractility, atherosclerosis of the ascending aorta, conduit availability, and graft geometry.

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Myocardial protection during OPCAB can be dramatically improved by expeditious construction of distal anastomoses and rapid perfusion of grafts. To prevent iatrogenic coronary artery injury during distal anastomosis, the authors prefer to occlude each coronary artery only proximal to the chosen anastomotic site with a soft Silastic vessel loop (Quest Medical, Allen, TX) and apply the minimum tension necessary to occlude antegrade flow. Coronary artery retrograde back bleeding into the anastomotic site is dispersed using a sterile, humidified, carbon dioxide blower (DLP, Medtronic, Minneapolis, MN). The blower should be directed toward the intima only during the actual moments of suturing to minimize endothelial injury. The solution used for humidification should be pH neutral crystalloid. Although the authors currently use the Medtronic Octopus III device (Medtronic, Minneapolis, MN) as a stabilizer, other stabilizing devices provide adequate immobilization of target vessels to facilitate surgical precision.

Perfusion-assisted direct coronary artery bypass While gentle manipulation of the heart and strict adherence to the basic principles of coronary exposure during OPCAB will allow the experienced OPCAB surgeon to complete the large majority of multivessel OPCAB cases with good hemodynamic stability, a downward spiral of hemodynamic instability can occasionally develop. The cumulative global effect of sequential periods of regional ischemia can lead to declining systemic arterial pressure. This may produce a decrease in coronary perfusion pressure, resulting in myocardial dysfunction, causing further decline in systemic arterial pressure. This feedback loop may become a vicious downward spiral. Perfusion-assisted direct coronary artery bypass (PADCAB) provides a disconnection between coronary perfusion pressure and systemic arterial pressure, and therefore interrupts or aborts this downward spiral [36-38]. During PADCAB, distal anastomoses are constructed as usual in OPCAB, and graft(s) are immediately connected to the outflow of a small pump circuit (Figure 14.1). Inflow to this circuit is provided by placement of a small cardioplegia-type catheter in the ascending aorta or femoral artery. The Quest Medical MPS (Quest Medical, Allen, TX) system constitutes the principal component of this circuit and allows exact control of

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intracoronary shunts (passive perfusion) compared to active perfusion using the PADCAB technique. In anesthetized canines, a 2.23-mm (90% of the native LAD diameter) intravascular shunt was placed in the LAD. Transmural myocardial blood flow was reduced by more than 60%. When hypotension was simulated by elevating the heart, subendocardial flow and regional oxygen consumption decreased further, with a decrease in oxygen supply/consumption ratio and a net production of lactate, indicating the presence of ischemia in the target myocardium. However, PADCAB perfusion of the target myocardium was associated with blood flow rates and subendocardial distributions equivalent to baseline, and hypotension did not alter the regional distribution or adequacy of oxygen supply relative to demand from either baseline or the nonhypotensive state. Therefore, an active perfusion mechanism may overcome the limitations of the intracoronary or aortocoronary shunt, especially during hypotension. Furthermore, the PADCAB technique allows intracoronary administration of cardioprotective agents to the revascularized segment to minimize reperfusion injury [39]. Figure 14.1 Perf usion-assisted direct coronary artery bypass system.

Summary coronary perfusion pressure. Temperature is also controlled and chemical additives may be included in the outflow circuit at precisely controlled concentrations. Thus, distal anastomoses may be constructed with venous or radial arterial grafts and perfused at any predetermined pressure, irrespective of systemic arterial pressure. Flows can be measured precisely to confirm and document graft patency. Grafted, collateralized coronary arteries may then be used to drive coronary perfusion retrograde through the collaterals to the collateralizing native coronary artery during grafting of that target. This multilimbed device distributes flow to the various coronary grafts and allows each to be perfused during construction of the LIMA-LAD anastomosis. Thus, the cumulative effect of sequential episodes of regional ischemia is reduced or eliminated. Similarly, perfusion via collaterals of adjacent myocardial regions may also contribute to improved myocardial protection. The addition of nitroglycerin, adenosine, or other coronary vasodilators may further improve regional and collateral myocardial perfusion. Muraki et al. [39] in our laboratory investigated the adequacy of oxygen supply versus demand with

In summary, the techniques utilized in performing multivessel OPCAB remain diverse and multifactorial [15,40,41]. Careful maintenance of stable systemic hemodynamics and individualized choice of graft sequence are of central importance. Recently refined techniques for atraumatic rotation of the heart and visualization of coronary anastomoses allow precise and controlled grafting of all coronary territories without cardiopulmonary bypass in the large majority of cases. Perfusion-assisted direct coronary artery bypass techniques, in which coronary perfusion pressure is independent of systemic arterial pressure, can avoid or abort a downward hemodynamic spiral, which may occasionally occur during complex, multivessel OPCAB.

References 1 Benetti F, Naselli G, Wood M et al. Direct myocardial revascularization without extracorporeal circulation: experience in 700 patients. Chest 1991; 100:312-16. 2 Buffolo E, de Andrade JCS, Branco JNR et al. Coronary artery bypass grafting without cardiopulmonary bypass. Ann ThoracSurg 1996; 61:63-6.

132 3 Edmunds LH Jr. Why cardiopulmonary bypass makes patients sick: strategies to control the blood-synthetic surface interface. In: Karp RB, eds. Advances in Cardiac Surgery, Vol 6. St Louis: Mosby, 1995. 4 Edmunds LH Jr. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1998; 66:812-16. 5 Puskas JD, Wright CE, Ronson RS et al. Clinical outcomes and angiographic patency in 125 consecutive off-pump coronary bypass patients. Heart Surg Forum 1999;2:216-21. 6 Puskas JD, Thourani VH, Marshall JJ et al. Clinical outcomes and angiographic patency in 200 consecutive offpump coronary bypass patients. Ann Thorac Surg 2001; 71:1477-83. 7 Bufkin BL, Shearer ST, Vinten-Johansen J et al. Preconditioning during simulated MIDCABG attenuates blood flow defects and neutrophil accumulation. Ann Thorac Surg, 1998; 66:726-32. 8 Thourani VH, Nakamura M, Duarte IG et al. Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass. / Thorac Cardiovasc Surg 1999; 117:383-9. 9 Wang N, Bufkin BL, Nakamura M et al. Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis. Ann Thorac Surg 1999; 67:1689-95. 10 Bonatti J, Hangler H, Hormann C et al. Myocardial damage after minimally invasive coronary artery bypass grafting on the beating heart. Ann Thorac Surg 1998; 66: 1093-6. 11 Perrault LP, Menasche P, Wassef M et al. Endothelial effects of hemostatic devices for continuous cardioplegia or minimally invasive operations. Ann Thorac Surg 1996; 62:1158-63. 12 Hansen PR. Myocardial reperfusion injury: experimental evidence and clinical relevance. Eur Heart J 1995; 16: 734-10. 13 Imasaka K, Morita S, Nagano I et al. Coronary artery bypass grafting on the beating heart evaluated with integrated backscatter. Ann Thorac Surg 2000; 70:1049-53. 14 Kotoh K, Watanabe G, Ueyama K et al. On-line assessment of regional ventricular wall motion by transesophageal echocardiography with color kinesis during minimally invasive coronary artery bypass grafting. / Thorac Cardiovasc Surg 1999; 117:912-17. 15 Chitwood WR Jr, Wixon CL, Elbeery JR et al. Minimally invasive cardiac operation: adapting cardioprotective strategies. Ann Thorac Surg 1999; 68:1974-7. 16 Downey JM. Ischemia preconditioning. Nature's own cardioprotective intervention. Trends Cardiovasc Med 1992; 2:170-6. 17 Richard V, Kaeffer N, Tron C et al. Myocardial ischemia/reperfusion/PTCA. Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion. Basic Sci Rep Circ 1994; 89: 1254-61. 18 Alkuhlaifi AM, Yellon DM, Pugsley WB. Preconditioning the human heart during aortocoronary bypass surgery. Eur] Cardiothorac Surg 1994; 8:270-5.

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19 Ovize M, Przyklenk K, Hale SL et al. Preconditioning does not attenuate myocardial stunning. Circulation 1992; 85:2247-54. 20 Downey JM, Cohen MV, Ytrehus K, Liu Y. Cellular mechanisms in ischemic preconditioning: the role of adenosine and protein kinase C. Ann NYAcad Sci 1994; 723:82-98. 21 Bankwala Z, Hale SL, Kloner RA. Alpha-adrenoceptor stimulation with exogenous norepinephrine or release of endogenous catecholamines mimics ischemic preconditioning. Circulation 1994; 90:1023-8. 22 Wall TM, Sheehy R, Hartman JC. Role of bradykinin in myocardial preconditioning. / Pharmacol Exp Ther 1994; 270:681-9. 23 Bilinska M, Maczewski M, Beresewicz A. Donors of nitric oxide mimic effects of ischaemic preconditioning on reperfusion induced arrhythmias in isolated rat heart. MolCellBiochem 1996; 160-61:265-71. 24 Wang P, Gallagher KP, Downey JM, Cohen MV. Pretreatment with endothelin-1 mimics ischemic preconditioning against infarction in isolated rabbit heart. JMol Cell Cardiol 1996; 28: 579-88. 25 Cleveland JC, Meldrum DR, Rowland RT, Banerjee A, Harken AH. Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive K+ channel. JMol Cell Cardiol 1997; 29:175-82. 26 Auchampach JA, Gross GJ. Adenosine Aj receptors, KATP channels, and ischemic preconditioning in dogs. Am JPhysiol 1993; 264: H1327-36. 27 Rivetti LA, Gandra SMA. Initial experience using an intraluminal shunt during revascularization of the beating heart. Ann TnoracS«rgl997;63:1742-7. 28 Lucchetti V, Capasso F, Caputo M et al. Intracoronary shunt prevents left ventricular function impairment during beating heart coronary revascularization. Eur ] Cardiothorac Surg 1999; 15:255-9. 29 Van Aarnhem EE, Nierich AP, Jansen EW. When and how to shunt the coronary circulation in off-pump coronary artery bypass grafting. Eur} Cardiothorac Surg 1999; 16(Suppl2):S2-6. 30 Dapunt OE, Raji MR, Jeschkeit S et al. Intracoronary shunt insertion prevents myocardial stunning in a juvenile porcine MIDCAB model absent of coronary artery disease. Eur J Cardiothorac Surg 1999; 15:173-8. 31 Griindeman PF, Borst C, van Herwaarden JA, Beck HJM, Jansen EWL. Hemodynamic changes during displacement of the beating heart by the Utrecht Octopus method. Ann Thorac Surg 1997; 63: S88-S92. 32 Griindeman PF, Borst C, Verlaan CWJ et al. Vertical displacement of the beating heart by the Octopus tissue stabilizer: influence on coronary flow. Ann Thorac Surg 1998;65:1348-52. 33 Griindeman PF, Borst C, Verlaan CWJ et al. Exposure of circumflex branches in the tilted, beating porcine heart: echocardiographic evidence of right ventricular deformation and the effect of right or left heart bypass. J Thorac Cardiovasc Surg 1999; 118:316-23. 34 Mathison M, Buffolo E, Jatene AD et al. Right heart circulatory support facilitates coronary artery bypass without

OPCAB myocardial protection

cardiopulmonary bypass. Ann Thome Surg 2000; 70: 1083-5. 35 Graver JM, Murrah CP. Elective intra-aortic balloon counterpulsation for high-risk off-pump coronary artery bypass operations. Ann Thome Surg 2000; 71:1220-3. 36 Guyton RA, Thourani VH, Puskas JD et al. Perfusionassisted direct coronary artery bypass: selective graft perfusion in off-pump cases. Ann Thome Surg 2000; 69: 171-5. 37 Puskas JD, Thourani VH, Vinten-Johansen J et al. Active perfusion of coronary grafts facilitates complex off-pump coronary artery bypass surgery. Heart Surg Forum 2001; 4(1): 64-8.

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38 Steele M, Palmer-Steele C. Perfusion technique for perfusion-assisted direct coronary artery bypass (PADCAB)JExtra Corpor Technol2000; 32:158-61. 39 Muraki S, Morris CD, Budde JM et al. Experimental offpump coronary artery revascularization with adenosineenhanced reperfusion. / Thome Cardiovasc Surg 2001; 121:570-9. 40 Flameng W. Role of myocardial protection for coronary artery bypass grafting on the beating heart. Ann Thorac Surg 1997; 63:518-22. 41 Puskas JP, Vinten-Johansen J, Muraki S, Guyton RA. Myocardial protection for off-pump coronary artery bypass surgery. Sem Thorac Cardiovasc Surg 2001; 13:82-8.

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Beating heart coronary artery bypass grafting: intraoperative strategies to avoid myocardial ischemia Kushagra Katariya, MD, Michael O. Sigler, MD, & TomasA. Salerno, MD

Coronary artery bypass grafting (CABG) is one of the most common surgical operations performed in the United States today. In 1962, Sabiston performed the first human aorto-coronary artery graft using a piece of saphenous vein as conduit to bypass a lesion in the right coronary artery (RCA), and in 1964 Garrett bypassed a lesion in the left anterior descending coronary artery (LAD) [ 1 ]. Kolessov, in the same year, anastomosed the left internal mammary artery (LIMA) to a marginal branch of the circumflex coronary artery [2]. All these early coronary artery bypass operations were done on the beating heart despite the availability of the heart-lung machine. After 1968, when coronary artery surgery became routine, the use of the heart-lung machine became more commonplace and was widely adopted to allow surgeons to work in a bloodless and still field to accurately perform vascular anastomoses onto coronary arteries. Since then, a great amount of effort has been expanded to refine techniques of extracorporeal circulation and identify new strategies of myocardial preservation to improve the safety of this technique. During this time period, when the volume of coronary artery bypass grafting (CABG) operations performed increased exponentially, myocardial revascularization on the beating heart was not abandoned completely. Buffolo from Brazil and Benetti from Argentina, separately, but at the same time continued to perform CABG surgery on the beating heart through the last two decades [3,4]. In

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the United States, Salerno, Subramanian and Pfister rekindled the technique in the early 1990s and over the last 5 years it has become more widely accepted and practiced. Several approaches have been proposed for the offpump technique of CABG surgery. In 1995, Benetti proposed [5] a minimally invasive operation via a small left anterior thoracotomy in the fourth intercostals' space to graft the LIMA to the LAD, a technique referred to as the MIDCAB (minimally invasive direct coronary artery bypass operation) or the LAST (left anterior small thoracotomy) approach. The initial results from various institutions were conflicting with respect to patency rates of the LIMA to LAD graft [6]. The motion of the heart prevented an accurate anastomosis through this small incision and this led to the development of devices to stabilize the specific area of the heart being worked on. These stabilizers, as they were called, created an area of relative stillness allowing accurate placement of sutures for the anastomosis. The technical limitations of the MIDCAB and LAST operations were soon realized, since these approaches could only be used for coronary arteries on the anterior and anterolateral surfaces of the heart, namely the LAD and its diagonal branches. Thus, only patients with single-vessel disease localized to these arteries are candidates for this procedure. Approaching the heart via a median sternotomy allows visualization of the

Beating heart CABG entire heart and allows the surgeon to bypass all the major coronary arteries. Using innovative techniques to manipulate and stabilize the heart and achieve myocardial protection, it is possible to achieve total revascularization for a patient with multivessel coronary artery disease. This technique, also popularly known as OPCAB (off-pump coronary artery bypass), has the most versatility for surgeons wanting to avoid extracorporeal circulation for coronary bypass operations. OPCAB via a median sternotomy has thus become the most commonly used technique for performing off-pump coronary artery surgery. The feasibility of performing total myocardial revascularization on the beating heart is largely dependent on the ability to expose all coronary targets and minimize myocardial ischemia and hemodynamic instability during the operation. As such, myocardial protection during the operation is extremely important to avoid ischemia-related complications intraoperatively as well as postoperatively. Manipulation of the heart is necessary during beating heart coronary artery bypass grafting, and this makes the myocardium more susceptible to ischemia. After completion of the coronary grafting, reperfusion injury in the revascularized myocardium also needs to be avoided. Intraoperative ischemia in the unprotected myocardium can lead to perioperative myocardial infarction with all its attendant complications, intraoperative arrhythmias and hemodynamic alterations, all of which may lead to inability to complete revascularization and thus an incomplete operation. It may also lead to intraoperative hemodynamic collapse necessitating the use of extracorporeal circulation for assistance. Intraoperative myocardial ischemia is commonly produced when the target coronary artery is occluded to allow precise placement of anastomotic sutures or placement of an intracoronary shunt. This ischemia may produce localized dysfunction, but over a period of multiple sequential occlusions, global dysfunction may result. This may be seen postoperatively as regional wall motion abnormalities on echocardiogram [7,8] or a state of global contractile dysfunction [9-13]. Ventricular tachyarrhythmias may result as a consequence of intraoperative ischemia due to myocardial stunning complicating the conduct of the operation. Subclinical myocardial injury during OPCAB by using cardiac troponin I protein as a marker has been documented in the literature [ 12].

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It is thus as, if not more, important to avoid myocardial ischemia during OPCAB as it is in coronary bypass grafting using the heart-lung machine. Various strategic maneuvers, drugs, and devices enable the surgeon to perform complete revascularization while still protecting the myocardium during the performance of OPCAB. The role of the anethesiologist during this operation cannot be overemphasized. The anesthesiologist is a critical member of the operating team and must be closely involved throughout the procedure. Routine monitoring of the patient's hemodynamic status, the EGG, and the intraoperative transesophageal echocardiogram (TEE) are just some of the important roles of the anesthesiologist. He/she must be aware of every step of the operation to be able to cooperate with the surgeon during the procedure. Maintenance of stable hemodynamic indices using mechanical or pharmacologic means of support at appropriate times during the operation is critical to the success of the procedure. Mechanical support may mean as little as positioning the operating table to allow easier manipulation of the heart and improved exposure of the target vessel. Throughout the OPCAB operation the heart is manipulated out of the pericardium and does not remain in the anatomic position. This leads to changes in the pattern of the EGG and TEE images. Despite this, constant attention needs to be paid to these monitoring techniques to determine the onset of myocardial ischemia as rapidly as possible. The routine use of a pulmonary artery (PA) catheter has declined tremendously since the advent of OPCAB, but whenever a PA catheter is in place, it supplies valuable information about the status of myocardial function. Any sudden or slow increase in the PA pressure with or without a drop in systemic blood pressure may signify myocardial ischemia and appropriate corrective action may need to be undertaken rapidly. It is equally important for the anesthesiologist to be proficient in the use of inotropic agents since these may help or hurt myocardial perfusion. It is rare at the present time to need much inotropic support during the performance of OPCAB surgery and the need to do so may also be a sign of impending or ongoing localized/global myocardial ischemia. Pharmacologic support during OPCAB may take many different forms. Preoperative administration of beta-blockers has been shown to conclusively reduce the incidence of perioperative myocardial infarction

136 in patients with coronary artery disease undergoing any kind of cardiac or noncardiac surgery [14]. Most patients undergoing coronary artery bypass grafting surgery would already be on beta-blocker therapy, but if they are not, it should be started. Beta-blocker drugs are thought to have a cardioprotective effect, thus reducing the overall incidence of perioperative myocardial infarctions. Ultra-short-acting beta-blockers were used commonly to induce bradycardia during the early stages of development of stabilizing devices to help achieve a less mobile target during performance of the distal anastomosis. Intravenous adenosine was also used for the same purpose. Multiple other agents have been tried as myocardial protecting agents such as selective Na+-H+ exchange inhibitors (Cariporide, Aventis Pharmaceuticals), ATP-dependent potassium channel-modifying agents [15]. Most of these agents are not used any more since the development of the new mechanical stabilizers. If anything, bradycardia maybe treated by the application of transient epicardial atrial or ventricular pacing to improve the cardiac index and hemodynamic status of the patient. In addition to these pharmacologic agents, intravenous nitroglycerine can be used judiciously during the operation to improve coronary perfusion via coronary vasodilatation. This needs to be monitored carefully by the anesthesiologist to avoid hypotension from excessive venodilatation. Some surgical teams have used a technique known as hypotensive anesthesia using small doses of arteriodilators to reduce the systolic blood pressure and the systemic vascular resistance and thus reduce the left ventricular stroke work index to reduce myocardial oxygen demand [16]. Continuous monitoring of the cerebral oximetry is performed during this period of relative hypotension to ensure adequate oxygen supply to the brain. The patient's temperature also needs to be monitored closely. During OPCAB surgery, it is not uncommon for the patient's body temperature to drift down over a period of time, which may lead to all the attendant complications of hypothermia. There is a sizeable amount of heat lost with the chest being open for a long time, and the intravenous fluids being administered should be heated to normothermic levels. In our practice, we keep the operating room significantly warmer than we would otherwise do and pay meticulous attention to maintaining normothermia throughout and after the operation. A Bair Hugger maybe used around the lower part of the body

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after closure of the saphenous vein excision site, or from the very beginning if no lower extremity conduit is being used.

Operative strategy and technique The operative strategy and technique employed by the cardiac surgeon has a tremendous impact on protecting the myocardium against ischemia. As mentioned previously, complete revascularization is the goal and is certainly achievable when OPCAB surgery is performed carefully keeping the basic tents of myocardial protection and stable hemodynamics in mind. Maintenance of stable hemodynamics ensures adequate coronary as well as cerebral and systemic perfusion. In the presence of diseased coronary arteries, it is especially important to keep the coronary perfusion as normal as possible due to the limited reserve for oxidative metabolism within the myocardium. Hemodynamic changes and instability may be seen at various stages during the operation. Cardiac manipulation to expose the various coronary targets causes mechanical disturbance leading to altered hemodynamics. It is very important that proper techniques are utilized to achieve the needed exposure. Most of these have focused on combinations of deep pericardial suture placement and cardiac displacement or herniation [ 16]. We use a single suture (LIMA suture) technique [17] to elevate the heart and allow easy manipulation and complete exposure of all coronary arteries. This technique entails placement of a single heavy suture (#1 Ethibond or silk) in the oblique sinus of the posterior pericardium (Figure 15.1). The suture is then passed through a long gauze packing, which is secured with a snare placed over the suture. Application of tension on the packing and snare in different directions allows elevation and lateral displacement of the heart. The exposure may be further enhanced, if needed, by rotation of the operating room table or raising or lowering the head of the table. To achieve adequate exposure of the lateral, posterior or inferior wall vessels, the gauze packing is pulled gently in a more lateral or inferolateral direction, thus allowing the apex to elevate and rotate as necessary. The operating table may be placed in the Trendelenburg position to allow the heart to fall away from the diaphragmatic surface of the pericardium, thus allowing for easier exposure of the branches of the right coronary artery. Likewise, the table may be

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Beating heart CABG

Figure 15.1 (a) Schematic representation of position for the LIMA suture. (Continued overleaf.)

rotated towards the patient's right side to improve exposure of the lateral wall of the heart including the high diagonal and obtuse marginal coronary arteries. While the heart is thus elevated and pericardium is being retracted, there may be some constriction of the vena cavae and thus it is important to remember not to pull up on the right side of the pericardium or to relax the right-sided pericardial sutures if these were placed before. This will allow unimpeded venous return to the right side of the heart and also prevent the heart from hitting the undersurface of the right hemisternum. The scope of this chapter does not allow complete description of the techniques used for these maneuvers but the accompanying figures (Figures 15.2-15.5) allow the reader to understand

the technique. A more complete description may be obtained from reference [17]. It has been reported previously that vertical displacement of the heart is associated with hemodynamic instability along with reduced cardiac index and blood pressure [18-20]. The use of the single suture technique minimizes cardiac displacement and abolishes the need for adjunctive exposure techniques such as cardiac herniation or placement of multiple deep pericardial sutures. Various different types of stabilizers are available to stabilize the area around the target vessel to allow performance of an accurate anastomosis. These may be broadly classified into those that use suction technique or those that use a compression technique to achieve this stabilization. Multiple other adjunctive

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Figure 15.1 (continued) (b) LIMA suture placement.

Figure 15.2 Position of the heart for distal anastomosis to the LAD.

devices are available that ostensibly improve exposure by aiding in the positioning of the heart by the use of suction applied to the apex of the left ventricle, which in turn can be used to verticalize the heart and expose

the lateral wall. The use of these devices may make it easier to expose the target vessels and thus reduce the amount of cardiac manipulation. Other devices are also available that allow for right heart circulatory sup-

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Figure 15.3 Position of the heart for distal anastomosis to the diagonal branch of the LAD.

Figure 15.4 Position of the heart for distal anastomosis to the obtuse marginal branch of the circumflex coronary artery.

port while performing OPCAB [20,21]. We do not believe that these devices are necessary for the performance of OPCAB to achieve complete myocardial revascularization safely and we do not use them in our practice. The use of an intra-aortic balloon pump (IABP) in patients who are unstable or have poor ventricular function may provide an additional degree of hemo-

dynamic assistance and stability with improvement in coronary perfusion, and may allow performance of OPCAB in such a group of high-risk patients [22]. In the presence of multivessel coronary artery disease with involvement of LAD, we usually elect to bypass this vessel first. Due to the anterior location of the LAD, minimal manipulation and elevation of the heart is required to achieve adequate exposure. Thus,

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Figure 15.5 Position of the heart for distal anastomosis to the posterior descending branch of the right coronary artery.

there is minimal hemodynamic instability while performing the graft. If the left internal mammary artery (LIMA) is being used to bypass the disease in the LAD, as is usually the case, it also allows for reperfusion of the most critical area of the myocardium right away, making it easier for the conduct of the remainder of the operation. As long as the pedicled LIMA graft has been harvested to an appropriate length, there is never any undue tension on the LIMA-LAD anastomosis, no matter how the heart is manipulated to allow the other distal anastomoses to be completed. Many other authors have commented on the strategies of graft sequencing and have proposed grafting of the collateralized vessels first [16,18,23], or to perform proximal anastomoses of the nonpedicled grafts prior to the distal anastomoses. In our experience, we have noted that performance of the LIMA-LAD anastomosis first reduces hemodynamic problems through the rest of the operation and thus allows for greater patient stability. Perhaps since the LAD and its branches together supply the largest area of myocardium, alleviating ischemia to these areas at an early stage during the operation makes for a more stable hemodynamic course while manipulating the heart to graft the other targets. The availability of the new anastomotic devices such as the Symmetry device (St Jude, Minneapolis, MN) allows for the performance of sutureless proximal anastomosis but makes it necessary to perform the proximal anastomosis before the distal. This

may be advantageous, since as soon as the distal anastomosis is performed that area of the myocardium is revascularized and ischemia is alleviated. In addition, the aorta does not need to be clamped and OPCAB surgery may be performed without ever clamping the ascending aorta. Performance of the distal anastomoses is the time at which maximal cardiac manipulation is undertaken and proper planning is necessary to try and keep any myocardial ischemia to its minimum. Once the target coronary artery has been identified and the area has been stabilized, the distal anastomosis needs to be performed with accuracy, which requires a near bloodless field. Various techniques are available to achieve this while protecting the myocardium. Most surgeons prior to coronary arteriotomy use proximal and distal snares around the target coronary artery to prevent flooding of the operative field. This produces some degree of ischemia distal to the arteriotomy site, especially if there are few or no collateral branches. There is also a certain amount of coronary artery injury if the snare is circumferential. Some people have resorted to using Silastic (Quest Medical, Allen, TX) loops around the artery to prevent injury. To prevent distal ischemia, intracoronary or aortocoronary shunts are available that allow some blood flow to pass through to the artery distal to the site of anastomosis. Intracoronary shunts allow some passage of blood while keeping the anastomotic site relatively bloodless and also allow temporary stenting of the coronary artery to

Beating heart CABG

help with accurate suture placement. There has been some discussion in the literature about shunts causing intimal injury at the anastomotic site [24-27] and thus these should be used only when necessary. If the myocardium distal to the anastomotic site has a good collateral supply and there is brisk back bleeding from the distal end of the arteriotomy, a shunt may not be necessary to maintain adequate myocardial protection. In the case of a diseased large dominant right coronary artery that needs a graft either to the main right or one of its large branches, however, a shunt should be used whenever possible since occlusion of this vessel for any length of time to facilitate performance of an anastomosis may create atrial tachy/ bradyarrhythmias. In our practice, it is routine not to use any snares proximally or distally around the target vessel and to use a blower-mister to keep the blood away from the field of work. The blower-mister utilizes a fine spray of CO2 along with normal saline solution to prevent any danger of air embolism. As soon as the coronary artery is opened, the appropriate sized intracoronary shunt is slipped into place and with the help of the blower-mister to keep the blood out of the field, the anastomosis can be performed while protecting the distal myocardium. It is important to correctly choose the size of the intracoronary shunt. Too small a shunt may not help with perfusion and blood will leak around it obliterating vision at the anastomotic site, while trying to insert too large a shunt may cause intimal injury or dissection of the coronary artery.

On-pump beating heart surgery OPCAB can be performed for the large majority of patients with coronary artery disease to achieve complete revascularization using the basic tenets of exposure and myocardial protection as outlined above. However, persistent hemodynamic instability may occasionally not allow progression of the procedure in an off-pump fashion. This may be due to several factors. Global ventricular dysfunction may occur from sequential periods of regional ischemia or the heart may not do well with even minimal manipulation, necessitating abandonment of the off-pump procedure. If the patient arrives at the operating room in a relatively unstable condition, further manipulation of a sick, ischemic heart may injure the myocardium and set the stage for the development of malignant ventricular arrhythmias, cardiogenic shock, or intraoperative

141

cardiac arrest. A vicious cycle is set up in this circumstance due to the decrease in cardiac output, leading to further deterioration of coronary perfusion superimposed on already ischemic myocardium. Various adjunctive techniques can be utilized to break this vicious cycle and rest the heart with adequate myocardial protection and still maintain normal systemic perfusion. Placing the patient on the heart-lung machine will achieve this. The operation can still be carried out on the beating heart using the previously mentioned techniques to achieve complete revascularization of all intended target coronary arteries. The heart can be emptied, the myocardium can be rested, and systemic perfusion is maintained. No crossclamping of the aorta is necessary and it is not necessary to give cardioplegia. Stabilizing devices can be used in the same fashion as in OPCAB to perform accurate anastomosis. Since the heart is kept beating and perfusion is being maintained by extracorporeal circulation, the demands of the myocardium will be met till such time that adequate revascularization can be completed. Another way to perform OPCAB with some adjunctive help is using perfusion assisted direct coronary artery bypass (PADCAB) [28-30]. With this technique distal anastomoses are constructed first, as is done in OPCAB, after which the grafts are proximally connected to the outflow of a small pump circuit. The inflow to this circuit is provided by a small cannula placed in the ascending aorta or the femoral artery. The circuit comprises a pump system called the Quest Medical MPS (Quest Medical, Allen, TX) which allows accurate control of coronary artery perfusion pressure as well as allowing the addition of various chemical additives in exact concentration at specified temperature. This enables maintenance of the coronary circulation despite changes in systemic pressure, but only after the construction of distal anastomoses. The system does allow delivery of cardioprotective agents such as nitroglycerine, adenosine, or electrolytes directly into the coronary circulation. In our practice, if the patient does not tolerate the OPCAB due to severe hemodynamic alterations, we prefer to use cardiopulmonary bypass to protect the heart but allow it to keep beating and the operation is completed without cross-clamping the aorta or ever having to stop the heart with cardioplegia. Once the proximal and distal anastomoses have been completed, it is extremely important to know that these anastomoses are patent and allow the grafts

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CHAPTER 15

to function as they are supposed to. We routinely measure flows in all grafts prior to closure of the chest to document patency of the anastomoses. In our prac-

10

tice we use the (Medistim) transit-time flowmeter, which is very simple to use in the operating room and allows correlation of flow to systole or diastole. Previously published studies have shown that routine

11

measurement of graft flows allows detection of anastomotic problems and/or conduit problems in 5-7%

12

of all cases, thus enabling the surgeon to correct the problem before the patient leaves the operating room

[23].

13

In summary, the avoidance of myocardial ischemia is an extremely important concept in beating heart coronary surgery. Central to this concept is the maint-

14

enance of stable hemodynamics during the operation for which multiple techniques are available. The above mentioned techniques allowing easy manipulation of the heart and affording good exposure of the target coronary arteries along with the use of atraumatic

15

stabilizing devices, enables accurate construction of anastomoses. Careful application of these techniques achieves excellent results for almost any patient with

16

multivessel coronary artery disease.

References 1 Westaby S. Landmarks in Cardiac Surgery. Oxford: Isis Medical Media, 1997:196. 2 Kolessov VL. Mammary artery—coronary artery anastomosis as a method for treatment of angina pectoris. J Thorac Cardiovasc Surg 1967; 54:535—44. 3 Buffolo E, Andrade JCS, Succi JE et al. Direct myocardial revascularization without CPB. Thorac Cardiovasc Surg 1985; 33:26-9. 4 Benetti FJ. Direct coronary artery with saphenous vein bypass without CPB or cardiac arrest. / Cardiovasc Surg 1985:26:217-22. 5 Benetti FJ. Video assisted coronary bypass surgery. / Cardiac Surg 1995; 10:620-5. 6 Buffolo E, Gerola LR. The evolution of coronary artery grafting on the beating heart. In: Salerno TA, Ricci M, Karmanoukian HL et al, eds. Beating Heart Coronary Surgery. Futura, Armonk, NY, 2001: 3-8. 7 Imasaka K, Morita S, Nagano I et al. Coronary artery bypass grafting on the beating heart evaluated with integrated backscatter. Ann Thorac Surg 2000; 70:1049-53. 8 Kotoh K, Watanabe G, Ueyama K et al. On-line assessment of regional ventricular wall motion by transesophageal echocardiography with color kinesis during minimally invasive coronary artery bypass grafting. / Thorac Cardiovasc Surg 1999; 117:912-17. 9 Bufkin BL, Shearer ST, Vinten-Johansen J et al. Preconditioning during simulated MIDCABG attenuates blood

17

18

19

20

21

22

23

flow defects and neutrophil accumulation. Ann Thorac Surg 1998; 66: 726-32. Thourani VH, Nakamura M, Duarte IG et al. Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass. / Thorac Cardiovasc Surg 1999:117:383-9. Wang N, Bufkin BL, Nakamura M et al. Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis. Ann Thorac Surg 1999; 67:1689-95. Bonatti J, Hangler H, Hermann Cetal. Myocardial damage after minimally invasive coronary artery bypass grafting on the beating heart. Ann Thorac Surg 1998; 66:1093-6. Perrault LP, Menasche P, Wassef M et al. Endothelial effects of hemostatic devices for continuous cardioplegia or minimally invasive operations. Ann Thorac Surg 1996; 62:1158-63. Eagle KA, Berger PB, Calkins H et al ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—Executive Summary. A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Anesth Analg 2002; 4:1052-64. Chitwood WR Jr, Wixon CL, Elbeery JR et al. Minimally invasive cardiac operation: adapting cardioprotective strategies. Ann Thorac Surg 1999; 68:1974-7. Novitzky D, Boswell B. Total myocardial revascularization without cardiopulmonary bypass using computer processed monitoring to assess cerebral perfusion. Heart Surg Forum 2000; 3:198-202. Bergsland J, Karmanoukian HL, Soltoski PR, Salerno TA. "Single suture" for circumflex exposure in off-pump coronary artery bypass grafting. Ann Thorac Surg 1999; 68:1428-30. Griindeman PF, Borst C, Van Herwaarden JA et al. Hemodynamic changes during displacement of the beating heart by the Utrecht Octopus method. Ann Thorac Surg 1997; 63: S88-S92. Grundeman PF, Borst C, Verlaan CWJ et al Vertical displacement of the beating heart by the Octuopus tissue stabilizer: influence on coronary flow. Ann Thorac Surg 1998; 65:1348-52. Griindeman PF, Borst C, Verlaan CWJ et al. Exposure of circumflex branches in the tilted, beating porcine heart: echocardiographic evidence of right ventricular deformation and the effect of right or left heart bypass. / Thorac Cardiovasc Surg 1999; 118: 316-23. Mathison M, Buffolo E, Jatene AD et al Right heart circulatory support facilitates coronary artery bypass without cardiopulmonary bypass. Ann Thorac Surg 2000; 70: 1083-5. Graver JM, Murrah CP. Elective intra-aortic balloon counterpulsation for high-risk off-pump coronary artery bypass operations. Ann Thorac Surg 2000; 71:1220-3. D'Ancona G, Ricci M, Kramnoukian HL et al. Graft patency verification in coronary artery bypass grafting: principles and clinical applications. In: Salerno TA, Ricci M, Karmanoukian HL et al. eds. Beating Heart Coronary Surgery. Armonk, NY: Futura, 2001:47-56.

Beating heart CABG

24 Rivetti LA, Gandra SMA. Initial experience using an intraluminal shunt during revascularization of the beating heart. Ann Thorac Surg 1997; 63:1742-7. 25 Lucchetti V, Capasso F, Caputo M et al. Intracoronary shunt prevents left ventricular function impairment during beating heart coronary revascularization. Eur I Cardiothorac Surg 1999; 15:255-9. 26 Van Aarnhem EE, Nierich AP, Jansen EW. When and how to shunt the coronary circulation in off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg 1999;16(Suppl2):S2-6. 27 Dapunt OE, Raji MR, Jeschkeit S et al. Intracoronary shunt insertion prevents myocardial stunning in a juve-

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nile porcine MIDCAB model absent of coronary artery disease. Eur] Cardiothorac Surg 1999; 15:173-8. 28 Guyton RA, Thourani VH, Puskas JD et al. Perfusionassisted direct coronary artery bypass: selective graft perfusion in off-pump cases. Ann Thorac Surg 2000; 69:171-5. 29 Puskas JD, Thourani VH, Vinten-Johansen J et al. Active perfusion of coronary grafts facilitate complex off-pump coronary artery bypass surgery. Heart Surg Forum 2001; 4:64-8. 30 Steele M, Palmer-Steele C. Perfusion technique for perfusion-assisted direct coronary arter bypass (PADCAB ).JExtracorp Techno/2000; 32:158-61.

CHAPTER 16

Beating heart coronary artery bypass in patients with acute myocardial infarction: a new strategy to protect the myocardium Jan F. Gummert, MD, PhD, Michael A. Borger, MD, PhD, Ardawan Rastan, MD, & Friedrich W. Mohr, MD, PhD

Introduction Acute myocardial infarction (MI) is an extremely common clinical entity, with more than 1 million people suffering an acute MI each year in the United States alone [1]. Despite advances in medical and interventional management, acute MI continues to carry a high risk of mortality with approximately 30% of such patients dying pre or posthospitalization. Therapeutic options for patients presenting with acute MI include medical management (including thrombolytics and antiplatelet agents), percutaneous transluminal coronary angioplasty (PTCA), and coronary artery bypass grafting (CABG). The vast majority of acute MI patients are currently treated with medical therapy alone, predominantly because of the speed and relative ease with which thrombolytic agents can be administered. The indications for PTCA following acute MI are controversial and beyond the scope of the current chapter. However, large series have demonstrated that approximately 10% of patients who undergo PTCA for acute MI subsequently require coronary bypass surgery [2]. Surgical revascularization is currently used in only a small minority of patients who present with acute MI. The purpose of this chapter is to describe a recently developed surgical option for patients presenting with acute MI—beating heart coronary bypass. Beating heart surgery represents a paradigm shift in myocar-

144

dial protection during coronary bypass since coronary perfusion is maintained at near physiologic levels [3]. Patients with acute infarction may particularly benefit from such physiologic perfusion. In addition, avoidance of cardiopulmonary bypass (CPB) may limit the development of postinfarction microcirculatory dysfunction (the "no-reflow" phenomenon), since CPB is known to be a potent stimulator of the inflammatory response [4]. Furthermore, temporary vessel occlusion during the construction of coronary anastomoses, a common concern during beating heart coronary bypass, is not as worrisome in acute infarction patients since the target artery is usually already occluded. Therefore beating heart CABG may be an optimal therapeutic option for patients with acute MI. The major issues to be addressed during beating heart CABG for acute MI are whether or not to perform complete revascularization (in patients with circumflex disease) and whether or not to employ CPB support, i.e. CABG with CPB support but without cardioplegic arrest (for patients with severe hemodynamic compromise). These issues and others will be discussed in more detail later in the chapter. This chapter is divided into several subsections. First, we will describe the current indications for CABG after acute MI and discuss the optimal timing for surgical intervention. Second, we will discuss the theoretical benefits of beating heart surgery for acute MI and present a summary of the most recent

Beating heart surgery for acute MI

literature on this subject. Finally, we will describe our own surgical methods for beating heart revascularization after acute MI and present our perioperative and intermediate-term results for these challenging patients.

Indications for coronary artery bypass grafting in acute myocardial infarction The current indications for coronary bypass following acute MI are not well denned. Several studies from the early 1980s reported very good results for CABG following acute MI, but the patient populations from these studies were significantly different from contemporary post-Mi patients (see below). In addition, these studies were performed before the advent of thrombolytics and coronary stents, developments that have significantly altered the management of such patients. DeWood and colleagues reported one of the largest cohorts of coronary bypass patients following acute MI in 1983 [5]. These investigators performed CABG in 701 postinfarction patients from 1971 to 1981. The overall inhospital mortality was 3.1% for patients presenting with nontransmural MI and 5.2% for patients with transmural infarction. Approximately two-thirds of transmural infarction patients were operated on within 6 h of symptoms, and their subsequent mortality was 3.8%. The mortality for patients operated on after 6 h was 8.0%. The 10-year survival for all patients was excellent at 90%. However, the average patient age for the entire cohort was only 55 years and nearly three-quarters of patients were in clinical class I or II preoperatively. More recent studies of CABG following acute MI have produced results that are not nearly so favorable. Sergeant et al. examined 269 patients who underwent coronary bypass for evolving MI (i.e. surgical revascularization between 1 and 15 h postinfarction) [6]. The inhospital mortality was 15.6% and 10-year survival was 66%. However, the patient population was significantly higher risk than the one reported on by DeWood et al. The mean patient age was 60 years and over one-half of patients were in cardiogenic shock or undergoing cardiopulmonary resuscitation prior to the operation. Similarly, Lee and colleagues recently performed a retrospective review of patients undergoing post-Mi CABG in 32 New York State hospitals between 1993 and 1996 [7]. Hospital mortality for

145

patients operated on within 1 day of their infarct (n = 1441) was 10.9%. Once again, this patient population was at significantly higher risk than the one reported by DeWood et al., with an average age of 65 years and an 8% prevalence of reoperative coronary bypass (vs. 0% in DeWood's study). Another controversial issue for post-Mi coronary bypass is the optimal timing of the procedure. Early surgical reperfusion may limit infarct extension, reduce ventricular dysfunction and subsequent remodeling, and decrease mortality [8]. Delayed surgery has been advocated by several investigators, however, because of the increased risk associated with early surgical therapy. In addition, delayed surgery may avoid the potential risk of reperfusion injury and hemorrhagic infarction. Furthermore, several randomized trials of early interventional therapy (predominantly PTCA) versus conservative therapy for acute coronary syndromes have failed to reveal a beneficial effect for early aggressive treatment [9], Many retrospective studies have examined the issue of optimal timing for post-Mi CABG. Creswell et al. reviewed 1273 patients who were operated on within 6 weeks of an MI and found a significantly increased risk of mortality for patients receiving early surgical therapy [10]. Likewise, Lee et al. studied 44 365 postMi CABG patients and found a mortality rate of 11.8% for those operated on within 6 h, 9.5% for 6 h to 1 day, and 2.8% for greater than 1 day postinfarct [7]. However, the increased risk associated with early surgery may simply reflect the increased risk factors, in particular cardiogenic shock, present in this patient population. The most common current opinion regarding timing of post-Mi surgery is that it should be delayed unless cardiogenic shock or mechanical complications (see below) are present [7]. Despite controversies regarding the optimal patient population and optimal timing of CABG after acute MI, results seem to be better than for patients treated with medical management alone. Every and colleagues in 1996 reviewed 1299 CABG patients who were admitted to 19 Seattle hospitals with acute MI over a 4-year period, and compared them to patients who were treated with medical therapy alone (n = 7541) [11]. CABG patients had lower hospital mortality than medically treated patients (7.2% vs. 11.4%, P < 0.001). In addition, CABG patients were less likely to undergo angiography or PTCA during 3 years follow up, and less likely to require rehospitalization when compared

146 to medical patients. CABG may also possess advantages over PTCA post-Mi since a more complete revascularization is possible. Coronary bypass remains an uncommon entity in post-Mi patients, despite its apparent efficacy. The main reason for this infrequent usage is probably related to technical aspects of cardiac surgery, rather than problems with surgical results. Such technical problems include the fact that cardiac surgery is not available in the majority of centers that admit patients with MI, it requires a well-organized and readily available team, and it may result in unacceptable delays in treatment when compared to thrombolytic therapy. Although CABG is uncommon in post-Mi patients, there are some generally agreed upon indications for surgical intervention postinfarction. These are: 1 cardiogenic shock; 2 evolving infarction despite thrombolytic and/or PTCA therapy; 3 contraindications to thrombolytic and/or PTCA therapy (e.g. bleeding diathesis, left main stenosis, etc.); 4 postinfarction angina with coronary anatomy unsuitable for PTCA; 5 acute coronary occlusion during PTCA; 6 early post-CABG MI secondary to acute graft occlusion; 7 acute mitral regurgitation; 8 ventricular septal defect; 9 myocardial free wall rupture. The last three indications are the mechanical complications of acute MI and are well recognized as definite indications for surgery. However, each of these complications requires reparative surgery under cardioplegic arrest and therefore will not be discussed any further in this chapter. Post-Mi CABG for the other six indications can be accomplished with beating heart surgical techniques. Of these six indications, postinfarction angina is the most common clinical entity. However, such patients are relatively stable and their surgery can often be performed under a delayed, semielective fashion. Surgical revascularization for the other five indications is usually performed under urgent or emergent conditions and the patients are at markedly increased risk. It is these patients who we will focus on during the discussion of our institutional results for beating heart CABG post-Mi (see "Our experience" below).

CHAPTER 16

A special note should be made about CABG for post-Mi cardiogenic shock. Cardiogenic shock is known to occur in 7-10% of patients hospitalized with acute MI. The SHOCK trial is the largest and most methodologically sound study of interventional therapy for post-Mi cardiogenic shock. A total of 302 such patients were randomized to receive initial medical stabilization or emergency revascularization within 6 h of presentation [12]. Of the 152 patients randomized to emergency revascularization, 36% underwent coronary bypass surgery and 64% PTCA. Six-month mortality was significantly lower in patients assigned to early revascularization (50% vs. 63%, P = 0.03), with further improvements realized for patients under 75 years of age. The SHOCK trial also produced the largest nonrandomized registry of patients with post-Mi cardiogenic shock (n = 1190) [ 13]. In this registry hospital mortality for the 136 patients who underwent CABG was 28%, a significant improvement over the 46% mortality for those patients treated with PTCA (n = 268). In addition, mortality rates for patients receiving revascularization (CABG or PTCA) were much lower than for those receiving medical therapy alone (89%, n = 334; P = 0.01). Some of this difference, however, may have been attributable to the higher risk profile of medically treated patients. It should also be noted that the improved mortality rates for CABG for cardiogenic shock obtained from the SHOCK registry are remarkably similar to pooled estimates obtained from 25 different studies [14]. We can therefore conclude that early revascularization, and CABG in particular, should be strongly considered in patients with postMi cardiogenic shock.

Beating heart surgery for acute myocardial infarction As stated in the Introduction, beating heart coronary bypass is a new treatment strategy for patients with acute MI. As such, there are relatively few studies in the literature on this topic. In this section we will review the techniques and results from the available literature. One of the earliest reports of off-pump CABG in post-Mi patients was reported by Benetti et al. from Argentina [15]. These investigators performed beating heart surgery within 10 h of acute MI in 32 patients over an 11-year period. Four patients (13%) were in

Beating heart surgery for acute MI preoperative cardiogenic shock. The results achieved were exceptional. No inhospital deaths occurred and none of the patients suffered from low cardiac output syndrome. Follow up revealed that one patient had died, one was in congestive heart failure (CHF), and one required redo CABG for angina. The authors concluded that beating heart CABG was an acceptable alternative for patients presenting with acute MI. Mohr et al. from Tel Aviv University published one of the most important papers on post-Mi beating heart CABG in 1999 [16]. Of the 1245 patients who were admitted to their institution with acute MI over a 3-year period, only 67 were referred for coronary bypass surgery. The authors reviewed their experience with the 57 surgical patients (mean age 58 years) who underwent CABG without CPB. All of the patients were operated on less than 1 week post-Mi, including 32 who underwent surgery within 48 h of their infarction and seven who were in cardiogenic shock. The investigators avoided beating heart CABG in patients with disease in the circumflex territory or with target coronary vessels of less than 1.5 mm in diameter (such patients underwent conventional CABG with CPB). They attempted to keep the patient's systemic blood pressure above 100 mmHg intraoperatively in order to maintain adequate coronary perfusion. Four patients required insertion of an intra-aortic balloon pump (IABP) because of hemodynamic instability. The mean number of coronary bypass grafts was 1.8, with 12% of patients receiving a graft to the circumflex territory. The left internal thoracic artery was used in 82% of patients. Approximately one-third of patients ended up with an incomplete revascularization, i.e. without revascularization of the circumflex territory. The postoperative results achieved by Mohr et al. were excellent. One patient (2%) died perioperatively and there were no strokes or fatal Mis. The mean hospital stay was 7 days. Late follow up (mean 46 months postoperation) revealed that eight patients (14%) had died, including five from cardiac causes. Angina returned in seven patients (12%), two of whom required PTCA and one who required redo CABG. Actuarial 5-year survival was 82%. Of the 54 hospital survivors who were available for follow-up, 79% had a completely uneventful perioperative and long-term outcome. These same investigators published another article in 2000 that focused on patients who underwent CABG within 48 h of acute MI [17]. A total of

147

77 patients underwent urgent or emergent post-Mi revascularization over a 6-year period, 40 of which were performed without CPB. The mean number of grafts was 3.0 for the on-pump group versus 1.9 for the beating heart group (P< 0.001). Perioperative mortality was lower for patients undergoing beating heart CABG (5%) than for those undergoing conventional CABG (24%, P = 0.01), even after controlling for other risk factors. Furthermore, beating heart CABG patients had significantly less requirements for postoperative inotropic or IABP support. Long-term follow up, however, revealed fewer deaths and fewer cardiac reinterventions in the conventional CABG group. The authors concluded that although beating heart CABG results in superior perioperative outcomes post-Mi, long-term outcomes appear to be better for patients who undergo conventional CABG. They hypothesized that the increased cardiac events in the beating heart group may be related to the increased incidence of incomplete revascularization. It is possible that so-called "hybrid procedures", i.e. beating heart revascularization of left anterior descending (LAD) and right coronary artery (RCA) lesions, combined with PTCA of the circumflex territory, could result in optimal outcomes for these high-risk patients [18]. Two other articles have been recently published on this topic. Vlassov et al. from Moscow reviewed 26 consecutive patients who underwent beating heart CABG within 96 h of acute MI [19]. The authors performed conventional off-pump coronary artery bypass (OPCAB) through a median sternotomy in 16 patients and minimally invasive direct coronary artery bypass (MIDCAB) through a left anterior thoracotomy in 10 patients. Four patients (15%) had preoperative cardiogenic shock. The mean number of coronary bypasses was 1.8, with 15% of patients receiving an incomplete revascularization. Two MIDCAB patients underwent a hybrid procedure with PTCA of the circumflex territory 10 days postoperatively. The perioperative mortality rate was 8%. Inotropic support was necessary in 35% of patients and 19% of patients required an IABP. Early postoperative angiography revealed patency of all studied grafts. In another recent study, D'Ancona et al. from Buffalo reviewed their experience with patients undergoing CABG less than 21 days post-Mi [20]. All post-Mi patients undergoing OPCAB (n = 97) were compared to those undergoing conventional

148

on-pump CABG (n = 421) over a 4-year period. The incidence of preoperative cardiogenic shock was low at less than 1%. The OPCAB group had a significantly higher prevalence of many risk factors including renal failure, CHF, and redo CABG, but the conventional group had more circumflex disease. Conventional CABG patients received significantly more coronary bypasses (3.5 vs. 1.8, P< 0.001). The authors failed to find any statistically significant differences in postoperative outcomes. However, there was a trend towards higher mortality in the OPCAB group (6% vs. 3%, P = NS). The authors for both of these recent studies concluded that beating heart CABG is a safe and viable treatment alternative for patients presenting with acute MI.

Our experience At the Leipzig Heart Center we have performed 1842 beating heart coronary bypass procedures between 1996 and 2000. These operations include those performed through a left anterior minithoracotomy (MIDCAB, n = 1077) as well as those performed through a median sternotomy (OPCAB, n = 765). Over this same time period, we have performed 1904 isolated coronary bypass procedures in patients with unstable angina and other acute coronary syndromes (Figure 16.1). A comparison of patients with and without a history of preoperative MI (i.e. acute and nonacute MI) revealed that perioperative mortality was significantly higher in those with previous infarction (8.0% vs. 4.1%, P < 0.001). As can be seen

CHAPTER 16

in Figure 16.1, however, mortality was significantly reduced if revascularization was performed under a beating heart technique. Perioperative mortality was 8.5% for post-Mi patients undergoing conventional CABG versus 4.3% for beating heart patients (P< 0.001). It is because of these encouraging results that we enacted an institutional policy of performing beating heart revascularization for patients requiring surgery after acute MI. We believe that maintaining near physiologic coronary perfusion in these difficult patients is an important advantage of this technique. Over the last 2 years, we have performed a total of 101 beating heart revascularizations in patients with acute MI. Approximately one-half (n = 49) of these patients had ST elevation upon presentation, while the remainder had non-ST elevation infarctions. All patients underwent surgery within 6 h of presentation to our hospital. The following methods and results will focus on these 101 patients.

Methods Our procedure of choice for post-Mi CABG is via a median sternotomy (i.e. OPCAB) approach. Our goal was to maintain a systemic blood pressure of greater than 100 mmHg during the procedure in order to maximize coronary perfusion. If the patient's hemodynamic status became unstable intraoperatively, we inserted an IABP and/or placed the patient on CPB support. Patients who were supported with CPB, however, did not undergo aortic cross-clamping or cardioplegic arrest. That is, we used a beating

Figure 16.1 Perioperative mortality rates for patients with unstable angina and other acute coronary syndromes (n = 1904) operated on between 1996 and 2000 at the Leipzig Heart Center. Mortality was significantly higher for conventional coronary bypass with cardioplegic arrest when compared to beating heart surgery, particularly in patients with a history of preoperative myocardial infarction. CABG, coronary artery bypass grafting; Ml, myocardial infarction.

Beating heart surgery for acute MI heart technique with CPB support in these high-risk patients. Our surgical technique was otherwise similar to that used for routine OPCAB surgery. Two retraction sutures were placed in the posterior pericardium. We used CTS retractors and stabilizers (CardioThoracic Systems Inc.; Cupertino, CA) for target vessel exposure and stabilization. A 4-0 polypropylene, pledgeted suture was placed around the target vessel proximal to the anastomotic site and was gently tightened with a tourniquet in order to achieve hemostasis. The coronary arteriotomy was performed 1 min thereafter, if no significant EGG or hemodynamic disturbances occurred. Intracoronary shunts were used if the target vessel had a subcritical stenosis, if there were signs of hemodynamic or electrocardiographic instability during vessel occlusion, or if coronary blood flow was excessive and obscuring the field of vision. We used the left internal mammary artery (LIMA) to bypass the LAD coronary artery whenever possible. Multiple arterial grafts were used in hemodynamically stable patients less than 70 years of age. All patients underwent intraoperative assessment of graft patency using transit time flow measurement (Cardio-Med Flowmeter CM 4000, Medi-Stim; Oslo, Norway). Those patients with a transit time flow of less than 15 ml/min underwent intraoperative monoplane angiography and/or surgical revision of the corresponding anastomosis. Results As previously stated, we performed beating heart CABG within 6 h of hospitalization for acute MI in 101 patients. The average patient age was 66 ± 11 years (mean ± SD) and 74% were male. The indications for surgery were post-Mi cardiogenic shock (26% of patients), evolving MI unresponsive to or unsuitable for lysis or PTCA (48%), early post-Mi angina (14%), or complications of PTCA (12%). In general, the risk profile for this group of patients was higher than for the populations in the studies previously discussed. An IABP was inserted preoperatively in 17% of patients, 19% were intubated and ventilated, and 18% underwent preoperative cardiopulmonary resuscitation (CPR). Table 16.1 displays other preoperative characteristics for this group of patients. The average number of coronary bypass grafts performed was 2.8 ± 0.9. We used the LIMA to bypass the LAD in 89% of patients, a vein graft in 6%, and the

149

Table 16.1 Preoperative characteristics of patients undergoing early post-Mi beating heart CABG (n = 101) at the Leipzig Heart Center. Variable

Prevalence (%) *

Diabetes

35

Hypertension

84

Renal failure Previous Ml

40

LVEF (%)

46±16

Previous CABG Thrombolysis

18

Glycoprotein llb/llla inhibitors CK(IU) CK-MB (IU)

13

4

19 735 + 1134

1081131

*Continuous variables are expressed as mean ± SD. Ml, myocardial infarction; LVEF, left ventricular ejection fraction, CABG, coronary artery bypass grafting; CK, creatine kinase, CK-MB, creatine kinase MB fraction.

LAD was not bypassed in 5%. Multiple arterial grafts were used in 22% of patients. The right coronary artery received one or more grafts in 66% of patients and 78% received one or more grafts to the circumflex territory. A total of 30 patients (30%) were placed on CPB intraoperatively because of hemodynamic instability (i.e. beating heart CABG with CPB support). CPB support was instituted immediately after arrival in the operating room in 10 patients and during exposure of the circumflex territory in 20 patients. The left ventricle was further unloaded in these patients with hemodynamic instability by inserting a suction vent in the pulmonary artery. As expected, the morbidity and mortality for this high-risk group of patients was higher than elective coronary surgery. An IABP was required postoperatively in 41% of patients, including the 17% who required preoperative IABP support. Stroke occurred in three patients, of which two were fatal. The average intensive care stay (including intensive and intermediate care unit stay) was 7.8 ± 9.8 days. A total of nine patients required resternotomies for bleeding and three patients required revision of one or more coronary bypass grafts. Inhospital mortality was 17%. However, mortality was significantly lower for patients without preoperative cardiogenic shock than for those with preoperative shock (9% vs. 38%, P = 0.001).

CHAPTER 16

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A special note should be made about postacute MI patients with circumflex disease. It has been our experience, as with other investigators, that such patients poorly tolerate surgical exposure of this territory. The options for these patients are to therefore: (i) place the patient on CPB support; (ii) perform an incomplete revascularization; or (iii) perform a hybrid procedure with subsequent PTCA of the circumflex lesion. It is our current practice to place such patients on CPB support with subsequent revascularization of the circumflex territory whenever possible. We have concluded from our experience with beating heart CABG post-Mi that it is a feasible and relatively safe procedure, and may result in a lower mortality than conventional coronary revascularization. However, a large proportion of patients may require intraoperative CPB support for hemodynamic instability, particularly if they had preoperative cardiogenic shock. Further studies are required to determine the optimal population and timing for post-Mi beating heart CABG, as well as to determine what the long-term outcome is for such patients.

Conclusions In conclusion, beating heart surgery after acute MI represents a paradigm shift in myocardial protection during coronary revascularization. It has been hypothesized that beating heart CABG may be the optimal surgical approach post-Mi because of maintenance of near physiologic coronary perfusion and avoidance of the deleterious inflammatory effects of CPB. However, relatively few studies exist in the literature to support or refute this hypothesis. The small number of publications is undoubtedly related to the recent development of this surgical technique and the small number of MI patients that present for surgical revascularization. A critical review of the available literature, as well as our own institutional results, reveals that beating heart CABG is feasible and safe in these technically challenging patients. Furthermore, preliminary evidence suggests that beating heart surgery post-Mi may result in lower perioperative mortality than conventional CABG. Beating heart CABG after infarction may be associated with a higher rate of incomplete revascularization and may result in more long-term cardiac events and reinterventions. Our own institutional results, however, suggest that more complete

revascularization is possible with the assistance of CPB support. Mortality remains significant for these highrisk patients, however, particularly if cardiogenic shock is the indication for surgery. Further studies are required before definitive conclusions can be made about beating heart CABG postMi. In addition, future studies should examine the results of hybrid beating heart CABG and PTCA procedures. It remains to be seen whether the theoretical benefits of beating heart revascularization result in improvements in patient outcomes postmyocardial infarction.

References 1 American Heart Association, http://americanheart.org/ statistics. 2 Stone GW, Brodie BR, Griffin JJ et al. Role of cardiac surgery in the hospital phase management of patients treated with primary angioplasty for acute myocardial infarction. Am J Cardiol 2000; 85:1292-6. 3 Flameng WJ. Role of myocardial protection for coronary artery bypass grafting on the beating heart. Ann Thome Surg 1997; 63:518-22. 4 Cohn WE, Ruel M. Invited commentary on acute myocardial infarction: OPCAB is an alternative approach for treatment. Heart Surg Forum 2001; 4:150-1. 5 DeWood MA, Spores J, Berg R Jr et al. Acute myocardial infarction: a decade of experience with surgical reperfusion in 701 patients. Circulation 1983; 68: II8-II16. 6 Sergeant P, Blackstone E, Meyns B. Early and late outcome after CABG in patients with evolving myocardial infarction. Eur J Cardiothorac Surg 1997; 11: 848-56. 7 Lee DC, Oz MC, Weinberg AD et al. Optimal timing of revascularization: transmural versus nontransmural acute myocardial infarction. Ann Thome Surg 2001; 71: 1198-204. 8 Kaul TK, Fields BL, Riggins SL et al. Coronary artery bypass grafting within 30 days of an acute myocardial infarction. Ann Thome Surg 1995; 59:1169-76. 9 Holmes DR. Acute coronary syndromes: extending medical intervention for five days before proceeding to revascularization. Am J Cardiol 2000; 86 (Suppl): 36M-41M. 10 Creswell LL, Moulton M}, Cox JL et al. Revascularization after acute myocardial infarction. Ann Thome Surg 1995; 60:19-26. 11 Every NR, Maynard C, Cochran RP et al. Characteristics, management, and outcome of patients with acute myocardial infarction treated with surgery. Circulation 1996 ; 94:1181-6. 12 Hochman JS, Sleeper LA, Webb JG et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. NEnglJMed 1999; 341:625-34. 13 Hochman IS, Buller CE, Sleeper LA et al. Cardiogenic shock complicating acute myocardial infarction—

Beating heart surgery for acute MI

etiologies, management and outcome: a report from the SHOCK trial registry. / Am Coll Cardiol 2000; 36: 1063-70. 14 Hochman JS, Gersh BJ. Acute myocardial infarction: complications. In: Topol, EJ, ed. Textbook of Cardiovascular Medicine. Philadelphia: Lippincott-Raven, 1998: pp. 437-80. 15 Benetti FJ, Mariani MA, Ballester C. Direct coronary surgery without cardiopulmonary bypass in acute myocardial infarction. / Cardiovasc Surg (Torino) 1996; 37: 391-5. 16 Mohr R, Moshkovitch Y, Shapira I et al. Coronary artery bypass without cardiopulmonary bypass for patients with acute myocardial infarction. / Thorac Cardiovasc Surg 1999; 118: 50-6.

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17 Locker C, Shapira I, Paz Y et al. Emergency myocardial revascularization for acute myocardial infarction: survival benefits of avoiding cardiopulmonary bypass. Eur J Cardiothorac Surg 2000; 17:234-8. 18 Zenati M, Cohen HA, Griffith BP. Alternative approach to multivessel coronary disease with integrated coronary revascularization. / Thorac Cardiovasc Surg 1999; 117: 439-46. 19 Vlassov GP, Deyneka CS, Travine NO et al. Acute myocardial infarction: OPCAB is an alternative approach for treatment. Heart Surg Forum 2001; 4:147-50. 20 D'Ancona G, Karamanoukian H, Ricci M et al. Myocardial revascularization on the beating heart after recent onset of myocardial infarction. Heart Surg Forum 2001; 4: 74-9.

CHAPTER 17

Beating heart coronary artery bypass with continuous perfusion through the coronary sinus Harinder Singh Bedi, MCH, FIACS

Introduction In recent times there has been resurgence in interest in the performance of coronary artery bypass surgery (CABG) without the use of cardiopulmonary bypass (CPB). While previously it was being used only in cases where cannulation, CPB, or hypothermia were not possible [1], it is now being used electively. Smoother postoperative recoveries, reduction in homologous blood transfusion requirement, a shorter ICU and hospital stay with quicker return to normal life are also expected. In developing countries, an important factor that has prompted the interest in beating heart procedures is the major cost saving with the avoidance of CPB. However with off-pump procedures there has been a compromise in the completeness of revascularization with most authors reporting ungrafted circumflex coronary artery disease [2,3]. Even with the beating heart technique using the octopus suction stabilizer for multivessel disease via median sternotomy, all three territories were not grafted [4]. This is one of the major causes of morbidity and mortality. The excellent long-term patency rates associated with conventional CABG must not be compromised for the sake of initial patient comfort or cost. Absolute prerequisites for beating heart surgery are a quiet bloodless field and avoidance of ischemia during the time the coronary artery is snared. During off-pump CABG (OPCABG) the target artery has to be snared in order to perform the arteriotomy and subsequent construction of the anastomosis without having continuous flow of blood in

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the field. Snaring of the artery invariably produces ischemia, which may not be tolerated especially when the heart is lifted and rotated to reach the lateral wall. The onset of ischemia leading to EGG changes and hemodynamic compromise leads to either conversion to CPB or to hasty completion of the anastomosis, which may have adverse effects on the accuracy of the suturing. To overcome the period of ischemia and for regional myocardial preservation we have devised a technique of perfusing the area of myocardium at risk via retrograde perfusion with oxygenated blood from the ascending aorta allowing performance of an unhurried and precise anastomosis.

Technique Preoperative preparation The salient features of preoperative preparation, anesthesia, method of access, and stabilization have been previously described [5]. These are described below in brief.

Maintenance of normothermia One of the problems with off-pump surgery is that the temperature of the patient tends to drift, decreasing by as much as 3-4°C if precautions are not taken. In all cases, the operating room (OR) is preheated to 25°C. The sedated patient is placed on a warm water blanket connected to a Sarns TCM II (Sarns, 3M HealthCare, Ann Arbor, MI). Before draping, an air blanket connected to a Bair Hugger (Augustine Medical Inc, Eden Prairie, MN, USA) is used to cover the patient. All scrub solutions and intravenous fluids are preheated

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to body temperature. After draping, the nozzle of the Bair Hugger is placed under the drapes (making sure that there is no direct contact with skin). With these measures the temperature drift is restricted to

Operative technique Surgical access in all cases is via median sternotomy. The skin incision is kept limited both superiorly and inferiorly by dissecting small skin flaps. We feel that a standard mid-sternotomy is the approach of choice for precise harvesting of both the internal mammary arteries, for retrograde cannulation of the coronary sinus (described below in "Technique for avoidance of ischemia and regional myocardial preservation") to access all areas of the heart for performance of the proximal anastomoses, and for ease of conversion to CPB should the need arise.

loupes (x3.5). Usually a single running suture is used, or infrequently two sutures beginning at the heel and toe of the anastomosis. An attempt is made to create two anastomoses with one suture by keeping one end extra long and using it for the second graft (using only one needle). The goal is to further reduce cost. The field is kept bloodless by use of a Visuflow blower (Research Medical, Inc, Midvale, UT), which produces a clear field without drying the tissues. Heparin is fully neutralized with protamine sulfate at the end of the procedure.

Maintenance of hemodynamic stability During construction of the anastomoses the heart rate is brought down to 50-70 beats/min by the use of intravenous beta-blockers with or without intravenous diltiazem infusion. The need to reduce heart rate has generally decreased with the use of cardiac stabilizers.

Initial assessment The pericardium is opened after sternotomy. The coronary artery anatomy is assessed for suitability for an off-pump procedure. All patients coming for elective CABG are candidates for OPCABG. The area that is the most difficult to approach off pump is the lateral and posterior wall. To expose these areas a very gentle trial lifting of the heart is preformed. Any gross changes in arterial pressure, pulmonary artery pressure, cardiac output, 12 lead ECG, and ST segment are carefully monitored. If the heart does not tolerate handling, further attempts at OPCABG are abandoned and conventional CPB is used. In all cases, pump standby is available with a perfusionist in the OR.

Cardiac wall stabilization Stabilization of the target area is achieved by a combination of methods. We started with the use of local pericardial stay sutures (exclusively in the first 100 cases of multivessel OPCABG) [5], then we went on to use various devices including the Diamond Grip Rib Spreader/Cardiac Stabilizer (Genzyme Corporation; Cambridge, MA), the Origin Cardiac Stabilizer and Stabilizer Foot (Origin, Menlo Park, CA), the Mechanical Stabilizer (CTS Inc, Cupertino, CA), and the Octopus 3-0 Tissue Stabilizer System (Octopus, Medtronic Inc., Minneapolis, MN), and recently the Starfish Heart Positioner (Medtronic Inc, Minneapolis, MN).

Distal anastomosis After heparinization (1.5 mg/kg heparin intravenously) the target area is immobilized and snared with a silicone vascular loop (Retract-O-Tape Air Cushion, Deknatel/DSP, Lubeck, Germany) and a blunt needle. Loops are passed deep under and around the coronary artery. An effort is made to isolate as little as possible of the coronary artery to minimize ischemia. The Retract-O-Tape is either snared with a thin silicone tube over a buttress of a piece of pericardium, vein or thymic tissue. The suture may be taken one more time around the artery and pulled up around the buttress. The anastomosis is constructed with a running 8-0 prolene (Ethicon, Somerville, NJ) (for arterial grafts) or 7-0 prolene (for vein grafts) suture with magnifying

Technique for avoidance of ischemia and regional myocardial preservation We have employed a new technique for perfusion of the myocardium while the coronary artery is snared [5-7]. We do not recommend the use of intraluminal shunts due to their inherent risk of damage to the intima, dislodgement of atheroma, creation of a dissection, and hindrance with suturing. We use perfusion of arterial blood through a retrograde coronary sinus cannula. The retrograde cardioplegia catheter with a self-inflating balloon (Gundry RSCP catheter, (Medtronic DLP, Grand Rapids, MI) or a 3M Sarns

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catheter (3M, Ann Arbor, MI)) is eased transitorily into the coronary sinus through a pursestring suture placed in the low right atrium by a standard technique [8] after systemic heparinization (1.5 mg/kg heparin intravenously). Insertion of the catheter is easy in a beating off-pump heart (vs. an empty on-pump heart) as the coronary sinus is full and distended. Also there is no venous drainage cannula in the right atrium. Its position is confirmed by palpation and by checking the pressure via the integral pressure line (20 mmHg or less). An antegrade cardioplegia cannula (Baxter (Research Medical Inc., Midvale, UT) or Jostra (Jostra Medizintechnik, Hirrlingen, Germany)) is positioned into the ascending aorta and is secured with a pursestring in a standard way. It is connected via a multiple perfusion set (Baxter, Research Medical Inc, Midvale, UT) to the coronary sinus cannula. After de-airing, oxygenated arterial blood at aortic pressure is allowed to perfuse the coronary sinus. The setup of the cannulas used is shown in Figure 17.1. The coronary sinus catheter pressure is carefully monitored. In most cases it is not allowed to go over 40 mmHg (mean), possibly due to the dimension and length of the connecting tubings. In four cases flow was reduced by turning the three-way stopcock until the pressure decreased to 40 mmHg (mean). The change in the pressure curve with perfusion on and off can be appreciated (Figure 17.2). Perfusion is allowed to continue throughout the procedure carefully monitoring pressure. The perfusion is turned off after the snares are released and antegrade flow (via in situ graft or free graft connected to a side arm of the multiport) is

Figure 17.1 The setup consisting of the antegrade and retrograde cannula and multiple perfusion cannula. A, antegrade cannula; M, multiperfusion cannula; R, retrograde cannula; B, self-inflating balloon of retrograde cannula; P, integral pressure line of retrograde cannula.

established. We have determined that perfusion occurs in the blocked areas (mentioned in the results). The fact that there is a two-way flow of blood (downstream via the normal way, and upstream via the coronary sinus to capillaries) is possible because of the inherent "leak" in the balloon of the catheter (S. Gundry, personal communication). In all cases,

Image Not Available Figure 17.2 Freeze frame of the monitor showing the coronary sinus pressure (labeled RV) with perfusion off (white star) and on (white arrow). Even at a systemic pressure of 153 mmHg systolic the mean coronary sinus pressure is 30 mmHg. Reprinted from [7], with permission from Society of Thoracic Surgeons.

Continuous myocardial perfusion during OPCABG

as soon as the distal anastomosis is performed, the free graft-saphenous vein graft (SVG) or radial artery (RA) is connected to a line of the multiport and is allowed to perfuse with oxygenated blood.

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Results

Follow up

The technique of retrograde perfusion has been used in 545 cases of multivessel OPCABG and in 124 cases of single and double-vessel OPCABG. There was no episode of ischemia documented by EGG changes or wall motion abnormalities, except in three patients in whom a large main RCA was being grafted. In these patients there was a 1-2 mm ST-segment elevation during the last stages of the suturing. This was managed while the anastomosis was hurriedly completed and the graft subsequently perfused. In view of the above problem with anastomosis to a large RCA and the fact that retrograde perfusion may not adequately perfuse the right ventricle [9], we now prefer, wherever possible, to graft a PDA rather than a large RCA. In all the rest of the anastomoses there was no period of EGG changes or gross hemodynamic instability. In fact now we are able to perform the anastomoses very meticulously (anastomosis time is now longer than in the earlier stages), so "racing against the clock" does not take place. Retrograde perfusion is quite safe since, in the majority of cases, the pressure in the coronary sinus does not increase above the arbitrary level of a mean of 40 mmHg [10] (Figure 17.2), even when the systemic pressure is high. We have confirmed adequacy of perfusion by the following facts: 1 EGG changes on snaring an artery, which revert to normal on starting retrograde perfusion. 2 Vigorous backbleeding of dark blood on temporary release of distal snare after arteriotomy (Figure 17.3), as seen during retrograde blood cardioplegia infusion indicating that the myocardium is being perfused and is utilizing the oxygen from the arterial blood perfused via the coronary sinus. This visual proof of perfusion was observed in 10 out of 10 cases in the LAD, 7 out of 10 cases in the circumflex area, and 5 out of 10 cases in the main RCA. 3 A good oxygen extraction ratio (across the LAD and circumflex area) of 46 ± 4% was noted in 10 patients by taking blood from the arteriotomy and analyzing it:

Mean follow-up time was 38 months (range 1-60 months), collected through direct patient contact in all cases. All patients had serial EGG, two-dimensional echocardiograms, and exercise testing 3 months postoperatively.

Oxygen extraction O2 content (arterial) ratio across _ O2 content (arteriotomy) xlOO myocardium O2 Content (arterial)

Sequence of grafting After trying different sequences, we have now developed a set routine [5]. The easiest grafts are done first and are allowed to perfuse. This generally translates to a left internal mammary artery (LIMA) or SVG to left anterior descending (LAD), followed by the right internal mammary artery (RIMA)/radial artery (RA)/SVG to right coronary artery (RCA)/posterior descending artery (PDA). When free grafts are used the conduit is connected to a side arm of the multiport cardioplegia set and is perfused by arterial blood from the ascending aorta. For the in situ LIMA and RIMA grafts perfusion starts as soon as the distal anastomosis is completed by opening of the bulldog clamp on the conduit. All proximal anastomoses are performed in the end—SVG with 6-0 prolene and RA with 7-0 prolene. The free RA is anastomosed directly to the aorta (mostly) or on to a SVG as a piggyback graft or to the LIMA as a Y graft (this is done before starting the first distal anastomosis). The choice for the proximal site of the RA depends on the position of the target arteries, the length of conduit available, the space available on the ascending aorta, and the size and flow of the LIMA.

Revascularization assessment criteria Electrocardiograms are recorded at admission, immediate postoperatively, and then daily for 3 days and predischarge. Serial myocardial fractions of creatine kinase (CK-MB) are determined immediately postoperatively and for 2 days postoperatively. Perioperative myocardial infarction was diagnosed in the presence of one or both of the following criteria: (i) CK-MB > 50IU and (ii) the development of new Q waves. Angiography was performed in 35 patients after informed consent on the day before discharge. Graft patency was shown at 97.8% [5].

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hemorrhage during and after the period of retrograde perfusion.

Conversion to cardiopulmonary bypass

Image Not Available

Figure 17.3 Intraoperative photograph showing vigorous backbleeding (black arrow) of dark blood from the site of arteriotomy with the distal snare not snugged down. Ante, antegrade cannula; R, retrograde cannula; A, site of arteriotomy. Reprinted from [7], with permission from Society of Thoracic Surgeons.

Oxygen content = 1.36 ml O2/g x Hb x O2 saturation + (0.003 x Po2) [9]. This high extraction is suggestive of the fact that the myocardium is using up the oxygen being delivered via the retrograde route. In 12 patients endarterectomy of the RCA was required [11]. This is surprisingly easy on the beating heart, which provides excellent traction-countertraction to get the atheroma out. Distally a complete endarterectomy was possible while proximally the atheroma was cut clean. The arteriotomy was allowed to bleed freely to avoid distal embolization. So far we have had no patient requiring endarterectomy of the left system.

Intraoperative complications In one patient with unstable angina while snaring down on the LAD it was realized that the right ventricular (RV) wall adjoining the LAD was edematous and unhealthy. There was excessive bleeding from the RV wall where the retract-O-tape needle had gone through. This did not respond to the usual methods of local pressure and reversal of heparin and needed pledgetted sutures for control. In no patient was there any evidence of myocardial edema, excessive distention from coronary veins, or

This was required in one patient, who had ST changes during a main RCA-RA grafting. The ST changes recurred after sternal closure. On reopening it was seen that the radial artery was in spasm. Although there was a response to topical papaverine/diltiazem and increasing the doses of intravenous diltiazem, it was decided to supplement the radial artery with a vein graft distal to the radial artery anastomosis site. This was performed on CPB without aortic cross-clamping. On probing the anastomoses it was found that a stitch had taken both walls of the radial artery graft. This was also corrected. The patient did well subsequently.

Discussion One of the main factors in off-pump CABG that will affect graft patency and the onset of any major adverse cardiac event is precision of the coronary anastomosis. If there is a "race against the clock" while performing the anastomoses on a beating heart then it can definitely jeopardize the accuracy of the suturing. Our technique is based on the fact that, in coronary artery disease, parts of the myocardium are underperfused and this is further exaggerated when the coronary artery is snared. Regional myocardial ischemia occurs when a coronary artery is snared during construction of an anastomosis. An intracoronary shunt may minimize ischemia during grafting. However, there is the concern that damage to endothelium [12], risk of dissection, dislodgement of an atheroma, risk of an air or particulate embolism, hindrance with suturing, and at times, difficulty in insertion can occur. One study showed that intravascular catheters caused significant endothelial dysfunction in normal porcine coronary arteries of the same magnitude as the intentional removal of endothelium by endoluminal rubbing of the intimal surface [12]. Insertion and removal of an intravascular device may cause coronary vasospasm in the acute period after surgery because of loss of endothelial coverage. The denuded site may become a referential site for platelet aggregation and activation of the coagulation pathways, which can lead to premature graft failure. Previous elegant work on pressure controlled intermittent coronary sinus occlusion (PICSO) (which

Continuous myocardial perfusion during OPCABG redistributes blood to inhomogeneously perfused ischemic zones) and arterial retroperfusion of the coronary sinus [13,14] (which delivers oxygenated blood) shows that retrograde perfusion reduces ischemia and salvages jeopardized myocardium in patients with coronary artery disease. Our method is a combination of both these principles. The basic fact on which these techniques work is that the coronary veins are valveless and form a dense network, the volume of which exceeds the arterial vasculature. Also in coronary artery disease this access route remains spared from the disease process. Probably a superior method physiologically may well be a combination of synchronized retroperfusion (SRP) (in which during systole balloon occlusion is released and normal venous drainage occurs—the delivery of retroperfusate being synchronized to diastole) and PICSO. SRP has been shown to relieve the severity of myocardial ischemia in patients with unstable angina [ 15]. Pratt formulated the concept of retroperfusion with arterial blood through coronary veins as early as the late 1890s [16]. In fact, the Beck II operation (ligation of the coronary sinus orifice and the placement of a saphenous vein graft from the descending aorta to the great cardiac vein) was being used as recently as the mid-1970s [17]. SRP has shown beneficial effects in patients undergoing angioplasties [18]. PICSO has been tried during early reperfusion after global cardioplegic arrest for CABG [ 19]. Svedjeholm et al. [20] reported a case of severe left main stenosis with thrombus that developed pronounced ST-segment depression and ventricular dilatation in spite of the institution of CPB. Retrograde perfusion on a beating heart using extension tubing from the aorta connected to the retroplegia cannula showed regression of EGG changes of ischemia and return of ventricular contractility. This report demonstrates the efficacy of arterial retroperfusion. Martin etal. have shown that LV-powered coronary sinus retroperfusion reduces infarct size in acutely ischemic pigs [21]. They used a shunt from the left ventricular apex to the coronary sinus along with partial coronary sinus occlusion (PICSO) to deliver oxygenated blood retrogradely after inducing ischemia by snaring the two largest diagonal branches of the LAD. There was significant reduction (53% with retrograde perfusion and 73% when PICSO was added) in the area of necrosis in the retroperfusion group versus the control areas. Our technique combines retroperfusion

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with PICSO (due to the self-inflating balloon of the retroplegia catheter). Sajja et al. [22] reported a small series where they used a similar technique of perfusion of the coronary sinus to improve hemodynamics in 15 cases of severe left main stenosis. They used the driving pressure from a 7F femoral artery sheath (instead of the ascending aorta in our technique) and showed an increase in mean arterial pressure, decrease in pulmonary artery diastolic pressure, and an improvement in left ventricular ejection fraction. The principle of their technique is the same as ours using the venous system to deliver oxygenated blood beyond areas of coronary arterial stenosis—due to disease (left main stenosis) or iatrogenic (due to snaring of the target artery). Their aim in using this technique was to "buy time" to harvest arterial conduits before the institution of CPB. It is a fact that manipulation of the heart by whatever technique causes unfavorable hemodynamic consequences. When these are coupled with the regional ischemia that is invariably produced when a coronary artery is snared, the combination can be dangerous. A combination of "little" effects (a "little" hemodynamic compromise, a "little" ischemia, a "little" aortic regurgitation due to lifting and tilting of the heart, a "little" drop in temperature, etc.) can combine to produce a "major" problem. We strongly believe that the ability to successfully and precisely perform an off-pump CABG lies in attention to details. Every little extra keeps us on the right side of the safety line, giving a safety net in what is essentially a "new" procedure. Reversion of EGG changes, as observed with our technique, has also been reported with perfusionassisted direct coronary artery bypass [23] where a pump is used for pressure-controlled blood delivery for selective graft perfusion, allowing immediate restoration of arterial blood to distal coronary beds after distal coronary anastomosis in OPCABG. "Active" perfusion using a pump is logically an excellent way of avoiding ischemia—but it is possible only after the distal anastomosis is constructed—which itself is a period of ischemia. Thus our concern with this technique is that it does not avoid ischemia during the construction of the first graft (which in the series reported is not the LIMA to LAD), and the flow to the area being grafted is dependent on the degree of collateralization between the perfused vessel and the vessel being grafted. Also, we are not sure that suprasystemic

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(snared coronary artery) to selectively oxygenate the microcirculation in that area. This would require special catheters and special techniques for optimal positioning. The beauty of the technique of coronary sinus and graft perfusion lies in its efficacy, simplicity (Figure 17.4), cost effectiveness, and ease of execution and

Image Not Available

control [7].

References

Figure 17.4 Intraoperative photograph showing simplicity of the technique and perfusion of grafts and coronary sinus. A, antegrade cannula; R, retrograde cannula; Ra, radial artery to posterior descending artery being perfused by a multiport from the ascending aorta; RA, right atrium; RIMA, right internal mammary artery to right coronary artery graft. Reprinted from [7], with permission from Society of Thoracic Surgeons.

perfusion of the grafts, as performed by Guyton et al. [23], is a good idea because of the inherent risk to the integrity and function of the endothelium of the vein or radial artery. We use a similar principle with the use of aortic pressure to deliver oxygenated blood via each free graft—by connecting the proximal end of the free graft to a limb of the multiport from the ascending aortic antegrade cannula as soon as the distal anastomosis is constructed. Another variation would be to perform all the proximal anastomoses first so that perfusion starts as soon as each distal is completed. With retrograde perfusion we have noted that the anastomotic time has actually increased, as we have been able to perform unhurried anastomoses taking each stitch under vision. The effect of this on graft patency should logically favorable. We still have to learn more about the dynamics of the coronary venous circulation. Possibly a good way for selective relief of ischemia would be to advance the coronary sinus catheter upstream as close as possible in the epicardial veins to the area of ischemia

1 Bedi HS, Arsiwala S, Sharma V et al. Coronary artery bypass grafting in patients with calcine aortitis. / Thoracic Cardiovascular Surg 1991; 102:163-4. 2 Tasdemir O, Vural KM, Karagoz H, Bayazit K. Coronary artery bypass grafting on the beating heart without the use of extracorporeal circulation: review of 2052 cases. / Thome Cardiovasc Surg 1998; 116:68-73. 3 Gundry SR, Romano MA, Shattuck OH, Razzouk AJ, Bailey LL. Seven year follow up of coronary artery bypasses performed with and without cardiopulmonary bypass.} Thorac Cardiovasc Surg 1998; 115:1273-8. 4 Reichenspurner H, Boehm DH, Welz A et al. Minimally invasive coronary artery bypass grafting: port-access approach versus off-pump techniques. Ann Thorac Surg 1998; 66:1036-40. 5 Bedi HS, Suri A, Kalkat MS et al. Multivessel global myocardial revascularization without cardiopulmonary bypass using innovative new techniques for myocardial stabilization and perfusion. Ann Thorac Surg 2000; 69: 156-64. 6 Bedi HS, Kalkat MS. Retrograde perfusion of oxygenated blood during off pump revascularization to avoid ischemia. Eur J Cardiothorac Surg 2000; 17:193—4. 7 Bedi HS. Selective graft and coronary sinus perfusion in off-pump CABG: is it necessary? [reply]. Ann Thorac Surg 2001; 71:1070-2. 8 Buckberg BD. Antegrade/retrograde blood cardioplegia to ensure cardioplegia distribution: operative techniques and objectives. / Card Surg 1989; 4:216-38. 9 Allen BS, Winkelmann JW, Hanafy H. Retrograde cardioplegia does not adequately perfuse the right ventricle. / Thorac Cardiovasc Surg 1995; 109:1116-26. 10 Eke CC, Gundry SR, Fukushima N, Bailey LL. Is there a safe limit to coronary sinus pressure during retrograde cardioplegia? Am Surg 1997; 63:417-20. 11 Bedi HS, Kalkat MS. Endarterectomy on a beating heart. Ann Thorac Surg 2000; 70:338-40. 12 Chavanon O, Perrault LP, Menasche P, Carrier M, Vanhoutte PM. Endothelial effects of hemostatic devices for continuous cardioplegia or minimally invasive operations. Ann Thorac Surg 1999; 68:1118-20. 13 Mohl W, Menasche P, Snyder HE, Roberts AJ. Current status of coronary sinus interventions. In: Karp RB, Laks H, Wechesler AS, eds. Advances in Cardiac Surgery, Vol 2. St Louis: Mosby Year Book, 1990: 31-62.

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14 Gundry SR. Modification of myocardial ischemia in normal and hypertrophied hearts utilizing diastolic retroperfusion of the coronary sinus. / Thorac Cardiovasc Surg 1982; 83:659-69. 15 Gore J, Weiner BH, Benotti JR. Preliminary experience with synchronized coronary sinus retroperfusion in humans. Circulation 1986; 74:381-8. 16 Pratt FH. Nutrition of the heart through vessels of the Thebesian and coronary veins. Am J Physiol 1898; 1: 86-103. 17 Moll DW, Dziarkowiak A, Edelman M. Arterialization of the coronary veins in diffuse coronary arteriosclerosis. ] Cardiovasc Surg 1975; 5: 520-5. 18 Hajduczki I, Kar S, Areeda J et al. Reversal of chronic regional myocardial dysfunction (hibernating myocardium) by synchronized diastolic coronary venous retroperfusion during coronary angioplasty. / Am Coll Cardiol 1990; 15:238-42.

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19 Mohl W, Simon P, Neumann F. Clinical evaluation of pressure-controlled intermittent coronary sinus occlusion: randomized trial during coronary artery surgery. Ann Thorac Surg 1988; 46:192-201. 20 Svedjeholm R, Hakanson E, Forsman M. Treatment of acute myocardial ischemia during early stages of surgery by an easily applicable method for emergency retroperfusion. Eur J Cardiothorac Surg 1999; 15:551-2. 21 Martin JS, Byrne MD, Ghez OY et al. LV powered coronary sinus retroperfusion reduces infarct size in acutely ischemic pigs. Ann Thorac Surg 2000; 69:90-5. 22 Sajja LR, Farooqi A, Yarlagadda RB, Mastan SS, Pothineni RB. Retrograde coronary sinus perfusion for severe left main stenosis. Asian Cardiovasc Thorac Ann 2000;8:290-1. 23 Guyton RA, Thourani VH, Puskas JD et al. Perfusion assisted direct coronary artery bypass: selective graft perfusion in off-pump cases. Ann Thorac Surg 2000; 69:171-5.

CHAPTER 18

On-pump beating heart surgery for dilated cardiomyopathy and myocardial protection Tadashi Isomura, MD & Hisayoshi Suma, MD

Introduction Myocardial protection for left ventricular (LV) restoration in severely dilated cardiomyopathy (DCM) is very important to prevent myocardial damage during an operation. It has been considered that cardioplegia does not distribute uniformly in the dilated akinetic muscle and that beating heart surgery may minimize myocardial damage during the operation. This chapter compares the operative results with cardioplegic heart arrest to those on beating heart and discusses the effectiveness of on-pump beating heart surgery for DCM.

Patients and methods From December 1996 to July 2001, LV restoration for DCM was performed in 160 patients. The mean age was 55 years and the preoperative NYHA grading was class IV in 78 patients and class III in 84 patients. The etiology was nonischemic DCM in 85 patients and ischemic DCM in 75 patients. Operations were performed electively for 129 patients and emergently in 31 patients. Based on the preoperative LV examination and intraoperative echocardiography, LV restoration was determined by either partial left ventriculectomy (PLV) in 73 patients, endoventricular circular patch plasty (EVCPP) in 62 patients, or the septal anterior ventricular exclusion (SAVE) operation in 25 patients. LV restoration was performed under cardioplegic arrest in 29 patients and on beating heart in 131 patients. The uses of postoperative mechanical support and hospital mortality were compared and studied.

160

Results In the nonischemic group, total pump time was 154 min under cardioplegic arrest, while it was 127 min in the on-pump beating surgery group. Postoperative intraaortic balloon pump (IABP) was used in 25% of the patients who received cardioplegic arrest, and in 8.7% of those on beating heart. The hospital mortality in elective operation was 18.2% with cardioplegic arrests and 7.4% with beating heart. In the ischemic group, total pump time was 149 min under cardioplegic arrest, while it was 137 min in the on-pump beating surgery group. Postoperative IABP was used in 15% of patients with cardioplegic arrest and in 12% of those on beating heart. The hospital mortality in elective operation was 11.1% with cardioplegia and 5.5% on beating heart. The overall survival rate at 4 years was 60.2% in the nonischemic group and 74.5% in the ischemic group.

Conclusion LV restoration for dilated cardiomyopathy was performed with less myocardial damage on the beating heart than under cardioplegic arrest. Beating heart surgery improved early and late postoperative results.

History Since Batista et al. reported partial left ventriculectomy (PLV) for DCM in 1996 [1], several reports have been published with varying mortality and morbidity. PLV is an effective procedure for DCM in some patients but not in all cases. Operative mortality in patients with congestive heart failure (CHF) was

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161

higher than in other established cardiac procedures. In 2000 Franco-Cereceda et al [2] reported that midterm postoperative results with PLV were not similar to those after cardiac transplantation. In 1998, Dor et al. [3] reported a new cardiac restoration technique, namely, endoventricular circular patch plasty (EVCPP) for ischemic cardiomyopathy. Conclusions were made that EVCPP was an alternative procedure to heart transplantation for dilated cardiomyopathy (DCM) after myocardial infarction. We have been performing LV restoration for nonischemic and ischemic DCM since 1996 [4]. In this article, we compare operative results of the procedures performed with cardioplegic cardiac arrest to that of on-pump beating heart surgery and discuss the myocardial protection strategies during LV restoration surgery for DCM.

Table 18.1 Clinical characteristics of LV restoration.

N

Age Years Range Female (no.) NYHA (no.) Class IV (Inotrope) Class III

Nonischemic DCM

Ischemic DCM

85

75

50+13

61 ±8

14-76

39-80 9

13 49

29

(37)

(19)

36

46

gated scintiscan, cine-MRI angiogram, and left ventriculogram, were performed in all patients before the operation. Based on the kinesis of the LV wall, operative procedures for LV restoration were selected.

Patients and methods From December 1996 to July 2001, LV restoration for DCM was performed in 160 patients. The ages ranged from 14 to 80 years, with a mean of 55 years. There were 138 men and 22 women; all patients had signs of NYHA class III or IV heart failure (Table 18.1). The etiology was nonischemic in 85 patients and ischemic in 75 patients. In the nonischemic group, idiopathic DCM was most common. In ischemic DCM idiopathic cardiomyopathy (ICM), patients with LV aneurysm were excluded. Patients involved were those with a left ventricular ejection fraction (LVEF) less than 30% and a left ventricular end systolic volume index (LVESVI) greater than 100 ml/m2. There was single-vessel disease in nine patients and multivessel disease in 66 patients (Table 18.2). Except in 31 emergent patients, examinations for LV function, including echocardiography with color kinesis, quantitative

Table 18.2 Etiology and coronary lesion in DCM with LV restoration.

Operative procedures In nonischemic DCM, the initial 16 patients received cardiac procedures. These included valve surgery and LV restoration under cardiac arrest with 34°C blood cardioplegia, with a mean aortic cross-clamping time of 79 + 33 min and a cardiopulmonary bypass (CPB) time of 154 + 57 min. In ischemic DCM, the initial 13 patients were operated under cardioplegic arrest with a mean aortic clamping time of 95 + 38 min and a CPB time of 149 + 65 min. Concluding our initial experience, the cardiac procedures except for mitral valvuloplasty via right-sided left atrium and multiple CABG were performed on beating heart and on CPB. The mitral valve replacement was performed via the left ventricle after left ventriculectomy, followed by LV restoration with the heart beating without aortic cross-clamping.

Etiology in nonischemic DCM*

Coronary lesion in ischemic DC/Wt

Idiopathic: 59 Valvular: 9

Single: 9

Dilated HCM: 7

Triple: 43

Sarcoidosis: 4 Myocarditis: 2

Left main: 3

Others: 4 A/ = 85.

Double: 20

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Figure 18.1 Diagram showing partial left ventriculectomy (PLV). The LV incision is incised on beating heart from the second diagonal branch to the apex of the LV along the LAD. The LV muscle is then palpated to identify the kinetic or akinetic part under unloaded beating condition and the LV muscle of the posterior lateral wall is excised between two papillary muscles or including one papillary muscle and the LV is closed in two layers with large monofilament sutures. During the beating heart procedure, air is vented from both the ascending aorta and right side of the upper pulmonary vein in addition to the deairing from the upper suture line of the left ventriculotomy just before completion of the LV closure.

Beating heart left ventricular surgery: partial left ventriculectomy (Figure 18.1) After the institution of CPB with ascending aorta and bicaval cannulation, mitral valvuloplasty was preformed via the left atrium (LA) under cardiac arrest. As the aortic-cross-clamp was removed the heart spontaneously began to beat. An LV incision was made close to the second diagonal branch down to the apex of the left ventricle along the left anterior descending coronary artery (LAD). The muscle of the left ventricle was palpated to identify the kinetic or akinetic areas under unloaded beating conditions. The muscle near the posterior lateral wall was excised between the two papillary muscles. The left ventricle was then closed in two layers with large monofilament sutures. During beating heart procedures while weaning from CPB, air was vented from both the ascending aorta and the right side of the upper pulmonary vein. Deairing from the upper suture line of the left ventriculotomy just prior to LV closure was also performed.

Endoventricular circular patch plasty (Figure 18.2) After completion of coronary artery bypass grafting (CABG) under cardioplegic arrest, the clamp was removed, reperfusion was initiated, and the heart began to beat. LV surgery was performed according to Dor's techniques. Under beating heart conditions while on CPB the left side of the LAD was incised and the anteroseptal wall palpated to determine placement of the pursestring stitch. After excluding the akinetic site of the anteroseptal wall a 2 x 3 cm oval-shaped Hemashield patch was placed to cover the defect. The incised wall was then closed with running sutures and air was evacuated in the same manner as the PLV procedures. Septal anterior ventricular exclusion (Figure 18.3) In case of a preoperative LVESVI greater than 150 ml/m2 and akinesis in the septal anterior wall, the

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163

Figure 18.2 Endoventricular circular patch plasty (EVCPP). Under the beating heart, the LV along the LAD is incised and the anteroseptal wall is palpated to decide the site of pursestring stitch. After exclusion of the akinetic site of the anteroseptal wall, an approximately 2 x 3 cm oval-shaped Hemashield patch is placed to cover the defect, and the incised wall is closed with running sutures. The air is evacuated in a similar way to the PLV procedure.

Figure 18.3 Septal anterior ventricular exclusion (SAVE). In the case of a preoperative LVESVI greater than 150 ml/m2 and akinesis in the septal anterior wall, this technique is used. The incision is made along to the left side of the LAD from the apex to the base of the LV beyond the second diagonal branch. The akinetic septal wall is palpated on beating heart and it is excluded by mattress stitches with 2-0 Ticrone and a longitudinal oval-shaped Hemashield patch is sutured between the septal and anterior wall and then the incised wall is closed with mattress and running sutures in double layers. The procedure is performed under the beating heart and deairing is similar to the other procedures.

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CHAPTER 18

Nonischemic DCM*

Ischemic DC/Wt

N

85

75

Elective/emergent (no.) PLV (Batista's op.) (no.)

65/20 70

64/11

EVCPP (Dor's op.) (no.)

-

62

SAVE op. (no.)

15

10

MVR/MVP (no.)

49/27

11/19

TAP/TVR (no.)

50/4

19/0

AVR (no.)

5

2

Table 18.3 Operative procedures.

3

* Previous MVR 5. t CABG# 3.0 ± 1.2/patient. PLV, partial left ventriculectomy; EVCPP, endoventricular circular patch plasty; SAVE, septal anterior ventricular exclusion; MVR, mitral valve replacement; MVP, mitral valve replacement; TAP, tricuspid annuloplasty; TVR, tricuspid valve replacement; AVR, aortic valve replacement.

akinetic wall was not resolved with EVCPP, thus we developed large exclusion of the akinetic segment with the SAVE procedure. An incision was made along the left side of the LAD from the apex to the base of the left ventricle beyond the diagonal number 2. The septal wall was sutured with a mattress suture with 2-0 Ticrone. A longitudinal oval-shaped Hemashield patch was sutured between the septal and anterior walls. The incised wall was then closed with mattress and running sutures in double layers. The procedure was performed under beating heart conditions. Deairing maneuvers were similar to the other procedures previously mentioned. Results The operation was performed electively in 129 patients and emergently for 31 patients. LV restoration PLV was selected in 73 patients, EVCPP in 62 patients, and SAVE operation in 25 patients. Concomitant mitral surgery was performed in 77 patients (91%) for nonischemic DCM, excluding previous mitral valve replacement (MVR) in five patients, and was performed in 30 patients (40%) for ischemic DCM (Table 18.3). In the nonischemic cardiomyopathy group, procedures including LV surgery were performed under cardioplegic arrest in the initial 16 patients and under beating heart conditions in 69 patients. Among these 69 patients, procedures including mitral or tricuspid operations in addition to LV surgery were performed under beating heart in 38 of those patients. The surgical procedures in those three subgroups are

summarized in Table 18.4. Weaning for CPB was easiest in the beating heart group. IABP was used before weaning CPB or in the ICU in groups of four, three, or six patients in these three subgroups, respectively. Left ventricular assist device (LVAD) was used in two patients out of 15 patients with emergent surgery (Table 18.4). In the ischemic cardiomyopathy group, procedures including LV surgery were performed under cardioplegic heart arrest in the initial 13 patients and under beating heart conditions in 62 patients. The surgical procedures in the two subgroups are summarized in Table 18.5. IABP was used before weaning CPB or in the ICU in two patients in the cardioplegic arrest group and in eight patients in the beating heart surgery group (Table 18.5). Thirty-day mortality occurred in seven patients and the total hospital mortality was 28 patients, including 18 patients who underwent emergent operation. The cause of hospital death was CHF in 15 patients, fetal arrhythmia in three patients, and multiorgan failure in 10 patients. There was no incidence of stroke after the operation. Follow-up visits showed that out of the 132 patients discharged from hospital there were 22 late deaths. The cause of death was CHF in 11 patients, sudden arrhythmia in four patients, and other causes in seven patients. Fourteen patients among the 22 late deaths (63%) died within 1 year after the operation due to cardiac causes. The survival rate at 4 years was 60.2% in the nonischemic group and 74.5% in the ischemic group including emergent operations.

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165

Table 18.4 Operative results in 85 patients with nonischemic DCM.

Number Cross-clamp time (min) Total ECCT (min) IABP (no. (%)) LVAD (no.) Elective/emergent (no.) Hospital death (no.) Mortality (no. (%)) Emergent Elective

Cardioplegic arrest

LV restoration on beating mitral plasty under cardioplegic arrest

Beating heart

16

31

38

79 ±33 154157 4(25)

53 ±24 138±44 3 (9.6)

-

—

-

2

11/5 6 (37.5% mortality)

27/4 3 (9.6% mortality)

27/11 9 (23.6% mortality)

4/5 (80) 2/11 (18)

2/4 (50) 1/27 (3.7)

6/1 1 (54 3/27(11)

118±35 3 (7.9) excluding preoperative use in 3

ECCT, extra corporeal circulation; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device. Table 18.5 Operative results in 75 patients with ischemic DCM.

LV restoration under cardioplegic arrest

Number Cross-clamp time (min) Total ECCT (min) IABP (no. (%)) LVAD Elective/emergent (no.) CABG no./patient Hospital death (no.) Mortality (no. (%))

LV restoration on beating heart

62

95 ±38 149 ±65 2(15%)

63 + 26 137 + 44 8(12%)

9/4

3.2±1.2 4 (30.7% mortality)

55/7 2.9+1.2 6 (9.7% mortality)

Emergent 3/4 (75%) Elective 1/9 (11%)

3/7(42%) 3/55 (5.4%)

LVAD, left ventricular assist device.

Discussion LV restoration was used to surgically treat patients with dilated cardiomyopathy. Procedures were performed in several institutions with various operative morbidities and mortalities [5-11]. The major operative mortality was reported to be prolonged or persistent heart failure, ventricular arrhythmia, or multiorgan failure due to persistent heart failure. In our recent report for LV restoration in 74 patients [12], we describe the risk factors for the operation. Emergent situations and larger ventricular volume are the risk factors. There was no significance in LV ejection fraction. In our series, after the intro-

duction of on-pump beating heart surgery without cardiac arrest the CPB time became shorter. It appeared that cardiac functional recovery was faster and the requirements for IABP to wean from CPB decreased. Beating heart surgery for DCM seemed to be effective in view of myocardial preservation during the procedures. We also found that palpation for identification of kinetic and akinetic parts of the heart muscle and selection for the type of surgery for exclusion of the akinetic site were important factors. For LV restoration, we tried to decrease the volume of the left ventricle to less than 100 ml/m2 of the LVESVI by exclusion of the akinetic segment. In our series, the hospital mortality in elective patients was 7.4% in the

166

nonischemic group and 5.4% in the ischemic group. In the late follow up, the 4-year cumulative survival rate was 60.2% in the nonischemic DCM and 74.5% in the ischemic DCM. In several patients the cardiac function was near complete recovery 1 year postsurgery. The effectiveness of the LV restoration seemed to be observed late after surgery, as was seen in the patients weaned from LVAD. Our early and midterm results regarding LV restoration for severely deteriorated DCM were acceptable. LV restoration under beating heart surgery conditions was found to be effective for improving ventricular function, resulting in favorable early and late surgical results.

References 1 Batista RJV, Santos JLV, Takeshita N. Partial left ventriculectomy to improve left ventricular function in end-stage heart disease. JCard Surg 1996; 1:96-7. 2 Franco-Cereceda A, McCarthy PM, Blackstone EH et al. Partial left ventriculectomy for dilated cardiomyopathy: is this an alternative to transplantation? / Thome Cardiovasc Surg 2001; 121: 879-93. 3 Dor V, Sabatier M, DiDinato M et al. Efficacy of endoventricular patch plasty in large postinfarction akinetic scar and severe left ventricular dysfunction: comparison with a series of large dyskinetic scars. / Thorac Cardiovasc Surg 1998; 116: 50-9.

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4 Suma H, Isomura T, Horii T et al. Nontransplant cardiac surgery for end-stage cardiomyopathy. / Thorac Cardiovasc Surg 2000; 119:1233-45. 5 McCarthy PM, Starling RC, Wong J et al. Early results with partial left ventriculectomy. / Thorac Cardiovasc Surg 1997; 114: 755-65. 6 Stolf NAG, Moreira LFP, Bocchi EA etal. Determinants of mid-term outcome of partial left ventriculectomy in dilated cardiomyopathy. Ann Thorac Surg 1998; 66:1585-91. 7 Grandinac S, Miric M, Popovic Z et al. Partial left ventriculectomy for idiopathic dilated cardiomyopathy: early results and six-month follow-up. Ann Thorac Surg 1998; 66:1963-8. 8 Batista RJV, Verde J, Nery P et al. Partial left ventriculectomy to treat end-stage heart disease. Ann Thorac Surg 1997; 64:634-8. 9 Angelini GD, Pryn S, Mehta D et al. Left-ventricularvolume reduction for end-stage heart failure. Lancet 1997;350:489. 10 Suma H, Isomura T, Horii T et al. Two-year experience of the Batista operation for nonischemic cardiomyopathy. } Cardiol 1998; 32:269-76. 11 Popovic Z, Miric M, Neskovic AN et al. Functional capacity late after partial ventriculectomy: relation to ventricular geometry and performance. Eur J Cardiothorac Surg 2001; 19:61-7. 12 Isomura T, Suma H, Horii T et al. Left ventricle restoration in patients with nonischemic dilated cardiomyopathy: risk factors and predictors of outcome and change of mid-term ventricular function. Eur J Cardiothorac Surg 2001;19:684-9.

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Myocardial protection with beta-blockers in valvular surgery Nawwar Al Attar, FRCS, MSC, FETCS, Mar do Scorsin, MD,phD, &Arrigo Lessana, MD, FETCS

Introduction Advances and new notions in myocardial protection have been developed over the years. Traditional cardioplegia has been challenged in its concepts, thus evolving from intermittent into continuous, cold into normothermic, and crystalloid into blood cardioplegia. The goal is avoidance of the deleterious effects of hypothermia and ischemia-reperfusion injury [1]. While the physical properties and delivery systems of cardioplegia have witnessed significant advances, despite the improvement of the chemical constitution of cardioplegia solutions with the use of various substrates, antioxidants, drugs (e.g. steroids, captopril) [2-4] alone or associated, most infusates continue to induce a hyperkalemic cardiac arrest. However, hyperkalemic solutions have been shown to have a detrimental effect on coronary endothelial cells in addition to the complications of consequent systemic hyperkalemia. For the above reasons, the search for alternative agents in warm cardioplegia is ongoing to avoid the complications of potassium solutions while providing adequate cardioprotection [5]. Beta-blockade has been shown experimentally to offer cardioprotection [6] conceivably through preconditioning, inhibition of adenosine triphosphate catabolism, the management of myocardial edema, reduced endothelial cell injury, modifying the interaction between activated leukocytes and the vascular endothelium, and probably other mechanisms [7]. Furthermore, in an experimental study, an ultra-short acting beta-blocker "landiolol" has been shown to have the potential to

enhance the postischemic cardiac function and recovery after warm cardioplegic arrest [8]. Clinically, beta-blockade limits the release of creatinine kinaseMB after coronary intervention, a sign of less myocardial damage [9].

Pathophysiology of valvular diseases and implications on myocardial protection Aortic valve disease Aortic stenosis This disease is characterized by a pressure-overloaded ventricle that develops concentric left ventricular (LV) hypertrophy and marked thickness of the interventricular septum. This leads to an increased vulnerability from ischemia and reperfusion. There is an increase in the time required for isovolumic relaxation, which may contribute to a relative decrease in endocardial coronary blood flow due to a delay in pressure decay. Coronary artery disease, myocardial bridging, septal perforator compression, coronary vasospasm, and small-vessel disease [10] are causes of angina or acute myocardial infarction with LV hypertrophy. There is a decrease in the endocardial-epicardial flow ratio from 1.2 to 0.9 and an increase in oxygen extraction that is highest in the endocardium [11,12]. Technically, in the presence of significant myocardial hypertrophy and fear of inadequate retrograde perfusion, cannulation of the left coronary ostium to measure oxygen saturation from the reflux may help in guiding the flow rate and pressure of cardioplegia

167

168

so as to keep oxygen saturation in the reflux above 35%. Aortic insufficiency This leads to a mixture of pressure and volume overload. Volume overload is the most important component and is responsible for the eccentric ventricular hypertrophy. There is early diastolic dysfunction and impaired LV relaxation. Owing to changes in diastolic perfusion pressure, coronary artery flow may be reduced. Furthermore myocardial oxygen consumption (Mvo2) is markedly increased due to the increased stroke volume and ejection pressure. It has been shown that diastolic aortic pressures of 40 mmHg or less dramatically reduce coronary artery blood flow and increase myocardial lactate production [13]. As in aortic stenosis, endocardial and epicardial blood flow ratios may decrease to as low as 0.76. The endocardium becomes increasingly ischemic with subsequent fibrosis and myofibrillar slippage. Technically, the instauration of antegrade cardioplegia through the aortic root is not feasible. Therefore either primary use of retrograde cardioplegia or direct cannulation of the coronary ostia maybe necessary.

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Mitral regurgitation We are concerned with chronic mitral regurgitation and the adaptive changes that occur over time. Mitral regurgitation increases left atrial pressure and reduces forward systemic flow. LV impedance is reduced, allowing a greater proportion of contractile energy to be expended in myocardial fiber shortening than in tension development [22,23]. Since increased shortening is less important as a determinant of myocardial oxygen consumption than other components (i.e. tension development and heart rate), mitral regurgitation causes only small increases in myocardial oxygen consumption [23,24]. LV mass increases; but unlike the conditions of LV pressure overload, the amount of hypertrophy correlates with the amount of ventricular dilatation so that the ratio of LV mass to end-diastolic volume stays within normal range [25-28]. Other valvular pathologies Other valvular pathologies are uncommon as presenting lesions and are usually secondary to the above. For tricuspid valve repair, the open right atrium allows for direct cannulation of the coronary sinus under vision in retrograde cardioplegia.

Mitral valve disease Mitral stenosis There is a diastolic gradient between the left atrium and ventricle. In pure mitral stenosis with LV inflow obstruction, the end-diastolic volume is normal or decreased, and LV end-diastolic pressure is usually low [14-16]. LV peak filling rate is reduced, as is stroke volume, and LV mass is normal or slightly below normal [15]. Inflow obstruction is more likely to be responsible for the decreased cardiac output than LV pump failure [17]; however, approximately 25-50% of patients with severe mitral stenosis have LV systolic dysfunction due to associated diseases (e.g. mitral regurgitation, aortic valve disease, ischemic heart disease, etc.) [14,16,18]. Right ventricular function may be disturbed following the development of pulmonary hypertension [14,19]. Clinically, increased right ventricular afterload as a result of mitral stenosis is frequently associated with normal right ventricular contractility [ 14]. Atrial-related complications subsequent to high left atrial pressure include left atrial hypertrophy, atrial fibrillation, and mural thrombi formation [16,20,21 ].

Esmolol as an innovative agent in warm blood cardioplegia To elucidate the performance of beta-blockers as cardioplegic and cardioprotective agents in warm heart surgery, we initially conducted a feasibility study that demonstrated the safety of the ultra-short-acting betablocker "esmolol" in small and large animals [29]. We then compared esmolol to potassium in 38 consecutive patients with isolated aortic valve stenosis. This pathology is particularly interesting, as it induces as a part of its natural history considerable concentric myocardial hypertrophy and thus a myocardium at increased risk. Technically, replacement of the aortic valve provides access to the coronary ostia, allowing sampling of the coronary blood reflux and providing another advantage in choosing this model.

Technical considerations of esmolol cardioplegia Pharmacology Esmolol HC1 (Brevibloc) is a betat-selective (cardio-

Myocardial protection with beta-blockers selective) adrenergic receptor blocking agent with a very short duration of action (elimination half-life is approximately 9 min). It is supplied as 2500 mg in 10 ml ampoules. Each milliliter contains 250 mg esmolol HC1 in 25% Propylene Glycol, USP, 25% Alcohol, USP and Water for Injection, USP, buffered with 17.0 mg Sodium Acetate, USP, and 0.00715 ml Glacial Acetic Acid, USP. Sodium hydroxide and/or hydrochloric acid are added, as necessary, to adjust the pH to 3.5-5.5. Peroperative considerations All patients were operated upon through midline thoracic incision and medial sternotomy. Heparinization at a dose of 3 mg/kg body weight was administered before cannulation and controlled by activated clotting time (ACT) measurements. The ascending aorta and right atrium were cannulated in a conventional way. For induction of cardioplegia, an aortic needle was inserted proximal to the aortic perfusion cannula. It also permitted deairing at the end of the procedure. The coronary sinus was cannulated through the right atrium with a self-inflating triple-lumen balloon cannula (DLP, Grand Rapids, Michigan) fixed by a snare of 4-0 prolene to prevent displacement of the catheter [30] throughout the maintenance phase of cardioplegia. Left ventricular venting was achieved by a trans-septal needle or a cannula inserted through the right superior pulmonary vein.

Study design We compared the effects of potassium and esmolol on myocardial oxygen consumption (Mvo2) and coronary-released nitric oxide (NO) in 38 patients with isolated aortic valve stenosis undergoing valve replacement with retrograde warm blood cardioplegia. The patients were randomly assigned to a continuous coronary infusion of either potassium (n = 18) or esmolol (n = 20). Patients on preoperative betablocker treatment, severe asthmatics, and those with other contraindications of beta-blocker therapy were excluded from the study. Myocardial oxygen consumption and coronary lactate release were analyzed by simultaneous blood samplings from the cardioplegia perfusion line and left coronary ostium (through a 4- or 6-mm angled balloon-tipped coronary cannula, Polystan, Denmark) 10 and 30 min after aortic crossclamping. Coronary NO release was also quantified by simultaneous measurements of NO2/NO3 (Griess

169

method) in the cardioplegia perfusion line and left coronary ostium, 30 min after aortic cross-clamping, and expressed as micromoles per minute. Hemodynamic parameters intra- and postoperatively were recorded by a Swan-Ganz catheter standardized with 0.5 Fio2. Pre- and postoperative echocardiographic measurements and plasma troponin I (Tnl) levels were obtained. Statistical analysis was tested by the paired Student t-test and ANOVA for repeated measures. The results are presented as means plus or minus the standard deviation (SD).

Cardioplegia protocol The general setup for retrograde cardioplegia follows the modified Toronto technique [31]. The protocol for potassium cardioplegia injection is determined by normograms relating coronary flow and patient's serum potassium concentration. The concentration of KCI solutions for induction of cardiac arrest is 25 mmol/L and the maintenance dose is 12 mmol/L [32]. A second syringe contains 50 ml of 10% magnesium chloride (0.49 mmol/L). The output is correlated to the injection rate from the cardioplegia pump at a factor of 0.5. The injection rate is adjusted to blood flow in the cardioplegia line through a Y tubing that allows the simultaneous injection through two electric syringe infusion pumps. Similarly, when employing esmolol cardioplegia, the two electric syringe infusion pumps and Y tubing allow injection of the following cardioplegic solutions: 1 Esmolol syringe: the solution of 2.5 g/10 ml is prepared by diluting 5 ml in 20 ml of sterile water. 2 Magnesium syringe: 10% magnesium chloride (0.49 mmol/L) containing 50 ml of undiluted product. The perfusion rate is as described above in the potassium group. In both groups, cardioplegia is started through antegrade perfusion by injection in the aortic root. After cardiac arrest, maintenance of cardioplegia is carried out by retrograde perfusion through the coronary sinus.

Induction of cardioplegia Esmolol is injected at a rate of 2 ml/min equivalent to a dose of 100 mg/min. Magnesium injection is at a rate of 2.5 ml/min giving a dose of 250 mg/min. This perfusion is continued

170

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until achieving extreme bradycardia and abolition of myocardial contraction. This is often accomplished with doses of esmolol between 200 and 500 mg and follows after 30-50 s in the esmolol group (and 1015 s in the potassium group). Concomitantly, 150 ml/h of magnesium is injected in the cardioplegia line.

Maintenance of cardioplegia Perfusion in the retrograde cardioplegia line of oxygenated blood is at a rate of 250 ml/min in order to achieve a pressure of 30-60 mmHg in the coronary sinus. In the maintenance phase, the injection rate of esmolol is reduced to 0.2 ml/min (=10 mg/min) to maintain an arrested heart or extreme bradycardia and hypocontractility. Likewise, the rate of magnesium perfusion is reduced progressively to around 100 ml/h (2-1 ml/min). Whenever necessary, cardioplegia injection was interrupted for short periods.

Results Although the cardioplegia flow rate and pressure were similar in both groups, after aortic cross-clamping, esmolol markedly reduced Mvo2 as compared to potassium, 9.6 ± 1 versus 19 ± 2 ml O2/min (P < 0.0001) at 10 min and 10.3 ± 2 versus 22 ± 6 ml O2/min (P< 0.0001) at 30 min, respectively. Coronary lactate production was similar in both groups at 10 and 30 min (all inferior to 0.22 mmol/min), indicating adequate myocardial perfusion in all patients. Furthermore, esmolol reduced coronary NO release (esmolol, 1.4 ± 0.2 }lmol/min) versus the potassium group (10.7 + 2.4 umol/min, P = 0.04) (Table 19.1). Cardiac index, ejection fraction, and Tnl remained unchanged postoperatively with either form of cardioplegia.

Discussion Potassium remains the principal component of almost all cardioplegic solutions. Heart arrest results

Esmolol

from the high extracellular potassium concentration which reduces transmembrane potassium gradients and membrane resting potential to approximately -50 mV, thus inhibiting the subsequent opening of sodium channels [33]. Despite the widespread and longstanding use of potassium, hyperkalemia has always been a major drawback. Its consequences may necessitate the use of insulin, staying for longer periods on cardiopulmonary bypass or other measures to eliminate the excess potassium and its numerous adverse effects [34]. Beta-blockers act by inhibiting the binding of catecholamines to adrenergic receptors on the cell membrane, reducing cellular metabolism and the number of activated calcium channels with consequent bradycardia and hypocontractility [35]. Esmolol has a short period of action, which facilitates monitoring, and control of its effect on the heart. Very high doses of esmolol cause severe bradycardia, and temporary pacing of the heart or brief inotropic support can counteract hypotension and its residual effects during weaning from cardiopulmonary bypass. A number of experimental studies have shown a marked increase in catecholamines in ischemic myocardial tissue [36] associated with deranged betaadrenergic mechanisms which correlates with and contributes to the increased incidence of arrhythmias and myocardial damage following acute myocardial ischemia and reperfusion [37]. This supports the idea that beta-blockers offer an additional mechanism of protection from postcardioplegic contractile dysfunction [38] and in compromised hearts. Intermittent ischemic episodes can thus be better tolerated, adding to the comfort of the surgeon during valve replacement or repair surgery. Improved outcome with continuous coronary perfusion of warm esmolol-enriched blood has been demonstrated when compared to crystalloid cardioplegia in coronary artery bypass surgery and more significantly in compromised hearts after failed percutaneous transluminal coronary angioplasty (PTCA) [39].

Potassium

P value

Table 19.1 Myocardial oxygen consumption (Mi/o2) and coronary nitric

Mvo2 (ml O2/min) at 10 min

9.6 ±1

19±2

<0.0001

oxide (NO) release in esmolol and

Mvo2 (ml O2/min) at 30 min

10.3 ±22

2±6

<0.0001

potassium groups.

Coronary NO release ^mol/min

1.4 ±0.2

10.7 ±2.4

0.04

Myocardial protection with beta-blockers Continuous cardioplegia perfusion is not without its pitfalls [40] and has been criticized for flooding the operative field and inadequate visualization. Intermittent cardioplegia with interruptions of 10-20 min has been shown to be well tolerated in myocardial revascularization procedures and is generally considered to be "safe" [41,42]. However, the same cannot be said for its use in valvular or congenital heart surgery, as these interruptions may prove to be inadequate. There has been no major study of the safe interval of interruption of the cardioplegia injection. Additionally, the risk for valve surgery is probably greater than that for coronary artery bypass grafting. This is due to a number of factors, those related to the valvular pathology itself with its consequences on the implementation of adequate myocardial protection as in aortic insufficiency, and those related to the secondary changes in the myocardium such as hypertrophy and/or dilatation. The use of esmolol in warm retrograde cardioplegia seems to offer a superior level of protection, as demonstrated by the significant reduction in myocardial oxygen consumption and probably other factors. This may consequently extend the safety limits of interruption of cardioplegia. Reduction of Mvo2 was historically believed to be achieved by hypothermia. Bernhard [43] andBuckberg [44], who showed that electromechanical arrest of the heart in normothermia reduced oxygen consumption from 80 to 90%, then rectified this. It is interesting to note that despite minimal myocardial contraction in the esmolol group, Mvo2 was lower than in the potassium group. It is believed that these minor contractions may in fact be beneficial by supporting myocardial fluid balance and preventing myocardial edema formation [45,46]. Nevertheless, the impact in terms of patient mortality has not been demonstrated clinically in patients undergoing coronary artery bypass grafting [47]. It has been observed that mammalian myocardium produces nitric oxide and that this seems to be regulated mainly by myocardial contractions [48] in addition to a number of other factors. Regarding cardiopulmonary bypass and myocardial protection, little data have been gathered about nitric oxide synthase (cNOS) and its importance. It has recently been shown that cardiopulmonary bypass itself increases the production of cNOS, which leads to an inflammatory reaction and organ injury [49], consequently playing a major role in post-cardiopul-

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monary bypass heart dysfunction. However, it is not clear whether this increase is due to cardiopulmonary bypass itself or heart ischemia during cardiac arrest. In our study, cNOS in the potassium group was consistently higher than in the esmolol group, suggesting either potassium-induced endothelial injury or improved myocardial protection with beta-blockers.

Conclusions Myocardial protection in valvular heart surgery carries a supplementary risk due to a number of factors, particularly heart chamber dilatation and hypertrophy. With continuous warm blood cardioplegia, the compromised myocardium is kept at near normal physiological conditions. Ultra-short-acting beta-blockers have shown superior cardioprotective effects in coronary bypass grafting and in an aortic stenosis model. Esmolol seems to be an interesting alternative cardioplegic agent compared to potassium, since it provides potentially superior myocardial protective effects by reducing myocardial oxygen consumption and preventing coronary endothelial activation.

Acknowledgments We would like to thank the staff of the Department of Cardiac Surgery at the Center Cardiologique du Nord.

References 1 Salerno TA, Houck JP, Barrozo CAM et al Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection. Ann ThoracSurg 1991; 51:245-7. 2 Salerno TA, Wasan SM, Charrette EJ. Glucose substrate in myocardial protection. / Thome Cardiovasc Surg 1980; 79: 59-62. 3 Menasche P, Piwnica A. Free radicals and myocardial protection: a surgical viewpoint. Ann Thorac Surg 1989; 47:939-45. 4 Gurevitch J, Pevni D, Frolkis I et al. Captopril in cardioplegia and reperfusion: protective effects on the ischemic heart. Ann Thorac Surg 1997; 63:627-33. 5 Noera G. When and why CPD in continuous warm blood cardioplegia?Ann ThoracSurg 1993; 56:1217-18. 6 Katayama O, Ledingham SIM, Amrani M et al. Functional and metabolic effect of adenosine in cardioplegia and reperfusion: protective effects on the ischemic heart. Ann Thorac Surg 1997; 63:449-55. 7 Wechsler AS, Abd-Elfattah A. Future cardioprotective considerations./Card Surg 1993; 8:492-502. 8 Yasuda T, Kamiya H, Tanaka Y et al. Ultra-shortacting beta-blockade attenuates postischemic cardiac

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dysfunction in the isolated rat heart. Eur J Cardiothorac Surg 2001; 19:647-52. Sharma SK, Kini A, Marmur JD et al. Cardioprotective effect of prior beta-blocker therapy in reducing creatinine kinase-MB elevation after coronary intervention. Benefit is extended to improvement in intermediate-term survival. Circulation 2000; 102:166-72. Griggs DM, Chen CC, Tchokoev W. Subendocardial anaerobic metabolism in experimental aortic stenosis. AmJPhysiol 1973; 224:607-12. 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/1991; 12:127-38. Marcus ML, Koyanagi S, Harrison DG et al. Abnormalities in the coronary circulation that occur as a consequence of cardiac hypertrophy. Am } Med 1983; 75: 62-6. Griggs DM Jr, Chen CC. Coronary hemodynamics and regional myocardial metabolism in experimental aortic insufficiency. / C/m Invest 1974; 53:1599-606. Carabello BA. Timing of surgery in mitral and aortic stenosis. Cardiol Clin 1991; 9:229-38. Kennedy JW, Yarnall SR, Murray JA et al. Quantitative angiocardiography: relationships of left atrial and ventricular pressure and volume in mitral valve disease. Circulation 1970; 41: 817-24. Choi BW, Bacharach SL, Barcour DJ et al. Left ventricular systolic dysfunction: diastolic filling characteristics and exercise cardiac reserve in mitral stenosis. Am J Cardiol 1995; 75:526-9. Bolen JL, Lopes MG, Harrison DC et al. Analysis of left ventricular function in response to afterload changes in patients with mitral stenosis. Circulation 1975; 52: 894-900. Schofield PM. Invasive investigation of the mitral valve. In: Wells FC, Shapiro LM, eds. Mitral Valve Disease. Oxford: Butterworth-Heineman, 1996:84. Schwartz R, Myerson RM, Lawrence LT et al. Mitral stenosis, massive pulmonary hemorrhage, and emergency valve replacement. NEnglJMed 1966; 275: 755-8. Roberts WC. Morphologic aspects of cardiac valve dysfunction. Am Heart J1992; 123:1610-32. Diker E, Aydogdu S, Ozdemir M et al. Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease. Am J Cardiol 1996; 77: 96-8. Fenster MS, Feldman MD. Mitral regurgitation: an overview. CurrProbl Cardiol 1995; 20:193-280. Brauwald E. Mitral regurgitation: physiologic, clinical and surgical considerations. N Engl J Med 1969; 281: 425-33. Carabello BA. The pathophysiology of mitral regurgitation. J Heart Valve Dis 2000; 9:600-8. Ross J Jr. Adaptations of the left ventricle to chronic volume overload. CircRes 1974; 34/35 (Suppl II:): 64-70. Spinale FG, Ishihra K, Zile M et al. Structural basis for changes in left ventricular function and geometry because of chronic mitral regurgitation and after correction of volume overload. / Thorac Cardiovasc Surg 1993; 106: 1147-57.

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27 Yun KL, Rayhill SC, Niczyporuk MA et al. Left ventricular mechanics and energetics in the dilated canine heart: acute versus chronic mitral regurgitation. / Thorac Cardiovasc Surg 1992; 104:26-39. 28 Yun KL, Rayhill SC, Niczyporuk MA et al. Mitral valve replacement in dilated canine hearts with chronic mitral regurgitation. Circulation 1991; 84 (Suppl III): 112-24. 29 Ede MYeJ, Gregorash L et al. Beyond hyperkalemia: beta-blockers-induced cardiac arrest for normothermic cardiac operations. Ann Thorac Surg 1997; 63: 721-7. 30 Lessana A, Pargaonkar S, Yu HQ et al. External stabilization of coronary sinus catheter. / Card Surg 1995; 10: 96-7. 31 Le Houerou D, Singh Al, Romano M et al. Minimal hemodilution and optimal potassium use during normothermic aerobic arrest. Ann Thorac Surg 1992; 54: 809-16. 32 Le Houreou D, Pargaonkar S, Lessana A. Cardioplegia delivery systems for warm cardioplegia. In: Salerno TA, eds. Warm Heart Surgery. London: Arnold, 1995: 50-2. 33 Goodman J, Gilman J. Pharmacological Basis of Therapeutics, 9th edn. New York: McGraw-Hill, 1995: 238-89. 34 Handy JR, Spinale FG, Mukherjee R et al. Hypothermic potassium cardioplegia impairs myocyte recovery of contractility and inotropy. / Thorac Cardiovasc Surg 1994; 107:1050-8. 35 Sum CY, Yacobi A, Kartzinel R et al. Kinetics of esmolol, an ultra-short acting beta blocker, and of its major metabolites. Clin Pharmacol Ther 1983; 34:427-34. 36 Lamaeris TW, de Zeeuw S, Albert G et al Time course and mechanism of myocardial catecholamines release during transient ischemia in vivo. Circulation 2000; 101: 2645-50. 37 Thandroyen FT, Muntz KH, Buja LM et al. Alteration in beta-adrenergic receptors, adenlyate cyclase, and cyclic AMP concentrations during acute myocardial ischemia and reperfusion. Circulation 1990; 82: 30-7. 38 Tevaearai HT, Walton GB, Eckhart AD, Keys JR, Koch WJ. Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by genemediated beta-adrenergic signaling modulation. Eur } Cardiothorac Surg 2002; 22: 733-7. 39 Hekmat K, Clemens RM, Mehlhorn U et al. Emergency coronary artery surgery after failed PTCA: myocardial protection with continuous coronary perfusion of betablocker-enriched blood. Thorac Cardiovasc Surg 1998; 46: 333-8. 40 Rescigno G, Nataf P, Raffoul R et al. Continuous warm blood cardioplegia pitfalls and solutions. Heart Surg Forum 1998; 1:142-5. 41 Chocron S, Kaili D, Yan Y et al. Intermediate lukewarm (20°C) antegrade intermittent blood cardioplegia compared with cold and warm blood cardioplegia. / Thorac Cardiovasc Surg 2000; 119:610-16. 42 Yasuda T, Kawasuji M, Sakakibara N etal. Ultrastructural assessment of the myocardium receiving intermittent antegrade warm blood cardioplegia. Cardiovasc Surg 1998; 6:282-7.

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43 Bernhard WF, Schwarz HF, Malick NP. Intermittent cold coronary perfusion as an adjunct to open heart surgery. SurgGynecolObstet 1960; 111: 744-50. 44 Buckberg GD, Brazier JR, Nelson R et al. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart. / Thome Cardiovasc Surg 1977; 73: 87-94. 45 Mehlhorn U, Allen SJ, Adams DL et al. Cardiac surgical conditions induced by beta-blockade: effect on myocardial fluid balance. Ann Thorac Surg 1996; 62:143-50. 46 Warters RD, Allen SJ, Davis KL et al. Beta-blockade as

173 an alternative to cardioplegic arrest during cardiopulmonary bypass. Ann ThoracSurg 1998; 65:961-6. 47 Mehlhorn U, Fattah M, Kuhn-Regnier F et al. Impact of myocardial protection during coronary bypass surgery on patient outcome. Cardiovasc Surg 2001; 9:482-6. 48 Rattier BG, Oddis CV, Zeevi A et al. Regulation of constitutive nitric oxide synthase activity by the human heart. Am} Cardiol 1995; 76:957-9. 49 Mayers I, Hurst T, Puttagunta L et al. Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts. / Thorac Cardiovasc Surg2001; 122: 746-52.

CHAPTER 20

Myocardial protection in minimally invasive valvular surgery RenePretre, MD &Marko I. Turina, MD

General considerations Muscular mass and metabolism Most chronic left-sided heart valve diseases produce an important increase in the muscular mass of the left ventricle with a relatively small increase in the size and capacitance of the coronary arteries [1]. The discrepancy results in a reduced reserve of the coronary perfusion and jeopardy of the vulnerable subendocardial layer [2]. Aortic valve stenosis with the accompanying hypertrophy of the left ventricle creates circumstances for an inadequate perfusion of the thick subendocardial layer. In this setting, many clinical studies demonstrated that the method of cardioplegic delivery was a relevant factor of outcome. Retrograde cardioplegia reaches with particular efficiency the subendocardial layers. The use of retrograde cardioplegia in conjunction with antegrade cardioplegic induction led to an improved recovery of the myocardium after ischemia and to improved clinical results [3-5]. This combined method of myocardial protection appears as the indispensable way to correctly protect a heart with an increased muscle mass when a prolonged period of ischemia is anticipated. Ventricular work is the most important determinant of energetic need of the myocardium. The need is reduced by more than 80% with the abolishment of the mechanical activity of the myocardium [6,7]. The further reduction of myocardial energetic needs that can be obtained by lowering temperature is marginal. Therefore, the main concern of any surgeon working under ischemic conditions is the attainment of complete electromechanical inactivity of the myocardium. Hypothermia, if it only slightly reduces metabolic needs, helps maintain electromechanical quietness. In

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many situations, it is also helpful to lower myocardial temperature in order to prolong the duration of myocardial stillness.

Cardioplegic delivery The majority of cardiac units (especially in teaching hospitals) combine two routes of cardioplegic delivery, and work with differential hypothermia of the heart and body (Table 20.1). Many units start myocardial protection with a warm antegrade cardioplegia, especially in risky situations (strained myocardium, reduced ventricular function, associated coronary artery disease). This warm induction could help cardiomyocytes under stress regenerate their stores of high-energy molecules before ischemia is induced. It could also help to maintain the microcirculation open for a harmonious subsequent distribution of cardioplegia within the myocardium. The choice of the subsequent temperature of cardioplegia largely

Table 20.1 Most common methods of myocardial protection. • Warm or cold induction of cardioplegia, first by antegrade, then by retrograde delivery • Maintenance of cardioplegia by continuous retrograde administration of cold (16-18°C) oxygenated blood in the coronary sinus at a pressure of 20-25 mmHg (corresponding to a flow rate of 150-200 ml/min) • Moderate body hypothermia (28-30°C) to prevent rewarming of the posterior wall of the left ventricle by adjacent tissue • Warm cardioplegic reperfusion prior to removal of aortic cross-clamp

Myocardial protection in valvular surgery depends on the surgeon's preference, and the magnitude or difficulty of the procedure. Many surgeons prefer normothermic cardioplegia when a straightforward operation is anticipated [8,9]. Some will also select this cardioplegia when the left ventricle is already severely damaged [10]. The majority of cardiac surgeons, however, employ a hypothermic cardioplegia combined with mild systemic hypothermia (Table 20.1). The method is particularly convenient and suitable for long procedures, typically those involving complicated annular reconstructions or reoperations. The egress of blood through the coronary ostia during retrograde perfusion of the myocardium does not disturb most of the steps of an aortic or a mitral valve repair or replacement. Therefore, a continuous retrograde perfusion of the heart with cold oxygenated blood results in an effective reduction of the ischemic stress on the myocardium [7]. At the end of the valvular procedure, a dose of normothermic, substrateenriched cardioplegia is often delivered shortly before release of the aortic cross-clamp. Most procedures on the tricuspid valve can be performed with a normal perfusion of the aortic root and coronary arteries. Most surgeons perform these operations on a beating and perfused heart.

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Embolism of air bubbles is more frequent in minimally invasive than in conventional surgery. The impossibility to puncture the heart apex results in a less efficient de-airing of the left heart cavities. The appearance of EGG changes during the reperfusion time (especially ST-segment elevation) should lead to prolonged circulatory support, ideally up to EGG normalization. Insufflation of CO2 in the operating field during the time when the left cardiac cavities are opened results in a swift subsequent dissolution of air bubbles in the blood. Finally, an active vent in the ascending aorta should be kept under moderate suction until air signals have disappeared in transesophageal echocardiography. Moderate filling of the left ventricle (by increase of venous return) and stimulation with small doses of inotropic agents result in a controlled expulsion of air bubbles into the vented ascending aorta.

Chest incisions The choice of chest incision in minimally invasive surgery is dictated by the position and orientation of the operated valve (Figure 20.1). Because mobilization of the heart is restricted, the incision of the chest wall should lie in the direct line of vision of the surgeon. A partial upper sternotomy (Figure 20.2) or

Reperfusion The period during which attention should be devoted to myocardial protection goes well beyond the duration of aortic cross-clamping (commonly considered as the period of myocardial ischemia), and extends to the time when the heart starts to resume activity and function. Adequate perfusion of the myocardium and progressive loading of the heart may require extremely fine tuning for successful weaning from cardiopulmonary bypass when ventricular function is severely depressed. In the minutes following removal of the aortic cross-clamp, i.e. during the time the heart remains in a plegic state after the hotshot cardioplegia, it is crucial to maintain the left ventricle adequately decompressed to ensure unrestricted myocardial perfusion. Decompression of the left ventricle is best obtained by a vent inserted in the left ventricle (usually via the right superior pulmonary vein or the roof of the left atrium). Venting the main pulmonary artery is another useful yet less effective method for decompressing the left side of the heart.

Figure 20.1 Anatomic position and orientation of the heart valves in relation to the chest wall.

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Figure 20.2 Partial sternotomies. Partial upper sternotomy for the aortic valve (A), J- or inverted C-sternotomy for the mitral valve (B), and partial lower sternotomy for the tricuspid valve (C).

Figure 20.3 Spatial relationship of the mitral valve with chest incisions. The valve lies inthe line of the surgeon's eye after a right thoracotomy (left arrow). Traction on the heart is necessary t o set it into direct vision after a sternotomy (superior arrow).

an anterior thoracotomy in the second or third intercostal space provides direct visual access to the aortic valve and aortic root. The exact position of the aortic annulus varies from patient to patient. Cohn and coworkers recommend that a chest CT or echocardiography should be carried out to precisely situate the

aortic valve in cases of redo surgery (a situation where mobilization of the heart is impossible) [ 111. The partial inverted T-sternotomy is lengthened to the fourth intercostal space when the aortic valve appears deeply seated. The mitral valve after a J- or an inverted Csternotomy (Figures 20.2 & 20.3) does not come into direct vision unless the heart (mainly the posterior wall) is mobilized. An anterolateral thoracotomy sets the valve into direct vision without further mobilization of the heart and appears appropriate in redo operations (Figure 20.3) (121. The tricuspid valve is frequently operated on in conjunction with mitral valve surgery and is readily accessed with the specific incisions of the mitral valve. A partial inferior sternotomy is also suitable for the rare cases of a procedure confined to the tricuspid valve.

Aortic valve surgery Cardioplegic delivery The use of a partial upper sternotomy (Figures 20.2 & 20.4) or a short anterior thoracotomy does not alter the way antegrade cardioplegia can be delivered but creates more difficult conditions to insert a retrograde cannula into the coronary sinus [ 13-16]. The cannula, which cannot be guided by the hand, should be inserted blindly or semiblindly. Most isolated aortic valve replacement-even when a stentless valve is

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Myocardial protection in valvular surgery

Figure 20.4 Operative view of the aortic root through a partial superior sternotomy.

used—can be performed in less than three-quarters of an hour. A heart with a normal or slightly reduced ventricular function will recover satisfactorily with intermittent doses of antegrade cardioplegia and does not necessarily need further protection via a retrograde cannula. Some surgeons use continuous antegrade perfusion of the coronary ostia. A soft, pliable cannula is directly inserted into the coronary ostia, curved at right angles to conform to the inside configuration of the aortic root and fixed on the aortic wall with a 4-0 monofilament stitch. The pitfalls of this technique include obstruction of the narrow operative field, regurgitation of blood around the cannula, and possible malperfusion of a large myocardial territory when the left main coronary artery is short. Finally, ostial injuries or late stenosis due to intimal hyperplasia can occur after direct cannulation. Complex procedures on the aortic valve (aortic root replacement, annular enlargement or reconstruction, or redo operation) or a severely damaged ventricle require enhanced myocardial protection. In these settings, it is also convenient for a surgeon not to be obligated to often interrupt a demanding procedure for regular delivery of cardioplegia, and to have an operative field relatively free of instruments. Use of a retrograde perfusion of the myocardium, usually continuously with cold blood, and mild systemic hypothermia create an excellent environment for the smooth performance of these complex procedures [7].

Insertion of the retrograde cardio cannula The use of multiple stay sutures on the pericardium brings the ascending aorta and the right atrium into

view. If it appears that the venous cannula will not leave room to subsequently access the right atrium, then the retrograde cannula should be inserted (blindly or under transesophageal echocardiographic guidance) prior to the venous cannula. The return of semipulsatile dark blood testifies the correct position of the retrograde cannula. The use of a vacuum or a centrifugal pump on the venous cannula improves venous return and allows insertion of smaller cannulas. Placement of the retrograde cannula after CPB has been instituted is possible in these situations. Venous return should be temporarily reduced to enlarge the right atrium and open the coronary sinus. The tip of the retrograde cannula can be spotted under the atrial wall and guided towards the atrioventricular groove near the inferior vena cava. Another elegant way to access the coronary ostium is the insertion of a Heartport transjugular coronary sinus catheter prior to sternotomy. The incremental cost and time entailed with this cannula and technique of insertion are definitely offset in reoperations (mainly by the avoidance of dissecting the right atrium) and certainly justified in many other difficult operations.

Redo operations on the aortic valve Reoperative procedures on the aortic valve are particularly suitable for a minimal incision because of the reduction of necessary pericardial dissection [11]. Full sternotomy and pericardial dissection are associated with increased blood loss and increased risk of heart and graft injury, mediastinal infection, and sternum instability. The insertion of a retrograde cannula is particularly helpful to complete antegrade cardioplegia, especially when previously inserted bypass grafts

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are patent. Resorting to peripheral cannulation for cardiopulmonary bypass and inserting a Heartport transjugular retrograde cannula limit subsequent dissection to the sole ascending aorta (Figure 20.4). The presence of a patent internal mammary artery graft, which increases the difficulties in obtaining electromechanical stillness, is no contraindication to the technique. Systemic cooling to 20-22°C associated with cold retrograde perfusion of the heart induces electromechanical quietness and provides satisfactory myocardial protection [11]. Short periods of reduced systemic perfusion may be necessary if retrograde flow of blood in the left coronary ostium obscures the operative field; a situation well tolerated under these temperatures. The morbidity from increased CPB time for systemic cooling and rewarming is well compensated by the avoidance of a difficult and potentially hazardous dissection of a patent internal mammary graft. Venting of the left ventricle is more difficult with limited pericardial dissection. Although an access to the left cardiac cavities is possible through the roof of the left atrium (between aortic root and right atrium), many surgeons may choose not to vent the heart in a straightforward reoperation. Once the prosthesis has been implanted and the aortotomy closed, it is appropriate to perfuse the heart with warm blood through the retrograde cannula, vent the ascending aorta, and wait until mechanical activity has resumed (sometimes with atrioventricular pacing) before removing the aortic cross-clamp [17]. The left ventricle should then be closely scrutinized by transesophageal echocardiography. Should it get distended with unsatisfactory contractions, the aortic cross-clamp should be reapplied, the ascending aorta kept vented, and warm blood delivered through the retrograde cannula until resumption of better function of the heart.

Mitral valve surgery In the framework of conventional surgical instrumentation, the mitral valve can be accessed with two reduced incisions: a partial sternotomy (J- or inverted C-incision) and an anterior right thoracotomy (Figures 20.2 & 20.3). Both incisions result in a cosmetically superior chest deformation compared to that after a full sternotomy. The incisions, however, have limitations. The exposure and the handling of the mitral valve—especially the anterior annulus and

CHAPTER 20

Figure 20.5 Operative view of the mitral valve through a partial sternotomy, and using a trans-septal approach extended in the roof of the left atrium.

the subvalvular apparatus—are difficult. Therefore, a partial sternotomy is not indicated for all types of valvular repair.

Limited sternotomy A J- or inverted C-sternal incision provides an access to the mitral valve by using a trans-septal approach [13,14]. The trans-septal incision sometimes needs to be extended in the roof of the left atrium (Figure 20.5) [ 18]. Since the ascending aorta and the coronary sinus lie under direct vision, the placement of cannulas and delivery of antegrade and retrograde cardioplegia raise no particular problems and can be performed in a conventional way. Many surgeons start with an antegrade cardioplegia to induce electromechanical quietness and pursue myocardial protection with a continuous retrograde perfusion of the myocardium, usually with cold blood (Table 20.1).

Right anterior thoracotomy A right anterior thoracotomy is used mainly in redo operations for cosmetic reasons and the avoidance of tight substernal adhesions and patent grafts. Previous implantation of an aortic stented prosthesis is another argument for using this approach [12,19,20]. The prosthesis renders the anterior annulus of the mitral valve unbendable. A right thoracotomy sets the mitral valve in the direct line of vision of the surgeon (Figure 20.3), while mobilization of the heart is necessary

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Myocardial protection in valvular surgery with a sternotomy, and may be particularly troublesome in limited sternal incisions. Opening the left atria along the interatrial groove accesses the valve. The access to the ascending aorta is limited; especially if a cosmetic small thoracotomy has been selected. Peripheral cannulation and percutaneous insertion of a Heartport retrograde cardioplegic cannula and an endoluminal aortic clamp can provide complete equipment for CPB and myocardial protection without obstructing the operative field. The Heartport endoluminal aortic clamp allows selective perfusion of the aortic root and, after delivery ofcardioplegia, can operate as a left ventricular vent and deairing aspirator during the reperfusion phase [17]. The catheters, however, are not available in most cardiovascular units. The aorta must then be instrumented in the usual fashion. With minimal dissection, it can be cross-clamped using a regular clamp inserted through the incision or a specially designed clamp inserted through a small counterincision in the second intercostal space [21]. A small cannula in the aortic root permits antegrade delivery of cardioplegia and subsequent deairing. Cannulation of the coronary sinus through the right atrium is possible blindly or under vision after opening of the right atrium. The latter approach is preferred when the tricuspid valve needs concomitant repair.

Redo operations on the mitral valve The advantage of an approach through an anterior thoracotomy with reduced dissection must be weighted against the increased difficulty of working on the subvalvular apparatus. The advantage is certainly decisive in redo operations for a paravalvular leak of a mitral prosthesis or for a mitral valve replacement when patent coronary grafts lie under the sternum. The stress on the myocardium can be reduced to a minimum in the case of paravalvular leak. Because the repair can be performed in a very short time, it is possible to avoid cross-clamping the aorta and, therefore, myocardial ischemia [12]. The prerequisite for this simplified approach is the presence of a competent aortic valve. Peripheral cannulation is preferred for cardiopulmonary bypass. The diaphragmatic surface of the heart is dissected (this part is usually not tightly adherent) for insertion of a fibrillator. The left atrium is opened during induced ventricular fibrillation, the paravalvular leak identified and closed with pledgeted stitches. Although

rarely necessary, one may still need to cross-clamp the aorta for very short periods of time (1 or 2 min) if distortion of the aortic annulus during insertion of the needle induces aortic regurgitation. At the end of the repair, a vent is inserted through the prosthesis for correct deairing and blood filling of the left ventricle, and is removed shortly after resumption of mechanical activity. The aortic root is vented until disappearance of air signals in transesophageal echocardiography.

Tricuspid valve surgery Secondary valvular dysfunction Isolated acquired diseases of the tricuspid valve requiring surgical repair are rare. The most common situation leading to repair of the tricuspid valve is a dysfunction secondary to chronic mitral valve disease and pulmonary hypertension. The ensuing tricuspid valve regurgitation is due to annular dilatation. The choice of chest incision in these cases is dictated by the mitral pathology and planned repair. Tricuspid valve repair, which usually merely consists of annular reduction plasty, can be performed with intact coronary perfusion, classically during the period of myocardial reperfusion. Both vena cava must be cannulated and isolated. The right atrium is opened and blood coming from the coronary sinus is aspirated with cardiotomy sucker.

Primary valvular dysfunction Bacterial endocarditis, Ebstein's anomaly, and primary dilatation of the right atrium are the most common pathologies leading to surgical repair confined to the tricuspid valve. A limited inferior sternotomy (Figure 20.2) is most appropriate for this approach, although a repair not involving the subvalvular apparatus can also be approached by a right anterior thoracotomy (an approach considered cosmetically superior in some patients) [15]. Here too peripheral cannulation for CPB may be advantageous, although the ascending aorta and both vena cava can also be directly cannulated. Lifting up the upper intact sternum gives satisfactory access to the ascending aorta. Temporary cannulation of the right atrial appendage allows complete collapse of the heart and opens the way to both vena cavae. Simple repair can be performed without aortic cross-clamping. A short period of induced ventricular

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fibrillation maybe necessary upon opening of the right atrium to close a patent foramen ovale or another atrial septum defect. Once an airtight septation of

9

both atria has been secured, the heart can be allowed to beat again without risk of sucking air into the left ventricle. It may be advantageous to have a completely bloodless field and a motionless heart when

10

complex repair on the subvalvular apparatus is necessary (transposition of papillary muscles in Ebstein

11

anomaly's or valvular replacement with a homograft). By lifting the upper sternum with an army navy retractor, the aorta can be cross-clamped and antegrade cardioplegia delivered in the usual way [22]. Access to

12

the coronary sinus is straightforward after opening of the right atrium. The left ventricle can be vented via

13

the right superior pulmonary vein or across the atrial septum. Myocardial protection is then performed in a

14

standard way. 15

References 1 Kauftnann P, Vassalli G, Lupi Wagner S, Jenni R, Hess OM. Coronary artery dimensions in primary and secondary left ventricular hypertrophy. / Am Coll Cordial 1996;28:745-50. 2 Julius BK, Spillmann M, Vassalli G, Villari B, Eberli FR, Hess OM. Angina pectoris in patients with aortic stenosis and normal coronary arteries. Mechanisms and pathophysiological concepts. Circulation 1997; 95: 892-8. 3 Menasche P, Piwnica A. Cardioplegia by way of the coronary sinus for valvular and coronary surgery. J Am Coll Cardiol 1991; 18:628-36. 4 Noyez L. Retrograde cardioplegia and aortic valve replacement. / Thorac Cardiovasc Surg 1993; 106:370. 5 Prater RW. Retrograde cardioplegia. / Heart Valve Dis 1999:8:118-19. 6 Buckberg GD. Studies of hypoxemic/reoxygenation injury. I. Linkage between cardiac function and oxidant damage. / Thorac Cardiovasc Surg 1995; 110 (4 Part 2): 1164-70. 7 Buckberg GD, Beyersdorf F, Allen BS, Robertson JM. Integrated myocardial management: background and initial application. / Card Surg 1995; 10:68-89. 8 Menasche P, Tronc F, Nguyen A et al. Retrograde warm

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blood cardioplegia preserves hypertrophied myocardium: a clinical study. Ann Thorac Surg 1994; 57:1429-34. Anderson WA, Berrizbeitia LD, Ilkowski DA et al. Normothermic retrograde cardioplegia is effective in patients with left ventricular hypertrophy. A prospective and randomized study. / Cardiovasc Surg (Torino) 1995; 36:17-24. Bel A, Aznag H, Paris B, Menasche P. Warm blood cardioplegia in high risk patients. Eur J Cardiothorac Surg 1997; 11:1118-23. Byrne }G, Karavas AN, Adams DH et al. Partial upper re-sternotomy for aortic valve replacement or re-replacement after previous cardiac surgery. Eur J Cardiothorac Surg 2000; 18:282-6. Pretre R, Ye Q, Zund G, Turina MI. Approach to the mitral valve through a right thoracotomy in potentially hazardous reoperation. / Card Surg 1999; 14:112-15. Cosgrove DM, Sabik JF, Navia JL. Minimally invasive valve operations. Ann Thorac Surg 1998; 65:1535-8. Svensson LG. Minimal-access "J" or "j" sternotomy for valvular, aortic, and coronary operations or reoperations. Ann ThoracSurg 1997; 64:1501-3. Doty DB, Flores JH, Doty JR. Cardiac valve operations using a partial sternotomy (lower half) technique. / Card Surg 2000; 15:35-42. Konertz W, Waldenberger F, Schmutzler M, Ritter J, Liu. J. Minimal access valve surgery through superior partial sternotomy: a preliminary study. J Heart Valve Dis 1996; 5:638-40. Grossi EA, Galloway AC, Ribakove GH et al. Impact of minimally invasive valvular heart surgery: a case-control study. Ann Thorac Surg 2001; 71: 807-10. Guiraudon GM, Ofiesh JG, Kaushik R. Extended vertical transatrial septal approach to the mitral valve. Ann Thorac Surg 1991; 52:1058-60. Dabritz S, Sachweh J, Walter M, Messmer BJ. Closure of atrial septal defects via limited right anterolateral thoracotomy as a minimal invasive approach in female patients. Eur J Cardiothorac Surg 1999; 15:18-23. Liu YL, Zhang HJ, Sun HS et al. Repair of cardiac defects through a shorter right lateral thoracotomy in children. Ann Thorac Surg 2000; 70: 738^1. Chitwood WR, Elbeery JR, Moran JF. Minimally invasive mitral valve repair using transthoracic aortic occlusion. Ann ThoracSurg 1997; 63:1477-9. Laussen PC, Bichell DP, McGowan FX et al. Postoperative recovery in children after minimum versus full-length sternotomy. Ann Thorac Surg 2000; 69:591-6.

CHAPTER 21

Intermittent warm blood cardioplegia in aortic valve surgery: an update M. Saadah Suleiman, PHD, Raimondo Ascione, MD, & Gianni D. Angelini, MD, FRCS

is superior to intermittent cold blood cardioplegia in coronary artery bypass graft surgery but not during Major advances have been made in the preservation of aortic valve surgery. The reason for this may lie in myocardial function during open-heart surgery since metabolic differences between the two pathologies. the introduction of cardioplegic arrest [ 1 ]. However, These observations add weight to the suggestion that despite variation in the composition of cardioplegia, results obtained with cardioplegic techniques in patients myocardial protection has been based primarily on undergoing coronary surgery cannot be uncritically hyperkalemic solutions [2]. This decreases electro- extended to patients requiring valve surgery. mechanical activity and therefore significantly reduces oxygen demand [3]. Hypothermia has also been used Cardiac hypertrophy as it can further reduce oxygen demand by decreasing basal metabolic rate. However, hypothermia may Anatomic studies have demonstrated that the upper have adverse effects like inhibiting the Na pump [4] to limit of a normal heart is 450 g in men and 400 g cause edema and shifting of the oxygen-hemoglobin in women [11]. These values have to be corrected for dissociation curve leftward [5]. It is not surprising epicardial fat, body mass, and age. The left ventricular therefore that the optimal temperature of cardioplegia myocardial weight to body height ratio should normremains controversial [3]. Continuous warm blood ally not exceed 36 g/m [2] in both genders [ 12]. Based cardioplegia has been widely advocated as a more on these values the agreed cut-off limit to separate physiological approach, but perfusion is often inter- normal from hypertrophied hearts by echocardiorupted to allow adequate visualization of the operat- graphyis50g/m[2,12]. Generally, cardiac hypertrophy occurs in response ive site [3]. Therefore, intermittent delivery has been proposed as an equally effective and more practical to an overload. Myocyte lengthening with the additechnique [6]. tion of new sarcomeres in series is the prevailing Myocardial protection techniques have been lar- mechanism following volume overloads, i.e. eccentric gely investigated in the clinical setting of coronary hypertrophy, in which ventricular chamber dilatarevascularization; little work has been carried out on tion is accompanied by a proportional increase in myocardial protection in patients with left ventricular wall thickness. Lateral expansion of myocytes with the hypertrophy where the choice of optimal cardioplegia addition of new sarcomeres in parallel represents remains controversial [6-10]. the typical pattern of myocyte growth after pressure Here we provide evidence that intermittent warm overload, i.e. concentric hypertrophy [11].

Introduction

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182

CHAPTER 21

Myocardial metabolic state in cardiac hypertrophy Heart muscle can adapt to environmental changes by altering the synthesis and degradation rates of specific proteins or, in the short term, by changing flux through metabolic pathways to maintain its state of equilibrium [13]. When the heart is subjected to a chronic overload, it enlarges and major restructuring of organelles and cellular function occurs. However little is known about alterations in the energy status of the hypertrophied myocyte [ 14]. Aortic insufficiency is associated with periods of adaptation that include changes in function, metabolism, and structure of the left ventricle culminating in heart failure [15]. Left ventricular hypertrophy is considered to be an independent risk factor giving rise to ischemia, arrhythmia, and left ventricular dysfunction [16]. Heart failure caused by aortic stenosis, aortic insufficiency, or both, is characterized by a decline in the phosphocreatine/ATP ratio [17]. However most studies suggest normal ATP and total adenine nucleotides in human heart failure [18]. This is consistent with most animal experimental models which also show that aerobic myocardial glycogen metabolism in hypertrophied heart is similar to normal heart [19,20]. Other studies suggest that overload hypertrophy (volume or pressure) may induce changes in the metabolism of the myocardium which may in turn lead to persistent modifications in mitochondrial function [21].

Susceptibility of hypertrophied hearts to ischemia-reperfusion injury Because of the controversy regarding the metabolic state of the hypertrophied myocardium, it is not surprising that the assessment of its susceptibility to ischemic insults is far from being completed. In severely hypertrophied myocardium, capillary density is reduced; the diffusion distance for oxygen and nutrients is increased and the ratio of energy production to energy consumption sites is decreased [ 16]. This is likely to make the heart more vulnerable to ischemic insults. Work on animal models has provided conflicting reports as to the effect of ischemia on hypertrophied heart. For example our work on pressure overload hypertrophic hearts isolated from spontaneously hypertensive rat (SHR) demonstrates that these are more susceptible to 40 min of global ischemia and 60 min reperfusion compared to control hearts isolated from normotensive

Figure 21.1 The susceptibility of hypertrophic hearts to ischemia-reperfusion injury. Rate pressure product of hypertrophic and normal Langendorff rat hearts following exposure to 40 min normothermic global ischemia and 60 min reperfusion. Pressure overload hypertrophic hearts were isolated from spontaneously hypertensive (SHR) rats compared to control hearts isolated from normotensive Wistar Kyoto (WKY) rats. * P< 0.05 versus corresponding preischemic value. ** P< 0.05 versus WKY preischemic value. Open bars, WKY; closed bars, SHR.

Wistar Kyoto (WKY) rats (Figure 21.1). In agreement with our work, most reports have shown that myocardial hypertrophy has increased susceptibility to ischemia with accelerated loss of high-energy nucleotides, greater accumulation of lactate, and earlier onset of contracture [20,22-25]. However reports continue to appear suggesting that hypertrophied heart may be more resistant to ischemia with no significant change in nucleotide metabolism [26].

Myocardial protection during aortic valve surgery Isolated stenosis of the aortic valve leads to left ventricular hypertrophy which makes myocardial protection difficult during cardiac surgery and the choice of optimal cardioplegia remains controversial [21]. Bel and associates [8], in a study on patients with heavily hypertrophied hearts, suggested that retrograde warm cardioplegia could effectively maintain myocardial aerobic patterns in patients operated on for aortic valve stenosis complicated with left ventricular hypertrophy, provided that oxygen supply was optimized by uninterrupted perfusion, high flow rates (200 ml/min), and high hemoglobin content (which was made pos-

Cardioplegia in aortic valve surgery sible by a low dilution cardioplegia delivery technique). In a randomized study Jin and coworkers [10] assessed the efficacy of antegrade crystalloid cardioplegia (21 patients), antegrade/retrograde cold blood cardioplegia (23 patients), and continuous retrograde warm (37°C) blood cardioplegia (20 patients) on hypertrophic hearts. Perioperative left ventricular (LV) function was assessed using transesophageal M-mode echocardiography, combined with high-fidelity LV pressure recording and thermodilution cardiac output, before bypass and 0.5, 1, 3, 6, 12, and 20 h after cross-clamp removal. They concluded that in the hypertrophied left ventricle, antegrade/retrograde cold blood cardioplegia offers the best preservation of myocardial physiologic response and ventricular function with less inotropic support. On the other hand, Calafiore and associates [6] in a retrospective study on 271 patients with hypertrophic hearts undergoing aortic valve surgery (operated on with intermittent antegrade warm (171 patients) or cold (100 patients) blood cardioplegia) demonstrated that warm cardioplegia provides lower cardiac-related mortality and morbidity in comparison with cold blood cardioplegia. Others have shown no difference in protection between continuous normothermic and intermittent hypothermic cardioplegia [7]. During the last few years our group has had a particular interest in myocardial protection in patients undergoing coronary artery bypass surgery [27-31]. Recently, we have been able to demonstrate that the protective effect of cardioplegic techniques used in patients with ischemic disease are not necessarily applicable to patients with aortic valve disease.

183

ness transmural biopsies of the left ventricular apical or anterolateral free wall (4-12 mg wet weight) were taken using a Trucut needle. The first biopsy was taken 5 min after institution of cardiopulmonary bypass (control), the second after 20 min of reperfusion following removal of the aortic cross-clamp. In addition to the two biopsies, a third biopsy (ischemic) was also collected, 30 min after cross-clamping the aorta. Each specimen was immediately frozen in liquid nitrogen until processing analysis of cellular metabolites. Figure 21.2 shows that intermittent antegrade

Image Not Available

Cardioprotection with intermittent warm or cold blood cardioplegia Warm is superior to cold in coronary artery bypass surgery The efficacy of intermittent antegrade warm versus cold blood cardioplegia (both with added Mg2+) was investigated in patients undergoing coronary artery surgery [32,33]. Ischemic stress was assessed by monitoring changes in cellular metabolites whereas reperfusion injury was determined by measuring the postoperative release of myocardial troponin I [32]. Metabolic changes were monitored during ischemia and after reperfusion in LV biopsies. Full wall thick-

c changes i n ischemically diseased hearts during ischemia and upon reperfusion. Myocardial changes in ATP (a) and lactate (b) in biopsies collected 30 min after cross-clamping the aorta (ischemia) and 20 min after reperfusion in hearts of patients undergoing coronary artery bypass surgery using intermittent cold or warm blood cardioplegia. Data are shown as mean ±SE. P<0.05 ischemia versus control biopsy. Control (open); 30 min after ischemia (hatched); 20 min after reperfusion (solid). Reproduced with permission from Suleiman etal.AmJ Phys/o/41: H1063-H1069,1997.

184

Figure 21.3 Reperfusion injury. Myocardial troponin I total release following coronary (a) or aortic valve surgery (b) using intermittent cold or warm blood cardioplegia. Data are presented as mean + SE and expressed as ng/ml. * P< 0.05 versus cold blood group.

warm blood cardioplegia is associated with better metabolic preservation during ischemia compared to cold blood cardioplegia. Reperfusion injury was determined by monitoring the concentration of myocardial troponin I (a sensitive marker of myocardial damage) [32] in blood samples collected prior to surgery, and 1,4,12,24, and 48 h postoperatively. Consistent with improved metabolic preservation using warm blood cardioplegia (Figure 21.2), these patients had also less reperfusion damage as shown by a reduced postoperative release of troponin I (Figure 21.3a).

Cold is superior to warm in aortic valve surgery Rather than uncritically apply the findings presented above, we decided to compare the two techniques of myocardial protection in the setting of aortic valve surgery. A significant accumulation of lactate during

CHAPTER 21

Figure 21.4 Metabolic changes in hypertrophic hearts during ischemia and upon reperfusion. Myocardial changes in ATP (a) and lactate (b) in biopsies collected 30 min after cross-clamping the aorta (ischemia) and 20 min after reperfusion in hearts of patients undergoing aortic valve surgery using intermittent cold or warm blood cardioplegia. Data are shown as mean ± SE (see patients' characteristics in Table 21.1). * P < 0.05 versus control biopsy in the same group. ** P< 0.05 versus reperfusion biopsy in cold blood group. Control (open); 30 min after ischemia (hatched); 20 min after reperfusion (solid).

ischemia was only evident in the warm blood group (Figure 21.4), consistent with significant anerobic metabolism. However, the warm ischemic electromechanical arrest did not significantly influence ATP concentration, although a trend was evident (Figure 21.4). It is likely that the period of ischemia (biopsies were collected after 30 min cross-clamping) interrupted by one reperfusion episode may not be sufficient to offset the balance between ATP supply (glycolysis) and demand (basal metabolism). However, as time progresses there will be an increase

185

Cardioplegia in aortic valve surgery

Table 21.1 Preoperative data. Variable

CoW blood 16

N

Male/female

Age (yr) Body surface area (m2) History of hypertension History of hypercholesterolemia History of smoking Ejection fraction Good (>49%) Fair (30-49%) Ventricular mass index (g/m2) Transvalvular peak gradient (mmHg) NYHA class

7/9

Warm blood 19

10/9

64.5 ±11. 9 1.8410.25

67.217.6

10

12

1.85 + 0.17

6

8

11

11

14

15

2

186134 84.5123.8

4 178129

83.6122.2 10

I

8

II

5

5

III

2

3

IV

Parsonnet score

1

13.4119.15

1

12.3516.75

Data are presented as mean ± standard deviation or number. Myocardial protection was achieved by using antegrade cold (6-8°C) or warm blood (34°C) cardioplegia, both with added K + and Mg2+to give a final concentration of approximately 20 mmol K + and 5 mmol Mg2+. The cold blood cardioplegia solution was a mixture of the patient's blood and St Thomas' I cardioplegia solution (4 blood : 1 St Thomas' I). The warm blood cardioplegia was the patient's blood with added K + and Mg2+. Following cross-clamping and opening of the ascending aorta, the cardioplegia solution was administered directly into the coronary ostia as a 1-litre bolus (700 ml in the left followed by 300 ml in the right) at a pressure of 150 mmHg. Infusions of 200 ml for each ostium were repeated at 15-min intervals. Exclusion criteria included: coronary artery disease, concomitant aortic regurgitation, left ventricular ejection fraction of less than 30%, history of congestive heart failure, diabetes mellitus, and reoperation. Eligibility for surgery was based on the medical history, echocardiography, and the most recent angiogram. The end points of the study were myocardial metabolic changes and myocardial injury.

in energy demand particularly as myocardial wall tension begins to increase and as energy supply decreases, as acidosis associated with lactate accumulation slows down glycolysis [34]. The reduced myocardial metabolic stress observed with the cold blood cardioplegia might be, in part, due to the effects of hypothermia itself, which might have reduced the oxygen demand of the hypertrophic heart. It has been shown that while the oxygen consumption of a normal normothermic, nonworking vented heart (6-8 ml O2/100 g/min) is reduced to 0.6-1.5 ml O2/100 g/min by potassium cardioplegia, cardioplegia itself at normothermia is not effective in reducing the basal energy requirement of the myocyte [35,36]. However, hypothermia may contribute to decrease this basal energy requirement of

the myocyte, as it has been shown that the potassiumarrested heart has a myocardial consumption of 0.31 ml O2/100 g/min at 22°C and of 0.135 ml O2/ 100g/minatlO-12°C[35]. The increased metabolic stress in the warm blood group was also associated with a significantly greater reperfusion injury (release of troponin I) compared to the cold blood group (Figure 21.3b). The results of this study suggest that the myocardial protection of hypertrophic hearts with intermittent antegrade warm blood cardioplegia is not as effective as in hearts with ischemic disease [32]. This might be explained by the fact that the two pathologies have different metabolic demands [37]. For example as the underlying disease is aortic stenosis, the hypertrophy

186

of the left ventricle leads to increases in both left ventricular end-diastolic volume and left ventricular end-diastolic pressure [38], which increase myocardial work and oxygen demand. In this situation, two of the primary determinants of myocardial oxygen demand (tension developed by the myocardium and duration of systole) are increased. At the same time, myocardial oxygen supply is impeded owing to an elevated enddiastolic pressure, causing a decrease in coronary perfusion pressure. Finally, the Venturi effect of the jet of blood flowing through the aortic valve and past the coronary arteries may reduce pressure in the coronary ostia enough to reverse systolic coronary blood flow. These factors make the heart more susceptible to ischemia, even in the absence of concurrent atherosclerotic coronary disease [38]. Although the results of this study show that the myocardial protection of hypertrophic hearts is superior when using cold blood cardioplegia, they also demonstrate a significant degree of myocardial injury associated with this method of cardioplegia. Potential improvements of this technique in patients with LV hypertrophy might be achieved by a final dose of warm blood cardioplegia "hot shot" prior to removal of the aortic cross-clamp, or by continuous delivery, which has been demonstrated to be beneficial in ischemic hearts [39-41].

Metabolic differences between hypertrophic and ischemically diseased hearts Hypertrophic hearts, unlike hearts with coronary disease, have a high myocardial concentration of ATP and lower concentration of lactate (Figure 21.5). This is consistent with known consequences of ischemia. In addition to lactate and ATP, there are significant differences in the concentrations of alanine and the branched chain amino acids leucine and valine [37]. Measurements of metabolites in hypertrophic hearts suggest that these hearts would be relatively more resistant to ischemia when compared to hearts with coronary disease. Our work using intermittent antegrade warm blood cardioplegia suggests that hypertrophic hearts are in fact more susceptible to ischemia and reperfusion injury compared to ischemically diseased hearts (Figures 21.2-21.4). It is plausible to assume that ischemically diseased hearts are preconditioned and therefore more resistant to ischemia and reperfusion damage compared to hypertrophic hearts.

CHAPTER 21

Image Not Available

Figure 21.5 ATP and lactate in hypertrophic and ischemically diseased hearts. A scattergram for the myocardial concentration (nmol/mg protein) of ATP and lactate for hypertrophic and ischemic hearts before open heart surgery. For each patient individual values (open squares) in each pathology are shown as well as the mean ± SEM. Reproduced from J Mol Cell Cardiol 30(11): 2519-2523, Suleiman eta/. 1998, by permission of the publisher Academic Press London.

However it is worth noting that the ischemic time (cross-clamp time) was relatively longer for valve surgery (approx. 45 min) compared to coronary surgery (approx. 35 min). Therefore a firm conclusion cannot be made from these studies. The use of hypothermia as an adjunct to cardioplegia conferred better protection on hypertrophic hearts compared to ischemically diseased hearts (Figures 21.2-21.4). Hypothermia is known to neutralize ischemic preconditioning during coronary artery bypass surgery [40].

Conclusions Evidence of metabolic derangement and reperfusion injury, indicating suboptimal myocardial protection, is seen in patients undergoing aortic valve surgery using either cold or warm blood cardioplegia. However,

187

Cardioplegia in aortic valve surgery

cold blood cardioplegia is associated with a relatively reduced metabolic derangement and myocardial reperfusion injury.

11

Potential improvements of this technique in patients with LV hypertrophy might be achieved by a final

12

dose of warm blood cardioplegia "hot shot" prior to removal of the aortic cross-clamp. Continuous delivery

13

of warm blood cardioplegia solutions, demonstrated to be beneficial in ischemic hearts [39-41 ], might also

14

improve myocardial protection of the hypertrophic heart and prevent the deleterious effects associated with the intermittent delivery [36,42].

15

Acknowledgments

16

This work was supported by the British Heart Foundation and the Garfield Weston Trust. We would like

17

to acknowledge the help and support of staff in the Department of Cardiac Surgery and the Myocardial Protection Group. 18

References 1 Melrose DG, Dreyer B, Bentall HH et al. Elective cardiac arrest. Lancet 1955; ii: 21-2. 2 Demmy TL, Haggerty SP, Boley TM et al. Lack of cardioplegic uniformity in clinical myocardial preservation. Ann ThoracSurg 1994; 57:648-51. 3 Mauney MC, Kron IL. The physiologic basis of warm cardioplegia. Ann ThoracSurg 1995;60:819-23. 4 Suleiman M-S, Chapman RA. Effect of temperature on the rise in intracellular sodium caused by calcium depletion in ferret ventricular muscle and the mechanism of the alleviation of the calcium paradox by hypothermia. Circulation Res 1990; 67:1238-46. 5 Buckberg GD. Update on current techniques of myocardial protection. Ann Thorac Surg 1995; 60:805 -14. 6 Calafiore AM, Teodori G, Bosco G et al. Intermittent antegrade warm blood cardioplegia in aortic valve replacement. J Cardiac Surg 1996; 11: 348-54. 7 Anderson WA, Berrizbeitia LD, Ilkowski DA et al Normothermic retrograde cardioplegia is effective in patients with left ventricular hypertrophy—a prospective randomised study. / Cardiothorac Surg 1995; 36:17-24. 8 Bel A, Aznag H, Faris B et al. Warm blood cardioplegia in high risk patients. Eur J Cardio-Thorac Surg 1997; 11: 1118-23. 9 Dorman BH, Hebbar L, Clair MJ et al. Potassium channel opener augmented cardioplegia—protection of myocyte contractility with chronic left ventricular dysfunction. Circulation 1997; 96:253-9. 10 lin XY, Gibson DG, Pepper JR. Early changes in regional and global left ventricular function after aortic valve

19

20

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24

25

26

27

replacement—comparison of crystalloid, cold blood and warm blood cardioplegia. Circulation 1995; 92:155—62. Olivetti G, Cigola E, Maestri R et al. Recent advances in cardiac hypertrophy. Cardiovasc Res 2000; 45:68-75. Spirito P, Seidman C, McKenna WJ et al. The management of hypertrophic cardiomyopathy. N Engl J Med 1997;336:775-85. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. CurrProb Cardiol 1994; 19:62-113. Rossi A, Lortet S. Energy metabolism patterns in mammalian myocardium adapted to chronic physiopathological conditions. Cardiovasc Res 1996; 31:163-71. Simko F. Spontaneous regression of left-ventricular hypertrophy in a rabbit model of aortic insufficiency: possible clinical implications. Med Hypothesis 1995; 45:556-8. Zhu YC, Zhu YZ, Spitznagel H et al. Substrate metabolism, hormone interaction and angiotensin-converting enzyme inhibitors in left-ventricular hypertrophy. Diabetes 1996; 45:859-65. Conway MA, Allis J, Ouwerker R et al. Low phosphocreatine/ATP ratio detected in vivo in the failing hypertrophied human myocardium using 31P magnetic resonance spectroscopy. Lancet 1991; 338:973-6. Regitz V, Fleck E. Adenine nucleotide metabolism and contractile dysfunction in heart failure—biochemical aspects, animal experiments and human studies. Basic Res Cardiol 1992; 87:321-9. Allard MF, Henning SL, Wambolt RB et al. Glycogen metabolism in the aerobic hypertrophied rat heart. Circulation 1997; 96:676-82. Do E, Baudet S, Verdys M et al. Energy metabolism in normal and hypertrophied right ventricle of the ferret heart. /Mo/ Cell Cardiol 1997; 29:1903-13. Janati-idrisis R, Besson B, Laplace M et al. In situ mitochondrial function in volume overload-induced and pressure overload-induced cardiac hypertrophy in rats. Basic Res Cardiol 1995; 90: 305-13. McAinsh AM, Turner MA, O'Hare D et al. Cardiac hypertrophy impairs recovery from ischemia because there is a reduced reactive hyperaemic response. Cardiovasc Res 1995; 30:113-21. Schonekess BO, Allard MF, Lopaschuk GD. Recovery of glycolysis and oxidative metabolism during postischemic reperfusion of hypertrophied rat heart. AmJPhysiol 1996; 40: H798-805. Takeuchi K, Buenaventura P, Caodanh H et al. Improved protection of the hypertrophied left-ventricle by histidinecontaining cardioplegia. Circulation 1995; 92:395-9. Zhang YD, Xu SC. Increased vulnerability of hypertrophied myocardium to ischemia and reperfusion injury: relation to cardiac renin-angiotensin system. Chin Med J 1995; 108:28-32. Ji LL, Fu RG, Mitchell EW et al. Cardiac hypertrophy alters myocardial response to ischemia and reperfusion in vivo. Acta Physiol Scand 1994; 151:279 -90. Caputo M, Dihmis W, Birdi I et al. Cardiac troponin T and troponin I release during coronary artery surgery

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28

29

30

31

32

33

using cold crystalloid and blood cardioplegia. Eur J Cardiothorac Surg 1997; 12:254-60. Caputo M, Dihmis WC, Bryan AJ et al. Warm blood hyperkalaemic reperfusion (hot shot) prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery. Eur J Cardiothorac Surg 1998; 13:559-64. Suleiman M-S, Fernando HC, Dihmis WC et al. A loss of taurine and other amino-acids from ventricles of patients undergoing bypass-surgery. Br Heart 1993; 69:241-5. Suleiman M-S, Dihmis WC, Caputo M et al. Changes in the intracellular concentration of glutamate and aspartate in hearts of patients undergoing coronary artery surgery. AmJPhysiol 1997; 272: H1063-9. Suleiman M-S, Moffatt A, Dihmis WC et al. Effect of ischemia and reperfusion on the intracellular concentration of taurine and glutamine in the hearts of patients undergoing coronary artery surgery. Biochim Biophys Acta 1997; 1324:223-31. Caputo M, Bryan AJ, Calafiore AM et al. Intermittent antegrade hyperkalemic warm blood cardioplegia supplemented with magnesium prevents myocardial substrate derangements in patients undergoing coronary artery bypass surgery. Eur J Cardiothorac Surg 1998; 14: 596-601. Mezzetti A, Calafiore AM, Lapenna D et al. Intermittent antegrade warm blood cardioplegia reduces oxidative stress and improves metabolism in the ischemic-reperfused human myocardium. / Thorac Cardiovasc Surg 1995; 109: 787-95.

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34 Halestrap AP, Wang X, Poole RC et al. Lactate transport in heart in relation to myocardial ischemia. Am J Cardiol 1997;80:17-25. 35 Buckberg GD, Brazier JR, Nelson RL et al. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. ] Thorac Cardiovasc Surg 1997; 73:87-94. 36 Landymore RW, Marble AE, MacAulay MA et al. Myocardial oxygen consumption and lactate production during antegrade warm blood cardioplegia. Eur J Cardiothorac Surg 1992; 6:372-6. 37 Suleiman M-S, Caputo M, Ascione R et al. Metabolic differences between hearts of patients with aortic disease and hearts of patients with ischemic disease. / Mol Cell Cardiol 1998; 30:2519-23. 38 Hensley FA, Martin DE. A Practical Approach to Cardiac Anesthesia, 2nd edn. Boston: Little Brown, 1995:296-325. 39 Gundry SR, Wang N, Bannon D et al. Retrograde continuous warm blood cardioplegia: maintenance of myocardial homeostasis in humans. Ann Thorac Surg 1993; 55:358-61. 40 Menasche P, Peynet J, Touchot B et al. Normothermic cardioplegia: is aortic cross-clamping still synonymous with myocardial ischemia? Ann Thorac Surg 1992; 54:472-8. 41 Tasdemir O, Katirciouglu SF, Kucukaksu DS et al. Warm blood cardioplegia: ultrastructural and hemodynamic study. Ann Thorac Surg 1993; 56: 305-11. 42 Matsura H, Lazar HL, Yang XM et al. Detrimental effects of interrupting warm blood cardioplegia during coronary revascularization. / Thorac Cardiovasc Surg 1993; 106: 357-61.

CHAPTER 22

Myocardial protection in surgery of the aortic root Stephen Westaby, PHD, MS, FETCS

30-40% of patients will need concomitant coronary bypass surgery or aortic arch replacement which may A wide variety of pathologic problems present for greatly extend myocardial ischemic time. By contrast, aortic root surgery [ 1 ]. These range from congenital improvements in vascular graft technology and the aortic stenosis with severe left ventricular hypertro- use of antifibrinolytic agents have reduced the risk of phy to annulo aortic ectasia with aortic regurgitation abnormal bleeding and shortened the duration of carand advanced left ventricular dysfunction. These con- diopulmonary bypass (CPB) and operating time [3]. In the 1980s, multivariant analysis showed proditions may be complicated by coronary anomalies (Figure 22.1) or diffuse coronary artery disease. In longed myocardial ischemic time to be a risk factor for those with primary aortic pathology, aneurysmal hospital death after aortic root replacement [4,5]. With improvements in myocardial protection, this is dilatation may extend into or around the aortic arch. Aortic root surgery has changed considerably over no longer the case. Problematic right ventricular dysthe past 20 years. Coronary button mobilization and function was often blamed on inadequate myocardial reimplantation has replaced the classic Bentall pro- protection but usually followed coronary air embolcedure and the Cabrol operation is virtually obsolete. ism or tension and kinking of a reimplanted right Valve conservation techniques now account for a coronary ostium (Figure 22.2). Again, improvements significant proportion of root operations [2]. In turn, in surgical technique have lessened the risk of this

Introduction

Figure 22.1 Patient undergoing aortic root replacement whose right coronary artery originates posteriorly above the left coronary sinus. Cardioplegia delivery directly into the anomalous coronary ostium is shown.

189

190

Figure 22.2 Traction on the right coronary button (a, arrowed) is avoided by performing the distal graft anastomosis before right coronary implantation (b).

complication. In experienced hands, hospital mortality for primary elective aortic root replacement or repair is now less than for coronary bypass surgery [ 1 ]. The Ross procedure and complex root repair take time and need not be hurried with the use of modern myocardial protective methods.

The surgical plan Operations on the aortic root require a clear surgical strategy based on comprehensive preoperative investigations. The importance of this plan increases with the need for additional procedures, including myocardial revascularization, mitral valve surgery, or extended aortic resection with hypothermic circulatory arrest. The method of cardioplegia delivery will be deter-

CHAPTER 22

mined by the presence of aortic regurgitation, coronary artery disease, or coronary anomalies. In patients with renal failure, the volume of cardioplegia solution may assume importance and for anuric patients perioperative hemofiltration is necessary. Preoperative assessment requires detailed imaging of root and arch anatomy (by CT or nuclear magnetic resonance imaging) and definition of coronary anatomy by angiography. Left ventricular function including the degree of left ventricular hypertrophy or dilatation is assessed by two-dimensional echocardiography. Those with a carotid bruit, a past history of stroke, or peripheral vascular disease may warrant angiography or Doppler ultrasound imaging of the carotid arteries. When the full requirement for surgical correction is defined, the surgical plan can be defined in detail. The author's preference is to connect coronary bypass grafts first then repair or replace the aortic root. If arch replacement is necessary, cooling to between 16°C and 18°C is undertaken during the root repair. The arch is then replaced and any additional hemostasis achieved during rewarming. This is the sequence of events in root replacement for acute type A dissection [6]. Others may prefer to perform arch replacement first then clamp and cannulate the graft and repair the root during rewarming [7]. This approach may reduce the risk of atheroembolism from aortic cross-clamping or pressurizing the false lumen in type A dissection repair. Irrespective of the strategy chosen, it is important that a clear sequence of events is defined and that the myocardial protective measures are carefully integrated in the plan. These include systemic and myocardial cooling before cross-clamp application, the method of cardioplegic delivery, and the use of topical myocardial cooling.

The author's technique For aortic root operations that do not require hypothermic circulatory arrest, we employ systemic cooling to 28°C, topical cooling with iced saline (4°C), and antegrade cold crystalloid cardioplegia (1000 ml St Thomas' Solution). A second dose of 200 ml is applied to each coronary artery prior to implantation of the coronary buttons into the graft. The degree of aortic regurgitation is determined preoperatively. At the onset of CPB an aortic crossclamp is applied just proximal to the anominate artery

Myocardial protection in aortic root surgery

and a vent inserted into the left ventricle. For patients with a competent aortic valve (usually congenital or complex aortic stenosis), cardioplegia is delivered directly into the aortic root. In the majority of patients, the aorta is transected between one and two centimeters above the sinotubular junction and cardioplegia delivered directly into the coronary ostia with a hand-held cannula. Usually 600 ml is delivered into the left main coronary and 400 ml into the right coronary arteries. Cold saline, but not ice, is applied to the pericardium. Ice may cause temporary phrenic nerve paralysis. The coronary buttons are then mobilized from the aortic wall and the native valve replaced or repaired. Approximately 30 min into the procedure a second dose of between 200 and 300 ml cardioplegia is delivered into each coronary before reimplantation into the Dacron conduit. The repair is usually complete in less than 60 min ischemic time, after which reperfusion and deairing are undertaken with a perfusion pressure between 40 and 50 mmHg. We consider the sequence of coronary button reimplantation to be important. The left coronary button is implanted first, followed by the distal anastomosis between the Dacron graft and native aorta. Only then is the site of right coronary button reimplantation determined. If the right coronary button is reimplanted before the distal anastomosis the change in alignment of the graft may cause tension and kinking of the right coronary (Figure 22.2). We believe this to be an important cause of right ventricular dysfunction in aortic root surgery. The second cause is right coronary air embolism irrespective of the deairing protocol. Intracoronary air is usually displaced by an increase in systemic perfusion pressure. For those who require additional procedures or the Ross operation, ischemic time is between 60 and 120 min. For coronary bypass patients, additional doses of cold cardioplegia solution can be delivered through the bypass conduits. During arch replacement with deep hypothermic circulatory arrest, the low systemic temperature (16°C) is protective and prevents myocardial rewarming. This relatively simple approach of myocardial protection has provided a hospital mortality of less than 2% for elective aortic root operations and an overall mortality of less than 5% when emergency procedures for acute type A dissection and endocarditis are included [ 1 ].

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Myocardial protection in other centers Other myocardial protective strategies have been described from specialized aortic surgery centers. David in Toronto maintains the systemic temperature at 32°C and directly cannulates both left and right coronary ostia for continuous perfusion with blood cardioplegia at 20°C [8]. The infusion rate is 200 ml/min until electrical activity ceases, then 40-60 ml/min depending on cardiac size and degree of hypertrophy. Coselli at Baylor employs a similar strategy with the systemic temperature between 28°C and 30°C and infusion of cold blood cardioplegia directly into the coronaries until the heart stops [9]. In some reoperations and in patients with coronary artery disease, retrograde cold blood cardioplegia is delivered via the coronary sinus. Lytle at the Cleveland Clinic similarly employs systemic cooling to 28°C then antegrade cold blood cardioplegia delivered directly into the coronary ostia after aortic cross-clamping [10]. After arresting the heart, retrograde cold blood cardioplegia is infused into the coronary sinus. Miller of Stanford employs systemic cooling to 28°C and uses cold blood cardioplegia infused directly into the coronary ostia [11]. Retrograde cardioplegia is delivered via the coronary sinus in the event of diffuse coronary artery disease, if the left main stem is short, or if there are separate origins to the left anterior descending and circumflex vessels. One liter of cardioplegia is employed initially and the myocardial temperature measured to ensure that this is below 10°C. When the ischemic period exceeds 60 min or if the myocardial temperature rises, a further dose of cardioplegia is used. Before release of the aortic crossclamp, this group employs an infusion of between 500 and 1000 ml of warm blood cardioplegia via a needle into the Dacron graft and uses this maneuver to check the integrity of the anastomoses. Two groups use lower systemic temperatures. Griepp at Mount Sinai cools to 20°C, applies the crossclamp, and delivers a single dose of antegrade cold crystalloid cardioplegia directly into the coronary ostia [12]. This simple and effective approach is supplemented by topical hypothermia with iced saline. Kouchoukos reduces the temperature of the perfusate to 15°C for 8-10 min to permit gradual cooling of the myocardium and prevent early ventricular fibrillation [13]. A probe is placed in the anterior septum

192 to continuously monitor myocardial temperature. When ventricular fibrillation occurs or after the perfusate temperature has stayed at 15°C for 2-3 min, the aorta is clamped. Blood cardioplegia at 4°C is then administered retrogradely through a ballooned-tipped catheter into the coronary sinus. This is delivered at 250 ml/min for 3 min or until a myocardial temperature of 12-14°C is achieved. Simultaneously, a cooling jacket is placed around the left ventricle to maintain hypothermia. Additional infusions of cardioplegia are given through the coronary sinus at 20- to 25-min intervals during the period of aortic clamping. The coronary arteries are not cannulated directly at any stage. These methods clearly differ in complexity but provide the same exemplary results in the hands of experienced surgeons. As a result, ischemic time no longer features as a risk factor for hospital death. In contemporary series CPB time, preoperative renal failure, coronary artery disease NYHA Class IV, and acute type A dissection are more likely to be associated with an adverse outcome. A well-planned, elective aortic root operation in a patient without advanced heart failure or renal impairment is unlikely to result in mortality. Failure to wean from CPB is more likely to occur through malposition of the reimplanted coronary ostia than inadequate myocardial protection.

References 1 Westaby S, Katsumata T, Vaccari G. Aortic root replacement with coronary button re-implantation: low risk and predictable outcome. Eur J Cardiothorac Surg 2000; 17: 259-65. 2 David TE, Feindel CM, Bos J. Repair of the aortic valve in patients with aortic insufficiency and aortic root aneurysm. / Thorac Cardiovasc Surg 1995; 109:234-352.

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3 Westaby S. Coagulation disturbances in profound hypothermia: the influence of antifibrinolytic therapy. Setnin Thorac Cardiovasc Surg 1997; 9:246-56. 4 Kouchoukos NT, Wareing TH, Murphy SF et al. Sixteenyear experience with aortic root replacement: results of 172 operations. Ann Thorac Surg 1991; 214:308-20. 5 Gott VL, Gillinou AM, Pyeritz RE et al. Aortic root replacement: risk factor analysis of a 17 year experience with 270 patients. / Thorac Cardiovasc Surg 1995; 109: 536-45. 6 Westaby S, Katsumata T, Freitas E. Aortic valve conservation in acute type A dissection. Ann Thorac Surg 1997; 64: 1108-12. 7 Yun KL, Miller DC. Technique of aortic valve preservation in acute type A aortic dissection. Oper Tech Card Thorac Surg 1996; 1:68-81. 8 David TE. When, why and how should the native aortic valve be preserved in patients with annulo-aortic ectasia or Marfan syndrome. Semin Thorac Cardiovasc Surg 1993; 5:93-6. 9 Coselli IS, Crawford ES. Composite aortic valve replacement and graft replacement of the ascending aorta plus coronary ostial re-implantation: how I do it. Semin Thorac Cardiovasc Surg 1993; 5:55-62. 10 Lytle BW. Composite aortic valve replacement and graft replacement of the ascending aorta plus coronary ostial re-implantation: how I do it. Semin Thorac Cardiovasc Surg 1993; 5: 84-7. 11 Miller CD, Mitchell RS. Composite aortic valve replacement and graft replacement of the ascending aorta plus coronary ostial re-implantation: how I do it. Semin Thorac Cardiovasc Surg 1993; 5: 74-83. 12 Ergin MA, Griepp RB. Composite aortic valve replacement and graft replacement of the ascending aorta plus coronary ostial re-implantation: how I do it. Semin Thorac Cardiovasc Surg 1993; 5: 88-90. 13 Kouchoukos NT. Composite aortic valve replacement and graft replacement of the ascending aorta plus coronary ostial re-implantation: how I do it. Semin Thorac Cardiovasc Surg 1993; 5:66-70.

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Myocardial protection in major aortic surgery Marc A. Schepensy MD, PhD e^ Andrea Nocchi, MD

Excluding the heart from the circulation means interruption of the coronary artery blood flow and this necessitates myocardial protection. As in isolated cardiac surgery, this is very often the procedure in major aortic surgery. Undeniably, myocardial protection in major aortic surgery is one of the cornerstones of success. In fact very complex aortic repairs are technically possible, but if the heart is neglected the results will be accordingly bad. Preoperative myocardial ischemia should be ruled out or treated before or during the aortic repair. This means that cardiac function has to be evaluated carefully. All possible ways of protecting the myocardium are discussed; our favored technique is then highlighted. Cardiac surgery began in 1897 when Rehn (18491930) closed a cardiac perforation thus saving the life of the patient [1]. In 1950 Bigolow et al. introduced hypothermia and inflow occlusion in order to increase the tolerable operative time [2]. The first heart-lung machine was introduced in 1953 [3] and this started the modern era of heart surgery. The first elective cardiac arrest by potassium-rich solution was described by Melrose et al. in 1955 [4]. Since then several techniques have been adopted, such as continuous coronary perfusion, fibrillatory and ischemic arrest, topical or general hypothermia, and cardioplegic arrest. In congenital and valvular surgery, potassium-rich cardioplegia has been the method of choice since 1970. It became routine for all intracardiac operations because energy requirements were decreased and energy losses were minimized during the arrest. A lot of techniques have been adopted for use in aortic surgery also. Barnard and Schire in 1963 used cardiopulmonary bypass and deep hypothermic cir-

culatory arrest in patients with aortic aneurysm and dissection [5]. In the beginning most interventions on the ascending aorta were performed using continuous coronary perfusion with cooled blood and a beating heart throughout the whole procedure (with separate cannulas into both coronaries after excision of the aneurysm or with a continuously cross-clamped proximal nondilated aortic segment) [6]. Better understanding of several aspects of myocardial protection in coronary artery surgery, together with awareness of the pathophysiology of reperfusion and oxygen free radical scavengers, has led to new developments such as the use of oxygenated cardioplegia solution, oxygenated crystalloid cardioplegia, blood cardioplegia, and retrograde cardioplegia. The addition of magnesium or calcium channel blockers, or low-calcium solutions, may help to stabilize cellular membranes. Acidosis by lactic acid during ischemia can be buffered by sodium bicarbonate, phosphate, or tris(hydroxymethyl)-amino-methane (THAM). Arrhythmias can be avoided by using procaine in the solution. Mannitol, albumin, or dexamethasone can counteract myocardial edema. Blood in the solution will act as a buffer; furthermore hemodilution can be reduced and oxygen can be added keeping the myocardium oxygenated. Most surgeons performing aortic surgery have developed their own preferred method of cardioprotection, frequently adopted from their experience in coronary artery or valve surgery. The oxygen requirements of the heart are reduced when arrested and cooled (at 20°C) to 0.3 ml/100 g/min versus 2-3 ml/100 g/min when fibrillating [7,8].

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The St Antonius method of protecting the myocardium during complex aortic surgery Aortic root surgery We think it is essential to measure continuously the temperature of the myocardium. For very extensive aortic root surgery (acute type A aortic dissection, Bentall operations, valve-sparing operations, ascending aortic replacement, arch replacement, elephant trunk, combinations of the previous, redo cases,...), we prefer to use a single shot of cold crystalloid cardioplegia (Cardioplegische Perfusionslosung, Fresenius Kabi, Bad Homburg, Germany), aiming to reach a septal myocardial temperature of about 10°C. The route of administration (via the root or directly into both ostia of the coronary arteries) depends on the pathology and the degree of aortic valve incompetence. In cases of dissection of the ascending aorta and aneurysm containing clots, we will never use root delivery but rather selective administration through both coronaries after having opened the root. Also in cases of severe aortic valve incompetence higher than grade I, we prefer selective cardioplegia through both coronaries; if the aortic valve insufficiency is less than grade I and if the left ventricle is vented adequately, administration through the root can be an option. Distention of the left ventricle can lead to subendocardial ischemia and immediate postoperative problems. The amount of cardioplegia given depends on the temperature that the myocardium reaches. During the first delivery we aim to arrive at a septal temperature of 10°C and this can be realized in most cases with only 1 L of cardioplegia, always combined with external cooling of the myocardium during the cardioplegic delivery with cold (4°C) Ringer's acetate. During the intervention the heart is packed in three wet gauzes (one positioned at the posterior side of the heart, one anteriorly, and one on the diaphragmatic side) with a device (a simple tip of an ordinary infusion system) between the gauzes and the heart that continuously irrigates the pericardial contents with cold (4°C) Ringer's acetate. It is important not to discontinue this cooling irrigation for long time periods because the temperature of the heart will increase rapidly. This cooling is mostly sufficient to keep the septal temperature of the myocardium as measured close to the left anterior descending artery or the posterior descending artery around 10-12°C for periods extending up to 3 h

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of cardiac ischemia. Only if the myocardial temperature rises above 15°C will we give another shot of cardioplegia, but this is done only very rarely. Regarding the location of the septal temperature probe, we choose the anterior septum because it is the most superficially located part of the myocardium within the pericardium and it is easy to reach. Probably it will rewarm first due to the warmth of the operative lights and the fact that this part is exposed to a warmer environment. It is important to turn the operating table 30 degrees to the left and slightly in antiTrendelenburg allowing the whole heart to remain continuously immersed in iced water; in this way the bulk of the heart is below the cold fluid level that fills the pericardium. This position of the table also prevents the water running into the superior part of the pericardium where we have to operate. If a myocardial region warms up early, we believe this can be avoided by repositioning the table. When coronary artery stenosis greater than 50% is present (which should be evaluated preoperatively), care should be taken not to underestimate the maldistribution of the cardioplegia since this may lead to postoperative myocardial ischemia [9]. Opponents of this cooling system might argue that the intervention resembles a continuous fight against water. However when the delivery and removal of the cold water (by a nasogastric tube positioned in the deepest part of the pericardium, below the heart, with intermittent or continuous moderate suction) is perfectly in balance, it seems to be a very elegant and easy way to keep the heart adequately protected for prolonged time periods without interrupting the surgeon's main surgical activity on the aorta higher up. In this way the surgeon does not loose time in the repetitive administration of cardioplegia every 20 min or so and he/she can continue to work in a concentrated way. We would caution against the use of ice slush without protecting the phrenic nerves (e.g. with a surgical glove) because phrenic nerve paralysis could be disastrous. We have no experience with retrograde delivery of cardioplegia in major aortic surgery; although it may be very effective, care should be taken of the distribution and preservation of the right ventricle since this can sometimes be a serious problem. With this technique, considerable amounts of cardioplegia may have been used yielding a high potassium level that

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Myocardial protection in major aortic surgery necessitates repetitive checking of blood gases and electrolytes.

Descending thoracic or thoracoabdominal aortic surgery In cases of descending thoracic or thoracoabdominal aortic surgery (aneurysms, dissections, trauma,...), the surgeon has the option to use simple crossclamping or left heart bypass. In both settings (as is also the case in major abdominal aortic surgery) the heart will continue to beat and there is no reason to give cardioplegia; however it is more complicated than that. Undoubtedly the former technique offers suboptimal protection of distal organs such as the kidneys and spinal cord; the latter technique certainly gives the surgeon more possibilities for treating these extensive diseases, with a lower risk of renal failure or paraplegia. It is known that cross-clamping the aorta might cause a serious increase in the afterload, with severe rhythm disturbances and even acute left ventricular failure. Left heart bypass unloads the circulation and the heart, and in this way it certainly protects the myocardium compared to simple cross-clamping [10]. When extracorporeal circulation is used for the treatment of descending thoracic or thoracoabdominal aortic lesions through a left chest incision, cooling the body will induce first bradycardia and later ventricular fibrillation. As long as the heart beats, there is no danger of distention. Therefore in this situation, the slightest degree of aortic valve incompetence will cause left ventricular distention. A left ventricular apical drain will overcome this very harmful effect to the heart. The administration of cardioplegia in this setting is not necessary, the heart is perfused with oxygenated cold (about 15°C) blood during the cooling phase. If circulatory arrest is used, the period of arrest should be limited to 30 min or less

in view of the deleterious effects on the brain. During this time period, there is no additional need to protect the heart in another way, although one could attempt to give cardioplegia by cross-clamping the ascending aorta and direct punction of the aortic root, although infusing cardioplegia in a diseased aortic segment is sometimes hazardous.

References 1 Rehn L. Uber penetrierende Herzwunden und Herznaht. Arch Klin Chir 1897; 55:315-17. 2 Bigolow WG, Lindays WK, Greenwood WF. Hypothermia —its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperatures. Ann Surg 1950; 132:1081-5. 3 Gibbon JH Jr. Application of a mechanical heart and lung apparatus to cardiac surgery. In: Recent Advances in Cardiovascular Physiology and Surgery. Minneapolis: University of Minnesota, 1953:107-13. 4 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Elective cardiac arrest. Preliminary communication. Lancet 1955; ii:21. 5 Barnard CN, Schire V. The surgical treatment of acquired aneurysms of the thoracic aorta. Thorax 1963; 18:101-5. 6 Sing MP, Bentall HH. Complete replacement of the ascending aorta and the aortic valve for the treatment of aortic aneurysm. / Thorac Cardiovasc Surg 1972; 63: 218-25. 7 Buckberg GD. A proposed "solution" to the cardioplegia controversy. / Thorac Cardiovasc Surg 1979; 77:803—15. 8 Buckberg GD. Strategies and logic of cardioplegic delivery to prevent, avoid, and reverse ischemic and perfusion damage. / Thorac Cardiovasc Surg 1987; 93:127-39. 9 Svensson LG, Crawford ES. Aortic dissection and aortic aneurysm surgery: clinical observations, experimental investigations and statistical analyzes. Part I. Curr Probl Surg 1992; 29: 819-912. 10 Schepens MA, Defauw JJ, Hamerlijnck RP, Vermeulen FE. Use of a left heart bypass in the surgical repair of thoracoabdominal aortic aneurysms. Ann Vase Surg 1995; 9: 327-38.

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Recent advances in myocardial protection for coronary reoperations Jan T. Christenson, MA, MD, PhD, PD, FETCS &Afksendiyos Kalangos, MD, PHD, PD, FETCS

Challenges in reoperative coronary artery bypass grafting Reoperative coronary artery bypass grafting (CABG) is an important clinical entity. Previous studies have noted an increase in the prevalence of redo CABG surgery over time as the age of our patient population increases [1-4]. However, increasing use of arterial conduits [5] and lipid-lowering agents [6,7] may result in a plateau in the number of reoperative procedures [8]. Coronary artery reoperation is a surgical challenge because the risk profile of patients undergoing reoperation is increasing [2,9]. Inhospital mortality and postoperative morbidity is higher than observed after the first operation [10]. In the vast majority of patients, years have elapsed since the first operation, and more than one-third of the patients have lost earlier normal left ventricular function [11,12]. Native coronary vessel disease has progressed and vein-graft atherosclerosis has developed. Lesions in a vein graft to the left descending coronary artery have been reported to predict a higher rate of death and cardiac events than native vessel disease in the same distribution area [13]. With increased age other concomitant diseases may also have been added to a higher surgical risk, such as diabetes, impaired renal function, and obstructive airway disease. Reoperative CABG is always associated with the ubiquitous risk of re-entry sternotomy injury to underlying structure, may they be patent grafts or the heart itself. Commonly an advancement of native

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coronary artery disease has occurred, often resulting in a more diffuse coronary artery disease that causes impedance to coronary arterial runoff, which is a major determinant of adequacy of myocardial revascularization. There may be the presence of partially open, atherosclerotic saphenous vein grafts, which carries an increased risk for distal embolization. There may be a shortage of adequate revascularization conduits, which may lead to inadequate or incomplete revascularization, compromising inflow to the myocardium. Moreover the operative risk increases incrementally with each subsequent coronary artery reoperation [14,15]. The relationship between hospital morbidity and aortic cross-clamping time underscores the need for optimal myocardial protection. Morbidity increases with cross-clamping time, regardless of cardioplegia mixture and the type of delivery [ 16]. The presence of high-grade obstructions in native coronary vessels and previously performed vein grafts, patent internal thoracic artery bypass grafts, and pericardial adhesions create unique challenges for cardioplegia delivery and myocardial preservation in the reoperative CABG population. Improved medical therapy, interventional cardiology, and complex coronary interventions save lives. Consequently, patients presenting for repeat CABG are typically older and often have severely reduced left ventricular function. Prevention of postoperative myocardial dysfunction is a primary goal of reoperative surgery and technical details therefore should aim at minimizing this risk, which means that one should focus

Coronary reoperations on the changing metabolic needs of the heart, prior to, during, as well as after surgical revascularization. In reoperative CABG patients therefore, requirements for the optimal myocardial management are paramount. Recent advances in surgical techniques including avoidance of patent grafts and a planned and organized recruitment of adequate bypass conduits, appropriate use of cardiopulmonary bypass, optimal cardioplegic solutions delivered by the most efficacious techniques at appropriate temperatures, and the role of preoperative intra-aortic balloon counterpulsation in high-risk reoperative CABG will be addressed.

Surgical considerations—no-touch technique/vein grafts/patent internal thoracic artery (ITA) grafts Redo CABG surgery may be required as a result of graft disease, progression of native coronary atherosclerosis, or a combination of these factors [2,17,18]. Increased risk at redo CABG is primarily due to atheroembolism from saphenous vein grafts, a widely recognized complication [17,19-21]. A patent LITA graft at reoperation decreases operative mortality, mainly as a result of preserved anterior wall function and absence of atherosclerotic embolization from the ITA graft [22]. However, a patent ITA graft at reoperation may also create specific technical challenges. There is an increased risk of ITA graft injury during reentry and dissection, and delivery of cardioplegia to the anterior aspect of the heart may be inadequate [23]. Temporary occlusion of the ITA graft and use of retrograde cardioplegia delivery results most often in adequate myocardial protection. However, identification and dissection of the ITA pedicle can be hazardous and injury to the graft may occur. If the ITA graft is not readily identified, systemic cooling has been recommended until the ITA graft is identified and controlled [23]. Even when vein grafts are patent and atherosclerotic, the first antegrade dose of cardioplegia is regarded as safe. However, these vein grafts should not be manipulated externally because of the risk of atheroembolism. Subsequent cardioplegia delivery through old, diseased grafts is not recommended. Patent atherosclerotic vein grafts should be divided first and replaced immediately [ 10]. The entire operation should be performed under one period of cross-

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clamping [10,18,24]. This technique is preferred to conserve space on the aorta and to reduce the threat of atheroembolism, which may result from repeated aortic manipulation. For patients with patent internal thoracic artery grafts from previous operation, an effort should be made to temporarily occlude the ITA pedicle, prior to the initial dose of cardioplegia [24], in order to achieve optimal myocardial protection [10].

Cardiopulmonary bypass— cannulation/hypothermic versus normothermic cardiopulmonary bypass The employment of a flexible CPB, oftentimes using femoral/femoral bypass, perhaps even before opening the sternum, is advocated. Core cooling is an accepted practice even though several recent reports have suggested that normothermic cardiopulmonary bypass provides a good total body protection during cardiac surgery and cold or warm cardioplegia is seemingly sufficient for adequate myocardial protection [25-27]. Normothermic CPB has the advantage of less systemic inflammatory response and shorter CPB time [25,27]. Hypothermic CPB could be considered if the patient's cerebrovascular status is such that an increased risk of intraoperative stroke is anticipated.

Cardioplegia—delivery/ temperature/solution/additives Cardioplegia delivery The presence of high-grade obstructive disease in previously performed vein grafts together with often proximal native artery stenoses create unique challenges for cardioplegia delivery and myocardial preservation in the reoperative CABG population. Initially antegrade cardioplegia delivery was the standard method. Retrograde cardioplegia was introduced to circumvent the inhomogenous distribution of cardioplegia associated with antegrade delivery, particularly in the presence of severe proximal coronary artery stenoses [20,28]. Retrograde cardioplegia may decrease the risk of atheroembolism during redo CABG. Retrograde delivery has been hypothesized to result in less embolization than antegrade delivery [29], and anecdotal evidence suggests that retrograde delivery of cardioplegia solution can dislodge atheroemboli that have

198 already occurred. Unfortunately, evidence was brought forward indicating that retrograde perfusion did not result in adequate perfusion of the right ventricle and did not provide as adequate capillary perfusion of the left ventricle as antegrade delivery [30-33]. This led to exploration of combined antegrade/retrograde cardioplegia delivery [34-36]. Ardehali and coworkers showed that in the human heart as much as two-thirds of retrograde cardioplegia is shunted through the thebesian veins and arterio-sinusoidal channels into the ventricular cavities and they claim it has a nutritive property [37]. This corresponds well with a paper by Taylor and Taylor [38] who show that even though the human heart is an external pump it is indeed also structured as an internal pump. In a series of 240 consecutive reoperations an intra/ postoperative intra-aortic balloon pump was used in 3.8% of high-risk patients when retrograde cardioplegia was delivered versus 14.5% in high-risk patients without retrograde cardioplegia [ 1 ]. These results are similar to those presented by Athanasuleas et al. [39], and indicate the value of uniform cardioplegic delivery in a difficult patient population. Simultaneous antegrade/retrograde administration with continuous warm noncardioplegic blood was introduced in 1994 [40]. It was indicated that combined antegrade and retrograde blood cardioplegia might decrease major morbidity incidence in comparison with antegrade blood or crystalloid cardioplegia [4]. Further refinement using the significant features of each of the previously described techniques was combined in a method called integrated myocardial management, proposed by Buckberg and coworkers [41 ]. A high-potassium amino-acid-enhanced mixture is used for induction, either cold or warm, and during the warm terminal reperfusion in all cases. A low potassium nonsubstrate-enhanced cold solution is used for maintenance and cardioplegia is delivered by both antegrade and retrograde routes. Retrograde cardioplegia alone or in combination with antegrade cardioplegia resulted in a significant reduction of mortality in a study recently presented by Borger et al. [8]. They concluded that the optimal myocardial protection strategy for redo CABG maybe retrograde cardioplegia, supplemented by antegrade perfusion of new vein grafts, in particular to the right coronary artery (RCA). Combined antegrade aortic root and retrograde coronary sinus cardioplegia infusion is now the method

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of choice for cardioplegic protection of the heart in the reoperative CABG patient [ 14]. No matter what type of cardioplegia solution is used, the use of the antegrade method to institute cardiac arrest, followed by subsequent sequential retrograde coronary sinus infusions, appears to maximize myocardial protection [42]. Several excellent coronary sinus cardioplegia cannulas are available. During infusion on CPB, an elevation of the coronary sinus pressure usually indicates that the coronary sinus cannulas are properly placed.

Cardioplegia solutions There continues to be considerable debate about the type and constituents of various myocardial preservation solutions. In general, it would appear that the majority of cardiac surgeons throughout the world now favor some form of blood cardioplegia for reoperations. In these high-risk reoperative CABG patients, it is thought that delivering as much oxygen as possible to the usually dysfunctional left ventricle, in these rather long and complicated cases, should obviously be an advantage. Oxygenated crystalloid cardioplegia has also been advocated [43], as have a variety of other cardioplegia solutions. However, these solutions have not been proven to have any significant advantage over one type or another, provided that surgery is done accurately, and that the cardioplegia solution is administered both antegrade and retrograde. However, the infusion of small amounts of cardioplegia following completion of each vein graft to test the patency of the anastomosis, and especially to provide cardioplegia distal to coronary artery stenosis to further cool the myocardium, is probably of importance [12,44]. Blood cardioplegia enhances myocardial protection by reducing arrhythmias, maintaining myocardial high-energy phosphate content during ischemia, and improving the rate of recovery of function. Blood cardioplegia has emerged as the preferred cardioprotective strategy because of its versatility. A blood vehicle for cardioplegic delivery blends rheology, buffering, and onconicity and antioxidant benefits [45] with its capacity to augment oxygen delivery, prevent ischemic injury, and limit reperfusion injury [41,46,47]. Blood cardioplegia delivered by antegrade and retrograde routes has become the most widely applied technique worldwide [48].

Coronary reoperations

Optimal cardioplegia temperature The standard method of delivering either blood or crystalloid cardioplegia consisted of intermittent hypothermic (8-10°C) infusions. Cold blood cardioplegia is the mainstay of myocardial protection by decreasing myocardial oxygen demand. However, Rosenkranz etal. showed that hypothermia does not reduce myocardial oxygen requirements much beyond the reduction achieved alone with hyperkalemic arrest [49]. Furthermore, impaired preoperative ventricular function presents a special problem and dysfunction may persist after grafting in ischemic energy-depleted hearts despite the avoidance of further injury with cold blood cardioplegia. This led to the adoption of warm induction [50]. However, normothermic cardioplegia has been shown to result in increased systolic function and preload recruitable stroke work compared to hypothermic cardioplegia. In addition, warm blood cardioplegia results in a greater lactate and acid washout with reperfusion compared to cold [51]. This led to the introduction of tepid (29°C) cardioplegia, which seems to extract the positive effects from both extremes. Tepid cardioplegia provides the metabolic benefit of cold cardioplegia while permitting the immediate recovery of left ventricular function associated with normothermic cardioplegia [33,52].

Role of preoperative intra-aortic balloon counterpulsation Intra-aortic balloon counterpulsation (IABC) is an established additional support to pharmacologic treatment of the failing heart after myocardial infarction, unstable angina, and following cardiac surgery [12,53,54]. IABC therapy results in more favorable myocardial supply and demand balance [55], reduces afterload, and augments the diastolic pressure [56,57], which in turn leads to an increased cardiac output. Augmented diastolic pressure results in redistribution of coronary blood flow toward ischemic areas of the myocardium [58,59]. Christakis and associates [60] reconfirmed suggestions earlier voiced by Gustensen et al. [61] and others [62,63] that use of preoperative IABC could lead to a preoperative reduction of myocardial ischemia, thereby improving the outcome of myocardial revascularization in patients with poor preoperative left ventricular function. Several studies have shown the efficacy of preoperative IABC therapy for patients with severely compromised preoperative

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function [64-67]. Furthermore the cost effectiveness of preoperative IABC therapy in high-risk patients has been demonstrated [66,68]. Since a large proportion of patients admitted for reoperative CABG have left ventricular dysfunction as well as other risk factors mentioned above, preoperative IABC therapy was thought to be beneficial as an additional and integrated part of myocardial protection for this cohort of high-risk patients. From a recent prospective randomized trial it was shown that preoperative IABC therapy for high-risk reoperative CABG patients significantly improved the cardiac index, thus presenting patients with a less ischemic or in many cases even a nonischemic myocardium at the time of aortic cross-clamping [69]. Furthermore it was reported that virtually all physiologic parameters were more favorable in those patients who had received preoperative IABC therapy. As with prior studies, the time on CPB was significantly shorter (86 min vs. 110 min in the control group). The cardiac index was significantly higher during the first 48 h postoperatively, with only 16.7% of the treatment group experiencing a low postoperative cardiac index compared with 54.2% of the controls. Only two patients (8.3%) in the preoperative IABC group also required counterpulsation support postoperatively, and in each of these instances the intraaortic balloon was successfully removed on the first postoperative day. This contrasted with a total of 9 (37.5%) of the control patients requiring postoperative IABC support, for an average of 4.1 days (ranging from 2 to 8 days). The improvement in postsurgical cardiac index was highly significant, as severely disturbed cardiac performance can often lead to difficulty in weaning the patient from CPB, resulting in a high rate of postoperative mortality. This was clearly reflected in the absence of any hospital mortality among the 24 patients who received preoperative IABC therapy, while four control patients (16.7%) died (P < 0.049), all between the first and fourth postoperative day. The mean length of stay in the ICU was also significantly reduced in the postoperative IABC group— 2.4 ± 0.8 days versus 4.5 + 2.2 days for the controls (P = 0.007). Finally, total hospital expenditures were reported that were lower for those patients who received preoperative IABC therapy and few (4.2%) IABCrelated complications (both instances of leg ischemia) occurred. Smaller sized balloon catheters (8F), better

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education and surveillance are major factors responsible for low lABC-related complications [70]. It was concluded that preoperative IABC therapy significantly improved cardiac index, leading to a less ischemic or even nonischemic myocardium at the time of aortic cross-clamping and thus overall improvement in patient outcome. An additional benefit of the improved cardiac performance observed in this study was an observed reduced requirement for pharmacologic inotropic support during the first 24 h following CPB[69].

Summary Despite continued improvements in cardioplegic techniques, low output syndrome following highrisk reoperative CABG remains an ongoing concern. With the use of different CPB techniques, oftentimes using femoral/femoral bypass, even before opening the sternum, antegrade/retrograde blood cardioplegia, and avoidance of the patent bypass grafts by the "no-touch" techniques, reoperative surgery risk for coronary artery disease has decreased significantly. The

Table 24.1 Summary of integrated management of reoperative CABG. • Identification of high-risk patients, e.g. for perioperative stroke • Preoperative intra-aortic balloon counterpulsation for patients with severe left ventricular dysfunction and unstable angina despite optimal medical regimen • Flexible cardiopulmonary bypass approach adjusted to the individual patient • A single cross-clamping interval for construction of both distal and proximal anastomoses • No-touch surgical technique, ligation, and replacement of atherosclerotic vein grafts • Clamping of patent ITA grafts during delivery of cardioplegia • Combined antegrade and retrograde tepid (29°C) blood cardioplegia • An initial dose of the hyperkalemic cardioplegia solution is administered through the aortic root to arrest the heart. This is followed by the continuous, retrograde administration of cardioplegia solution through an indwelling coronary sinus catheter. Coronary sinus pressure is continuously monitored to maintain a pressure of approximately 40 mmHg, which usually relates to a cardioplegia flow rate of 150-200 ml/min

CHAPTER 24

major bulk of patients succumbing after reoperative CABG today are those who develop multisystem organ failure in the late postoperative period [71]. It is possible that the development of new additives with various properties may provide added protection, allowing for reduction of morbidity and mortality following redo CABG [71]. However, an already established modality is probably underused. IABC has been shown to diminish this risk of low post-operative cardiac output [72] and subsequent risk for multiorgan failure preoperatively [73,74], and should be part of the integrated management in high-risk reoperative CABG surgery (Table 24.1).

References 1 Rosengart TK. Risk analysis of primary versus reoperative coronary artery bypass grafting. Ann Thorac Surg 1993; 56: S74-7. 2 Loop FD, Lytle BW, Cosgrove DM et al. Reoperations for coronary atherosclerosis: changing practice in 2509 consecutive patients. Ann Surg 1990; 212:378-85. 3 Gosgrove DM, Loop FD, Lytle BW et al. Predictors of reoperation after myocardial revascularization. / Thorac Cardiovasc Surg 1986; 92: 811-21. 4 Akins CW, Buckley MJ, Daggett WM et al. Reoperative coronary grafting: changing patient profiles, operative indications, techniques, and results. Ann Thorac Surg 1994; 58:359-64. 5 Earner HB, Sundt TM. Multiple arterial grafts and survival. CurrOpin Cardiol 1999; 14: 501-5. 6 The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. NEnglJMed 1997; 336:153-62. 7 Christenson JT. Preoperative lipid control with simvastatin protects coronary artery bypass grafts from obstructive graft disease. Am J Cardiol 2001; 88:896-9. 8 Borger MA, Rao V, Weisel RD et al. Reoperative coronary bypass surgery: effect of patent grafts and retrograde cardioplegia. Ann Thorac Surg 2001; 121: 83-90. 9 Yau TM, Borger MA, Weisel RD, Ivanov J. The changing patterns of reoperative coronary surgery: trends in 1230 consecutive reoperations. / Thorac Cardiovasc Surg 2000; 120:156-63. 10 Loop FD. The value and conduct of reoperations for coronary atherosclerosis. Sent Thorac Cardiovasc Surg 1994;6:116-19. 11 Loop FD, Lytle BW, Gill CC et al. Trends in selection and results of coronary artery reoperations. Ann Thorac Surg 1983; 36: 380-8. 12 Schmuziger M, Christenson JT, Maurice J et al. Reoperative myocardial revascularization. an analysis of 458 reoperations and 2645 single operations. Cardiovasc Surg 1994; 5: 623-9.

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13 Lytle BW, Loop FD, Taylor PC et al. Vein graft disease: the clinical impact of stenosis in saphenous vein bypass grafts to coronary arteries. / Thorac Cardiovasc Surg 1992; 103:831-40. 14 Christenson JT, Schmuziger M. Third-time coronary bypass operation. Analysis of selection mechanisms, results and long-term follow-up. Eur ] Cardiothoracic Surg 1994; 8: 500-4. 15 Brenowitz JB, Johnson WD, Kayser KL et al. Coronary artery bypass grafting for the third time or more. Results of 150 consecutive cases. Circulation 1988: 78:1-166-70. 16 Loop FD, Higgins TL, Panda R et al. Myocardial protection during cardiac operations. / Thorac Cardiovasc Surg 1992; 104:608-18. 17 Fitzgibbon GM, Kafka HP, Leach AJ et al. Coronary bypass graft fate and patient outcome: angiographic follow up of 5065 grafts related to survival and reoperation in 1388 patients during 25 years. JAm Coll Cardiol 1996; 28:616-55. 18 Christenson JT, Schmuziger M, Simonet F. Reoperative coronary artery bypass procedures: risk factors for early mortality and late survival. Eur J Cardiothoracic Surg 1997; 11:129-33. 19 Perrault L, Carrier M, Cartier R et al. Morbidity and mortality of reoperation for coronary artery bypass grafting: significance of atheromatous vein grafts. Can ] Cardiol 1991; 7:427-30. 20 Savage EB, Cohn LH. "No touch" dissection, antegraderetrograde blood cardioplegia, and single aortic cross-clamp significantly reduce operative mortality of reoperative CABG. Circulation 1994; 90: II-140-3. 21 Brener SJ, Loop FD, Lytle BW et al. A profile of candidates for repeat myocardial revascularization: implications for selection of treatment. / Thorac Cardiovasc Surg 1997; 114:153-61. 22 Christenson JT, Velebit V, Maurice J, Simonet F, Schmuziger M. Risks, benefits and results of reoperative coronary surgery with internal mammary grafts. Cardiovasc Surg 1995; 3:163-9. 23 Gillinov AM, Casselman FP, Lytle BW et al. Injury to a patent left internal thoracic artery graft at coronary reoperation. Ann Thorac Surg 1999; 67:382-6. 24 Graver JM, Hodakowsky GT, Shen Y et al. Third-time coronary artery bypass operations: surgical strategy and results. Ann ThoracSurg 1996; 62:1801-7. 25 Christenson JT, Maurice J, Simonet F, Velebit V, Schmuziger M. Normothermic versus hypothermic perfusion during primary coronary artery bypass grafting. Cardiovasc Surg 1995; 3: 519-24. 26 Lehot JJ, Villard J, Piriz H et al. Hemodynamic and hormonal responses to hypothermic and normothermic cardiopulmonary bypass. / Cardiothorac Vase Anesth 1992; 6:132-9. 27 Singh AK, Feng WC, Bert AA, Rotenberg FA. Warm body, cold heart surgery. Clinical experience in 2817 patients. Eur J Cardiothorac Surg 1993; 7:225-30. 28 Rosengart TK, Krieger K, Lang SJ et al. Reoperative coronary artery bypass surgery: improved preservation of myocardial function with retrograde cardioplegia. Circulation 1993; 88: II-330-5.

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29 Gundry SR, Razzouk AJ, Vigesaa RE, Wang N, Bailey LL. Optimal delivery of cardioplegic solution for "redo" operations. / Thorac Cardiovasc Surg 1992; 103:896-901. 30 Partington MT, Acar C, Buckberg GD et al. Studies of retrograde cardioplegia. I. Capillary blood flow distribution to myocardium supplied by open and occluded arteries. / Thorac Cardiovasc Surg 1989; 97:605-12. 31 Menasche P, Subayi JB, Veyssie L et al. Efficacy of coronary sinus cardioplegia in patients with complete coronary artery occlusions. Ann Thorac Surg 1991; 51:418-23. 32 Crooke GA, Harris LH, Grossi EA et al. Biventricular distribution of cold blood cardioplegic solution administered by different retrograde techniques. / Thorac Cardiovasc Surg 1991; 102:631-7. 33 Rao V, Ikonomidis JS, Weisel RD, Cohen G. Preconditioning to improve myocardial protection. Ann NYAcad Sci 1996; 793:338-54. 34 Bhayana JN, Kalmbach T, Booth FV, Mentzer RM, Schimert G. Combined antegrade/retrograde cardioplegia for myocardial protection: a clinical trial. / Thorac Cardiovasc Surg 1989; 98:956-60. 35 Drinkwater DC, Laks H, Buckberg GD. A new simplified method of optimizing cardioplegic delivery without right heart isolation. Antegrade/retrograde cardioplegia. / Thorac Cardiovasc Surg 1990; 100:56-63. 36 Hayashida N, Weisel RD, Shirai T et al. Tepid antegrade and retrograde cardioplegia. Ann Thorac Surg 1995; 59: 723-9. 37 Ardehali A, Laks H, Drinkwater DL, Gates RN, Kaczer E. Ventricular effluent of retrograde cardioplegia in human hearts has transversed capillary beds. Ann Thorac Surg 1995;60:78-82. 38 Taylor JR, Taylor AJ. The thebesian circulation to developing conducting tissue, a nutrient-nodal hypothesis of cardiogenesis. Can} Cardiol 1999; 15:859-66. 39 Athanasuleas CL, Riemer DW, Buckberg GD. The role of integrated myocardial management in reoperative coronary surgery. Sem Thorac Cardiovasc Surg 2001; 13: 33-7. 40 Ihnken K, Morita K, Buckberg GD et al. The safety of simultaneous arterial and coronary sinus perfusion: experimental background and initial clinical results. JCard Surgl994; 9:15-25. 41 Buckberg GD, Beyersdorf F, Allen BS, Robertson JM. Integrated myocardial management. Background and initial application. / Card Surg 1995; 10:68- 89. 42 Chitwood WR Jr. Retrograde cardioplegia: current methods. Ann Thorac Surg 1992; 53: 352-5. 43 Shanewise JS, Kosinski AS, Goto JA, Jones EL. Prospective randomized trial comparing blood and oxygenated crystalloid cardioplegia in reoperative coronary artery bypass grafting. / Thorac Cardiovasc Surg 1998; 115:1166-71. 44 Silverman NA, Schmitt MD, Levitsky S et al. Optimal intraoperative protection of myocardium distal to coronary stenoses. / Thorac Cardiovasc Surg 1984; 88:424-31. 45 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. / Thorac Cardiovasc Surg 1986; 91:428-35.

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46 Robertson JM, Vinten-Johansen J, Buckberg GD et al. Safety of prolonged aortic clamping with blood cardioplegia. I. Glutamate enrichment in normal hearts. / Thome Cardiovasc Surg 1984; 88:395-401. 47 Allen BS, Okamoto F, Buckberg GD et al. Studies of controlled reperfusion after ischemia. XV. Immediate functional recovery after 6 hours of regional ischemia by careful control of conditions of reperfusion and composition of reperfusate. / Thorac Cardiovasc Surg 1986; 92:621-35. 48 Robinson LA, Schwarz GD, Goddard DB et al. Myocardial protection for acquired heart disease surgery: results of a national survey. Ann Thorac Surg 1995; 59: 361-72. 49 Rosenkranz ER, Okamoto F, Buckberg GD. Safety of prolonged aortic clamping with blood cardioplegia. II. Glutamate enrichment in energy-depleted hearts. J Thorac Cardiovasc Surg 1984; 88: 395-401. 50 Buckberg GD, Brazier JR, Nelson RL et al. Studies of the effects of hypothermia on regional myocardial flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating and arrested heart. / Thorac Cardiovasc Surg 1977; 73: 87-94. 51 Hayashida N, Ikonomidis JS, Weisel RD et al. The optimal cardioplegic temperature. Ann Thorac Surg 1994; 58: 961-71. 52 Hayashida N, Isomura T, Sato T et al. Minimally diluted tepid blood cardioplegia. Ann Thorac Surg 1998; 65: 615-21. 53 Aksnes J, Abdelnoor M, Platou ES, Fjeld NB. Mortality in patients supported by intra-aortic balloon pump in course of cardiac surgery was related to perioperative myocardial infarction. Eur } Cardio-Thoracic Surg 1996; 10:408-11. 54 Hammermeister KE, De Rouen TA, Dodge HT. Variables predictive of survival in patients with coronary disease. Circulation 1979; 59:421-30. 55 Lazar HL, Yang XM, Rivers S et al. Retroperfusion and balloon support to improve coronary revascularization. J Cardiovasc Surge 1992; 23: 538-44. 56 Bolooki H. Clinical Application of Intraaortic Balloon Pump. New York: Futura, 1984. 57 Weber KT, Janicki JS. Intraaortic balloon counterpulsation —a review of physiological principles, clinical results, and device safety. Ann Thorac Surg 1974; 17:602-36. 58 Gill CC, Wechsler A, Newman G, Oldman H. Augmentation and redistribution of myocardial blood flow during acute ischemia by intra-aortic balloon pumping. Ann Thorac Surg 1975; 16: 44-53. 59 Watson JT, Willerson JT, Fixler DE, Sugg NL. Temporal changes in collateral coronary blood flow in ischemic myocardium during intra-aortic balloon pumping. Circulation 1974; 50 (Suppl): 11-249-54. 60 Christakis GT, Weisel RD, Fremes SE et al. Coronary artery bypass grafting in patients with poor ventricular function. J Thorac Cardiovasc Surg 1992; 103:1083-92.

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61 Gustensen J, Goldman BS, Scully HE, Huckell VF, Adelman AG. Evolving indications for preoperative intraaortic balloon pump assistance. Ann Thorac Surg 1976; 22: 535-46. 62 Christenson JT, Maurice J, Simonet F et al. Effect of low left ventricular ejection fractions on the outcome of primary coronary bypass grafting in end-stage coronary artery disease. / Cardiovasc Surg 1995; 36:45 -51. 63 Naunheim KS, Schwartz MT, Pennington DG et al. Intraaortic balloon pumping in patients requiring cardiac operations. Risk analysis and long-term follow up. J Thorac Cardiovasc Surg 1992; 104:1654-60. 64 Christenson JT, Simonet F, Badel P, Schmuziger M. Optimal timing of preoperative intra-aortic balloon pump support in high risk coronary patients. A prospective randomized study. Ann Thorac Surg 1999; 68:934-9. 65 Christenson JT, Schmuziger M, Simonet F. Effective surgical management of high-risk coronary patients using preoperative intra-aortic balloon counterpulsation therapy. Cardiovasc Surg 2001; 9: 383-90. 66 Dietl CA, Berkheimer MD, Woods EL et al. Efficacy and cost-effectiveness of preoperative IABP in patients with ejection fraction of 0.25 or less. Ann Thorac Surg 1996; 62:401-9. 67 Holman WL, Li Q, Kiefe CI et al. Prophylactic value of preincision intra-aortic balloon pump. Analysis of a statewide experience. / Thorac Cardiovasc Surg 2000; 120: 1112-19. 68 Christenson JT, Simonet F, Schmuziger M. Economic impact of preoperative intra-aortic balloon pump therapy in high-risk coronary patients. Ann Thorac Surg 2000; 70:510-15. 69 Christenson JT, Badel P, Simonet F, Schmuziger M. Preoperative intra-aortic balloon pump enhances cardiac performance and improves the outcome of redo CABG. Ann Thorac Surg 1997; 64:1237-44. 70 Ferguson JJ, Cohen M, Freedman RJ et al The current practice of intra-aortic balloon counterpulsation: results from the Benchmark registry. J Am Coll Cardiol 2001; 38:1456-62. 71 Cohen G, Borger MA, Weisel RD, Rao V. Intraoperative myocardial protection: current trends and future perspectives. Ann Thorac Surg 1999; 68:1995-2001. 72 Christenson JT, Simonet F, Badel P, Schmuziger M. Evaluation of preoperative intra-aortic balloon pump support in high risk coronary patients. Eur J Cardiothorac Surg 1997; 11:1097-103. 73 Christenson JT, Schmuziger M, Maurice J, Simonet F, Velebit V. Gastrointestinal complications after coronary artery bypass grafting. / Thorac Cardiovasc Surg 1994; 108:899-906. 74 Christenson JT, Simonet F, Schmuziger M, Badel P. Preoperative intra-aortic balloon counterpulsation (LABC) reduces the risk of gastrointestinal complications following CABG in high-risk coronary patients. Today's Therapeutic Trends 2001; 19:9-22.

CHAPTER 25

Myocardial protection during minimally invasive cardiac surgery Saqib Masroor, MD, MHS d- Kushagra Katariya, MD

This chapter reviews the current status of myocardial protection during minimally invasive cardiac surgery including robotic cardiac surgery. Obviously, the cardiac physiology and metabolism is similar no matter what the approach to the heart. The same principles of myocardial preservation apply to minimally invasive surgery as to conventional cardiac surgery. The peculiar demands and critical technical issues arise from the limited access that a surgeon has to the left ventricle, aortic root, and coronary sinus, structures crucial to aortic clamping/occlusion and delivery of cardioplegia. In our discussion of minimally invasive cardiac surgery, we have excluded so-called "directaccess" minimally invasive mitral valve surgery such as the techniques reported from the Brigham & Womens Hospital and the Cleveland Clinic [1,2]. These approaches are still quite invasive and require some degree of partial sternotomy or thoracotomy with rib spreading and/or cartilage resection.

Evolution of minimally invasive cardiac surgery Even though Carpentier et al. reported the first video-assisted mitral valve repair in 1996 using ventricular fibrillation [3], enthusiasm in minimally invasive cardiac surgery did not catch on until the advent of port-access technology which allowed endovascular aortic occlusion, cardioplegia delivery, and left ventricular (LV) decompression [4]. Today, we can safely cross-clamp the aorta transthoracically or occlude it endovascularly and deliver cardioplegia either antegrade or retrograde by percutaneous means. These developments have been crucial to the successful application of robotics to clinical cardiac surgery.

Finally, the cardiac surgeon's dream of totally endoscopic cardiac surgery has come true in part due to technologic advances in the field of robotics. The fine movements of the surgeon can now be transmitted to instruments introduced through tiny 5-mm ports in the chest wall. While the conduct of the operation may seem futuristic, with the surgeon (not even scrubbed) sitting comfortably in front of the three-dimensional viewing screen away from the patient, the basic principle of cardiac surgery has remained the same, i.e. myocardial protection.

Animal studies Early studies in dogs by Schwartz et al. [5] demonstrated the adequacy of myocardial protection during closed chest cardiopulmonary bypass (CPB) and cardioplegic arrest. Using port-access technology, the experimental group of animals underwent femoral vein-femoral artery CPB, endovascular aortic occlusion, and antegrade cold blood cardioplegic arrest. The heart was successfully vented through the aortic root as well as a pulmonary artery. The latter was vented through a catheter placed percutaneously via the right internal jugular vein. The control group of animals underwent median sternotomy and open CPB. The authors showed that with cardiac arrest of 60 min by intermittent delivery of cardioplegia every 15 min, animals in both groups had similar post-CPB LV function as measured by the stroke work-diastolic length relationship, the preload recruitable work area, and elastance. Measuring myocardial temperatures in the right and left ventricular free walls, the authors achieved similar degrees of hypothermia in both groups of animals. Histologic and ultrastructural

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examination did not reveal any evidence of intracellular or intercellular edema, myofilament or mitochondrial abnormalities, or membrane rupture. These results should be interpreted with caution, since longer periods of cardiac arrest (which are not uncommonly seen in robotic coronary surgery) were not assessed in this study. Moreover, these were normal hearts and thus not compromised by preexisting LV hypertrophy or depressed LV function. In addition, the effect of nonhomogenous distribution of cardioplegia could not have been assessed in these hearts with normal coronary arteries. The same group later reported their results with successful video-assisted thoracoscopic mitral valve replacement in dogs using the port-access technique for CPB [6]. After induction of cardiac arrest by antegrade cardioplegia, subsequent doses of cardioplegia were delivered retrograde every 15 min, via a percutaneously placed coronary sinus catheter. The mean cross-clamp time was 55.6 + 10.3 min and the authors reported a well-maintained postoperative LV function. Since then, many reports have been published of successful conduct of minimally invasive/robotic cardiac surgery in humans with acceptable morbidity and mortality. The procedures have included totally endoscopic coronary artery bypass (TECAB) [7-10], TECAB on a beating heart (TECAB-BH) [8,11,12], mitral valve repair and replacement [3,8,13-15], combined mitral valve/coronary bypass [16], atrial septal defect (ASD) repair [17], and surgical treatment of atrial fibrillation [18]. Cold blood cardioplegia is preferentially used in most institutions, although cold crystalloid cardioplegia has also been reported. Ventricular fibrillation is now only used as a bail-out technique when there are problems with the delivery of antegrade and retrograde cardioplegia solutions during the surgery. In subsequent sections we describe the strategies of myocardial protection as applied to valvular and coronary surgery; however, data can be extrapolated to other surgeries on the arrested heart such as the ASD repairs and treatment of atrial fibillation.

Valve surgery Minimally invasive mitral valve repair or replacement can be performed either by using video-assisted thoracoscopy or by totally endoscopic robotic telemanipulation. Unfortunately most studies that have

CHAPTER 25

been published in the literature emphasize the actual conduct and adequacy of the surgery. While they do mention the complications associated with the procedure, they fail to mention the presence or absence of postoperative low cardiac output syndrome and the postoperative use of inotropes. In one study only, Mohr et al. [ 14] describe their experience with minimally invasive mitral valve surgery using the Heartport device and a three-dimensional videothoracoscopic system. They used antegrade cold crystalloid cardioplegia in 51 patients undergoing mitral valve repair or replacement. Interestingly, two patients developed persistent low cardiac output and died, nine patients required prolonged inotropic support, and eight had supraventricular tachycardia. The mean cross-clamp time was 72 + 27 min and hospital mortality was 9.8%. Of the five patients who died, two died of persistent low cardiac output—both these patients required additional procedures after their mitral valve surgery. One patient was found to have aortic dissection upon weaning from CPB. Another patient had the ascending aorta replaced after a median sternotomy but died of persistently low cardiac output. The final patient underwent successful mitral valve repair which failed on the third postoperative day. He then underwent mitral valve replacement (the paper does not mention if this was done as an open or closed chest procedure) but the patient died of persistent low cardiac output also. Such findings have not been reported in other reports which used cold blood cardioplegia [13,15]. One explanation for these results may be inadequate myocardial protection by cold crystalloid cardioplegia when longer cross-clamp times are encountered. Deairing the heart can be a concern in minimally invasive surgery because of limited access to the left ventricle and the predilection of the right coronary artery to air embolism in the minithoracotomy position. Attention to detail is important at this crucial stage of the operation. First of all, transesophageal echocardiography is important for accurate diagnosis of cavitary air and to monitor the success of the deairing maneuvers. Continuous CO2 insufflation should be used during the procedure because it displaces air and is rapidly absorbed. In addition, the patient should be aggressively ventilated and shaken from side to side to remove residual air before unclamping the aorta. Once undamped, the aortic root should continue to be vented until transesophageal echocardiography reveals no residual air and the EGG reveals no

Minimally invasive cardiac surgery ST elevation attributable to air embolism. Meticulous adherence to this protocol has allowed surgeons to achieve similar embolic stress rates between patients operated on with port-access or conventional surgery with no reported postoperative LV dysfunction [15,19]. Open chest beating heart valve surgery as a strategy for myocardial protection has been described in Chapter 34. Minimally invasive surgery with CO2 insufflation produces an even lower risk for any significant air embolism. Moreover, the maneuverability of the endoscopic camera might afford a better exposure of the valve being worked on. It will be interesting to see if in future beating heart valve surgery is indeed tried at any center as a myocardial protection strategy.

Coronary artery bypass surgery Coronary artery bypass has been performed both on an arrested heart (TECAB) and more recently a beating heart (TECAB-BH). The operative strategy has involved using either single or bilateral mammary arteries to bypass lesions in a single- or double-vessel distribution [7,8,12]. When working on the arrested heart, cold crystalloid or blood cardioplegia has been administered in an antegrade fashion using the portaccess technology. Dogan [7] has reported a mean creatine kinase MB fraction (CK-MB) level of 14.2 + 10.9 U/L and 18.2 + 13.1 U/L 6 h after the procedure in single-vessel and double-vessel TECAB. This is similar to what has been reported in literature with conventional coronary artery bypass (CABG) on an arrested heart [20]. Interestingly, in the TECAB study [7], total CK levels were 586 + 514 after a single-vessel operation and 1797 + 1884 after a double-vessel operation. This correlates with a mean cross-clamp time of 61 + 16 min for single-vessel and 99 + 55 min for doublevessel TECAB. The clinical significance of this difference in CK-MB release between the two groups is unknown at present, but in patients undergoing percutaneous transluminal coronary angioplasty, elevation of CK-MB was associated with a higher likelihood of postprocedure cardiac events and mortality [21]. We also know that the longer the cross-clamp time, the greater is the myocardial dysfunction and damage [22]. It can then be said that for single-vessel bypass, TECAB can be performed with a degree of myocardial protection that is comparable to that achieved during

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a conventional CABG. With double-vessel bypass, the cross-clamp times are more than double those with CABG, and hence there is an increased likelihood of inadequate myocardial protection using the currently available myocardial protection strategies. Beating heart coronary surgery via median sternotomy has been associated with up to 41% lower CK-MB release compared to CABG, when the mean cross-clamp times have been in the 40-min range. While this difference has not been shown to be clinically significant in the open chest approach, it may reach clinical significance in the TECAB operation, where the cross-clamp times have been more than twice as long and CK-MB release even higher. This hypothesis has not been put to a test yet, since TECAB-BH is a relatively new and more technically challenging procedure. Myocardial preservation during TECAB-BH can be improved by using intracoronary shunts. Certain intraoperative pharmacologic interventions might improve myocardial protection also. Beta-blockers can slow the heart rate which decreases myocardial oxygen consumption (with its attendant beneficial effects on myocardial metabolism and preservation) and facilitates the conduct of the surgery [23]. Adenosine can have a similar technical benefit of slowing the heart while also attenuating the reperfusion injury to the myocardium [23,24]. In conclusion, current data support the following inferences regarding myocardial protection in minimally invasive cardiac surgery: 1 The technology for delivery of either antegrade or retrograde cardioplegia for minimally invasive cardiac surgery is as reliable as that for open conventional cardiac surgery. 2 For periods of cardiac arrest of less than 60 min, adequate myocardial protection may be achieved in an arrested normal heart using either cold crystalloid or cold blood cardioplegia. 3 The deficiencies of cold crystalloid cardioplegia become clinically apparent with longer cross-clamp times, thereby increasing the morbidity and mortality. 4 While a comparable degree of myocardial protection can be achieved with either open or closed chest approaches, the limitations of current myocardial protection strategies in robotic surgery arise from the prolonged cross-clamp times associated with it. Stated in another way, open chest operations on the heart would probably have similar outcomes from a myocardial preservation standpoint (i.e. incidence

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of low cardiac output syndromes, arrhythmias) if they involved similarly long periods of cardiac arrest. 5 Beating heart surgery as a myocardial protection strategy can be a useful strategy in selected patients requiring coronary artery bypass. However this procedure demands a high degree of technical proficiency and a steep learning curve. 6 Beating heart valve surgery is still just a concept in minimally invasive cardiac surgery. With continued research in the field of myocardial protection and ischemia-reperfusion injury, and the development of proximal and distal anastomotic devices (to decrease the operative times in coronary bypass surgery), the future of minimally invasive cardiac surgery certainly holds great promise.

Acknowledgment The authors wish to acknowledge the help of Mohan Thanikachalam, MD, in the preparation of this manuscript.

References 1 Aklog L, Adams D, Couper GS et al. Techniques and results of direct-access minimally invasive mitral valve surgery: a paradigm for the future. / Thorac Cardiovasc Surg 1998; 116: 705-15. 2 Cosgrove DM, Sabik JF, Navia JL. Minimally invasive valve operation. Ann Thorac Surg 1998; 65:1535-9. 3 Carpentier A, Loulmet D, Carpentier A. First open heart operation (mitral valvuloplasty) under videosurgery through a minithoracotomy [French]. Comp Rend Acad Sci 1996; 319:219-23. 4 Fann JI, Pompili MF, Stevens JH et al. Port-access cardiac operations with cardioplegic arrest. Ann Thorac Surg 1997;63(6Suppl):S35-9. 5 Schwartz DS, Ribakove GH, Grossi EA et al. Minimally invasive cardiopulmonary bypass with cardioplegic arrest: a closed chest technique with equivalent myocardial protection. / Thorac Cardiovasc Surg 1996; 111: 556-66. 6 Schwartz DS, Ribakove GH, Grossi EA et al. Minimally invasive mitral valve replacement: port-access technique, feasibility and myocardial functional preservation. / Thorac Cardiovasc Surg 1997; 113:1022-31. 7 Dogan S, Aybek T, Andreben E et al. Totally endoscopic coronary artery bypass grafting on cardiopulmonary bypass with robotically enhanced telemanipulation: report of forty-five cases. / Thorac Cardiovasc Surg 2002; 123:1125-31. 8 Mohr FW, Falk V, Diegeler A et al. Computer-enhanced 'Robotic' cardiac surgery: experience in 148 patients. / Thorac Cardiovasc Surg 2001; 121:842-53.

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9 Damiano RJ, Ehrman WJ, Ducko CT et al. Initial United States clinical trial of robotically assisted endoscopic coronary artery bytpass grafting. / Thorac Cardiovasc Surg 2000;119:77-82. 10 Mohr FW, Falk V, Diegeler A, Autschbach R. Computerenhanced coronary artery bypass surgery. / Thorac Cardiovasc Surg 1999; 117:1212-15. 11 Kappert U, Cichon R, Schneider J et al. Closed-chest coronary artery surgery on the beating heart with the use of a robotic system. / Thorac Cardiovasc Surg 2000; 120: 809-11. 12 Boyd WD, Rayman R, Desai ND et al. Closed-chest coronary artery bypass grafting on the beating heart with the use of a computer-enhanced surgical robotic system. /Thorac Cardiovasc Surg 2000; 120:807-9. 13 Schroeyers P, Wellens F, De Geest R et al. Minimally invasive video-assisted mitral valve surgery: our lessons after a 4-year experience. Ann Thorac Surg 2001; 72: S1050—4. 14 Mohr FW, Falk V, Diegeler A et al. Minimally invasive port-access mitral valve surgery. / Thorac Cardiovasc Surg 1998:115:567-76. 15 Chitwood WR, Wixon CL, Elbeery JR et al. Videoassisted minimally invasive mitral valve surgery. / Thorac Cardiovasc Surg 1997; 114:773-82. 16 Zimmerman-Klima PM, Philpott JM, Elbeery JR, Lalikos JF, Chitwood WR, JR. Combined minimally invasive mitral valve repair and direct coronary artery bypass. A new alternative to sternotomy. Chest 2002; 122:344-7. 17 Torraca L, Ismeno G, Quarti A, Alfieri O. Totally endoscopic atrial septal defect closure with a robotic system: experience with seven cases. Heart Surg Forum 2002; 5: 125-7. 18 Kottkamp H, Hindricks G, Autschbach R et al. Specific linear left atrial lesions in atrial fibrillation. Intraoperative radiofrequency ablation using minimally invasive surgical techniques. JAm Coll Cardiol 2002; 40:475-80. 19 Schneider F, Onnasch JF, Falk V et al. Cerebral microemboli during minimally invasive and conventional mitral valve operations. Ann Thorac Swrg2000;70:1094-7. 20 Dijk DV, Nierich AP, Jansen EWL et al. Early outcome after off-pump versus on-pump coronary bypass surgery. Results from a randomized study. Circulation 2001; 104: 1761-6. 21 Califf RM, Abdelmeguid AE, Kuntz RE et al. Myonecrosis after revascularization procedures. / Am Coll Cardiol 1998; 31:241-51. 22 Kirklin JW, Conti VR, Blackstone EH. Prevention of myocardial damage during cardiac operations. N Engl} Med 1979; 301:135-41. 23 Chitwood WR, Wixon CL, Elbeery JR, Francalancia NA, Lust RM. Minimally invasive cardiac operations: adapting cardioprotective strategies. Ann Thorac Surg 1999; 68: 1974-7. 24 Owall A, Ehrenberg J, Brodin LA, Juhlin-Dannfelt A, Sollevi A. Effects of low-dose adenosine on myocardial performance after coronary artery bypass surgery. Ada AnaesthesiolScand 1993; 37:140-8.

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Current concepts in pediatric myocardial protection Bradley S. Allen, MD

Repair of congenital heart defects is becoming more frequent in infants and neonates. Despite major advances in the surgical correction of congenital cardiac disease, perioperative myocardial damage remains the most common cause of morbidity and death following technically successful cardiac operations [ 14]. As many as 90% of patients who do not survive the perioperative period show varying combinations of gross, microscopic, or histochemical myocardial necrosis which is most severe in the subendocardium of the left or right ventricle, depending on which chamber is affected by the basic cardiac lesion [1,5]. This necrosis occurs in the absence of coronary artery obstruction and may affect the entire subendocardium in patients with valvular and congenital heart disease. Poor protection can also lead to endocardial fibrosis with late cardiac dysfunction despite a "successful surgical outcome" [1]. Protection of the neonatal heart is further complicated by a reduced response to inotropic agents compared to the adult [2,4,6]. Thus, preservation of myocardial function in neonates during cardiac operations assumes even greater importance, because a perioperative insult is less well tolerated and more difficult to treat. This chapter provides an overview of current concepts and recent advances in pediatric myocardial protection, and details our experimental and subsequent clinical experience in protecting the pediatric heart undergoing operative repair. It examines the management of cardiopulmonary bypass prior to ischemic arrest, and subsequent cardioplegic strategy, as both are critical to avoiding a perioperative injury. Only by optimizing protection can the patient fully benefit from the successful surgical correction of an underlying congenital abnormality.

Preoperative considerations Pediatric hearts are usually subjected to physiologic stresses (i.e. hypoxia) that are quite different from those seen in the adult, and in some cases these changes can affect not only the heart, but also all organ systems. Experimentally, it has been demonstrated that normal immature myocardium has a greater tolerance to ischemia when compared to mature myocardium [2,4,7]. Nonetheless, in clinical practice this is rarely observed, and the immature myocardium is generally far more susceptible to injury during cardiac surgery [4,8-10]. This is almost certainly the result of the negative effects upon the myocardium of the various abnormal physiologic conditions for which operations are undertaken. Nowhere are these effects greater than in the neonate, where a preoperative stress is almost always present prior to surgery. In addition, there may be intrinsic differences in myocardial energy reserves from one patient to another, regardless of preoperative conditions. For example, ATP levels may be reduced up to 50% in some "normal" unperturbed hearts [11]. These metabolic changes are further influenced by the physiologic stresses of acute or chronic hypoxia, and pressure or volume overload.

Volume and pressure overload Volume overloading of the pediatric heart occurs in many conditions, such as left-to-right shunts, single ventricle with mixed circulation, and severe atrioventricular valve insufficiency. The ability of the immature myocardium to compensate for this is limited, as these hearts normally function at a high diastolic volume, and therefore have a limited diastolic reserve

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[4,6,12]. Ventricles hypertrophy and eventually dilate, their myocardial oxygen requirements increase, and their structural and metabolic properties change. Each of these changes has a negative effect upon the response of the myocardium to surgical stress or ischemia. Similarly, congenital lesions that mechanically obstruct ventricular outflow or result in increased arterial resistance lead to ventricular hypertrophy. Ventricular hypertrophy quickly causes reduced diastolic compliance and results in lower high-energy phosphate levels and inefficient oxygen utilization [13-15]. Hypertrophy effects regional myocardial blood flow resulting in relative hypoperfusion of the subendocardium, which may become ischemic during tachycardia or exercise [1]. Marked hypertrophy can also impair adequate cardioplegic distribution to the vulnerable subendocardium, as well as predispose to an ischemia-reperfusion injury with the initiation of bypass [ 1 ]. As with volume overloading, these changes make the heart more susceptible to an ischemic insult, and may negatively influence the function of the remaining ventricle.

Hypoxia Hypoxia is a common physiologic stress in pediatric patients, and is present in most neonates undergoing operative repair. Acute hypoxia and acidosis may occur as a consequence of many congenital heart defects, and can result in depletion of glycogen, ATP, and Kreb's cycle intermediates, leading to myocardial dysfunction [4,8-10,16]. Such substrate- and energy-depleted hearts are far less tolerant of future ischemic insults. Significant acute hypoxia forces the myocardium to rely upon anerobic metabolism, and when acidosis is present, this further heightens these deleterious effects. Hypoxia may also cause a reduced response to catecholamines [2-4]. Chronic hypoxia leads to cyanosis, a condition frequently encountered in infants and children undergoing open-heart surgery. In spite of compensatory mechanisms, cyanotic hearts also develop substrate depletion and metabolic derangements when compared to normoxic hearts, resulting in a relatively greater intolerance to ischemia [2,4,8-10]. Reoxygenation and cardiopulmonary bypass management Because congenital malformations of the heart frequently lead to preoperative physiologic abnormal-

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ities ("stress") that are quite different from those seen in the adult, the concerns during cardiopulmonary bypass are not necessarily the same. The most common preoperative stress in adults is ischemia, secondary to coronary artery disease, and the major concern is avoidance of a "regional" myocardial reperfusion injury with the reintroduction of blood [1]. By contrast, the most common preoperative stress in pediatric patients is hypoxia (cyanosis) [2,4,9,17]. The major concern therefore is whether a reoxygenation injury (similar to a reperfusion injury) occurs with the abrupt reintroduction of oxygen. The occurrence of such an injury could be even more detrimental, as it would result in "global" damage, since hypoxia affects the entire body, not just the heart. Cyanosis depletes the myocardium of endogenous antioxidants, and a growing body of experimental and clinical evidence indicates that this may make the cyanotic immature heart more susceptible to an oxygen-mediated injury when molecular oxygen is restored [18-23]. The reversal of hypoxemia occurs with initiation of extracorporeal circulation and precedes the surgical ischemia used for operative repair in children with cyanotic disease. The conventional method of starting cardiopulmonary bypass (CPB) in infants and children with hypoxemia is to abruptly raise oxygen tension (Po2) to approximately 400500 mmHg. Does this sudden reintroduction of oxygen cause an "unintended injury," and if so, can it be prevented? Such an injury might help explain why the cyanotic heart is more vulnerable and less tolerant to subsequent surgical ischemia than the normoxic heart [4,8-10,23,24]. We initially examined the consequences of hypoxia and reoxygenation using an in vivo piglet model to simulate the hypoxic (cyanotic) infant undergoing surgical repair [25,26]. Neonatal piglets underwent 60 min of ventilator hypoxia by lowering the fraction of inspired oxygen to 8-10%, producing an arterial oxygen tension of 25-35 mmHg, and an oxygen saturation of 65-70%. This was a "pure" hypoxic stress without any evidence of ischemia [26]. Animals were then abruptly reoxygenated by increasing the ventilator fraction of inspired oxygen (Fio2) to 100%, or placed on cardiopulmonary bypass at a Fio2 of 100%, simulating the usual clinical practice. Abrupt reoxygenation by either method caused an oxygen free radical mediated injury, resulting in a reduction in cardiac output, depressed left ventricular (LV)

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Figure 26.1 Percent recovery of end-systolic elastance (EES) compared to baseline values, at the end of hypoxia, and after the abrupt reintroduction of oxygen (reoxygenation, 100% Fio2), either by increasing the oxygen in the ventilator or initiating cardiopulmonary bypass. * P< 0.05 versus hypoxia.

function, elevated pulmonary vascular resistance, and pulmonary alveolar damage manifested by a reduction in the arterial/alveolar (a/A) ratio (Figure 26.1). This injury was independent of the method of reoxygenation, and so it appears to be primarily related to the sudden reintroduction of oxygen, and not the effects of CPB. This unintended reoxygenation injury could explain why hypoxic (cyanotic) infants are more sensitive to surgical ischemia, and often experience myocardial dysfunction despite performing an apparently technically successful operation with "good" myocardial protection [2,4,8-10,18,19,27]. Maintaining normoxemia (Po2 80-100 mmHg) rather than hyperoxemia during the initiation of CPB substantially reduces oxidant damage and decreases the extent of myocardial dysfunction (Figures 26.2 & 26.3). These benefits coincide with the Po2-dependent nature of the reoxygenation injury, because free radical production and myocardial injury after reoxygenation of isolated heart preparations are proportionate

Figure 26.2 Myocardial tissue antioxidant reserve capacity (measurement of oxygen free radical production) in animals undergoing cardiopulmonary bypass after abrupt reoxygenation at a Po2 of 400-500 mmHg, gradual reoxygenation at a Po2 of 80-100 mmHg, or leukodepletion. * P< 0.05 versus Po2 400-500 mmHg.

Figure 26.3 Percent recovery of end-systolic elastance (EES) compared to baseline values in hypoxic animals undergoing cardiopulmonary bypass, after abrupt reoxygenation at a Po2 of 400-500 mmHg, gradual reoxygenation at a Po2 of 80-100 mmHg, or leukodepletion. * P< 0.05 versus Po2 400-500 mmHg. Reprinted from [24], with permission from Elsevier.

to oxygen tension [28,29]. The avoidance of hyperoxemia during reoxygenation in cyanotic infants to reduce injury may in a sense be comparable with controlling the initial reperfusate following ischemia to avoid a reperfusion injury [ 1,30]. Although white blood cells are involved mainly in the maintenance of the immune system, under certain pathologic conditions of altered physiology they may cause damage to myocardial, pulmonary, and vascular tissue [31-33]. Activated white cells have been shown to play a major role in the generation of oxygen free radicals after ischemia, and it seems logical they should also be active in the reoxygenation injury, since both ischemia and hypoxia subject tissue to low oxygen levels [31,33,34]. The detrimental effects of white blood cells (WBCs) can be prevented either by removing the leukocytes or blocking their actions. Leukocyte depletion is a readily available method, which allows the surgeon to safely minimize the harmful effects of neutrophils, without risking side effects of pharmacologic interventions aimed at altering leukocyte function, or preventing the free radical injury through the use of exogenous oxygen radical scavengers. The effect of leukocyte removal was tested in neonatal piglets following the same acute (60 min) hypoxic stress [17,25,26]. When neutrophils were reduced by a leukocyte-depleting filter, the detrimental effects of sudden reoxygenation were obviated, with a marked reduction in oxygen free radical formation, preservation of LV contractility and diastolic compliance, maintenance of pulmonary alveolar capillary gas exchange (a/A ratio), and only a slight rise in pulmonary vascular resistance (Figures 26.2 & 26.3). This occurred despite using an Fio2 of 100%. In fact,

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the increase in pulmonary vascular resistance was even less than in nonhypoxic (control) animals subjected to CPB, suggesting that leukocyte nitration should be used in all pediatric operations where postoperative pulmonary hypertension could be problematic. Several experimental and clinical studies support this implication, and in fact have documented a reduction in pulmonary injury with leukonltration even in noncyanotic infants [35,36]. Clinical studies Despite these findings, many surgeons still doubt the existence and the clinical significance of suddenly restoring oxygen to the hypoxic heart. They point out that the majority of studies, which have documented this injury, have utilized an acute hypoxic injury, which in contrast to the chronically hypoxic infant may not allow sufficient time to develop compensatory adaptation. This adaptation, they argue, may allow the chronically hypoxic patient to avoid an injury with the reintroduction of oxygen. Nevertheless, the postreoxygenation changes seen after acute hypoxemia parallel those reported in cyanotic patients who undergo reoxygenation during bypass [18,19]. Moreover, a recent report by Corno and associates demonstrated an identical injury in animals subjected to 2 weeks of chronic hypoxia [37]. Such an unintended injury may explain clinical reports showing that cyanotic hearts are more vulnerable than noncyanotic hearts to ischemia/reperfusion damage despite comparable cardioplegic protection and shorter ischemic times [2,4,8-10,38,39]. To more critically examine the clinical relevance of the reoxygenation injury, myocardial tissue antioxidant reserve capacity was analyzed in cyanotic and acyanotic patients before and 10 min after initiating bypass [26,40]. This allows quantification of oxygen free radical formation during reoxygenation, and is the same test used in numerous experimental studies of acute hypoxia. It therefore allows for a direct comparison of acute versus chronic hypoxia [22,25,40—42]. Furthermore, antioxidant reserve capacity also predicts the ability of the heart to withstand a subsequent ischemic challenge, and there appears to be direct linkage between antioxidant depletion, oxidant damage, and cardiac and pulmonary dysfunction [22,25,41,42]. Normal hearts with abundant antioxidants develop only minor functional impairment after aortic clamping, whereas hearts with a limited antioxidant reserve

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Figure 26.4 Percent increase in myocardial tissue antioxidant reserve capacity in acyanotic and cyanotic infants after reoxygenation using cardiopulmonary bypass. *P<0.05.

capacity exhibit marked contractile depression after cardioplegic arrest [9,18,19,38,39,41,43]. There was no difference in prebypass myocardial antioxidant reserve capacity between cyanotic and acyanotic patients. This parallels our experimental findings after acute hypoxia [25]. Initiating bypass in low-risk acyanotic infants (atrial septal defect, ventricular septal defect) caused minimal change in the antioxidant reserve capacity, inferring that in the absence of hypoxia only a small quantity of oxygen free radicals are generated. By contrast, abrupt reoxygenation of cyanotic infants resulted in a significant depletion of endogenous tissue antioxidants (Figure 26.4). This suggests that abrupt reoxygenation of chronically hypoxemic infants generates abundant oxygen free radicals, since prebypass endogenous tissue stores of antioxidants were not different between acyanotic and cyanotic hearts. This, again, parallels our experimental studies [25]. Cyanotic infants reoxygenated using a Po2 of 400-550 mmHg (Fio2 100%) had the greatest loss of myocardial antioxidant reserve capacity (highest malondialdehyde formation) indicating the largest exposure to oxygen free radicals (Figure 26.5). Moreover, the generation of malondialdehyde was four to six times greater in cyanotic infants compared to acute hypoxic animals, implying a greater production of oxygen free radicals with reoxygenation after chronic cyanosis [25,40]. This supports the experimental work of Corno and associates, who also observed greater production of oxygen free radicals following chronic hypoxia [37]. The most probable explanation for these results is that chronically hypoxic animals (or patients) often become ischemic during periods of increased stress (tachycardia) or exercise [21,44]. This subjects them to both a hypoxic and ischemic stress. By contrast, acute experimental hypoxia results in no ischemia [26]. It is therefore not surprising that

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Table 26.1 Limiting the reoxygenation injury in clinical

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practice. Bypass protocol: • Wash and leukodeplete blood prime • Inline arterial filter • Initiate bypass using normoxic management

Figure 26.5 Percent increase in antioxidant reserve capacity in cyanotic infants after reoxygenation with cardiopulmonary bypass using a Po2 of 400-500 mmHg, gradual reoxygenation at a Po2 of 80-100 mmHg, or white blood cell (WBC) filtration. The more malondialdehyde (MDA, nmol/g protein) produced by an oxidant challenge (4 mmol t-butyl hydroperoxide), the greater the loss of endogenous tissue antioxidants, indicating exposure to increased levels of oxygen free radicals during reoxygenation. * P<0.05. Reprinted from [35], with permission from Society of Thoracic Surgeons.

a combination of hypoxia and ischemia results in a more severe injury with reperfusion. This oxidant injury probably explains why ventricular function is often temporarily depressed in cyanotic infants undergoing extracorporeal membrane oxygenation, even in the absence of surgical ischemia [45,46]. Initiating bypass using a normoxic strategy (Po2 80-100 mmHg) reduced the change in antioxidant reserve capacity, and using WBC filtration, which further lowered oxygen radical formation, maximized this effect (Figure 26.5). This is once again precisely what was demonstrated in the experimental setting after acute hypoxia, where a lower production of oxygen free radicals correlated with an improvement in myocardial and pulmonary function [17,25,26]. Although no patient reoxygenated with leukocytedepleted blood had a substantial change in the antioxidant reserve capacity, the generation of oxygen free radicals was further suppressed by combining normoxia and WBC filtration [40]. Indeed, the antioxidant reserve capacity in these infants was unchanged from baseline values, and even lower than in acyanotic patients, indicating the effects of lower oxygen levels and white cell filtration are additive. Based on this extensive experimental and clinical infrastructure, we currently recommend using a normoxic bypass strategy combined with leukodepletion in all hypoxic (cyanotic) patients (Table 26.1). We also use this strategy in normoxic patients with ventricular hypertrophy or pulmonary hypertension. Marked ventricular hypertrophy from pressure volume overload can lead to subendocardial ischemia,

(Po2 80-100 mmHg)

and a reperfusion injury can be limited by the same bypass strategy. Leukodepletion also reduces pulmonary injury even in noncyanotic patients, and so it helps limit problems with postoperative pulmonary hypertension [35,36]. The bypass circuit is primed and initiated using a normoxic strategy (Po2 80-100 mmHg), and the Fio2 increased slowly over the next 10-20 min to maintain a Po2 of 100-150 mmHg. In clinical practice hyperoxemic bypass is performed routinely but is likely never needed, because a Po2 of 400-500 mmHg confers only negligible increase in O2 content compared to a Po2 of 100-150 mmHg. In both instances the oxygen saturation is essentially 100%. Moreover, a bypass Po2 greater than 180 mmHg has been associated with impairment of peripheral perfusion [47]. If a blood prime is used, it is always washed and leukodepleted, and a leukodepleting filter is placed in the arterial line for the entire procedure. I strongly believe blood for the bypass prime should always be leukodepleted, since oxygen free radical formation is greatest with the initial reintroduction of oxygen. This is the most important time to limit WBC exposure. In addition, banked blood contains a large amount of activated WBCs, which can cause pulmonary damage even in the absence of hypoxia [35,36]. Inefficient WBC filters, coupled with leukodepletion during times which are less critical, probably explains why some investigators have failed to demonstrate a clinical advantage with WBC filtration, despite overwhelming experimental evidence as to their benefit [25,26,35,40,48-50]. The bypass prime is also left hypocalcemic, as we (unpublished data) and others have demonstrated that hypocalcemia can substantially reduce the reperfusion/reoxygenation injury with the initiation of bypass [51,52].

Cardioplegia Cardioplegia application to pediatric congenital heart surgery has made tremendous gains over the past

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10 years. However, recovery and outcome statistics continue to point out the need for improvements in this increasingly younger patient population. Neonatal myocardial protection remains suboptimal, resulting in an increased operative mortality compared with the results for older children and adults [2-4,9]. In general, improvements have benefitted from the adult cardiac experience. However, in view of the structural, functional, and metabolic differences, extrapolation of adult cardioprotective strategies to the neonate is fundamentally imprudent and potentially harmful [2,4,6,7,12,53]. Myocardial protective strategies and cardioplegia solutions must be studied in the infant heart if neonatal protection is to be truly optimized. Despite the prevalence of hypoxia or other physiologic changes in the neonatal population, few experimental studies have included "stressed" hearts when examining cardioplegia solutions in pediatric hearts. By contrast, in clinical practice, congenital lesions usually result in hypoxia or pressure volume overload, and therefore, "normal" (nonstressed) hearts are probably uncommon, especially in the neonatal population. Including stressed hearts in any investigation of cardioplegia solutions is extremely important, because stressed hearts are less tolerant to ischemia, and more sensitive to changes in the method of cardioplegic protection [2—4,8,9]. They therefore provide information concerning the patients most vulnerable to postoperative dysfunction. This is why adult studies often use an acute ischemic stress to investigate cardioplegia strategies, even though it does not exactly mimic the clinical conditions of chronic angina or cardiogenic shock [ 1 ]. However, since pediatric hearts do not usually experience severe preoperative ischemia,

the stress must be changed to one that is clinically relevant, such as hypoxia. The type of experimental model is also important, as there are marked differences between an in vivo and an isolated heart preparation. In contrast to studies in the adult, most neonatal investigations have used an isolated heart model. Although this allows for precise experimental control, it does not mimic the clinical conditions of the operating room. For instance, bronchial blood return and noncoronary collateral flow are absent in the isolated heart but may have a profound effect in the in vivo model, because the cardioplegia solution may be washed away, changing the cellular environment [1,38,39]. Hypothermia, which may provide a dominate protective effect, is easier to maintain in the isolated heart preparation, whereas the heart is constantly rewarmed in the intact animal setting [1,38,39]. Results from isolated heart preparations may therefore be misleading, and not clinically applicable. These differences probably explain the conflicting results obtained by different investigators, especially with regards to blood versus crystalloid solutions and cardioplegia calcium concentration [38,39]. Because of these concerns we investigated different cardioplegic strategies in both "normal" (nonstressed) and "hypoxic" (stressed) neonatal hearts using an in vivo intact animal model that simulates the operating room. Our warm and cold blood cardioplegia solutions are shown in Tables 26.2 and 26.3, and we modified the solution, or the method of delivery, to investigate each component. Blood versus crystalloid While blood cardioplegia predominates in the adult

Table 26.2 Warm induction and reperfusate blood cardioplegia solution. Reprinted from [24], with permission from Elsevier.

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Table 26.3 Cold blood cardioplegia solution. Reprinted from [24], with

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permission from Elsevier.

* When mixed in a 4 : 1 ratio with blood.

patient undergoing open heart surgery, crystalloid cardioplegia is still widely used in the pediatric population, and most investigations have demonstrated little or no difference between blood and crystalloid cardioplegia [1,2,54-56]. Our studies support these results, as we also found that both blood and crystalloid (St Thomas) cardioplegia provide excellent myocardial protection of "normal" neonatal hearts not subjected to a preoperative stress; with complete preservation of myocardial function [39]. However, subjecting the neonatal piglet to a hypoxic "stress" profoundly altered these results. Blood cardioplegia solutions not only protected the heart from further damage, but also facilitated repair of the injury caused by hypoxia and reoxygenation; resulting in complete preservation of myocardial and vascular function. Conversely, crystalloid cardioplegia solution was unable to adequately protect the hypoxic heart, resulting in postbypass myocardial and vascular dysfunction (Figure 26.6). Blood cardioplegia has several advantages over crystalloid cardioplegia, which help explain these findings [ 1 ]. With blood, the heart is arrested in an oxygenated environment, so that no loss of highenergy phosphate stores occurs during the short

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Figure 26.6 Blood versus crystalloid cardioplegia. Recovery of LV systolic function in nonhypoxic (normal) and hypoxic hearts undergoing 70 min of cardioplegic arrest with blood or crystalloid cardioplegia solution. Contractility is measured by the end-systolic elastance (EES) and expressed as a percentage of control (baseline) values. * P< 0.001. Reprinted from [42], with permission from Elsevier.

period of electromechanical activity before asystole [1]. By contrast, several investigators have reported significant decreases in high-energy phosphates during the few heartbeats occurring during induction with crystalloid cardioplegia. When given as a warm induction, blood cardioplegia can "resuscitate" the injured myocardium, thereby allowing it to better tolerate the subsequent ischemia (see "Cardioplegic induction" below) [1,57]. Blood cardioplegia provides oxygen and nutrients during multidose infusions to enhance cellular metabolism and replenish depleted energy storage [1]. Lastly, since the hypoxic heart may be more susceptible to a reperfusion injury after ischemia, use of a warm blood cardioplegic reperfusate may limit this injury (see "Reperfusion" below).

Calcium and magnesium An important consideration regarding myocardial protection is calcium concentration, because high levels have been implicated as a major component in cellular injury during ischemia and reperfusion [1, 2,58,59]. The neonatal heart maybe more susceptible to a calcium-mediated cellular injury because the sarcoplasmic reticulum of the immature myocardium possesses a diminished capacity to sequester calcium and because of different characteristics of the calcium transport system [2,4,53]. Although hypocalcemic cardioplegia solutions provide superior protection of adult hearts, the ideal cardioplegia calcium concentration in newborns continues to be debated, and both hypocalcemic and normocalcemic solutions have been shown to provide superior protection of the normal heart [ 1,2,4,54,60]. As in the case of blood versus crystalloid cardioplegia, these seemingly conflicting results are probably secondary to the experimental model (in vitro vs. in vivo) and the preoperative state of the heart. Our studies in nonhypoxic ("normal") hearts support most previous investigations, as we also saw complete

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Figure 26.7 Hypocalcemic versus normocalcemic cardioplegia. Recovery of LV systolic function in nonhypoxic (normal) and hypoxic hearts undergoing 70 min of cardioplegic arrest with hypocalcemic (Low) or normocalcemic (NL) cardioplegia solution. Contractility is measured by the end-systolic elastance (EES) and expressed as a percentage of control (baseline) values. * P< 0.001. Reprinted from [47], with permission from Elsevier.

preservation of myocardial and vascular function with either a normocalcemic or hypocalcemic blood cardioplegia solution [1,2,4,38,54,60]. By contrast, subjecting the neonatal heart to hypoxia ("stress") profoundly altered the results. Hypocalcemic cardioplegia solutions allowed for repair of the injury caused by hypoxia and reoxygenation, resulting in complete preservation of myocardial and vascular endothelial cell function. Conversely, there was an increased cellular injury when normocalcemic solutions were used to protect hypoxic hearts, manifested by depression in postbypass myocardial and endothelial cell function (Figure 26.7). These findings should not be surprising, because an increased sensitivity to calcium was also observed when adult hearts were subjected to an ischemic stress [1,61]. In clinical practice, there are often transient fluxes in the cardioplegia ionized calcium concentration due to variability in pH, hemodilution, temperature, potassium, and, perhaps most importantly, systemic calcium levels in the bypass circuit. The ischemic neonatal myocardium is therefore at risk of exposure to potentially higher or lower cardioplegic calcium levels than originally intended, which may increase the risk of a calcium-mediated injury. Any unintended transient calcium increase assumes even greater importance in pediatric myocardial protection because immature myocytes are less able to handle a given calcium load when compared to the adult [2,53,58,60]. In addition, despite concerns over calcium injury, many pediatric surgeons continue to use normocalcemic cardioplegia solutions. The addition of magnesium, which inhibits cellular calcium entry, may solve this dilemma by preventing

damage from higher cardioplegic calcium concentrations. Magnesium is lost during ischemia, leading to an increase in postoperative arrhythmias and possible impairment of magnesium-dependent cellular reactions [62-66]. Replacing extracellular magnesium by enriching cardiologic solutions has been shown to decrease the incidence of postoperative arrhythmias as well as improve myocardial protection by a variety of pathways [62-67]. The most important of these is probably magnesium's ability to modulate intracellular calcium levels by inhibiting calcium entry across the cellular membrane, as well as displacing calcium from the binding sites of the sarcolemmal membrane [62-64,67]. This prevents mitochondrial calcium uptake, which can lead to uncoupling of oxidative phosphorylation with a decrease in ATP production. Postischemic calcium entry is further limited because magnesium prevents an influx of sodium, which during reperfusion is exchanged for calcium. Supplemental magnesium can also facilitate asystole at lower potassium concentrations [1]. This is important because high potassium concentrations can damage vascular endothelial cells directly, as well as enhance endothelial and myocyte calcium entry. In the absence of magnesium enrichment, a hypocalcemic cardioplegia solution results in complete preservation of myocardial function in hypoxic (stressed) hearts [38,62]. Magnesium supplementation was, however, found to be beneficial if the hypoxic (stressed) neonatal heart was protected with a normocalcemic cardioplegia solution [62]. Instead of a significant cellular injury, magnesium enrichment protected the heart from further damage, resulting in complete preservation of myocardial and vascular endothelial cell function (Figure 26.8). Magnesium, therefore, offsets the detrimental effects of highcalcium cardioplegia solutions in hypoxic hearts. Indeed, there appears to be a specific interrelationship between magnesium and calcium that has led to the perception that magnesium may not be necessary when a hypocalcemic cardioplegia solution is utilized [62-64,67]. Whether magnesium enrichment can improve the protection afforded by hypocalcemic blood cardioplegia solution remained unanswered by this study, since hypoxic hearts regain complete function when protected with hypocalcemic cardioplegia alone. In order to answer this question, neonatal hearts had to undergo a more severe stress (hypoxia and ischemia).

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Figure 26.8 Postbypass percent recovery of end-systolic elastance (EES) compared to baseline in hypoxic neonatal piglets undergoing 70 min of cardioplegic arrest. Note: Magnesium enrichment of the normocalcemic cardioplegia solution offset the detrimental effects of high levels of calcium in hypoxic piglets, resulting in complete return of systolic function. * P< 0.001. Reprinted from [48], with permission from Elsevier.

Hypoxia is associated with metabolic adaptations that allow normal aerobic metabolism to persist in the resting state. However, this compensatory mechanism is expended readily with stress, as atrial pacing or catecholamine infusion causes myocardial lactate production, indicating ischemia with a shift toward anaerobic metabolism [21,44]. This metabolic shift may occur in cyanotic patients during the stresses of daily life, such as exercise, emotional upset, and tachycardia, and become compounded during anoxic spells. A combined hypoxic-ischemic stress, therefore probably more closely resembles the chronic hypoxic (cyanotic) patient, and was used to determine if magnesium improves hypocalcemic cardioplegia solutions [4,9, 10,16,17,21,44,68]. Following an hypoxic-ischemic stress, neither hypocalcemic blood cardioplegia without magnesium nor normocalcemic cardioplegia with magnesium was able to provide adequate protection [69]. By contrast, adding magnesium to hypocalcemic cardioplegia solutions substantially improved myocardial protection and allowed for complete recovery of metabolic and myocardial function (Figure 26.9). This beneficial effect is similar to the improved results obtained in adults with calcium channel blockers, which also inhibit calcium entry [1,61]. Calcium channel blockers, however, have a prolonged effect, which may depress postoperative myocardial function, making them a less attractive cardioplegic additive. Because calcium and magnesium have an interrelationship, similar results might have been obtained in the absence of magnesium by further lowering the cardioplegic calcium concentration. However, this is potentially dangerous, as myocardial recovery may

Figure 26.9 Postbypass LV systolic function as measured by the end-systolic elastance (EES) and expressed as percent of recovery of baseline in neonatal piglets undergoing a hypoxic-ischemic stress. Note: Hearts protected with a hypocalcemic cardioplegia solution alone exhibited marked loss of systolic function. By contrast, there is complete preservation of systolic function when magnesium is added to hypocalcemic cardioplegia solution. However, magnesium enrichment was not able to offset the detrimental effects of a normocalcemic cardioplegia solution in hypoxic-ischemic hearts, resulting in diminished systolic function. * P< 0.001.

be reduced when the cardioplegic calcium is less than 100 mmol/L, and although unlikely, a calcium paradox can occur if levels are reduced to less than 50 mmol/L [1,29,59,61,64]. The optimal dose of magnesium therefore probably depends on the cardioplegic calcium concentration in as much as the beneficial effects of magnesium and hypocalcemia are additive as well as interdependent.

Operative strategy The strategies for clinical cardioplegia may be separated into the phases of (i) induction, (ii) maintenance, and (iii) reperfusion. Cardioplegic induction A brief (5 min) infusion of warm blood cardioplegia solution can be used as a form of active resuscitation in energy-depleted (ischemic) adult hearts which must undergo subsequent aortic clamping [1,70,71]. Normothermia (37°C) optimizes the rate of cellular repair, and enrichment with the amino acids aspartate and glutamate improves oxygen utilization capacity, resulting in improvement in postoperative functional recovery and patient survival [1,71,72]. This extra oxygen is used to repair ischemic cell damage, as well as to replete energy stores, thereby allowing the myocardium to better tolerate the obligatory period of aortic cross-clamping needed for cardiac repair. Warm blood cardioplegic induction is therefore often a part of the myocardial protection strategy in adult

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hearts subjected to a preoperative ischemic stress or hemodynamic instability [1,70,71]. In the "normal" infant myocardium, myocardial energy stores are greater, and unlike adult hearts, preoperative ischemia is uncommon since there is no coronary occlusion [2,4,73]. This has led to the perception that warm induction, as well as amino acid supplementation, is unnecessary [2,4,73]. Pediatric hearts are, however, often stressed by other factors such as hypoxia, or pressure volume overload, which although different from ischemia, can result in substrate and energy depletion [2,4,8,10,16,39,41,42]. In the nonhypoxic (normal) heart, we found cardioplegic induction temperature was not important, as there was complete preservation of myocardial function and metabolic activity with either warm or cold induction [74]. There was also no significant increase in oxygen uptake over basal metabolic rates during cardioplegic induction, indicating no increased metabolic activity during warm induction. This is not surprising as nonhypoxic (normal) hearts should not need to be resuscitated, and cold blood cardioplegia has been shown to provide excellent myocardial protection in normal neonatal hearts undergoing 2 h of aortic cross-clamping [2,4,75]. Hearts subjected to the stress of hypoxia followed by reoxygenation, however, undergo an oxygenmediated injury which depresses systolic and global myocardial function, and increases diastolic stiffness significantly [25,39,41,42]. Cold cardioplegic induction (with or without amino acids) prevents further damage, but does not improve the injury caused by reoxygenation. Conversely, providing a warm cardioplegic induction for 3-5 min facilitates repair of the hypoxic-reoxygenation injury resulting in complete preservation of myocardial function [74] (Figure 26.10). However, the benefits of warm induction are only realized if the cardioplegia contains the amino acids aspartate and glutamate, as warm induction without substrate enrichment was no better than cold induction. Quite interestingly, the oxygen uptake during warm induction in hypoxic neonatal hearts was not significantly increased over basal metabolic rates. Therefore, in contrast to adults, which increase oxygen uptake fivefold during warm induction, the primary mechanism of amino acid supplementation in hypoxic (stressed) neonatal piglets does not appear to be secondary to increased metabolic activity [1,74]. This

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Figure 26.10 Warm versus cold cardioplegic induction. Recovery of LV systolic function in hypoxic hearts undergoing reoxygenation on cardiopulmonary bypass without ischemia or 70 min of cardioplegic arrest with an aspartate/glutamate-enriched cardioplegic induction. Contractility is measured by the end-systolic elastance (EES) and expressed as a percentage of control (baseline) values. * P< 0.001. Reprinted from [24], with permission from Elsevier.

maybe due to the fact that ischemia and hypoxia result in different myocardial injuries [42]. With ischemia, there is significant depletion of ATP resulting in the loss of cellular ionic gradients [1,15,30,70,76]. Warm induction allows the heart to generate substantial quantities of ATP, making it possible to re-establish these ionic gradients, which explains the large increase in oxygen uptake seen in ischemic adult hearts during warm induction [1,70]. Conversely, in our acute hypoxic model there is no ischemia, as oxygen delivery is maintained during hypoxia preserving ATP levels [26]. Since ATP levels are not reduced, there should be no loss of cellular ionic gradients. Therefore, oxygen uptake during warm induction does not need to be significantly increased over basal levels, because cellular ionic gradients do not need to be re-established. Evidence that amino acids can act through a mechanism other than by increasing energy production could explain why some investigators have shown no active incorporation of amino acids into the Krebs cycle, despite substantial evidence that they improve myocardial protection [1,2,77]. Nevertheless, chronically hypoxic or hypertrophied (pressure-volume overload) hearts can become ischemic during exercise or periods of increased stress [ 1,4,8,9,16,21,44]. Warm induction may therefore be even more beneficial in the clinical setting, since these patients will have reduced ATP levels prior to ischemic arrest. Maintenance All hearts receive some noncoronary collateral blood flow via pericardial connections, and this may be even

Current concepts in pediatric myocardial protection

217

Table 26.4 Modified cold blood maintenance (continuous) solution. Reprinted from [24], with permission from Elsevier.

more significant in the patient with aortopulmonary collaterals [1,2]. The volume of this flow is variable, but is sufficient to wash away all cardioplegia solutions. Myocardial temperature increases after the cardioplegia solution is discontinued, as the heart is rewarmed by the noncoronary collateral blood flow, which has the same temperature as the systemic perfusate. Efforts at controlling noncoronary collateral flow by reducing either systemic flow rate or systemic perfusion pressure, or by using profound levels of systemic hypothermia (<25°C), must be tempered by the recognition of the possible hematologic consequences of deep hypothermia, and the potential deleterious effects of hypoperfusion of other vital organs (brain and kidney) at low systemic flow rates. Moreover, recurrent ventricular activity is uncommon if systemic temperature is kept between 25 and 30°C despite cardioplegic washout. Periodic replenishment of the cardioplegia solution at 10- to 20-min intervals counteracts noncoronary collateral washout. Multidose cardioplegia is necessary even if electromechanical activity does not return, since low-level electrical activity may precede recurrence of visible mechanical activity, and can lead to delayed recovery if cardioplegic replenishment is not provided [1,78]. Periodic replenishment: (i) maintains arrest; (ii) restores desired levels of hypothermia; (iii) buffers acidosis; (iv) washes acid metabolites away which inhibit continued anaerobiosis; (v) replenishes high-energy phosphates if the cardioplegia solution is oxygenated; (vi) restores substrates depleted during ischemia; and (vii) counteracts edema with hyperosmolarity. Replenishment of oxygenated cardioplegia solutions over 2 min allows enough time for the heart to use the delivered oxygen, and myocardial oxygen uptake may exceed basal demands by as much as 10-

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fold during each replenishment [ 1 ]. To further limit ischemia, maintenance infusions can also be run continuously when visualization is not impaired. For this strategy, we utilize a new nonpotassium-modified cardioplegia solution (Table 26.4; see "Modified integrated cardioplegia" below).

Reperfusion Although ischemia alone undeniably leads to cell death, most investigators believe that within clinical relevance this injury occurs primarily during reperfusion [1,79-82]. Cells that looked completely normal at the end of ischemia, may show extensive functional, metabolic, and structural alterations following reperfusion [1,72,83]. A reperfusion injury may contribute to the impaired cardiac performance which develops immediately after operation, and to the eventual myocardial fibrosis which may result following surgical correction of congenital or acquired cardiac diseases [1,2,72,83]. The potential for this damage exists during most pediatric cardiac procedures, because the aorta must be clamped to produce a quiet, bloodless field. Previous studies in adults have shown that the fate of the ischemic myocardium is determined more by the method of reperfusion than the duration of ischemia itself [1,30,83]. The cardiac surgeon is in the unique position to counteract this reperfusion damage, since the conditions of reperfusion and the composition of the reperfusate are under his/her immediate control. Follette was the first to show that postischemic reperfusion damage after global ischemia could be avoided in adult hearts by substituting a brief warm blood cardioplegic infusion during the initial phase of reperfusion for the unmodified blood that would normally be provided by aortic unclamping [83].

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CHAPTER 26

Applying these principles, Teoh etal. and Kirklin etal. found that use of a warm blood cardioplegic reperfusate improved metabolic and functional recovery, thereby decreasing mortality in adult patients undergoing cardiac operations [72,84]. Warm blood cardioplegia solutions are therefore often used in adult hearts to limit the reperfusion injury following surgical ischemia [1,70]. The use of a warm cardioplegic reperfusate, however, is rarely used in infants, perhaps due to the belief that the infant heart is more tolerant to ischemia [2,4,73]. Experimentally, it has been demonstrated that normal immature myocardium has a greater tolerance to ischemia when compared to mature myocardium [2,4,7]. Nonetheless, in clinical practice this is rarely observed, and several experimental and clinical studies have found that the hypoxic neonatal heart is more sensitive to ischemia than the adult [2-4,9,10,39]. Compared to uncontrolled reperfusion with normal blood, infusing a nonsubstrate-enriched warm blood cardioplegic reperfusate for 3-5 min prior to removing the aortic clamp slightly improved postbypass functional recovery in hypoxic piglets undergoing 70 min of arrest. However, enriching the terminal warm cardioplegic reperfusate with the amino acids aspartate and glutamate vastly improved its efficacy, resulting in complete functional recovery [80] (Figure 26.11). By contrast, Follette and others saw a much greater improvement with a warm reperfusate without amino acids in adults [1,83,84]. This increased sensitivity to surgical ischemia in acutely hypoxic neonates undergoing cardioplegic arrest parallels the findings in cyanotic infants and chronically hypoxic animals [2,3,8-10,16]. Moreover, Taggart and associ-

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Figure 26.11 The effect of different methods of reperfusion on the recovery of LV systolic function following cardioplegic arrest as measured by the endsystolic elastance (EES) and expressed as percentage of control (baseline). * P< 0.001 versus unmodified blood; ** P< 0.001 versus all groups. Reprinted from [68], with permission from Elsevier.

ates recently demonstrated that both acyanotic and cyanotic infants undergoing corrective surgery were more prone to a reperfusion injury compared to adults [85]. This may explain why Chaturvedi and coworkers, using a conductance catheter to measure pressure-volume loops, demonstrated postoperative ventricular dysfunction even in infants undergoing simple repair of an atrial septal defect when the heart was protected by cold cardioplegia alone [86]. Use of a warm substrate-enriched cardioplegic reperfusate is therefore probably indicated in all infants, and this is our current clinical practice.

White blood cell filtration Despite the success of these studies, myocardial recovery was incomplete with our standard blood cardioplegia solutions if the pediatric heart was subjected to a combination of hypoxia and ischemia [24,68,87]. As mentioned previously, a combined hypoxic-ischemic stress probably more closely resembles the chronic hypoxic (cyanotic) patient, as hypoxic hearts frequently become ischemic during periods of increased stress or exercise [10,16,21,44,68]. This led us to look for additional modalities which might improve the efficacy of warm cardioplegia solutions in limiting reperfusion damage. We were intrigued by the studies of Bryne and associates who demonstrated a reduction in reperfusion damage by leukodepleting normal blood following myocardial ischemia, and wondered if WBC filtration might exhibit an adjunctive effect when used in conjunction with cardioplegia solutions [31]. We investigated the efficacy of leukodepleting our standard substrate-enriched (Asp/Glut) blood cardioplegia solution using neonatal piglets subjected to a hypoxicischemic stress followed by 70 min of cardioplegic arrest [87]. This is a more severe stress, and reperfusing the heart with normal (unmodified) blood by removing the aortic cross-clamp caused substantial oxygen free radical production, resulting in such significant reperfusion damage that bypass could not be discontinued (Figure 26.12). Conversely, the reperfusion injury was reduced in hearts reperfused with our standard warm substrate-enriched blood cardioplegia solution. These hearts, however, still sustained a significant oxygen free radical mediated reperfusion injury resulting in coronary vascular and mitochondrial damage, and depressed myocardial function (Figures 26.12 & 26.13). By contrast, oxygen

Current concepts in pediatric myocardial protection

219

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Figure 26.12 Production of oxygen free radicals during myocardial reperfusion as measured by conjugated dienes in hypoxic-ischemic piglets reperfused with either unmodified blood, aspartate/glutamate (Asp/Glut) blood cardioplegia alone, or leukodepleted Asp/Glut blood cardioplegia (WBC filter). *P< 0.001.

Figure 26.13 Postbypass recovery of LV systolic function as measured by end-systolic elastance (EES) and expressed as percentage of control (baseline) in hypoxic-ischemic piglets protected with aspartate/glutamate (asp/glut) blood cardioplegia with or without a WBC filter. * P< 0.001.

Figure 26.14 Total WBC and neutrophil count in blood cardioplegia pre and post the Pall BC-1 leukodepleting (WBC) filter. *P<0.001.

free radical production was almost eliminated if the blood cardioplegia was leukodepleted by passing it through a cardioplegic (Pall BC-1, Pall Biomedical, Glencove, NY) WBC filter (Figure 26.12). This filter is very efficient at removing WBCs in a single pass, and can accommodate flows up to 500 ml/min, making it ideal for blood cardioplegia (Figure 26.14). By avoiding the reperfusion injury, mitochondrial and vascular function were preserved, resulting in complete recovery of myocardial function (Figure 26.13).

Figure 26.15 Myocardial oxygen free radical formation (malondialdehyde) during cardioplegic reperfusion in pediatric patients. * P<0.05. Adapted from Sawa & Matsuda [XX].

Although experimental studies have shown the efficacy of leukocyte-removal filters in attenuating the reperfusion injury, transfer to the clinical setting has been slow [25,31,33,34,87]. Pearl et al. reported that leukocyte depletion improved graft function in transplanted human hearts [88]. However, Sawa and Matsuda were the first to investigate leukocyte depletion as an adjunct to blood cardioplegia in pediatric patients [89,90]. In 50 pediatric patients undergoing open heart surgery for congenital heart disease, 25 received blood cardioplegia without leukocyte depletion (BCP group), whereas the remaining 25 received leukocyte-depleted blood cardioplegia (LDBCP). The difference in plasma concentrations of malondialdehyde between coronary sinus effluent and arterial blood just after reperfusion in the LDBCP group was significantly lower than that in the BCP group, indicating lower oxygen free radical production with WBC filtration (Figure 26.15). The LDBCP group also showed significantly lower plasma concentrations of human heart fatty acid-binding protein and CK-MB than did the BCP group, indicating less tissue damage, and the maximum dose of catecholamine needed for hemodynamic stability was significantly smaller. These results parallel our experimental studies in neonatal hearts, and support the use of this modality to reduce cardiac injury. With respect to the clinical application of leukocyte-depleted blood cardioplegia, the direct insertion of the leukocyte removal filter into the cardioplegia circuit is easy. No serious complications have occurred in any patient studies [17,25,26,40] (J Ortolano, personal communication). From a clinical standpoint, the two major concerns of the WBC filtrations have been the possible increased rate of infection, especially in the setting of immunosuppression, and the concomitant platelet depletion. However, the total body WBC and platelet counts are minimally affected

220

because only approximately 20-30% of the total blood volume is filtered during cardioplegic infusions, and platelet elimination with this filter is only about 60% [17,87,89] (J Ortolano, personal communication). Moreover, recent studies have demonstrated that neutrophil depletion during surgery may actually decrease the infection rate, and neutrophil levels quickly return to normal by arrival in the ICU [ 25,40,91 ]. Certain limitations of the cardioplegic WBC filter must be kept in mind. This filter requires approximately 200 ml for priming, and this amount is large in comparison with the total volume used for priming the pediatric CPB circuit. The increased priming volume enhances hemodilution and may prevent cardiac surgery without blood components in certain subsets of low-risk pediatric patients. Consequently, WBC filtration of cardioplegia solutions may not be indicated in pediatric patients with excellent cardiac function who otherwise will not require a blood transfusion. A second limitation relates to the finite capacity of the cardioplegia WBC filter. In neonates and infants, it is possible to leukocyte deplete all cardioplegic infusions without overloading the filter, as the volume of cardioplegia is quite a bit less than in adults. However, older children and adults require much larger volumes of cardioplegia, and since the cardioplegia WBC filter has a finite capacity, repeated cardioplegic administration may lessen the ability of the filter to effectively remove leukocytes during the critical period of reperfusion. As such, the filter should probably only be used for the terminal cardioplegic reperfusate in these older patient groups. Although this approach has been shown to still significantly improve myocardial protection, the potential benefit may be reduced [89,92]. This limitation is important, as inappropriate use of WBC filters coupled with leukodepletion during times which are less critical probably explains why some investigators have failed to demonstrate a clinical advantage with WBC filtration of cardioplegia solutions. Hopefully, as more surgeons realize the benefits of leukodepletion, filters will be developed with smaller priming volumes for infants, while allowing for complete leukocyte depletion with multiple infusions in children and adults.

Distribution In order to be effective, cardioplegia must be adequately distributed to all myocardial segments. It

CHAPTER 26

is safer to clamp the aorta for up to 4 h with good cardioplegic delivery, than for as little as 30 min when the same cold cardioplegia solution is given with inadequate distribution [ 1 ]. In the presence of coronary artery occlusion, improved protection has been demonstrated with retrograde as opposed to antegrade delivery techniques [1,93,94]. Fortunately, in the vast majority of pediatric procedures, excellent cardioplegic distribution may be achieved using the antegrade approach alone, as coronary occlusion is not an issue. Nonetheless, there may be an increasing role for retrograde-delivered cardioplegia in pediatric patients, particularly in situations where there is significant aortic insufficiency, or when frequent antegrade infusions are impossible, such as during an arterial switch procedure (see "Modified integrated cardioplegia" below). Retrograde delivery may also be indicated in all patients with depressed function, or marked ventricular or septal hypertrophy, since retrograde supplies different myocardial beds, and provides superior septal and subendocardial perfusion [ 1,93,95 ]. Pressure Antegrade cardioplegia is often delivered without directly monitoring the infusion pressure. The surgeon or perfusionist can therefore only estimate the actual perfusion pressure [1,96]. This may result in cardioplegia being delivered at a pressure that is higher or lower than desired. Furthermore, even if the pressure is monitored, the optimal cardioplegia infusion pressure remains essentially unknown, especially in neonates. Although a high cardioplegic perfusion pressure is thought to be deleterious, especially to ischemic tissue, the definition of high remains undefined [ 1,2,97]. Nevertheless, an adequate cardioplegic pressure is needed to insure distribution to all areas of the myocardium [ 1 ]. What pressure is required, and the consequences of even moderate elevation of cardioplegic infusion pressure in neonatal hearts, is unknown, especially in the hypoxic (stressed) heart that may be more prone to pressure injury [2,8,10,38,39]. In order to answer this question, we protected neonatal hearts with blood cardioplegia delivered either at high (80-100 mmHg) or low (30-50 mmHg) pressure [98]. In nonhypoxic (noninjured) hearts, we found complete preservation of myocardial and vascular function using either low or high cardioplegia infusion pressure, indicating that either cardioplegia infusion pressure provides good protection (Figure

221

Current concepts in pediatric myocardial protection

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Figure 26.16 Effect of different cardioplegic infusion pressures on LV systolic function in normal (nonhypoxic) and hypoxic hearts as measured by the end-systolic elastance (EES) and expressed as percent recovery of baseline values. * P< 0.001. Reprinted from [76], with permission from Society of Thoracic Surgeons.

26.16). However, there was still an increase in myocardial edema even in normal (nonhypoxic) hearts when an infusion pressure of 80-100 mmHg was used. Although function was preserved, this implies some myocardial damage as a result of higher infusion pressure. By contrast, subjecting the neonatal heart to hypoxia profoundly altered the effect different cardioplegia infusion pressures had on the myocardium. A low cardioplegia infusion pressure not only protected the heart from further damage, it also allowed the cardioplegia to facilitate repair of the injury caused by hypoxia and reoxygenation, resulting in complete preservation of myocardial and vascular endothelial cell function (Figure 26.16). This supports the safety of a cardioplegic infusion pressure of 30-50 mmHg, and implies it is high enough to ensure adequate myocardial distribution, because without adequate distribution, myocardial protection is poor. Conversely, protection was poor when cardioplegic infusions were delivered at a slightly higher (80-100 mmHg) pressure. This was manifested by postbypass myocardial and vascular endothelial cell dysfunction, increased edema, and decreased ATP levels. A pressure port is integrated into most adult commercial cardioplegia systems to allow monitoring of the cardioplegia delivery line. Before the availability of antegrade (and retrograde) cannulas with a lumen for direct pressure monitoring, intravascular pressures were estimated by observing the pressure recorded on the pressure port of the cardioplegic delivery system, and subtracting from it the known pressure drop in the delivery system. This requires the perfusionist to intermittently calibrate the system (especially if different-sized cannulas are used), and makes it necessary to calculate intravascular pressure with each change in cardioplegic flow rate.

Direct intravascular pressure measurement is the only reliable method for determining either aortic or coronary sinus pressure during cardioplegic delivery [1,99]. This conclusion was reached in adults by obtaining simultaneous measurement of intravascular pressure in either the aorta or coronary sinus during cardioplegic infusions and comparing it to calculated pressure from the known pressure drop in the tubing system at flow rates ranging from 50 to 300 ml/min [1,96,99]. This demonstrated that: (i) calculated pressure does not accurately reflect the measured intravascular pressure during either antegrade or retrograde delivery; and (ii) the variability between calculated and measured intravascular pressure increases as either antegrade or retrograde cardioplegic flow rate is raised. This discrepancy between the calculated and measured intravascular pressure probably results from differences related to calibration with roller pumps, and wide fluctuations in cardioplegic delivery system pressure which can develop when temperature, flow, and viscosity are varied in systems containing rigid and compliant components. Direct intravascular measurement circumvents this problem and provides the surgeon with a more reliable pressure measurement [1,96,99]. With smaller cannulas and vascular beds, errors in calculating the cardioplegic infusion pressure may be magnified, and change quicker in neonates. Direct aortic monitoring should be used in pediatric patients to prevent inadvertent elevations in pressure, since even small changes in pressure may significantly affect neonatal myocardial protection, especially in the hypoxic heart.

Modified integrated cardioplegia Following cardioplegic arrest, most surgeons deliver intermittent cardioplegia every 10-20 min to maintain myocardial arrest, restore hypothermia, buffer acidosis, and wash away acid metabolites [1,2]. This is traditional, but a dry field is not always required between cardioplegic doses. Therefore, to further limit ischemia and improve protection, we introduced the concept of "integrated" cardioplegia, which consists of infusing a maintenance solution of unmodified cold (4°C) blood between intermittent cardioplegic doses whenever visualization is not impaired by coronary perfusion [1,94,100]. Cold unmodified blood is used for the maintenance infusions, since hypothermia alone tends to keep the heart arrested, it allows the infusions to be safely interrupted when a dry field

222

is required for optimal visualization, and avoids the administration of large quantities of potassium. Despite excellent clinical results in adult patients, the "standard" integrated strategy has never been evaluated experimentally, and it is rarely used in pediatric patients [ 1,94,100]. Indeed, several studies in pediatric hearts have suggested that multiple intermittent cardioplegic infusions are no better, and may even be worse, than a single cold infusion [2,4,39]. Postoperative myocardial dysfunction, however, remains the primary cause of morbidity and mortality in the pediatric patient, occurring most frequently in the presence of cyanosis [2,4,9,10,101]. Hypoxic hearts are more prone to accelerated depletion of ATP during surgical ischemia, as well as predisposed to a reoxygenation injury with the reintroduction of oxygen [10,25,39]. They are also less able to tolerate myocardial ischemia [2,4,8-10,16,38,39]. Consequently, compared to the normoxic adult heart, the cyanotic (hypoxic) pediatric heart is more vulnerable to inadequacies in myocardial protection, and might derive an even greater benefit from an integrated approach which limits ischemia. To parallel this experimentally, we used "stressed" (hypoxic-ischemic) neonatal hearts to evaluate the conventional techniques of: (i) intermittent cardioplegia; and (ii) standard integrated protection. The standard integrated strategy, however, has the potential problem of producing a reperfusion injury, since it exposes the ischemic heart to multiple infusions of cold unmodified blood, which Rebeyka and associates showed is dangerous in infants [102]. We therefore also evaluated a new approach, which replaces the cold unmodified blood normally used for the maintenance infusions, with a cold modified (nonpotassium, magnesium-enriched, CPD, THAM) blood solution (Table 26.4). We termed this the modified "integrated" strategy. Using a modified nonpotassium "cardioplegic-like" blood solution for the maintenance infusions has the potential advantage of reducing any reperfusion injury, since cardioplegia limits reperfusion damage following ischemia, and the heart is ischemic between cardioplegic doses [1,80,83]. Hyperkalemia is avoided by not adding potassium, and the heart kept arrested by hypothermia, as well as changes in magnesium and calcium. To more closely mimic clinical experience, we also determined if the method of delivery (antegrade vs. retrograde) affected results. This simulates operations such as an arterial

CHAPTER 26

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Figure 26.17 Recovery of LV systolic function as measured by end-systolic elastance (EES) and expressed as percentage of control (baseline) in stressed (hypoxic-ischemic) piglets. Note: Intermittent cardioplegia preserves function at the same levels as stressed hearts not subjected to cardioplegic arrest. By contrast, adding maintenance infusions of unmodified cold blood (standard integrated strategy) partially resuscitated the heart and improved contractility. However, this effect was maximized if a modified solution was used for the maintenance infusions (modified integrated strategy) resulting in complete return of systolic function. * P<0.001 versus intermittent, ** P< 0.001 versus all. Reprinted from [24], with permission from Elsevier.

switch, where antegrade perfusion is not possible after the initial cardioplegia dose. From this study we concluded that: 1 The conventional techniques of intermittent multidose blood cardioplegia alone or with maintenance infusions of cold unmodified blood ("standard integrated" strategy) provides inadequate protection of the "stressed" (hypoxic-ischemic) neonatal heart. 2 Infusing a cold, modified nonpotassium maintenance blood solution between intermittent cardioplegia doses (modified integrated strategy) completely resuscitates the "stressed" neonatal heart, restoring myocardial, metabolic, and vascular function. 3 The modified solution is equally effective delivered antegrade or retrograde (Figure 26.17). This implies that maintenance infusions of a cold modified solution do more than just limit ischemia during cardioplegic arrest, they also actively resuscitate the stressed heart, since a modified maintenance solution (modified integrated strategy) improved recovery to a greater extent than unmodified blood (standard integrated strategy), despite the fact that both of these approaches reduce ischemia equally by providing oxygenated blood during myocardial arrest. Previously, only warm blood cardioplegia has been demonstrated to have the ability to resuscitate the stressed heart [ 1,57,94]. Why such a dramatic improvement occurs when a modified maintenance solution

Current concepts in pediatric myocardial protection is infused at 4°C is unknown, but it suggests that the solution is working through a mechanism which is not dependent on enzymatic activity. It is possible that the same effect would have occurred if the modified solution had been infused at normothermia. However, keeping the heart warm is potentially dangerous, as it is less tolerant to ischemic intervals any time infusions are interrupted, or if cardioplegic distribution is not adequate to all myocardial segments. The maintenance infusions are always delivered at a measured pressure of 30-50 mmHg, because infusing intermittent cardioplegia at higher pressures is detrimental to stressed neonatal hearts [98]. The modified solution used for the maintenance infusions is based on our multidose cardioplegia solution, but the potassium is removed to avoid postbypass hyperkalemia [1,38,39, 94]. Moreover, potassium is probably not required, as the cold arrested heart tends to stay that way if it is maintained at 4°C [1]. Nevertheless, to insure myocardial quiescence, potassium cardioplegia is usually given every 20-30 minutes, or whenever the continuous infusions are interrupted, since the arrested heart can develop small amplitude ventricular fibrillation which is not always visible, but results in increased oxygen consumption and ischemia [78]. This study also has implications concerning the method of cardioplegic delivery. Compared to antegrade delivery, retrograde delivery may provide superior perfusion of the vulnerable LV subendocardium and septum, especially in the setting of coronary occlusion or ventricular hypertrophy. This study suggests that another reason for the pediatric heart surgeon to use retrograde cardioplegia is to provide cardioplegic delivery whenever frequent antegrade infusions are not possible (i.e. arterial switches), as it seems to supply adequate protection at hypothermia. In contrast to adults, however, protection of the right ventricle is often more important in pediatrics due to the frequent problems of right ventricular (RV) hypertrophy and postoperative pulmonary hypertension [2,4]. The pediatric surgeon must therefore be careful about relying solely on retrograde delivery, since it may not supply adequate nutritive flow to the RV free wall, especially at normothermia [93,103, 104]. This is the reason we always deliver at least a portion of the terminal warm reperfusate (hot shot) antegrade, as it helps compensate for any inadequacies in RV free wall protection by repairing cellular damage that may have occurred during cold cardioplegic

223

arrest. Nevertheless, in patients with marked ventricular hypertrophy, the surgeon should also consider delivering a portion of the warm reperfusate retrograde, as antegrade delivery to the septum and subendocardium may be compromised in this setting. Inadequate septal protection can significantly impair RV function, since the septum is responsible for a substantial part of RV function [ 105].

Clinical studies We have now incorporated the above principles into our clinical practice at the Heart Institute for Children and the University of Illinois at Chicago. We use a blood plasma bypass prime in neonates and young infants, and a crystalloid prime in children. The bypass calcium levels are not normalized, but allowed to become hypocalcemic, because a hypocalcemic prime helps limit the reoxygenation/reperfusion injury that can occur with the initiation of bypass [51,52]. As described earlier (see "Reoxygenation and cardiopulmonary bypass management" above), we utilize a normoxic bypass strategy, always leukodeplete the bypass prime when blood is used, and place an inline arterial WBC filter in all cyanotic and highrisk (i.e. pulmonary hypertension) patients. The blood cardioplegia solutions are similar to the ones in our experimental studies (Tables 26.2-26.4). However, in order to deliver the desired calcium concentration, we have reduced the amount of citrate. The cardioplegic calcium level is the concentration of calcium after it is mixed with blood from the bypass prime. Using citrate reduces calcium levels. If one uses a normocalcemic bypass prime, as in our experimental studies, then the amount of citrate should be the same as depicted in Tables 26.2 and 26.3. However, if the bypass circuit is kept hypocalcemic (as we do in our clinical practice), then the amount of citrate in the cardioplegia solution is reduced to achieve these same levels. Nevertheless, it is important not to let the delivered calcium level become too low. Levels lower than 0.2 mmol/L may be detrimental to myocardial protection, as well as predispose to a calcium paradox. Furthermore, if all the available calcium is bound, excess citrate will then bind with magnesium, resulting in extremely low calcium and magnesium levels. To offset any problem with higher than intended cardioplegic calcium levels, we add magnesium to our cardioplegia solutions, as magnesium can limit the

224

detrimental effects of calcium, especially during the critical period of reperfusion. Magnesium may have several other benefits. Normothermic hearts require higher potassium levels to maintain myocardial arrest during cardioplegia induction or terminal reperfusion (hot shot) [1]. Because high potassium levels can directly injure endothelial cells, as well as predispose to calcium influx, magnesium allows the potassium concentration to be reduced while maintaining myocardial arrest [29,59,62,63]. When the heart is warm, ion fluxes and cellular reactions are faster, and the cell is more susceptible to a calcium-mediated reperfusion injury [1]. Because magnesium competes with calcium, it should be beneficial during these critical times [63,64]. Magnesium should also provide greater protection against postoperative arrhythmias, and Hearse and others have documented that cardioplegic magnesium concentrations as high as 16 mEq/L are safe in both adult and pediatric patients [63-67]. To the best of our knowledge, we have never had a problem with postbypass hypermagnesemia. Nevertheless, to offset any potential problems, we always normalize the systemic ionic calcium in the upper range of normal prior to discontinuing cardiopulmonary bypass, as any adverse effects of hypermagnesemia are easily reversed by calcium. Moreover, magnesium is rapidly depleted by ultrafiltration, and levels are usually normal by arrival in the ICU. Our clinical cardioplegia protocol consists of 35 min of cold induction, followed by 2-min cold multidose infusions every 10-15 min, with finally all patients receiving a 3- to 5-min terminal warm substrate-enriched reperfusate prior to removing the aortic cross-clamp. A cold modified (nonpotassium) blood maintenance solution is always infused continuously whenever it does not impair optimal visualization (modified integrated strategy). We are just starting to use a 3- to 5-min warm induction in highrisk patients. Infusions are given antegrade whenever possible, but retrograde delivery is used in all patients where antegrade infusions are not possible at least every 10-15 min (i.e. arterial switch), or if there is marked septal hypertrophy. However, at least a portion of the terminal warm reperfusate is always given antegrade. Cardioplegia is delivered at a continuously measured aortic root or coronary sinus pressure of 30-50 mmHg. I also believe a cardioplegic WBC filter is extremely important, especially during the terminal warm reperfusate, and plan to use them

CHAPTER 26

routinely once a filter with a prime less than 100 mm3 is introduced. To assess the clinical efficacy of this approach, we retrospectively examined all patients undergoing an open-heart procedure at The Heart Institute for Children or University of Illinois Chicago during a 2year period. There were 567 patients with an overall mortality of 5%, and most importantly, almost no patient died as a result of postoperative myocardial failure (Table 26.5). To better assess the validity of our bypass and cardioplegia strategy, we performed a more detailed examination of all patients undergoing a Norwood procedure between July 1996 and December 2001, since these patients are very high risk, and their hearts are severely stressed. These dates were chosen as this is when we began to routinely use both a bypass strategy of normoxia and leukodepletion, as well as modified integrated cardioplegic protection. There were 93 patients, 51 with a diagnosis of hypoplastic left heart syndrome (HLHS), and 42 with a variant (HLHV) of hypoplastic left heart syndrome. The overall survival was 77% (75% HLHS, 81% HLHV). More importantly, there was excellent preservation of myocardial function, both initially, as assessed by echocardiogram, and several months later, when evaluated by angiogram prior to the Glenn procedure (Table 26.6). This is in contrast to other reports which often describe depressed myocardial function following successful repair of cyanotic lesions [2,4,9,106,107]. Indeed, the surgical survival in the 38 patients undergoing a Norwood procedure in the 2 years prior to instituting this strategy (January 1993 to June 1996) was only 53%. The only major changes we made between these two time intervals was the routine use of a leukodepleted normoxic bypass strategy, and infusing a continuous modified maintenance cardioplegia solution (modified integrated strategy) during the period of myocardial ischemia. I acknowledge that other factors might have accounted for the increased survival and improved postoperative cardiac function. However, despite lack of a control group, I believe these results, as well as the extensive experimental infrastructure, support the safety and efficacy of this approach. In conclusion, significant advances have been made in the technical performance of operations for congenital heart disease, but postoperative organ dysfunction remains problematic, especially in cyanotic infants [2-4,9,10]. These studies provide direct

Current concepts in pediatric myocardial protection

Table 26.5 Clinical results. Reprinted from [24], with permission from Elsevier.

225

Operation

Number

Closure ventricular septal defect

106

Closure atrial septal defect

71

Aortic valve procedures

53

RV outflow tract reconstruction

53

Fontan procedure

49

Norwood procedure

39

Repair tetralogy of Fallot

39

Bidirectional Glenn shunt

36

Atrioventricular canal repair

33

Rastelli repair

16

Arterial switch

15

Mitral valve procedure

14 8

Ross procedure Repair total anomalous venous return

8

Aortic arch reconstruction

4

Anomalous coronary repair

4

Ebstein's repair

4

Repair truncus arteriosis

4

Double switch procedure

3

Repair interrupted aortic arch

3

Repair tetralogy of Fallot/atrioventricular canal

3

Kono's procedure

2

Age distribution Neonates (<1 month)

79

Infants (1-12 months)

205

Children (<12 months)

283

29 (29/568)

Mortality* * Mortality rate = 5%.

Table 26.6 Norwood operation clinical results. 93 patients (7/1/96 to 12/31/2001) 51 HLHS, 42 HLHV Age 7 days (range 2-44 days) Weight 3090 g (range 1680-5195 g) Overall perioperative survival 77% (72/93 patients) HLHS 75%, HLHV 81% HLHS right ventricular function Fractional shortening (Echo); preoperative 37 ± 8% vs. postoperative 35 + 9% Ejection fraction (angiogram) at time of Glenn shunt

evidence that: (i) an unintended oxygen free radical mediated injury occurs in cyanotic infants with the initiation of bypass resulting in myocardial and pulmonary damage; (ii) this reoxygenation injury can be reduced by using a bypass strategy which incorporates normoxia and WBC filtration; and (iii) excellent protection of the hypoxic-ischemic heart is possible by using a comprehensive blood cardioplegic strategy. Incorporating these strategies into operative management will allow surgeons to limit damage in these high-risk infants, leading to a reduction in morbidity and mortality.

56 ± 8% Priorperioperative survival 53% (1/1/93 to 6/30/96, 38 patients) HLHS, hypoplastic left heart syndrome; HLHV, hypoplastic left heart variant; Echo, echocardiogram.

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CHAPTER 27

Myocardial preconditioning in the experimental model: a new strategy to improve myocardial protection Eliot R. Rosenkranz, MD, Jun Feng, MD, PhD, & Hong-Ling Li, MD, MSC

Open-heart operations require a period of elective cardioplegic arrest to facilitate the surgical repair. Although current methods of inducing and maintaining arrest using hyperkalemic cardioplegia solutions are effective, postreperfusion depression of myocardial performance remains an important cause of postoperative morbidity and mortality. In 1986, Murry et al. [1] described the phenomenon of ischemic preconditioning in dogs in which a brief period of regional myocardial ischemia made the heart more tolerant to a subsequent, more prolonged period of ischemia. The molecular mechanisms responsible for ischemic preconditioning are presently incompletely understood, although several studies have shown that activated distinct isoforms of the enzymes protein kinase C (PKC), tyrosine kinase (TK), and nitric oxide (NO) may be important effectors required for preconditioning to occur [2-5] and may be targets for pharmacologic induction of the preconditioned phenotype. Similarly, several mediators released from the ischemic myocardium during ischemia and reperfusion, including adenosine and bradykinin [6], may be important initiators of the preconditioned state when given exogenously prior to a period of prolonged ischemia. These observations lead us to conclude that pharmacologic agents given before or in combination with hyperkalemic cardioplegia might be a strategy to reduce or prevent postreperfusion myocardial depression after surgical procedures. This chapter reviews our hypothesis that myocardial ischemia tolerance can be improved by pretreat-

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ing the heart with agents that activate the distinct molecular pathways that have been associated with the ischemic preconditioning phenomenon and may be a new approach towards protecting the heart during open-heart surgery. The first portion of this chapter will outline the preconditioning phenomenon and describe our current understanding of the molecular mechanisms responsible for preconditioning the myocyte in response to ischemia or cell stress. Several recent reviews in the literature describe the molecular mechanisms behind the preconditioning phenomenon in greater detail [7-11], which is beyond the scope of this chapter. In the second part of this chapter, we will first describe experimental work conducted in our research laboratory that suggests that pretreating the heart with pharmacologic agents before and during cardioplegic arrest can improve myocardial ischemia tolerance by mechanisms that have been associated with mediating the ischemic preconditioning process. Then we will review a series of studies from our laboratory that suggest that the superior ischemia tolerance noted in the immature heart compared to the adult heart may be due to more highly activated molecular mechanisms of the preconditioning phenomenon in the immature animal.

The discovery of ischemic preconditioning In 1981, Reimer [12] noted that repletion of ATP following a brief episode of ischemia occurred very

Experimental myocardial preconditioning slowly, suggesting that repeated ischemic episodes might lead to cumulative myocyte injury. Surprisingly, however, further ischemic episodes did not produce any additional depletion, indicating that the rate of ATP breakdown rate must have been reduced during the subsequent ischemic periods. Subsequently, Reimer [13] noted that four 10-min periods of transient ischemia resulted in less myocardial necrosis than that seen in hearts exposed to a single 40-min period of coronary occlusion. Murry et al. [1] extended these observations by showing that four 5-min periods of coronary occlusion, each separated by 5 min of reperfusion, led to a significant reduction in infarct size following a subsequent period of prolonged regional coronary ischemia. They called this method of enhancing ischemic tolerance "preconditioning with ischemia", which has been reproduced in most animal species including humans [14-18].

General biology of ischemic preconditioning The four aspects of the general biology of ischemic preconditioning to be considered are: (i) the number and duration of preconditioning episodes of ischemia required to precondition the heart; (ii) the duration of reperfusion that is needed between ischemic preconditioning episodes; (iii) the duration of the subsequent period of sustained ischemia during which myocyte death can be prevented; and (iv) the breadth of protection by ischemic preconditioning. Although the original preconditioning protocol was composed of four 5-min episodes of ischemia [ 1 ], there is general agreement that preconditioning can be induced with a variety of protocols. Single or multiple coronary occlusions of 2.5, 5, or 10 min have been shown to be protective in dogs [16,19,20], rabbits [15,21], pigs [22], and rats [23,24]. Although multiple brief periods of ischemia appear to be superior to single ischemic episodes in inducing the preconditioned phenotype, there appears to be a diminishing return after more than four ischemia episodes. The minimum duration of reperfusion required between the preconditioning episode and the prolonged period of ischemia has not been established. Studies have shown a limitation of necrosis when 5-min periods of reperfusion were used and a marked decrease in ischemic metabolism when longer (20-

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min) reperfusion periods are used [1]. By contrast, protection is substantially attenuated if the period of prolonged ischemia is delayed for 2 h after the preconditioning episodes [19]. In the rat, the effects of preconditioning with three, 3-min coronary occlusions were largely lost when the period of intervening reperfusion was extended from 5 min to 1 h. This phenomenon is often referred to as early preconditioning, due to the limited envelope of the protection period, and appears to be induced by activation of mediators already present in the myocyte and independent of mRNA expression and protein synthesis. It is characterized by being nearly immediate in onset, but the benefit is of limited duration. By contrast, if one exposes the heart to several repetitions of multiple brief ischemia-reperfusion cycles, a more longlasting period of ischemia tolerance is induced (delayed preconditioning). This process requires the activation of more complex signal transduction pathways that may involve gene activation and synthesis of as of yet incompletely defined effector proteins [9,25,26]. Ischemic preconditioning has classically been studied using myocardial necrosis as an endpoint [ 1,16,22]. In addition, preconditioning offers a wide range of protection against the complications of ischemiareperfusion including regional and global myocardial dysfunction and a reduction in reperfusion arrhythmias. Several studies have demonstrated that preconditioning can enhance the recovery of contractile function in addition to reducing infarct size in the myocardial "region at risk" [27-32].

Proposed signal transduction pathways for ischemic preconditioning Although ischemic preconditioning has been extensively studied, its mechanisms of induction, the molecular pathways that mediate the signal transduction, and the end effector of the process are incompletely understood. Several recent reviews in the literature provide more complete details of the evolving understanding of the preconditioning phenomenon [7-11 ]. The preconditioned phenotype can be triggered by a number of initiator agents that are released locally in ischemic myocardium, including adenosine, acetylcholine, bradykinin, norepinephrine, nitric oxide, reactive oxygen species, opioid receptor activators,

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CHAPTER 27

Figure 27.1 Molecular pathways. Proposed molecular pathways leading to the early preconditioned state. PKC, protein kinase C; TK, tyrosine kinase; MAP kinase, mitogen-activated protein kinase; KATP channel, ATP-sensitive potassium channel; NO, nitric oxide.

etc. [6,33-36]. In addition, the preconditioned state can be activated in response to cell stress (heat, pacing, cell-surface tension, etc.). These initiator substances bind to G-protein linked cell membrane receptors, which via phospholipase-C and phospholipase-D amplify the signal by the activation of a complex, and incompletely defined, signal transduction pathway (Figure 27.1). The signal transduction pathway requires the activation of families of serine-threonine protein kinases including protein kinase C (PKC) [2,4,6,37], tyrosine kinase (TK) [5,37,38], and the mitogen-activated protein kinases (MAPK) [39,40]. The signal appears to be regulated by the activation of specific isoforms of each of the kinase families such as PKC-e, Src-TK [39], and p38 MAPK [40], p44/p42 MAPK [41], and JNK [42], members of the MAPK superfamily. Kinase activation presumably leads to phosphorylation of as yet unidentified proteins [43], which may regulate the early preconditioned phenotype and appear to participate in the pharmacologically induced preconditioned state. Kinase activation may also amplify the preconditioning signal by activation of inducible nitric oxide synthase (iNOS) resulting in generation of NO (Figure 27.2). In vascular endothelial cells and myocytes, bradykinin activates constitutive (endothelial) NO synthase (eNOS) resulting in nitric oxide (NO) generation [44,45]. In an elegant series of studies using a model of late ischemic preconditioning, Bolli and associates [39,46,47] sug-

gested that NO is a required mediator of ischemic preconditioning and is responsible for activating the more distal signal transduction pathways leading to the preconditioned state. Bolli et al. [47], Jones et al. [48], and Takano et al. [33] demonstrated that the initial ischemic preconditioning stimulus results in release of NO via activation of eNOS. NO reacts with reactive oxygen species (ROS), such as oxygen radical (O2~), formed during reperfusion of ischemic myocardium, which then combine to generate peroxynitrite (ONOO~) [46,48]. Pretreatment of the heart with NOS inhibitors or oxygen radical scavengers block early and late preconditioning. NO, ROS, and peroxynitrite induce the translocation and activation of PKCe, which plays a critical role in the preconditioning signal transduction pathway. The protective effects of late preconditioning are then amplified by activation of a TK-dependent signal cascade which results in activation of iNOS gene product as evidenced by an increase in iNOS mRNA [48,49]. NO generation then may in turn activate nuclear transcription factors including nuclear factor KB (NF-KB) [25,26,43,50] and heat-shock protein (HSP-27) [51]. Activated transcription factors appear to turn on several genes that may account for the more prolongedacting phenomenon of delayed preconditioning. The terminal effect (end effector) of the preconditioning signal transduction pathway is not completely understood, although the majority of evidence points

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Experimental myocardial preconditioning

Image Not Available Figure 27.2 Proposed molecular pathway for bradykinin (BK) pretreatment resulting in preconditioning the heart. eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; NFicB, nuclear factor KB; PKC, protein kinase C; NO, nitric oxide; KATP, ATP-sensitive potassium channel. Reprinted from Annals of Thoracic Surgery, Vol. 70, Feng J, Li H, Rosenkranz E. Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways, pp. 2119-2124, © 2000, with permission from Society of Thoracic Surgeons.

to the ATP-sensitive potassium (KATP) channel playing this role [10,11,35,52-54]. The KATP channel is found in both myocyte sarcolemmal membranes and mitochondrial membranes, the latter of which appears to be the true end effector of both ischemia and pharmacologically induced preconditioned phenotypes [55-60] (see p. 249).

ized by decreased energy utilization by one or multiple metabolic pathways during a subsequent episode of ischemia [1,61,62] (Figure 27.1). Similarly, there is less accumulation of glycolytic products during ischemia, indicating a reduced rate of glycolysis and therefore a reduced rate of ATP hydrolysis.

Cellular effects of preconditioning

The preconditioned phenotype is characterized by a reduction in energy utilization and energy generation, including by glycolysis. However, preconditioning may enhance subsequent recovery of myocardial function by enhancing postreperfusion glucose uptake via activation of glucose transport proteins [63]. We have demonstrated that pharmacologic preconditioning with bradykinin enhances translocation of glucose transporter 4 via PKC-dependent pathways, which may play a mechanistic role in enhancing ischemia tolerance (see p. 246).

Carbohydrate metabolism

Precisely what determines the development of irreversible myocyte injury during ischemia and following reperfusion is not known, although injury to the mitochondria is likely since abnormalities of energy metabolism and calcium homeostasis appear to be of central importance. Preconditioning in many ways results in a downcycling of the metabolic state of the myocyte. The preconditioning stimulus leads to a reduction in myocardial ATP content by approximately 30% [ 1 ]. However, during subsequent prolonged ischemic episodes, the rate of decline of ATP and creatine phosphate are reduced. Thereafter, levels of both ATP and creatine phosphate do not differ significantly from controls. Exposure of myocardium to a brief stress results in a rapid adaptation, which is character-

Concurrent stunning Brief episodes of ischemia and reperfusion can produce a profound but reversible depression of contractile function, called myocardial stunning [62,64]. During ischemia the actin-myosin ATPase reduces ATP and

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it was suggested that preconditioning might act by stunning the heart, thereby reducing energy demand during the subsequent prolonged ischemic challenge [65,66]. However, this hypothesis has become less attractive for several reasons. While the classical, early protective effects of preconditioning last for one to two hours, it takes substantially longer, often several days, to achieve full recovery from stunning. Others [7,18] have shown a clear dissociation between the temporal profiles of recovery from the two processes.

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teomics utilizing microchip arrays hold promise in identifying genes and gene products that are activated by various preconditioning stimuli.

Experimental studies of pharmacologic preconditioning

Shortly after the description of the preconditioning phenomenon by Murry [1], several investigators began evaluating the potential for clinically harnessing this powerful process, particularly by means of pharmacologic induction. Since the preconditioning Free radicals and reactive phenomenon has been demonstrated in most animal oxygen species Reactive oxygen species (ROS) have long been associ- species and several different organ systems, numerous ated with the damage caused by ischemia and reperfu- approaches have been taken to determine if human sion. There is strong evidence implicating ROS as a myocardium can be ischemically preconditioned, and trigger of and mediator for the preconditioning stim- if so, could pharmacologic agents be employed to ulus and signal transduction pathways [67], parti- electively induce the preconditioned phenotype to cularly in relation to the opening of mitochondrial mitigate the effects of ischemic episodes incurred by KATP channels [68-70]. Similarly, preconditioned acute coronary syndromes or during cardiac surgery mitochondria generate less ROS after reperfusion. [8,18,75,76]. In vitro studies have confirmed that human atrial ROS generation during the brief ischemia-reperfusion cycles have also been linked to the induction of and ventricular myocytes can be preconditioned, delayed preconditioning since administration of 2- involving the same metabolic pathways identified in mercaptopropionyl glycine (2-MPG), which inhibits animal models [77-80]. In clinical situations, several ROS production, or free radical scavengers such as examples of preconditioning have been proposed. It superoxide dismutase and catalase during the precon- had long been recognized that patients with sympditioning stimulus, prevent the anti-infarction effects toms of angina have a lower mortality rate and complication rate (shock, arrhythmias, etc.) after an acute of preconditioning [46,49,71]. myocardial infarction, which may represent preconditioning, induced by the preceding angina episodes Genetic mechanisms As noted above, the time course of induction and [81,82]. Similarly, patients with "warm-up angina" maintenance of early preconditioning is too brief to frequently note a decrease in their exercise-related allow for new protein generation or gene activation. symptoms and a reduction in ST-segment changes By contrast, evidence suggests that repeated cycles of prior to a second period of exercise if they have had ischemia-reperfusion result in gene activation via the angina symptoms at the initiation of exercise [83,84]. activation of transcription factors [25,26,43,50]. Thus, This reduction in symptoms lasts for 1-2 h, which is a a brief episode of ischemia might induce the transcrip- similar duration to the beneficial effects of classical, tion of new mRNA and subsequent synthesis of one early preconditioning as discussed earlier [85]. Simor more proteins that protect the myocardium [9]. ilarly, diabetic patients treated with oral sulfonylurea Activation of target genes, as evidenced by increased antihyperglycemic agents, such as glibenclamide, levels of mRNA and protein transcription, includes have been shown to have a disproportionately high iNOS, cyclooxygenase-2 (COX-2) [72], aldolase incidence or death after myocardial infarction. This reductase [73], Mn superoxide dismutase (SOD) [74], appears to be due to the pharmacological mechanand HSP-27 [9,51]. These gene products then may ism of their action, which involves inhibition of the serve to reduce the injury associated with ROS gener- KATP channel, which appears to be an important end ated during reperfusion (aldolase, SOD), or serve to effector of preconditioning as discussed above [86]. Examples of ischemic and pharmacologic preinduce or amplify preconditioning (iNOS, HSP-27). Future studies employing applied genomics and pro- conditioning have also been shown clinically during

Experimental myocardial preconditioning coronary angioplasty and cardiac surgery. Several investigators have reported a reduction or elimination of angina, ST-segment elevation, enzyme release, etc. after successive balloon inflations during percutaneous transluminal angioplasty (PTCA). This benefit of repeated episodes of brief ischemia and reperfusion during PTCA is out of proportion to the presence of collateral vessels and has a duration of benefit that is quite similar to that seen in experimental models of early preconditioning (1-2 h) [87-90]. In addition, the benefits of repeated balloon inflations during PTCA can be blocked by preangioplasty administration of glibenclamide [91] (KATPblocker) or induced by the pretreatment administration of intracoronary bradykinin which has been shown to be a potent trigger of preconditioning [76]. During cardiac surgery, preservation of ATP, a reduction of troponin T release, and better global and regional myocardial function have been suggested by several studies in which a preconditioning protocol was employed prior to the period of prolonged aortic cross-clamping. Protocols have involved repeated cycles of 2-3 min of aortic cross-clamping followed by 2-5 min of reperfusion [18,92-94]. It is important to recognize that at the present time we cannot draw direct mechanistic parallels between the ischemic preconditioning process and pharmacologic treatments that are aimed at improving global myocardial function after cardiac surgery. There is evidence that although many parts of the induction of the preconditioning cascade and mediators involved in the intracellular transduction of the signal are found both in ischemic preconditioning and pharmacologic preconditioning, other data suggest that there is a divergence of the molecular pathways depending on the triggering event (i.e. ischemia vs. a pharmacologic agent). Further research will be required to more clearly define the relationships between the various triggers of preconditioning, the sequential and parallel intracellular cascades that mediate the signal and the end effectors of the signal that are responsible for conferring the preconditioned phenotype. Despite these limitations in our knowledge, our laboratory has focused on studying the preconditioning phenomenon as it can be applied to: (i) pharmacologic pretreatment of the heart prior to simulated cardiac surgery; and (ii) understanding why the immature heart is innately more tolerant than the mature heart to equivalent periods of myocardial ischemia. The

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remainder of this chapter will review our findings and summarize our understanding of how pharmacologic preconditioning may by employed as an important adjunct to or substitute for traditional methods of intraoperative myocardial protection.

Pharmacologic pretreatment to improve myocardial ischemia tolerance As discussed earlier, several mediators released by ischemic myocardium, including adenosine and bradykinin, can induce the preconditioned phenotype in the heart when administered exogenously before a period of more prolonged ischemia. These observations lead us to test the hypothesis that pretreating the heart with bradykinin before a period of cardioplegic arrest would improve postreperfusion myocardial function. Utilizing the isolated rabbit heart as a model (described below), we have confirmed this hypothesis and have identified some of the molecular pathways involved in the mediation of bradykinin-induced pharmacologic preconditioning.

Bradykinin as a pharmacologic preconditioning agent Bradykinin is a member of a family of kinins that are peptides released by the myocardium during ischemia and it is activated by cleavage from a precursor peptide catalyzed by the enzyme kallikrein [95]. The heart has an intrinsic kallikrein-kinin system that under normal circumstances produces very low concentrations of bradykinin in the plasma. Active bradykinin is rapidly degraded (<15 s) principally by kininase II that is the same enzyme as angiotensin converting enzyme (ACE) [96]. Therefore, bradykinin is an attractive agent to use as a pretreatment in that it is rapidly degraded and as such, should have few if any systemic side effects. Bradykinin exerts several cardioprotective effects, including: an increase in coronary blood flow [97]; an improvement in ventricular performance [36]; a decrease in reperfusion arrhythmias [98]; a reduction in lactate dehydrogenase and creatine kinase release [99]; a reduction in tissue ATP depletion [99]; and a reduction in infarction size [100]. These beneficial effects occur via stimulation of the bradykinin B2 receptor, since administration of HOE 140, a selective inhibitor of the bradykinin B2 receptor, before

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ischemic preconditioning abolished its salutary effects [100]. Bradykinin may also play an important role in protecting the human heart from ischemia. ACE inhibitors reduce infarct size and mortality associated with myocardial ischemia [95,96] by increasing the level of bradykinin in coronary sinus blood [45]. There is accumulating evidence that bradykinin improves myocardial tolerance to ischemia through molecular mechanisms that have been associated with ischemic preconditioning. These pathways have been discussed earlier in this chapter and are outlined in Figure 27.1. Downey and others [15,101] have demonstrated that several mediators, including bradykinin, trigger preconditioning in the rabbit heart by this receptor-mediated process. After the receptor is activated, an intracellular signal transduction cascade is initiated, which in the rabbit involves activation of the PKC family of serine-threonine kinases [99]. Discrete PKC isoforms translocate from the cytosol to the cell membrane after ischemic preconditioning, resulting in PKC activation [45]. Activated PKC in turn phosphorylates downstream substrate proteins that propagate the intracellular signal, resulting in enhanced resistance to myocardial ischemia. The PKC hypothesis has been a focus of controversy despite extensive laboratory investigation. PKC inhibitors effectively block preconditioning in rat, rabbits, and humans, but less reliably in dogs and pigs [ 14]. It has recently been shown that activation of both TK and PKC are required for ischemic preconditioning of rat [15], rabbit [2,15], and pig [4] hearts. In keeping with this observation, neither PKC nor TK inhibition alone prevented ischemic preconditioning. Only combined inhibition of both kinases prevented preconditioning, suggesting that both kinases play parallel roles in mediating preconditioning [4]. The precise interaction between PKC and TK activation after receptor activation is unresolved [5]. TK plays an initiating role for many cell functions that occur in response to environmental stress, including ischemia. Parallel receptor TK-dependent pathways and PKCdependent pathways may be activated simultaneously or individually by a specific preconditioning stimulus. This is supported by studies that have demonstrated that TK activation can directly phosphorylate PLC, resulting in diacyl glycerol phosphate (DAG)-induced PKC activation [102]. Alternatively, TK may be activated downstream from PKC, as evidenced by increases in TK activity after direct PKC activation [5].

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Propagation of the signal beyond PKC and TK appears to involve activation of the discrete mitogen-activated protein kinase called p38MAP-kinase [103,104]. Activated p38MAP-kinase phosphorylates several substrates including transcription factors and other kinases, which in turn phosphorylate the end effectors of the preconditioning stimulus [ 104]. As discussed earlier in this chapter, NO has been identified as both a trigger and a mediator of delayed ischemic preconditioning. Activation of endothelial bradykinin receptors leads to the formation of prostaglandin I2 (PGI2) and NO in cultured endothelial cells [ 105 ]. In anesthetized dogs, infusion of bradykinin produces an increase in coronary blood flow by stimulating B2 receptors and the release of NO [106]. Bradykinin also has beneficial metabolic effects in normal and ischemic hearts, including preservation of tissue ATP, creatine phosphate, and glycogen, as well as reducing lactate production. Bradykinin also has been shown to potentiate the effects of insulin on glucose uptake, activation of glucose transporters, and glucose oxidation [107,108]. Exogenous bradykinin exhibits an insulin-like effect on glucose metabolism and potentiates insulin-stimulated glucose uptake in skeletal and cardiac muscle [109-113].

Experimental model used in bradykinin pretreatment studies New Zealand white rabbits (1.5-2.0 kg) were used in this series of studies. Rabbits were anesthetized with sodium pentobarbital (60 mg/kg, IV), anticoagulated with heparin (2000 U/kg, IV), and the heart was rapidly exposed. The aorta was cannulated and the heart was retrogradely perfused in situ to avoid ischemia. The heart was then excised and mounted in an organ chamber on a Langendorff perfusion system. The heart was retrogradely perfused at 75 mmHg with a modified Krebs-Henseleit buffer (KHB) which was equilibrated with 95% O2 and 5% CO2, adjusted to a pH of 7.35-7.4. Myocardial temperature was maintained at 37°C by regulation of the organ chamber temperature. Mean coronary flow (ml/min) was measured by timed collection of effluent from the right ventricle exiting the heart from the severed pulmonary artery. Isovolumetric measurement of left ventricular (LV) performance was made using a compliant latex balloon connected to a pressure transducer which was inserted in the left ventricle across the mitral valve. A

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Experimental myocardial preconditioning

Figure 27.3 Standard protocol for pharmacologic preconditioning with bradykinin. CP, cardioplegic infusion.

calibrated syringe attached to the pressure transducer system was used to fill the balloon with a volume of saline needed to maintain a left ventricular enddiastolic pressure (LVEDP) of 10 mmHg during measurement of baseline LV performance and was used for subsequent measurements of LV performance after reperfusion. Left ventricular performance was assessed by the measurement of left ventricular developed pressure (LVDP, mmHg) and LVEDP (mmHg). Positive and negative first derivatives of LVDP (+dP/dt and -dP/dt, mmHg/s) were calculated as indices of ventricular contractility and compliance, respectively. A standard protocol was used (Figure 27.3) in which hearts were stabilized for 20 min on Langendorff retrograde perfusion after which baseline measurement of LV performance and coronary flow were recorded. According to the specific protocol being tested, hearts received differing treatments. Control hearts received standard KHB during the entire pretreatment period. Pretreatment agents, with or without metabolic inhibitors, were administered during the 20-min pretreatment interval. At the conclusion of the 20-min pretreatment period, LV performance and CF were measured again in all hearts to determine if pretreatment altered these parameters compared to baseline measurements. All hearts then underwent 50 min of cardioplegic arrest induced with St Thomas' cardioplegia solution which was gassed with 95% O2 and 5% CO2 at pH 7.4 and infused at 60 mmHg via a separate perfusion column. The time to mechanical arrest was recorded. The cardioplegia solution was supplemented with the same dose of pretreatment agents and metabolic inhibitors that was used during the pretreatment interval. After conclusion of the cardioplegic ischemic period, postreperfusion LV performance and CF were recorded and compared to preischemic values. Advantages and limitations of the isolated heart preparation The primary advantage of the isolated perfused heart is the elimination of extrinsic neural input and hor-

monal factors. A disadvantage of the isolated heart perfused with low-viscosity media lacking red cells is the abnormally high coronary flow rate as compared to the blood-perfused heart. Most of the energy needs of the in vivo myocardium are met through the oxidation of plasma free fatty acids, lactate, and glucose. In isolated hearts, glucose is the substrate used in the perfusion fluid and results in a limited store of high-energy phosphate. The Langendorff preparation is stable and can be maintained for many hours, although it does not perform external work while beating. The work output and oxygen requirement of the Langendorff preparation is considerably less than the ejecting heart in vivo. In spite of these limitations, the isolated rat heart perfused with glucose has been widely used in studies of myocardial metabolism in both normal and pathologic conditions.

Bradykinin pretreatment improves ischemia tolerance of the rabbit heart Utilizing the model outlined above, we performed a series of experiments to test the hypothesis that bradykinin pretreatment and cardioplegia supplementation would improve the ischemia tolerance of the isolated rabbit heart exposed to a period of warm, cardioplegic ischemia. The subsequent sections of this portion of the chapter present data that support this conclusion and demonstrate the mechanisms of its action.

Recovery of ventricular performance and coronary flow in bradykininpretreated hearts Bradykinin pretreatment was administered in a dose of 0.1 [imol for 10 min prior to arresting the heart with St Thomas' cardioplegia solution that was also supplemented with 0.1 umol bradykinin (Figure 27.4). Postreperfusion recovery of LV performance and coronary flow are show in Figures 27.5-27.9. Bradykinin pretreatment resulted in a significant increase in baseline coronary flow (CF) and a slight increase in LVDP prior to ischemia (Figures 27.5 & 27.9). Bradykinin

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Figure 27.4 Experimental protocol: group 1 hearts received no pretreatment before arrest with St Thomas' cardioplegia solution (StTCP). Group 2 hearts were pretreated with bradykinin (BK) before arrest with StTCP supplemented with BK. Hatched bars, ischemic period; KHB, Krebs-Henseleit buffer.

Figure 27.5 Recovery of left ventricular developed pressure (LVDP). Bradykinin (BK) significantly improved the recovery of LVDP throughout the period of reperfusion.

Figure 27.6 Recovery of LV contractility (+dP/dt). Bradykinin (BK) pretreatment significantly improved the recovery of contractility compared to control hearts.

Figure 27.7 Recovery of left ventricular end-diastolic pressure (LVEDP). LVEDP rose significantly in both groups of hearts during ischemia and declined during reperfusion. LVEDP was significantly lower in the bradykinin-treated hearts. BK, bradykinin.

Figure 27.8 Recovery of LV compliance (-dP/dt). Bradykinin (BK) pretreatment significantly improved the recovery of compliance compared to untreated control hearts.

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with the preconditioning cascade (Figure 27.1), we tested the hypothesis that bradykinin pretreatment of the heart triggers molecular signal transduction pathways that are similar to those involved in ischemic preconditioning.

Bradykinin pretreatment activates protein kinase C

Figure 27.9 Recovery of coronary flow (CF). Bradykinin (BK) increased coronary flow during the pretreatment period and significantly improved its recovery during reperfusion.

pretreatment significantly improved the recovery of systolic performance throughout the entire period of reperfusion after 50 min of cardioplegic arrest. At the end of 60 min of reperfusion, the recovery of LVDP (53 ± 5 mmHg vs. 27 + 4 mmHg, P < 0.01; Figure 27.5), and +dP/dtm3x (1025 ± 93 mmHg/s vs. 507 ± 85 mmHg/s, P < 0.01; Figure 27.6) were significantly enhanced by bradykinin pretreatment compared to control hearts. The continuous recovery of LVEDP and -dP/dtmax in the two study groups is presented in Figures 27.7 and 27.8, respectively. LVEDP remained at baseline level in bradykinin-pretreated hearts during the stabilization and pretreatment intervals. During cardioplegic ischemia, LVEDP rose significantly in both groups and then gradually declined during the 60-min period of reperfusion. Ventricular compliance, as measured by-dP/dtmax, showed a gradual rise during reperfusion. After 60 min of reperfusion, bradykinin-treated hearts had a significantly lower LVEDP (28 + 3 mmHg vs. 52 ± 5 mmHg, P< 0.01) and a higher -dP/dtmax (669 ± 60 mmHg/s vs. 368 ± 65 mmHg/s, P < 0.05) than control hearts. Figure 27.9 shows the profile for the recovery of CF. Bradykinin pretreatment improved the recovery of CF throughout the entire period of reperfusion, and at the end of 60 min of reperfusion, the recovery of CF was significantly enhanced in pretreated hearts. In the next series of studies, we looked at the mechanisms by which bradykinin pretreatment improved postischemic recovery of ventricular performance in our model. By using specific inhibitors of discrete sites in the molecular pathways that have been associated

Activation of specific PKC isoforms, such as PKCe, has been shown to be a key step for triggering and mediating ischemic preconditioning [3,6,14,37,46]. For PKC to become active, it must be translocated from the cytosol fraction of cell proteins to the cell membrane. Thus, this study tested the hypotheses that: (i) bradykinin pretreatment of the heart results in activation of PKC; (ii) activation of PKCe results from its translocation from the cytosol to membrane fractions; and (iii) the beneficial effects of bradykinin pretreatment could be blocked by pretreatment with an inhibitor of PKC. PKC activation To quantify PKC activation, adult rabbit hearts were placed on Langendorff retrograde perfusion. Control hearts remained perfused with KHB for a total of 40 min without further interventions. Bradykinintreated hearts received an infusion of 0.1 |0,mol bradykinin for 5 min followed by 30 min of KHB. PKC activation was then blocked in a third group of hearts that received a 5-min infusion of both 0.1 (imol bradykinin and 20 jlmol chelerythrine, a specific PKC blocker, followed by 30 min of KHB. At the end of each experiment, hearts were immediately frozen in liquid nitrogen. Protein fractions from frozen heart samples were purified and the cytosol and membrane fractions separated by centrifugation. PKC activity was quantified in each of the fractions using an ELISA (enzyme-linked immonosorbent assay) system that utilizes synthetic PKC pseudosubstrate and monoclonal antibody that recognizes the phosphorylated form of the pseudosubstrate. Activity was expressed as optical density (OD) read on a spectrophotometer at 492 nm. As shown in Figure 27.10, bradykinin pretreatment for 5 min led to a significant increase of PKC activity in the membrane fraction (0.99 ± 0.07 vs. 0.66 ± 0.08 OD, P < 0.05). This increase in PKC activity in the membrane fraction was accompanied by a decrease in enzyme activity in the cytosol fraction. By contrast, pretreatment with chelerythrine abolished

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Figure 27.10 Protein kinase C activity in the cytosol and membrane protein fractions. Bradykinin pretreatment (black bar) significantly increased the PKC activity in the membrane fraction, which was accompanied by a parallel decrease in the cytosol fraction, presumably due to translocation of PKC from the cytosol to the membrane. Chelerythrine (Chel) blocked the activation of PKC in the membrane fraction.

the bradykinin-induced increase in PKC activity in the membrane fraction (0.69 + 0.02 vs. 0.66 ± 0.08 OD) in membrane fractions. Chelerythrine also reduced PKC activity in the cytosol fractions (0.87 ± 0.02 vs. 1.15 ± 0.02 OD,P< 0.05). PKCe translocation Tissue samples from the hearts in the previous experiment were analyzed by Western immunoblotting to quantify the amount of PKCe in the cytosol and membrane fractions to confirm that PKC activation was the result of translocation of this discrete isoform of the enzyme. Proteins were separated by SDSPAGE technique and then transferred to polyvinylidenedifluoride (PVDF) membranes, which were incubated first with monoclonal mouse-anti rabbit PKCe antibody and then with horseradish peroxidaseconjugated secondary antibody. The labeled bands were visualized colorimetrically, quantified by an image scanning densitometer, and reported as densitometer

units. The content of PKCe in the cytosol and membrane fractions for each of the groups is shown in Figure 27.11. Administration of bradykinin for 5 min induced significant PKCe translocation from the cytosol fraction (untreated controls 0.91 ± 0.13 OD vs. 5 min bradykinin 0.46 ± 0.07 OD, P < 0.05) to the membrane fraction (untreated controls 0.55 ± 0.03 OD vs. bradykinin 1.32 ± 0.30, P < 0.05). Chelerythrine blocked the translocation of PKCe that was induced by bradykinin. These results corresponded nicely to the PKC activation measured in the previous study. Ventricular performance and coronary flow To determine if PKC inhibition altered the efficacy of bradykinin pretreatment in improving the recovery or ventricular performance after ischemia and reperfusion, we pretreated hearts with a combination of 0.1 (ilmol bradykinin and 20 (irnol chelerythrine for 10 min prior to a period of 50 min of cardioplegic ischemia using the same protocol described earlier.

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Figure 27.11 Content of PKCe in the cytosol and membrane protein fractions. Bradykinin pretreatment resulted in translocation of PKCe from the cytosol to the membrane fraction. This parallels the greater activation of PKC shown in Figure 27.9. Chelerythrine (Chel) blocked translocation of PKCe. PKC translocation did not occur in untreated control hearts.

Prior pilot studies confirmed that chelerythrine in the doses used did not alter baseline ventricular performance or coronary flow in the normal heart. As shown in Figures 27.12 and 27.13, PKC inhibition by combining chelerythrine with bradykinin abolished the protection afforded by bradykinin pretreatment. The recovery of ventricular systolic (LVDP and +dP/dt) and diastolic (LVEDP and -dP/df) function in hearts treated with the combination of chelerythrine and bradykinin was no different from control hearts. This was not due to an alteration in coronary flow, since this did not differ in chelerythrine-treated hearts compared to those receiving bradykinin alone. The results of this series of studies confirmed that bradykinin pretreatment activated PKC as a part of the mechanism of its induction of protection from cardioplegic ischemia. Limitations of these studies included our inability to measure the isolated activity of the PKCe isoform activity in contrast to total PKC activity. In addition, chelerythrine is not completely specific for PKC, and may have caused low-grade inhibition of other serinethreonine protein kinases.

Bradykinin pretreatment activates tyrosine kinase Over 1000 tyrosine kinases have been identified which play a variety of roles in normal cell function [9]. In noncardiac tissues, the Src family of tyrosine kinases has been shown to play an important role in response to stress and tyrosine kinase activation has been identified as a part of the triggering and signal transduction cascade that mediates the ischemic preconditioning phenomenon [4,5,39,44,114]. This study tested the hypothesis that bradykinin pretreatment improved postischemic myocardial function by activating the molecular pathways associated within the preconditioning phenomenon, including activation of tyrosine kinase. The same isolated adult rabbit heart model described earlier was used in this study. Bradykinin-treated hearts received 0.1 (imol bradykinin for 10 min, followed by 50 min of cardioplegic ischemia induced by an infusion of 0.1 (imol bradykinin-enriched St Thomas' cardioplegia solution. As shown in Figures 27.5-27.9, bradykinin pretreatment resulted in

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Figure 27.12 Recovery of left ventricular systolic performance after PKC inhibition. Bradykinin pretreatment significantly improved the recovery of left ventricular developed pressure (LVDP) and contractility (+dP/df) compared to untreated control hearts. PKC inhibition with chelerythrine (Chel) attenuated the benefits of bradykinin after reperfusion.

Figure 27.13 Recovery of left ventricular diastolic performance after PKC inhibition. Bradykinin pretreatment also improved the recovery of left ventricular end-diastolic pressure (LVEDP) and compliance (-dP/dt) after reperfusion, which was attenuated by PKC inhibition by the coadministration of chelerythrine (Chel).

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Figure 27.14 Experimental protocol. Group 1 hearts received no pretreatment before undergoing 50 min of cardioplegic ischemia. Group 2 hearts were pretreated with the combination of bradykinin (BK) and genistein (Gen), a blocker of tyrosine kinase. StTCP, St Thomas' cardioplegia solution; KHB, Krebs-Henseleit buffer.

a significant improvement in the recovery of postreperfusion ventricular performance and a return of coronary flow compared to nonpretreated control hearts. Seven additional hearts were exposed to 40 (imol genistein, a selective inhibitor of tyrosine kinase [115], before being pretreated with 0.1 |0,mol bradykinin (Figure 27.14). These hearts were then arrested with St Thomas' cardioplegia solution that contained both bradykinin and genistein. In pilot

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Figure 27.15 Recovery of left ventricular developed pressure (LVDP) after pretreatment with bradykinin and genistein. Bradykinin pretreatment resulted in a significant improvement in the recovery of LVDP compared to control. Blocking tyrosine with genistein prevented the salutary effect of bradykinin. Reprinted from Annals of Thoracic Surgery, Vol. 68, Feng J, Rosenkranz E. Bradykinin pretreatment improves ischemia tolerance of the rabbit heart by tyrosine kinase mediated pathways, pp. 1567-1572. © 1999, with permission from the Society of Thoracic Surgeons.

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Figure 27.16 Recovery of LV compliance (-dP/dt) after pretreatment with bradykinin and genistein. Bradykinin pretreatment resulted in a significant improvement in the recovery of-dP/dtcompared to control. Blocking tyrosine kinase with genistein prevented the salutary effect of bradykinin. Reprinted from Annals of Thoracic Surgery, Vol. 68, Feng \, Rosenkranz E. Bradykinin pretreatment improves ischemia tolerance of the rabbit heart by tyrosine kinase mediated pathways, pp. 1567-1572. © 1999, with permission from the Society of Thoracic Surgeons.

studies, 40 jimol genistein had no effect on ventricular performance or coronary flow in the normal Langendorff-perfused rabbit heart. As shown in Figures 27.15-27.17, genistein blocked the beneficial effects of bradykinin pretreatment. Recovery of systolic and diastolic ventricular function and coronary flow in these hearts did not differ from nonpretreated control hearts. The results of this study confirmed that tyrosine kinase activation participates in the molecular pathway responsible for bradykinin's salutary

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Figure 27.17 Recovery of coronary flow (CF) after pretreatment with bradykinin and genistein. Bradykinin pretreatment resulted in a significant improvement in the recovery of coronary flow compared to control. Blocking tyrosine kinase with genistein prevented the salutary effect of bradykinin. Reprinted from Annals of Thoracic Surgery. Vol. 68, Feng J, Rosenkranz E. Bradykinin pretreatment improves ischemia tolerance of the rabbit heart by tyrosine kinase mediated pathways, pp. 1567-1572. © 1999, with permission from the Society of Thoracic Surgeons.

effect on the recovery or postischemic ventricular performance. Limitations of this study included our inability to determine where in the signal transduction sequence tyrosine kinase was located. In addition, we do not know which tyrosine kinase isoform was being activated by bradykinin and we did not measure tyrosine kinase activity.

Bradykinin pretreatment requires activation of nitric oxide Activation of the bradykinin B2 receptor in vascular endothelial cells and in myocytes results in nitric oxide (NO) generation due to activation of the endothelial (eNOS) and inducible (iNOS) isoforms of nitric oxide synthase (NOS), respectively [44,45]. As detailed earlier in this chapter, NO generated during ischemic preconditioning has been shown to reduce the incidence of ischemia- and reperfusion-associated arrhythmias and is associated with triggering the induction of the late form of ischemic preconditioning [9,47-49]. NO released by ischemic endothelium or supplied endogenously in nonischemic hearts from NO donors have both been shown to activate PKCe which is required for the preconditioning signal transduction cascade

[46,116]. The role of NO as a trigger and mediator of the early phase of ischemic preconditioning is less certain. This study tested the hypotheses that: (i) bradykinin pretreatment of the heart activates the bradykinin B2 receptor and induces the preconditioned state of the rabbit heart via molecular pathways that involve generation of nitric oxide; and (ii) the benefits of bradykinin pretreatment can be prevented by administration of either B2 receptor blocker (HOE 140) or an inhibitor of NOS (N-Q-nitro-L-argininemethyl ester (L-NAME)). Our standard model of the isolated adult rabbit heart and the experimental protocol described earlier were employed in this study as well (Figure 27.18). Control hearts received no pretreatment prior to inducing arrest with standard St Thomas' cardioplegia solution. Bradykinin-pretreated hearts received a 10-min infusion of 0.1 urno! bradykinin prior to 50 min of arrest with bradykinin-enriched St Thomas' cardioplegia solution. To confirm that bradykinin induced protection from ischemia via activation of the bradykinin B2 receptor, six hearts were treated with 0.1 Jlmol HOE 140, a selective bradykinin B2 receptor antagonist, prior to pretreatment with 0.1 Limol bradykinin and cardioplegic arrest with St Thomas' cardioplegia solution containing both HOE 140 and bradykinin. Finally, to confirm that bradykinin's salutary affect required activation on NOS, seven hearts were treated with 100 [imol L-NAME, an inhibitor of both iNOS and eNOS, prior to 0.1 n,mol bradykinin pretreatment and cardioplegic arrest. Both HOE 140 and L-NAME prevented the beneficial effects of pretreating the heart with bradykinin prior to cardioplegic ischemia. As shown in Figures 27.19 and 27.20, the recovery of ventricular systolic and diastolic performance after reperfusion was equivalent to that seen in nonpretreated control hearts. The results of this study demonstrated that the beneficial effects of bradykinin pretreatment of the heart prior to a prolonged period of global ischemia are mediated via NO, presumably produced by activation of eNOS in response to the triggering signal induced by activation of the bradykinin B2 receptor. As shown in Figure 27.2, we believe that bradykinin pretreatment results in activation of eNOS and generation of NO. NO then may act as a second messenger between the vascular endothelium and the myocyte resulting in activation of the PKC- and TK-dependent signal transduction pathway leading to the preconditioned

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Figure 27.18 Experimental protocol. Group 1 hearts received no pretreatment. Group 2 hearts were pretreated with bradykinin (BK) before undergoing 50 min of ischemia and 60 min of reperfusion. Group 3 hearts received a combination of bradykinin and HOE 140, a blockerof thebradykinin B2 receptor. Group 4 hearts received a combination of bradykinin and /V-a-nitro-L-arginine-methyl ester (i-NAME). KHB, Krebs-Henseleit buffer; STCP, St Thomas' cardioplegia; CP, cardioplegia. Reprinted from Annals of Thoracic Surgery, Vol. 70, Feng J, Li, H, Rosenkranz E. Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways, pp. 2119-2124. © 2000, with permission from the Society of Thoracic Surgeons.

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Figure 27.19 Recovery of left ventricular developed pressure (LVDP) after pretreatment with bradykinin (BK) in combination with HOE 140 or i-NAME. As shown earlier, bradykinin pretreatment improved the recovery of LVDP after reperfusion compared to untreated control hearts. By contrast, blockade of the bradykinin B2 receptor with HOE 140, or blockade of nitric oxide synthase with L-NAME prevented the benefit of bradykinin pretreatment. Reprinted from Annals of Thoracic Surgery, Vol. 70, Feng J, Li H, Rosenkranz E. Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways, pp. 2119-2124. ©2000, with permission from the Society of Thoracic Surgeons.

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Figure 27.20 Recovery of left ventricular end-diastolic pressure (LVEDP) after pretreatment with bradykinin (BK) in combination with HOE 140 or i-NAME. As shown earlier, bradykinin pretreatment improved the recovery of LVEDP after reperfusion compared to untreated control hearts. By contrast, blockade of the bradykinin B2 receptor with HOE 140, or blockade of nitric oxide synthase with i-NAME, negated the benefit of bradykinin pretreatment. Reprinted from Annals of Thoracic Surgery, Vol. 70, Feng J, Li H, Rosenkranz E. Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways, pp. 2119-2124. © 2000, with perm ission from the Society of Thoracic Surgeons.

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state. Coadministration of L-NAME blocked NO generation, which prevented activation of the proposed protective mechanisms. Limitations of this study included our inability to measure NOS activity. In addition, we cannot determine if bradykinin is acting on iNOS or eNOS, since L-NAME inhibits all isoforms of NOS. In this study, we did not measure activation of PKC or TK, and as such we cannot prove that NO resulted in their activation. Finally, it is possible that NO directly activates the KATP channel independent of the signal transduction cascade outlined above.

Bradykinin induces translocation of glucose transporter 4 In skeletal muscle and adipocytes [109] bradykinin increases glucose uptake due to enhanced translocation of glucose transporters 1 and 4 (GLUT 1 and 4) from intracellular membrane pools to the sarcolemmal membranes. Both GLUT 1 and GLUT 4 must be translocated from intracellular membrane fractions to sarcolemmal membrane fractions for activation, which results in an increase in glucose transport. In cardiac myocytes, GLUT 1 is responsible for basal glucose uptake, whereas GLUT 4 is responsible for insulin-induced glucose transport [117-119]. In all tissues, including the heart, insulin results in the activation of tyrosine kinase, which in turn activates phosphatidylinositol 3-kinase (PI3-K) leading to the translocation of GLUT 1 and 4 to the sarcolemmal membrane [ 120]. As described earlier, we have shown that bradykinin pretreatment results in tyrosine kinase activation in order to induce myocardial ischemia tolerance in the isolated adult rabbit heart. This group of studies tested the hypotheses that; (i) bradykinin pretreatment induces GLUT 4 translocation in rabbit myocardium; and (ii) bradykinin-induced GLUT 4 translocation requires activation of both PKC and PI3-K. GLUT 4 translocation The first study in this series quantified the changes in GLUT 4 protein content in the myocardial intracellular and sarcolemmal membrane fractions in response to bradykinin pretreatment. Control adult rabbit hearts were perfused on a Langendorff apparatus with standard KHB for 20 min. Five other hearts were pretreated with 0.1 (imol bradykinin for 10 min followed by 10 min of perfusion with standard KHB. Tissue

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samples were then processed by differential sucrose gradient centrifugation to separate high-density membranes (sarcolemmal membrane fraction) from the low-density membranes (intracellular membrane fraction). Western immunoblotting was used to quantify the GLUT 4 content in the two membrane populations. Aliquots were loaded onto 10% SDS-PAGE gels and the protein blots were transferred to PVDP membrane. The membrane was first incubated with monoclonal mouse antirat GLUT 4 primary antibody and then with horseradish peroxidase-conjugated secondary antibody. The immunolabeled bands were visualized colorimetrically and the protein quantified by scanning image densitometry. As shown in Figure 27.21, bradykinin pretreatment resulted in a twofold increase in GLUT 4 content in the sarcolemmal membrane fraction of the bradykinin-treated hearts compared to the control hearts. This was associated with a proportional decrease in the GLUT 4 protein content of the intracellular membrane fraction in the bradykinin-treated hearts (Figure 27.22), suggesting that GLUT 4 was translocated from the intracellular to the sarcolemmal fractions. PI3K activity The second study in this series was aimed at determining if bradykinin-stimulated GLUT 4 translocation occurred via the same metabolic pathways associated with insulin, namely PI3-K activation. We first measured the activation of PI3-K in bradykinin-pretreated hearts by Western immunoblotting. Whole tissue protein samples were obtained from control hearts perfused with standard KHB for 5 min and from hearts pretreated with 0.1 (imol bradykinin for 5 min. Proteins were separated in SDS-PAGE, transferred to PVDF membranes, the immunoblots resolved with monoclonal antibody that recognized the phosphorylated (activated) form of PI3-K, and then the protein content of the bands was quantified by laser scanning densitometry. As shown in Figure 27.23, bradykinin pretreatment resulted in a threefold increase in PI3-K activity compared to nonpretreated hearts (0.43 densitometer units (DU) vs. 1.16 DU). We then tested the effect PI3-K inhibition had on the recovery of ventricular performance after cardioplegic ischemia and reperfusion in bradykinin-pretreated hearts. Utilizing our standard isolated heart model and protocol (Figure 27.3), hearts were pretreated with 3 [imol wortmannin, an inhibitor of PI3-K, prior to

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Figure 27.21 Translocation of glucose transporter 4 (GLUT 4) to the sarcolemmal membrane fraction. Hearts treated with bradykinin had a significantly greater amount of GLUT 4 protein translocated to the sarcolemmal membrane than untreated control hearts.

Figure 27.22 Glucose transporter 4 (GLUT 4) content in the intracellular membrane fraction. Bradykinin-treated hearts had a significant reduction in GLUT4 content in the intracellular membrane fraction, which likely represents translocation of GLUT 4 protein to the sarcolemmal membrane fraction as shown in Figure 27.21.

pretreatment with 0.1 Jimol bradykinin and 50 min of cardioplegic ischemia with St Thomas' solution supplemented with both wortmannin and bradykinin. The recovery of ventricular performance compared to control hearts (no pretreatment) and bradykininpretreated hearts is shown in Figure 27.24. PI3-K inhibition completely prevented the beneficial effect of bradykinin. These results support our hypothesis that bradykinin activates PI3-K as part of the molecular pathway by which it reduces ischemic injury.

GLUT 4 translocation requires PKC activation Our next study tested the hypothesis that PKC activation is required for bradykinin-induced GLUT 4 translocation and activation. Control hearts received no pretreatment. Six other hearts were pretreated with 0.1 (imol bradykinin for 10 min. Six others received 20 umol chelerythrine, a PKC inhibitor, before bradykinin pretreatment and then in combination with bradykinin pretreatment for 10 min. After 10 min of KHB perfusion, subcellular membrane

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Figure 27.23 Phosphatidylinositol 3-kinase (PI3-K) activation. Bradykinin-treated hearts had a significant increase in PI3-K activity compared to untreated control hearts.

Figure 27.24 Recovery of left ventricular developed pressure (LVDP) after pretreatment with bradykinin alone or in combination with wortmannin (Wort). As shown earlier, bradykinin pretreatment resulted in significantly better recovery of LVDP after ischemia and reperfusion compared to untreated control hearts. By contrast, hearts treated with the combination of bradykinin and wortmannin, an inhibitor of PI3-K, had poorer recovery, which was equivalent to untreated control hearts.

fractions were prepared in all hearts by differential centrifugation and GLUT 4 content in sarcolemmal and intracellular membrane fractions were measured by Western immunoblotting as described earlier. As

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Figure 27.25 Glucose transporter 4 (GLUT 4) content in the sarcolemmal membrane protein fraction of hearts treated with bradykinin with or without chelerythrine (Chel). Heart treated with bradykinin had a significantly greater translocation of GLUT 4 protein to the sarcolemmal membrane fraction compared to untreated controls. By contrast, hearts treated with the combination of bradykinin and chelerythrine, an inhibitor of protein kinase C (PKC), did not have translocation of GLUT 4.

shown in Figures 27.25 and 27.26, bradykinin pretreatment significantly increased GLUT 4 content in the sarcolemmal fraction, which was accompanied by an equivalent decrease of GLUT 4 in the intracellular membrane fraction. By contrast, pretreatment with chelerythrine prevented bradykinin-induced translocation of GLUT 4 from the intracellular membrane to the sarcolemmal membrane fraction. From this series of studies, we concluded that in the heart, there are similarities in insulin and bradykinin signal transduction pathways. Thus, both insulin and bradykinin may activate tyrosine kinase, PKC, and MAP kinase [109,110,121,122], as well as increase the release of NO from endothelium and myocytes [45,108,123]. NO increases the rate of glucose transport and metabolism in skeletal muscle, independent of its vasodilatory effects. Bradykinin has also been shown to mimic insulin-induced translocation of glucose transporters in insulin-resistant rat hearts [124]. Our data supports the contention that bradykinin stimulates glucose uptake via translocation of GLUT 4, mediated by PKC and PI3-K-dependent pathways,

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Figure 27.26 Glucose transporter 4 (GLUT 4) content in the intracellular membrane protein fraction of hearts treated with bradykinin with or without chelerythrine (Chel). Hearts treated with bradykinin had a significant decrease in GLUT 4 protein in the intracellular membrane fraction compared to untreated controls due to its translocation to the sarcolemmal fraction (Figure 27.25). By contrast, hearts treated with the combination of bradykinin and chelerythrine, an inhibitor of protein kinase C (PKC), did not have a decrease in intracellular GLUT 4 protein, suggesting that PKC activation is required for translocation of GLUT 4 protein from the intracellular to the sarcolemmal membrane.

and may represent one of the mechanisms responsible for bradykinin's salutary effects as a pretreatment prior to global myocardial ischemia.

The KATP channel as an end effector of the preconditioning phenomenon As discussed earlier, the KATP channel has been proposed as the end effector of the ischemic preconditioning phenomenon, responsible for conveying protection from subsequent ischemic episodes [10,11, 52,54,55,59,60,125,126]. The KATP channel is found in most tissues and opens in response to depletion of intracellular ATP. The channel appears to play several regulatory roles, including adjustment of membrane potentials by regulating the flux of potassium and calcium ions across cell and organelle membranes. The evidence for opening these channels that are involved in preconditioning comes from studies in which blocking these channels prevented the effects of both ischemic preconditioning [127-129] and pharmaco-

249 logic preconditioning induced by adenosine [54,125, 128,130] or acetylcholine [131]. In addition, treating hearts with KATP channel-openers mimics preconditioning, and several of the putative triggers of ischemic preconditioning, including bradykinin, have been shown to open KATP channels in myocytes [35,52, 57,70,127,132-134]. Administration of pharmacologic potassium channel openers (PCOs) has been shown to improve myocardial ischemia tolerance [127] and have been used in cardioplegia solutions [135-140]. Cardiac myocytes contain two distinct KATP channels, one in the sarcolemmal membrane (sarc-KATP) and the other, in the mitochondrial inner membrane (mito-KATP). Opening of sarc-KATP channels shortens the action potential duration, which inhibits calcium entry into the myocytes via L-type channels and prevents calcium overloading during reperfusion. Membrane hyperpolarization also inhibits calcium entry into the cell by preventing the reversal of the sodium-calcium exchanger that normally extrudes calcium in exchange for sodium [55-57,132,133,135-142]. These processes were initially considered to be the mechanism by which PCOs induced cardioprotection. However, studies by Grover demonstrated that shortening of action potential duration is not a prerequisite for the cardioprotective effect of PCOs or ischemic preconditioning, suggesting that the mechanism of cardioprotection is more likely due to an intracellular effect on the mito-KATP channel, not the sarco-KATP channel [55,57,132,133,141]. Although the mechanism responsible for the protective effects of mito-KATP channel opening has not been elucidated, several potential mechanisms have been proposed. Opening of the mito-KATP channel leads to depolarization of the intramitochondrial membrane, which causes a transient swelling of the intramitochondrial space. This leads to increased respiration via the electron transport chain and a subsequent increase in ATP production. Mitochondrial membrane depolarization reduces calcium entry, thus reducing calcium overloading of the mitochondria, which is typically seen in hearts undergoing a reperfusion injury. Finally, opening the mito-KATP channel may induce potassium influx into mitochondria and result in a burst of free radical generation that sets the myocardium in a preconditioned state [10,55,69,142,143]. Based on these observations, we hypothesized that combining a mito-KATP channel opener with

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Figure 27.27 Experimental protocol. Control hearts received no pretreatment prior to undergoing 50 min of ischemia. Hearts pretreated with the KATP channel opener diazoxide (DZ) received 10 min of DZ pretreatment and DZ supplemented cardioplegia. Hearts treated with 5-hydroxydecanoate (5-HD), an inhibitor of the mitochondrial KATP channel, received 5HD alone for 10 min then in combination with DZ for an additional 10 min and finally the combination of 5-HD and DZ in combination with St Thomas' cardioplegia (STCP). CP, cardioplegia; KHB, Krebs-Henseleit buffer. Reprinted with permission from Feng J, Li H, Rosenkranz ER. Diazoxide protects the rabbit heart following cardioplegic ischemia. Molecular and Cellular Biochemistry 2002; 233:133-138.

cardioplegia may have an additive protective effect on the ischemic rabbit heart. To test this hypothesis, we first looked at the efficacy of enriching cardioplegia solution with diazoxide, a selective mito-KATP channel opener, in terms of protecting the rabbit heart from global ischemia [133]. We then tested whether pretreatment with sodium 5-hydroxydecanoate (5-HD), a selective mitochondrial KATP channel blocker, could prevent the protective effects of diazoxide. Our standard protocol was used (Figure 27.27). Control hearts received no pretreatment. Diazoxide-pretreated hearts received 30 (imol diazoxide-enriched KHB. 5-HD treated hearts received 100 (imol 5-HD prior to pretreatment with a combination of 30 jllmol diazoxide and 100 |0,mol 5-HD. After 50 min of cardioplegic arrest with St Thomas' cardioplegia solution that contained either diazoxide alone or the combination of diazoxide and 5-HD, postreperfusion LV performance and CF were determined and compared between the pretreatment groups. Pretreatment with diazoxide alone resulted in a significant increase in coronary flow prior to cardioplegic arrest, which was prevented when 5-HD was combined with diazoxide (Figure 27.28). As shown in Figures 27.29 and 27.30, the recovery of systolic and diastolic ventricular performance was significantly improved in response to pretreatment with diazoxide

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Figure 27.28 Recovery of coronary flow in hearts treated with diazoxide and 5-hydroxydecanoate (5-HD). Diazoxide pretreatment resulted in a significant increase in coronary flow prior to ischemia, which was attenuated by the combined treatment with diazoxide and 5-HD. After reperfusion, diazoxide-treated hearts had a significantly better recovery of coronary flow compared to control hearts. This benefit of diazoxide pretreatment was lost in hearts treated with 5-HD. Reprinted with permission from Feng J, Li, H Rosenkranz ER. Diazoxide protects the rabbit heart following cardioplegic ischemia. Molecular and Cellular Biochemistry 2002; 233:133-138.

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Figure 27.29 Recovery of left ventricular developed pressure (LVDP) in hearts treated with diazoxide with or without 5-hydroxydecanoate (5-HD). Hearts treated with diazoxide had a significantly better recovery of LVDP after reperfusion compared to untreated control hearts. This benefit of diazoxide was prevented in hearts treated with 5-HD. Reprinted with permission from Feng J, Li H, Rosenkranz ER. Diazoxide protects the rabbit heart following cardioplegic ischemia. Molecular and Cellular Biochemistry 2002; 233:133-138.

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Figure 27.30 Recovery of left ventricular end-diastolic pressure (LVEDP) in hearts treated with diazoxide with or without 5-hydroxydecanoate (5-HD). Hearts treated with diazoxide had a significantly lower LVEDP after reperfusion compared to untreated control hearts. This benefit of diazoxide was lost in hearts treated with 5-HD. Reprinted with permission from Feng J, Li H, Rosenkranz ER. Diazoxide protects the rabbit heart following cardioplegic ischemia. Molecular and Cellular Biochemistry 2002; 233: 133-138.

and diazoxide-enriched cardioplegia solution, which was completely prevented by the addition of 5-HD. There were no significant differences in the recovery of 5-HD-treated hearts compared to nonpretreated

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control hearts. Figure 27.28 shows the profile for the recovery of coronary flow during 60 min of reperfusion in the three groups. Diazoxide pretreatment significantly improved the recovery of coronary flow throughout the entire period of reperfusion. By contrast, pretreatment with 5-HD also blocked this effect of diazoxide on the recovery during reperfusion. The benefits of diazoxide pretreatment mimic those seen with ischemic preconditioning against infarction. Diazoxide is 1000-2000 times more potent in opening the mito-KATP channel compared to the sarc-KATP channel, and recent studies by Liu et al. [56,60] and Sato et al. [57] confirmed that diazoxide is a selective mito-KATP opener in the rabbit myocardium. The results of our study extend these observations by demonstrating that diazoxide combined with hyperkalemic cardioplegia improved the myocardial functional recovery. Conclusions The studies reviewed in the preceding section confirmed our initial hypothesis that bradykinin pretreatment could improve the recovery of ventricular function after a period of global myocardial ischemia. Our studies, combined with those in the literature, support the hypothesis that bradykinin activates a number of the molecular pathways that have been shown to be involved in triggering and mediating the ischemic preconditioning phenomenon. Further work is needed to determine the sequence of the molecular pathways involved and to determine the end effect of the signal transduction pathway that confers the preconditioned phenotype. Once this data is in hand, surgeons will be able to more rationally combine pharmacologic preconditioning with more traditional methods of perioperative myocardial protection.

Is the immature heart "preconditioned" to tolerate ischemia? Cardiac surgical procedures on adults and children require a quiescent, bloodless surgical field to carry out the operation. Aortic cross-clamping with cardioplegic arrest has been the standard approach for several decades and has been associated with good outcomes in adult patients in whom the majority of myocardial protective strategies have been developed. By contrast, postoperative myocardial dysfunction

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remains a clinical problem in pediatric patients. Several studies suggest that the methods of cardioplegic arrest and the composition of the cardioplegia solutions may be responsible for this discrepancy compared to the adult patients [ 144-153]. Experimental studies suggest that the immature heart tolerates ischemia better then the mature heart due to endogenous metabolic advantages in the immature heart [144-148], including greater glycogen stores and more prolonged anerobic utilization of glucose, amino acids, and lactate for both aerobic and anerobic ATP generation [149,154-156]. During ischemia, ATP depletion is delayed due to both decreased utilization and slower catabolism by 5'nucleotidase [155,157]. Postischemic reperfusion is better tolerated by the immature heart due to less organelle and cell membrane damage caused by oxygen free radicals and by calcium paradox [158]. In addition, there is recent data that suggests that the immature heart may possess endogenous activation of molecular pathways that have been associated with the ischemic preconditioning phenomenon [149,156, 159,160]. We have conducted a series of experiments aimed at testing the hypotheses that the immature heart is inherently more tolerant of ischemia because it can more avidly call upon molecular pathways that have been associated with the preconditioning phenomenon. Paradoxically, these molecular pathways appear to become less active with maturation [161,162]. PKCe is upregulated in the neonatal

heart The ischemically preconditioned adult heart shares many of the metabolic advantages inherent in the immature heart, including reduced utilization of ATP during ischemia and less cell and organelle damage after reperfusion [61]. Based on these observations, we hypothesized that the immature heart is endogenously preconditioned, possessing greater stress-induced activation of the signal transduction enzymes, particularly PKCe, which are responsible for ischemic preconditioning. To test this hypothesis, we performed a series of studies designed to characterize the effects of age on the isolated rabbit heart's tolerance to ischemia as measured by the return of heart performance after 20 min of global ischemia. Secondly, we evaluated the role played by PKCe in the age-dependent variation in ischemia tolerance by measuring the basal level of PKCe activity in both the neonatal and the adult heart

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and quantifying its translocation to the membrane fraction in response to ischemia and reperfusion. Experimental model and methods New Zealand white rabbits (7-to 10-day-old-neonates, 130-150 g, or adults, 1.5-2.5 kg) were used in these studies. Neonatal rabbit hearts were perfused on a Langendorff apparatus at a perfusion pressure of 45 mmHg with a modified Krebs-Henseleit buffer (KHB). Adult rabbits were perfused at 75 mmHg with the same modified KHB. Mean coronary flow (CF, ml/min) and indices of LV performance were assessed in neonatal and adult rabbit hearts as described earlier in this chapter. A standard protocol was used throughout the study (Figure 27.31). All hearts were stabilized for 20 min on Langendorff retrograde perfusion, after which baseline measurement of LV performance and coronary flow were recorded. Control neonatal and adult hearts were perfused for 60 min without ischemia. Ischemic neonatal and adult hearts underwent 20 min of unprotected ischemia at 37°C without reperfusion. Finally, ischemic/reperfused neonatal and adult hearts underwent 20 min of unprotected ischemia at 37°C followed by 30 min of KHB reperfusion. Recovery of LV performance and coronary flow were measured in the hearts undergoing ischemia and reperfusion. At the end of each experiment, all hearts were immediately frozen in liquid nitrogen and stored at -80°C for subsequent PKCe analysis. PKC activity was quantified in each of the fractions using an ELISA system that was described earlier in this chapter. Western immunoblotting was used to quantify PKCe translocation from the cytosol to the membrane as described earlier. Recovery of LV function after ischemia and reperfusion The recovery of both systolic and diastolic LV performance (Figures 27.32 & 27.33) was significantly better in the newborn rabbit hearts compared to their adult counterparts. Neonatal hearts had complete recovery of both systolic and diastolic ventricular function by the end of the 30-min reperfusion period. By contrast, LV systolic performance in the adult hearts remained 30-40% below preischemic level at the end of reperfusion. Diastolic function gradually improved, but remained below preischemic level at the end of reperfusion. Coronary flow returned to near preischemic level in both newborn and adult hearts.

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Figure 27.31 Experimental protocol. Control hearts underwent perfusion with Krebs-Henseleit buffer (KHB) without ischemia, after which a sample was obtained for measurement of protein kinase C (PKC) activity and content. Hearts undergoing ischemia alone underwent 20 min of ischemia without reperfusion, after which a sample was obtained for PKC activity and content. Hearts undergoing ischemia and reperfusion underwent 20 min of ischemia followed by 30 min of reperfusion, after which a sample was obtained.

Figure 27.32 Recovery of left ventricular developed pressure (LVDP) in neonatal versus adult hearts. Neonatal hearts had complete recovery of LVDP after ischemia compared to 60% recovery in adult hearts.

PKCe content and activity in cytosol and membrane protein fractions Figures 27.34 and 27.35 show the relative content of PKCe in the cytosol and membrane fractions obtained from the control, ischemia, and ischemic/reperfused groups. Before ischemia, there was no significant

Figure 27.33 Recovery of left ventricular end-diastolic pressure (LVEDP) in neonatal versus adult hearts. LVEDP in neonatal hearts returned to baseline values after reperfusion. By contrast, LVEDP remained significantly elevated in adult hearts.

difference between adult or neonatal hearts in their content of PKCe in the membrane or cytosol fractions. In both neonatal and adult hearts, PKCe content of the cytosol protein fraction was unchanged

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Figure 27.34 PKCe content in cytosol protein fraction. PKCe remained unchanged in neonatal and adult hearts during ischemia, compared to baseline control values. After reperfusion, PKCe increased in the cytosol of neonatal hearts, but decreased in adult hearts.

Figure 27.35 PKCe content in the membrane protein fraction. PKCe increased significantly in the membrane fraction of neonatal hearts during ischemia and reperfusion. By contrast, PKCe declined during these time periods in adult hearts. These findings suggest that PKCetranslocation occurred in neonatal hearts and may be responsible for the greater ischemia tolerance seen in neonatal hearts as shown in Figures 27.32 and 27.33.

during ischemia. In neonatal hearts, however, PKCe was translocated to the membrane fraction during ischemia, resulting in a significant increase in PKCe content. After reperfusion, PKCe rose significantly in both the cytosol and membrane fractions in the neonatal hearts. By contrast, in the adult hearts, PKCe declined in both fractions during reperfusion. PKC activity paralleled these findings. As shown in Figure 27.36, membrane fraction PKC activity rose significantly in the neonatal hearts both during ischemia and during reperfusion, which was paralleled by a proportionate fall in cytosol fraction PKC activity. By contrast, membrane fraction PKC activity was unchanged in the adult hearts during ischemia and reperfusion (Figure 27.37). From these data we concluded that the neonatal Figure 27.36 PKC activity in neonatal hearts. PKC activity rabbit heart is more tolerant to the stress of unpro- increased in the membrane protein fraction during ischemia and reperfusion, with a parallel decline in PKC tected ischemia due to its greater activation of the activity in the cytosol protein fraction. These findings molecular pathways that have also been associated correspond with the translocation of PKCe noted in with ischemic preconditioning. Although baseline Figures 27.34 and 27.35.

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KATP channel opening improves ischemia tolerance in the immature heart

Figure 27.37 PKC activity in adult hearts. PKC activity did not change significantly in the cytosol or membrane protein fractions during ischemia or reperfusion.

levels of PKCe in the membrane and cytosol fractions of the neonatal and adult hearts were equivalent before ischemia, neonatal hearts showed a significantly greater translocation of PKCe from the cytosol to the membrane fraction and a significant increase in membrane PKC activity during ischemia and reperfusion. By contrast, PKCe content declined and PKC activity was unchanged in both fractions in the adult hearts. We believe this confirms our hypothesis that the better ischemia tolerance of the neonatal heart is due to greater activation of endogenous molecular mechanisms associated with preconditioning which appears to decline with maturation. A limitation of this study was our inability to measure the specific activity of the PKCe isoform.

Figure 27.38 Recovery of LV performance after glibenclamide pretreatment. Blockade of KATP channel activation by administration of glibenclamide resulted in a significant decrease in the recovery of LV developed pressure and LV contractility (+dP/dr). Reprinted from Journal of Surgical Research, Vol. 90, Feng J, Li H, Rosenkranz E. Pinacidil pretreatment extends ischemia tolerance to neonatal rabbit hearts, pp. 131-137. © 2000, with permission from Elsevier.

To further study the mechanisms by which the immature heart tolerates ischemia better than the mature rabbit heart, we looked into the role that the KATP channel may play in this process. Our first study tested the hypothesis that the KATP channel is "endogenously activated" in the immature heart or it may be more responsive to ischemia than in the adult heart. This study was designed to determine if KATP channel blockade before unprotected global myocardial ischemia would reduce postischemic recovery of LV performance. Seven control neonatal rabbits received an intraperitoneal injection of 2 ml of normal saline 10 min before sacrifice. Five other neonatal rabbits received an intraperitoneal injection of 0.3 mg/kg glibenclamide, a KATP blocker, 10 min before sacrifice. The hearts from both groups of rabbits were retrogradely perfused on a Langendorff apparatus at 37°C for 20 min, after which baseline preischemia LV performance and coronary flow were recorded. Hearts from control rabbits received only KHB. Hearts from the glibenclamide-pretreated rabbits received KHB supplemented with 10 junol glibenclamide. All hearts were then subjected to 20 min of 37°C global ischemia and were then reperfused with KHB without additional supplementation. After 10 min of reperfusion, recovery of LV performance and coronary flow were measured. Glibenclamide pretreatment significantly reduced baseline LV developed pressure and +dP/drmax before global ischemia (Figure 27.38). After 10 min of unprotected 37°C ischemia and 20 min

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of reperfusion, untreated control hearts recovered 84% of preischemic LV systolic function (LVDP and +dP/dtmax), 91% of compliance (-dP/dtmax), and 96% of CF. By contrast, glibenclamide-pretreated hearts had significantly poorer recovery of LV systolic function after ischemia and reperfusion. LVDP and +dP/df recovered only 67% and 62% of their preischemic values while -dP/dfmax and CF recovered 78% and 77% of preischemic values. These data confirmed that inhibition of KATP channel activation with glibenclamide significantly reduced the recovery of LV performance after normothermic ischemia in neonatal hearts. Recovery of LV performance in untreated adult rabbit hearts was 54% of preischemic values, which was not significantly different from that seen in the immature hearts in which the KATP channel had been blocked. Therefore, increased endogenous KATP channel activation may contribute to the greater ischemia tolerance of immature rabbit hearts. This finding is consistent with recent studies reported by Baker et al. [156] using isolated neonatal rabbit hearts in which they found that the benefit of ischemic preconditioning was prevented by KATP inhibition with 5-hydrodecanoate. It is important to note that

in our study the animals were pretreated with KATP inhibitor before the heart was isolated. This was done to prevent an ischemic preconditioning stimulus during removal of the heart. This is the most likely reason why baseline preischemia LV performance in glibenclamide-pretreated hearts was significantly less than that in untreated hearts.

Pinacidil pretreatment improves ischemia tolerance of the neonatal heart Our next series of studies tested the role of KATP channel openers either as cardioplegic agents alone or as additives to cardioplegia solutions used to protect immature rabbit hearts. We first tested the hypothesis that pinacidil, a potassium channel opener, is a more effective cardioplegic agent than St Thomas' cardioplegia solution during global ischemia in the immature myocardium. Neonatal rabbit hearts were retrogradely perfused at 45 mmHg KHB for 20 min and were then divided into three groups according to the pretreatment they received (Figure 27.39). Six control hearts received standard KHB during the entire pretreatment period. Six pinacidil-pretreated

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Figure 27.39 Experimental protocol. Control hearts received no pretreatment prior to 90 min of ischemic arrest. Pinacidiltreated hearts were pretreated with pinacidil, a KATP channel opener, as the only pretreatment prior to 90 min of ischemia. St Thomas' cardioplegia (StTCP) treated hearts received a 3-min infusion of StTCP before 90 min of ischemia. Reprinted from Journal of Surgical Research, Vol. 109, Feng J, Li H, Rosenkranz E. K(ATP) channel opener protects neonatal rabbit heart better than St Thomas' solution, pp. 69-73. © 2003, with permission from Elsevier.

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Figure 27.40 Recovery of left ventricular developed pressure (LVDP) after reperfusion. Neonatal hearts pretreated with pinacidil had significantly better recovery of LVDP than hearts treated with StTCP. Reprinted from Journal of Surgical Research, Vol. 109, Feng J, Li H, Rosenkranz E. K(ATP) channel opener protects neonatal rabbit heart better than St Thomas' solution, pp. 69-73. © 2003, with permission from Elsevier.

Figure 27.41 Recovery of left ventricular end-diastolic pressure (LVEDP) after reperfusion. Neonatal hearts pretreated with pinacidil or StTCP had significantly better recovery of left ventricular diastolic function (LVEDP) after reperfusion, compared to untreated control hearts. Reprinted from Journal of Surgical Research, Vol. 109, Feng J, Li H, Rosenkranz E. K(ATP) channel opener protects neonatal rabbit heart better than St Thomas' solution, pp. 69-73. © 2003, with permission from Elsevier.

hearts received 50 ^imol pinacidil-enriched KHB during the 3-min pretreatment interval without St Thomas' cardioplegia solution at the onset of ischemia. Five others received a 3-min infusion of St Thomas' cardioplegia solution at the onset of ischemia. All hearts were then subjected to a simulated 90-min operation during which no further cardioplegia solution was administrated. Postreperfusion LV performance and coronary flow were recorded at the end of 60 min of reperfusion and were compared to baseline values. The 3-min infusion of pinacidil significantly increased baseline coronary flow prior to ischemia, compared to untreated control hearts. Pinacidil treatment significantly improved the recovery of systolic performance compared to untreated control hearts throughout the period of reperfusion (Figure 27.40). At the end of 60 min of reperfusion, the recovery of LVDP (47 + 3.8 mmHg vs. 32 ± 2.5 mmHg, P < 0.05) and +dP/dtmax (885.4 ± 74 mmHg/s vs. 643.7 ± 65 mmHg/s, P < 0.05), were significantly greater in pinacidil-treated hearts compared to untreated control hearts (Figure 27.41). By contrast, St Thomas' cardioplegia did not significantly improve the recovery of systolic function compared to untreated control hearts (LVDP: 39 ± 4.1 vs. 32 ± 2.5 mmHg; + dP/dfmax: 716.2 + 81 mmHg/s vs. 643.7 ± 65 mmHg/s) or hearts treated with pinacidil. By contrast, both pinacidil and

St Thomas' cardioplegia significantly enhanced the recovery of diastolic function compared to untreated control hearts (Figure 27.41). At 60 min of reperfusion, -dP/dtmax was significantly higher in pinacidiltreated hearts (994.2 + 86 mmHg/s) and St Thomas' cardioplegia-treated hearts (877.4 + 73 mmHg/s) compared to untreated control hearts (673.6 ± 69 mmHg/s, P < 0.05). Similarly, postreperfusion LVEDP in pinacidil-treated (10.5 ± 0.9 mmHg, P < 0.05) and St Thomas' cardioplegia-treated hearts (11.8 ± 0.6 mmHg, P < 0.05) were significantly lower than untreated control hearts (17.4+1.2 mmHg). Finally, the recovery of coronary flow was significantly greater in both the pinacidil (5.9 + 0.4 ml/min, P < 0.05) and St Thomas' cardioplegia-treated (5.7 ± 0.3 ml/min, P < 0.05) hearts, compared to the untreated control hearts (4.2 ± 0.2 ml/min). The results of this study confirmed that St Thomas' cardioplegia solution does not protect the neonatal heart as effectively as it protects the mature, adult heart. Secondly, pretreatment of the heart with the KATP channel opener pinacidil provided superior protection from global ischemia than St Thomas' solution, in that it preserved both systolic and diastolic function after reperfusion. Pinacidil is both a sarc-KATP and mito-KATP channel opener. As discussed earlier, opening of the mito-KATP channel plays a more important role

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in conferring protection from myocardial ischemia [10,56,60,133] by reducing mitochondria! calcium overload and causing matrix swelling, which enhances ATP synthesis and stimulates mitochondrial respiration [52,55]. Opening of mito-KATP channels may also reduce the deleterious effects of ischemia by causing a degree of mitochondrial uncoupling which reduces the production of cytotoxic reactive oxygen species (ROS) during reperfusion [69]. Uncoupling also decreases mitochondrial ATP production, which may in turn stimulate glycolytic ATP production and enhance glucose uptake. We concluded from these data that KATP channel opening agents used as a pretreatment, or as an additive to cardioplegia solution, may be an important new approach to intraoperative protection of the immature heart during open heart surgery.

Conclusions This series of studies in the immature heart suggest that mechanisms that have been associated with the ischemic preconditioning phenomenon may be endogenously activated in the immature animal and may explain why the immature heart is more tolerant to ischemic stress than the adult heart. Why should this phenotype exist in the immature heart? The fetal heart functions normally in an environment of low oxygen tension and it would make ideologic sense that the metabolic defense mechanisms that protect the heart from low oxygen supply would be most active in the fetus by activation of genes that code for the needed enzymes. When the fetus emerges as a newborn into an oxygenated environment, some of these genes may be downregulated since an environment rich in oxygen allows aerobic metabolism to provide the energy needed for normal cardiac function. Downregulation of these genes may occur over time, and thus may still be active in the neonate but become less active as the neonate matures. Similarly, neonates with cyanotic heart defects may maintain their "fetal phenotype" and not mature in terms of their loss of ischemia tolerance, since recent data suggest that hearts from cyanotic animals possess the greatest ischemia tolerance compared to acyanotic or adult hearts [159]. Finally, the ischemic preconditioning phenomenon may represent reactivation of these "fetal genes" that transiently reproduce the fetal heart's tolerance to periods of low oxygen tension

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during periods of ischemia. If future research proves these speculations to be true, then new pharmacologic approaches aimed at specifically activating these genes and their products may revolutionize our current thinking and approaches towards protecting the heart during open heart surgery.

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142 Halestrap A. The regulation of the matrix volume of mammalian mitochondria in vivo and in vitro and its role in the control of mitochondrial metabolism. Biochim BiophysActa 1989; 973:355-82. 143 Obata T, Yamanaka Y. Block of cardiac ATP-sensitive K+ channels reduces hydroxyl radicals in the rat myocardium. Arch Biochem Biophys 2000; 378:195-200. 144 Avkiran M, Hearse D. Protection of the myocardium during global ischemia: is crystalloid cardioplegia effective in the immature myocardium? / Thorac Cardiovasc Surg 1989; 97:220-8. 145 Baker J, Boerboom L, Olinger G. Age-related changes in the ability of hypothermia and cardioplegia to protect ischemic rabbit myocardium. / Thorac Cardiovasc Surg 1988; 96:717-24. 146 Baker J, Boerboom LGO. Cardioplegia-induced damage to ischemic immature myocardium is independent of oxygen availability. Ann Thorac Surg 1990; 50: 9349. 147 Baker J, Olinger G, Boerboom L. Protection of the ischemic immature heart—effect of perfusate reinfusion and composition. / Thorac Cardiovasc Surg 1993; 41: 274-9. 148 Bove E, Stammers A. Recovery of left ventricular function after hypothermic global ischemia. Age-related differences in the isolated working heart. / Thorac Cardiovasc Surg 1986; 91:115-22. 149 Julia P, Kofsky E, Buckberg G et al. Studies of myocardial protection in the immature heart. I. Enhanced tolerance of the immature versus the adult heart to global ischemia with reference to metabolic differences. J Thorac Cardiovasc Surg 1990; 100:879-87. 150 Kempsford R, Hearse D. Protection of the immature heart: temperature-dependent beneficial or detrimental effects of multidose crystalloid cardioplegia in the neonatal rabbit heart. / Thorac Cardiovasc Surg 1990; 99: 269-79. 151 Lynch M, Bove E, Zweng T et al. Protection of the neonatal heart following normothermic ischemia: a comparison of oxygenated saline and oxygenated versus nonoxygenated cardioplegia. Ann Thorac Surg 1988; 45: 650-5.

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152 Magovern J, Pae W, Waldhausen J. Protection of the immature myocardium: an experimental evaluation of topical cooling, single-dose, and multiple-dose administration of St Thomas' Hospital cardioplegic solution. / Thorac Cardiovasc Surg 1988; 96:408-13. 153 Wittnich C, Maitland A, Vincente W, Salerno T. Not all neonatal hearts are equally protected from ischemia during hypothermia. Ann Thorac Surg 1991; 52:1000-4. 154 Grice W, Konishi T, Apstein C. Resistance of neonatal myocardium to injury during normothermic and hypothermic ischemic arrest and reperfusion. Circulation 1987; 76 (SupplV): V-150-5. 155 Grosso M, Banerjee A, St Cyr J et al. Cardiac 5'-nucleotidase activity increases with age and inversely relates to recovery from ischemia. / Thorac Cardiovasc Surg 1992; 103:206-9. 156 Baker J, Curry B, Olinger G, Gross G. Increased tolerance of the chronically hypoxic immature heart to ischemia: contribution of the KATP channel. Circulation 1997; 95:1278-85. 157 Pridjian A, Bove E, Boiling S et al. Developmental changes in myocardial protection in response to 5'nucleotidase inhibition. / Thorac Cardiovas Surg 1994; 107:520-6. 158 Liu H, Gala P, Anderson S. Ischemic preconditioning, effects of pH, Na and Ca in newborn rabbit hearts during ischemia and reperfusion. / Mol Cell Cardiol 1998; 30:685-97. 159 Rafiee P, Shi Y, Kong X et al. Activation of protein kinases in chronically hypoxic infant human and rabbit hearts. Role in cardioprotection. Circulation 2002; 106: 239-45. 160 Awad W, Shattock M, Chambers D. Ischemic preconditioning in immature myocardium. Circulation 1998; 98 (Suppl II:): 11206-13. 161 Tani M, Suganuma Y, Hasegawa H et al. Changes in ischemia tolerance and effects of ischemic preconditioning in middle-ages rat hearts. Circulation 1997; 95: 2559-66. 162 Burns P, Krukenkamp I, Caldarone C et al. Is the preconditioning response conserved in senescent myocardium? Ann Thorac Surg 1996; 61:925—9.

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New concepts in myocardial protection in pediatric cardiac surgery Bindu Bittira, MD, MSC, DominiqueShum-Tim, MD, MSc, Christo I. Tchervenkov, MD

Introduction The practice of safe and effective cardiac surgery is not possible without adequate myocardial protection. Over the years, many studies have been carried out to examine previous techniques for myocardial protection and to refine novel ones such that complex and long procedures may be performed with decreasing morbidity and mortality. This chapter will attempt to highlight the most recent advances in the protection of the pediatric myocardium during and following cardiac surgery. The scientific and clinical evolution of cardioplegia (techniques and composition) will be covered, focusing on the most recently published literature. Finally, the revolutionary concept of primary corrective surgery versus palliative surgery will also be reinterpreted in light of these recent methods of myocardial protection.

The immature versus the adult myocardium There are numerous structural features and significant metabolic differences between the immature and adult myocardium, which greatly influence and affect their responses to ischemia and various protective methods. There are a great number of papers describing the differences between mature and immature myocytes in terms of anatomy, physiology, and pharmacology. However, since many of these are from animal experiments, the relevance of these experimental data to clinical application is not clear [ 1,2].

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Immature hearts have greater surface area to wall thickness ratios and smaller myocardial cells. Immature myocardial cells are composed of noncontractile elements including nuclei, mitochondria, and membranes [3,4]. Metabolically, immature hearts consist of fewer mitochondria than those of adults but have higher aerobic activities with increased cytochrome c oxidase activity. During development, the myocytes become more complex in their external shape with the myofibrils becoming larger and reorienting along the longitudinal direction of the cell [5]. Immature hearts also have more glycogen content, and depend less on fatty acids as a fuel source with a greater anerobic glycolytic capacity than in adults [6]. With the differences in the content of these calciumdependent organelles, such as the sarcoplasmic reticulum and the transverse tubular system, functional differences are noted in the immature myocardial response to calcium channel blockers, as well as to inotropic agents [7]. Since the immature myocardium differs in its sensitivity to extracellular calcium during normal contraction and during ischemia, the response of the immature myocardium to many pharmacologic agents differs from that of adult hearts. This makes intraoperative and postoperative regulation of blood pressure and cardiac output more challenging [8,9]. Biochemical changes also occur during myocardial maturation. The immature heart has a greater glycolytic capacity than the adult, due to its ability to use various substrates for oxidation, including carbohydrates, medium- and short-chain fatty acids, ketones, and amino acids [ 10]. The relative protection

Pediatric myocardial protection: new concepts afforded by the immature myocardium to anoxic ischemia has been associated with its increased ability to use anerobic glycolysis to produce energy. However, the principal substrates used in the mature heart are long-chain fatty acids. Additionally, mature myocardium has a more complex mitochondrial crystal pattern with several more complex enzymes involved in fatty acid metabolism [ 10].

Responses to global myocardial ischemia Despite numerous investigations [4,6,11], whether the immature heart is less sensitive or not to the effects of hypoxia and ischemia than the adult heart remains unsettled. However there are, as discussed earlier, distinguishing characteristics between the two, which may have an important effect on the immature myocardial response to ischemia. In the ischemic myocardium, all oxygen-dependent processes cease almost immediately. While anerobic glycolysis initially generates some ATP, this process is inadequate for the energy required for normal physiologic events. While immature hearts are capable of greater glycolytic activity than adult hearts, there is greater lactate production, which leads to a fall in tissue pH [12]. This prevents the production of ATP via the glycolytic pathway, and as ionic intracellular gradients are disrupted, intracellular edema and cell lysis occur. The role of myocardial protection is to prevent irreversible cell death and to promote a physiologic transition to normal contractile function following reperfusion. The differences in myocardial calcium metabolism allow younger myocardium to work more efficiently than adult myocardium for the volume of oxygen consumed. This is in part due to the differences in sarcoplasmic reticulum content and T-tubules between the adult and pediatric hearts [13]. In mature myocardium, the sarcoplasmic reticulum is the predominant source of calcium ions for excitation-contraction coupling, while the sarcoplasmic reticulum of the immature heart is more poorly developed. The immature myocardial cell is deficient in T-tubules and is incapable of internal release and reuptake of calcium for contraction and is instead dependent on transmembrane calcium transport for the development of tension. This greater dependence on the transsarcolemmal movement of calcium as a source of calcium available for contraction translates to more

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intracellular calcium concentrations through the Na+-Ca2+exchange mechanism which further enhances Na+-K+ ATPase activity [13]. These developmental differences in the methods of calcium handling have important implications in the response to ischemia due to the role of calcium in irreversible cardiac injury after ischemia and reperfusion. In addition to the structural differences between adult and pediatric hearts, many biochemical mechanisms account for infant hearts having an improved tolerance of global ischemia when compared to adult hearts. In comparison to adult myocardium, younger myocardium exhibits less ATP breakdown after global ischemia and reperfusion [14]. There is also less 5'-nucleotidase activity in pediatric than adult hearts, correlating with a better functional recovery after global ischemia. Newborn hearts exhibit greater quantities of conjugated dienes after normothermic ischemia and reperfusion than adult hearts do, suggesting that younger hearts generate more free radicals than their adult counterparts. The importance of this free radical injury before and after cardiopulmonary bypass has been challenged by investigators [13-15,16], but nonetheless has important implications in the administration of cardioplegia solutions. Important work has shown the differences in protection offered to older and younger hearts with the use of particular cardioplegia solutions. Immature myocardium was not as well protected by both Roe and Bretschneider solutions [17], while superior protection was seen with St Thomas' and Tyers solutions. The absence of calcium in Bretschneider and Roe solutions, which are used in adult myocardial protection, may explain this discrepancy. Other studies, however, negate these findings, showing that calcium and sodium contents of cardioplegia solutions offer little benefit in functional preservation [ 18]. Recent work suggests that prearrest cold perfusion adversely affects postischemic myocardial recovery [19]. The exact mechanism by which this contracture occurs after prolonged cold perfusion remains unknown, although the loss of intracellular calcium homeostasis has been implicated [20]. Another contrast between pediatric and adult myocardium is in their response to multidose cardioplegia. While adult hearts subjected to longer periods of global ischemia benefit from periodic readministration of cardioplegia, immature hearts may be subjected to more ischemic damage [21-23] with multiple doses.

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Cardioplegia The concept of myocardial protection has been evolving since its introduction in the 1950s. Since crystalloid cardioplegia was first introduced into the clinical setting, results of open-heart surgery for adult patients have improved significantly. However, pediatric cardiac surgeons are still in conflict over the optimal techniques of myocardial protection, since most are based on experimental and clinical work carried out on adult hearts. A host of new adjuncts to cardioplegia solutions and new modes of delivery, as well as controversial issues regarding temperature and sites of administration, have been debated over the past few years. Experimental and clinical investigations have increased our understanding of cold blood cardioplegia, warm blood cardioplegic reperfusion with warm induction, antegrade and retrograde delivery, and continuous, cold, noncardioplegic blood perfusion in the adult population. Although these techniques were originally designed to protect the adult heart, some of them have been adapted for pediatric cardiac surgery [24]. While these current methods of myocardial protection during adult open-heart surgery have shown good myocardial preservation [25,26], myocardial protection in pediatric cardiac surgery may be suboptimal, resulting in greater morbidity and mortality [27]. Despite the anatomic, architectural and physiologic differences between the two age groups, very few comprehensive studies have been performed to assess the effects of cardioplegia on the immature heart.

Crystalloid cardioplegia One experimental study [19] which reflected the differences in cardiopulmonary bypass and surgical management in the pediatric population, suggested that prolonged cold perfusion of the nonarrested newborn heart in preparation to reach deep hypothermia prior to aortic cross-clamping, impaired functional recovery and was therefore detrimental. This study was designed to identify the consequences of perfusing a nonarrested newborn heart under hypothermic conditions for a prolonged period of time. In each case, newborn piglets were randomly assigned to four groups and subjected to varying periods of cold perfusion with or without ischemic insult. The hearts were studied in a crystalloid perfused Langendorff heart

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model and examined histologically for ultrastructural damage to the myocardial cells. The results showed that in the groups subjected to prolonged cooling, the functional recovery was significantly impaired. When further followed by a period of ischemic arrest, the myocardial injury was potentiated, and severe contracture resulted. The effects of prolonged myocardial cold perfusion before cardiac arrest was offered as one explanation for the suboptimal myocardial protection seen in neonates. In addition, Imura et al. [28] showed that highpotassium, cold-cardioplegia solution commonly used to protect adult hearts, had variable degrees of myocardial protection, depending on the age and level of cyanosis of the child. The authors monitored myocardial metabolic changes following ischemia in acyanotic children undergoing open-heart surgery using St Thomas' cardioplegia solution. They used postoperative troponin I as a measure of reperfusion injury as well as other intraoperative and postoperative clinical parameters to determine the subsequent clinical outcome. These parameters included: an intraoperative requirement for inotropes to wean patients from cardiopulmonary bypass; postoperative inotropic support; length of inotropic and ventilatory support; as well as intensive care and hospital stay. Myocardial biopsies were also collected from the right ventricular free wall and adenine nucleotides, purines, lactate, and free amino acids were measured in all biopsies collected. For the first time, they were able to show that the outcome after pediatric openheart surgery is age dependent. Children showed more resistance to reperfusion injury than neonates. However, cyanotic children had a significantly worse outcome and more reperfusion injury compared to acyanotic children. The most recent studies all suggest that a single dose, rather than multiple doses of cardioplegia solution result in improved recovery of function after ischemia. No additional protection was offered when multiple doses of St Thomas' cardioplegia solution were compared with a single dose in the neonatal rabbit [29], while other investigators found worse recovery of function with multiple, rather than single doses of St Thomas' cardioplegia solution [30]. Current cardioplegic techniques have improved based on this experimental data, showing that cold-crystalloid cardioplegia in pediatric cardiac surgery is associated with significant ischemic stress and subsequent

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Pediatric myocardial protection: new concepts myocardial injury [27], depending also on the age and pathophysiology of the child's condition. The introduction of warm myocardial protection had a striking impact on modern cardiac surgery, representing a radical change from a conventional idea. The benefits of combined antegrade-retrograde infusion of blood cardioplegia solution are well known in adult coronary and valvular heart operations, and many of these advantages are applicable to pediatric patients. Myocardial perfusion with warm blood was applied successfully in a clinical setting by Lichtenstein, Salerno and associates in Toronto, Canada [31,32]. They used continuous, antegrade or retrograde perfusion of the heart with warm (37°C) hyperkalemic blood to arrest the heart's electromechanical activity, with results comparable to those achieved with cold ischemic arrest.

Cardioplegia administration One of the first studies to show the safety of combined antegrade-retrograde infusion of blood cardioplegia solution in pediatric patients was conducted by Drinkwater et al. [33] They reported the safety of retrograde in conjunction with antegrade infusion of blood cardioplegia solution in 123 pediatric patients whose ages ranged from 1 week to 16 years and whose weights, correspondingly, ranged from 3.6 to 72.7 kg. A cardioplegia cannula, modified for pediatric use, was introduced in one of two ways at the time of operation. For patients with bicaval cannulation and right atriotomy, the retrograde cannula was directly introduced into the coronary sinus without the malleable stylet. For larger patients (> 15-20 kg) with a single venous cannula, it was introduced over the stylet through a pursestring suture in the atrial wall. This initial positive experience showed that this combined technique could provide adequate myocardial protection with excellent surgical outcome in the repair of complex, congenital heart malformations. Since retrograde cardioplegia delivery was first reported clinically by Lillehei et al. [34] and reproposed by Menasche [35], the essential problem as to whether retrograde perfusion of the coronary sinus provides adequate nutrient flow to the heart, especially the right coronary artery, remains unsolved. Despite the multitude of studies, the use of retrograde cardioplegia in adults did not gain popularity until the late 1970s, when various authors documented inadequate myocardial protection during antegrade

cardioplegic infusion in the presence of coronary artery stenosis [34]. Yet its application in the pediatric population remains limited, because coronary artery stenosis is rarely encountered in this age group.

Blood cardioplegia Blood cardioplegia, since its introduction in 1977, has played a dominant role in adult cardiac surgery. However, the role and advantages of blood cardioplegia in pediatric cardiac surgery have been less well defined, leaving pediatric cardiac surgeons divided in their use of blood versus crystalloid cardioplegia solutions [36]. Corno and coworkers found that in the neonatal piglet model, cardioplegia solutions containing blood improved functional recovery when compared with crystalloid cardioplegia solutions or hypothermia alone [37]. This addition of blood to cardioplegia solutions may be beneficial as a result of the provision of free radical scavenging capacity through the catalase in red blood cells and the buffering capacity of blood proteins. However, the superiority of blood cardioplegia in pediatric cardiac surgery has not previously been challenged in a controlled clinical trial until recently. Young et al. [38] administered multiple doses of cold (4°C) blood cardioplegia solution antegradely in addition to topical cooling during ischemic arrest in 138 pediatric patients (ages ranging from 1 day to 15 years). The technical disadvantage of using retrograde and warm blood cardioplegia for some pediatric patients, especially newborn infants, prompted the use of blood as an additive to the current cardioplegic strategy. Systemic hypothermic perfusion of 30°C was achieved in all patients; the aorta was cross-clamped and antegrade cardioplegia administered. Although the optimum systemic perfusate temperature at which aortic cross-clamping should occur has been raised by some investigators [36,38^0], the authors chose a moderately hypothermic temperature for aortic cross-clamping. Despite the significant limitations of this study, it suggested that the use of a blood cardioplegic strategy for congenital heart disease offered no obvious benefits when only antegrade hypothermic dosing was used [41]. The study also failed to show any benefit of blood cardioplegia in cyanotic patients. The use of blood cardioplegia failed to show any significant advantages using the clinical criteria in this particular study. Crystalloid cardioplegia was associated with less inotropic support although no better ventricular

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function was found when compared with blood cardioplegia.

Substrate enhancement Since ischemia has been known to reduce the level of high-energy phosphates in the myocardial cell and the level of ATP has been correlated to the recovery during the reperfusion period, investigators have attempted to enhance the levels of phosphate precursors so that ATP levels may be readily restored [42]. There is some evidence that the addition of adenosine to cardioplegia solutions [43,44] or its administration during reperfusion [45] may result in better recovery of ATP levels and contribute to overall improved function during the postischemic recovery period. Similarly, the rationale for the addition of glucose in cardioplegia solutions was to provide substrate to be used by the ischemic cell. However, as noted earlier, multiple cardioplegia doses may provide more substrate for metabolism, but have been associated with either no improvement or a worse outcome in the pediatric myocardium.

The integrated approach to cardioplegia While the integrated cardioplegic approach using warm, cold, antegrade and retrograde techniques in addition to substrate enhancement may be beneficial for the pediatric population, the efficacy of these integrated cardioplegic techniques has not been assessed in clinical trials in neonates or young infants. Nevertheless, there are compelling reasons for adapting a blood cardioplegic strategy, as experimental evidence has suggested the superiority of blood cardioplegia for cyanotic patients [38,46]. Since the duration of aortic cross-clamping time is a major determining factor in the outcome of various cardioplegic strategies in the clinical setting, considering these variations, further studies need to be done to elucidate the potential benefits of various substrate enhancements, preconditioning agents, or hyperpolarizing substances. One such study by Borowski et al. [47] assessed the technical applicability and clinical value of continuous coronary perfusion with oxygenated blood as a method for myocardial protection. Thirty pediatric patients underwent open-heart procedures on the beating heart for the repair of simple and complex cardiac malformations using a self-designed perfusion system. It uses a pressure- and volume-controlled continuous hypothermic coronary perfusion in com-

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bination with ultra short betaj-receptor blockade (esmolol) and nitroglycerin for myocardial protection. They found that this technique was feasible for the repair of simple and complex malformations. However, in small children under 3 years of age, the repair of interventricular defects is technically more challenging with the use of this technique than with conventional cardioplegic arrest. While no recent consensus exists about the ideal composition of cardioplegia, a nationwide survey of institutions in the United States showed that blood cardioplegia in conjunction with hypothermia was the strategy mostly used for pediatric myocardial protection in the past decade [48,49]. The administration of cardioplegia was guided more by formulas than clinical criteria, with circulatory arrest being used more frequently in larger institutions. Still, ongoing clinical trials abound, attempting to clarify the effectiveness of various substrate enhancement strategies [47] in order to provide better cardiac performance in the postoperative period.

New advances in mechanical devices that improve cardioprotective strategies Classification of the major areas of research can be made into two distinct areas of myocardial protection: (i) pharmacologic support, as in the form of substrate enhancement, which has been outlined previously, as well as infusion of platelet activating factor antagonists (PAFA); and (ii) mechanical delivery systems and the addition of filters incorporated in the delivery pump. The earliest methods of cardioplegic delivery included infusions of concentrated solutions directly into the aortic root via hand-held syringes. Unfortunately, such methods caused a heterogeneous distribution of solutions and the need for more precise and controlled delivery techniques to ensure uniform distributions and cardiac standstill. Since then, the pressurized bag technique and roller pump delivery have been used for the delivery of both blood and crystalloid cardioplegia. There has also been tremendous variation in the type of delivery cannulas that have been used over the past four decades. In 1956, Lillehei et al. [34] described the administration of hypothermic crystalloid cardioplegia via direct cannulation into the coronary sinus, achieving retrograde flow in those with aortic regurgitation. However,

Pediatric myocardial protection: new concepts the aortic root administration techniques provided simple methods of cardioplegic delivery for either congenital heart disease or acquired valvular dysfunction. This format is most often accomplished by placing a large bore (12-18 gauge) needle directly in the aortic root several centimeters above the aortic valve. A variation of this involves direct cannulation of the coronary ostia. However, the several devices available to cannulate the coronary ostium for cardioplegic delivery in adults are not useful in pediatric patients. If the catheter tip is the same as or slightly larger than the coronary ostium, then ostial damage is prone to occur [50]. Chiu et al. [51] have successfully used the DLP 4Fr pediatric cardioplegic cannula during the arterial switch operation. Although retrograde cardioplegia has been advocated in this setting, the authors showed the versatility of their cannula, which was used before and after their aortotomy. In view of the difficulties in neonatal myocardial protection and easy catheter dislocation and the hazard of coronary sinus injury using retrograde infusion, the authors utilized a pediatric cannula for antegrade aortic infusion of cardioplegia, and inserted the same cannula into the coronary ostium for direct injection after the aortotomy.

Filters The need to assure the purity and safety of blood cardioplegia solutions, as well as recent work that has shown injury from both reperfusion and the inflammatory reaction, has prompted the use of filters directly in the cardioplegic heat exchanger devices [52]. The use of leukocyte-depleting filters added into the cardioplegic circuit for reducing neutrophilmediated reperfusion injury seems promising [16]. The most recent clinical interest has focused on the evaluation of the use of leukocyte-depleted blood cardioplegia and mechanical neutrophil depletion for pediatric heart surgery. However, the concern remains of inducing neutrophil-mediated reperfusion injury for every administration of blood cardioplegia during further reoperation. While the possible cytotoxicity of blood cardioplegia as a risk for myocardial reperfusion injury has not been quantified, the risk remains even under conditions of cold blood cardioplegia administered to hypothermic myocardium during cardioplegic arrest. Hayashi et al. [53] studied the effect of leukocyte depletion in a clinical setting, and have shown that it reduced the extent of myocardial damage after

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reperfusion. While blood cardioplegia is considered superior to crystalloid cardioplegia in certain aspects, it contains leukocytes and platelets, potentially causing capillary plugging after myocardial ischemia and reperfusion during cardioplegia administration. The authors were able to show the clinical myocardial protective effect of leukocyte-depleted blood cardioplegia by evaluating plasma concentrations of malondialdehyde, human heart fatty acid-binding protein, and maximum creatine kinase-MB (CK-MB) levels [53]. Although leukocyte-depleted blood cardioplegia may provide better cardioprotection, the mechanism of cytotoxicity to blood cardioplegia remains unclear and more work needs to be done before frequent use of leukocyte depletion is recommended. The use of leukocyte-depleting filters in the cardiopulmonary bypass line as well as infusion of the platelet-activating factor antagonist (PAPA) CV6209 to prevent activation of polymorphonuclear leukocytes has been studied in the chronic cyanotic animal model for congenital heart disease. Leukocytedepleted perfusion was shown to decrease operative morbidity and mortality, reduce inotropic drug requirements, and increase left ventricular contractility [54]. The role of platelet activating factor antagonism in protecting against reperfusion injury to the myocardium has also been favorable [55,56]. Sawa and associates [56] showed that with controlled reperfusion, CV-3988 was more effective than terminal leukocyte depletion, suggesting that neutrophils may play a more minor role in myocardial reperfusion injury than platelet activating factor. The compensatory changes to the myocardium offered by chronic hypoxia and the myocardial response to oxygen free radical injury was studied by Allen et al. [57] in the context of leukocyte depletion as well. The reoxygenation injury, characterized by a decrease in systolic contractility, a decrease in diastolic compliance, and increased pulmonary vascular resistance, was seen with abrupt reoxygenation and reperfusion following 1-2 h of acute hypoxia. This reoxygenation injury has been shown to be modulated by oxygen free radicals and can be modified by leukocyte depletion or by reoxygenating at a lower oxygen concentration [56,57]. In this study, white blood cell filtration substantially reduced the number of leukocytes before and after cardiopulmonary bypass was initiated for 30 min. While there are limitations within this study, it did show evidence of decreased

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oxygen free radical production by decreasing the oxygen concentration in the circulation during cardiopulmonary bypass or more effectively by leukocyte filtration. In addition to mechanical devices which may alter the injury caused by oxygen-derived free radicals, substances such as d-alpha-tocopherol (vitamin E) have also been studied [58]. Newborn piglet hearts were pretreated with vitamin E given by oral gavage for 4 days before perfusion studies were carried out. The postischemic functional recovery of vitamin E-pretreated groups was improved significantly in a Langendorff heart model. The study showed that oral vitamin E improved the ischemic tolerance of the newborn myocardium and therefore might be considered a valuable, effective and inexpensive method of myocardial protection [58].

Ultrafiltration Cardiopulmonary bypass in neonates and infants using hypothermia with hemodilution is associated with a host of vascular changes. There may be a tremendous capillary leak syndrome with an increase in total body water, tissue edema, and organ dysfunction affecting the brain, lungs, and heart. Capillary leak, which is caused by a systemic inflammatory response, is a result of the contact of blood elements to the nonendothelialized synthetic surfaces of the cardiopulmonary bypass circuit [59]. Ultrafiltration is one of the more novel concepts in myocardial protection, affecting not only intraoperative myocardial functioning but also postoperative hemodynamics. A number of strategies have been employed to reduce capillary leak and the accumulation of extravascular water during bypass. These include high hematocrits at relatively high temperatures, postoperative peritoneal dialysis, postoperative continuous arteriovenous hemofiltration, infusion of the salvaged circuit volume, and aggressive diuresis [60]. Conventional Ultrafiltration is carried out during the rewarming phase of cardiopulmonary bypass [61]. Recently, modified Ultrafiltration (MUF) has been used to limit the deleterious effects of cardiopulmonary bypass as well. The recognized benefits are multiple, and include improvements in left ventricular function, an increased hematocrit and subsequent decrease in transfusion requirements, improved hemostasis, modification of complement activation, improved pulmonary compliance, and cerebral metabolic recovery [62-64].

Modified Ultrafiltration In MUF, the cardiopulmonary bypass circuit is altered so that blood is pumped in a retrograde fashion from the aortic cannula through the hemocentrator, and returned to the right atrium. This results in warmed, hemoconcentrated oxygenated blood returning to the heart and pulmonary vasculature. The benefits of MUF when compared with standard Ultrafiltration were first shown by Naik et al. [64,65] in 1991, as measured by bioelectrical impedance and later confirmed in 1993. In their studies, fluid balance, total body water (TBW), and hemodynamics were evaluated postoperatively. There was a reduction in blood loss, improved hemostasis, a reduction in blood product transfusion, and a reduction in TBW in the MUF group. Other investigators have overwhelmingly supported these findings [66], and the benefits on the cardiovascular system have also been shown [67]. Davies et al. [68] measured weight, left ventricular systolic function, myocardial cross-sectional area, and inotropic drug support in infants undergoing cardiopulmonary bypass with and without MUF. He showed that the increase in end-diastolic length and fall in end-diastolic pressure seen after MUF is consistent with an improvement in left ventricular compliance resulting from a reduction in myocardial edema. The improvement in hemodynamics seen in all patients after MUF was correlated with a fall in total body water, and subsequent increase in hematocrit values as well as improved left ventricular systolic function, which continued for at least 24 h postoperatively. While this study was conducted in patients undergoing hypothermia and hemodiluted cardiopulmonary bypass with crystalloid cardioplegia, it provokes the testing of MUF with either warm cardiopulmonary bypass or blood cardioplegia, to see whether there will be a further improvement in postcardiopulmonary bypass systolic function. The MUF technique therefore represents a major improvement in the management of patients who are at a high risk of fluid accumulation.

Hypothermia and circulatory arrest versus low-flow cardiopulmonary bypass Systemic hypothermia has been regarded as an essential component of cardiac surgery. Hypothermia offers tissue and organ protection by decreasing metabolic

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Pediatric myocardial protection: new concepts requirements during cardiopulmonary bypass and cardiac arrest, and provides a margin of safety in the event of technical difficulties developing with the cardiopulmonary bypass circuit. In pediatric cardiac surgery, there is often the need for adequate intracardiac exposure in a bloodless field, and a reduction in perfusion flow rate to counteract the high volume of left heart return, particularly in cyanotic children. However, the optimal temperature and flow at which bypass should be conducted is still debated. Despite the technical advantages offered by both deep hypothermic circulatory arrest and low-flow bypass, there are reports which show their damaging effects. Flow reduction negatively affects parenchymal cells, endothelial cells, and inflammatory cells [69]. Flow reduction also impairs the organ function already compromised by hypothermia. Several deleterious effects of cardiopulmonary bypass are also exaggerated by reduced perfusion flow rates and hypothermia, including metabolic acidosis, neurologic sequela, reduced platelet aggregation, and increased vascular resistance. Based on this theory, Corno et al. [70] investigated the possibility of performing surgical procedures for congenital heart defects under normothermic (37°C) high-flow (3.0 L/m2/min) leukocyte-depleted perfusion. The inconvenience of inadequate surgical visualization, using the normothermic high-flow technique, was overcome with proper surgical exposure, adequate cannulation, and venous drainage. This technique balanced the benefits of ideal intracardiac exposure and surgical comfort with more physiologic levels of tissue perfusion, and was a viable alternative option. While a lot of interest in hypothermic arrest has concentrated on the neurologic outcome [7174], few authors have looked at the postoperative course and non-neurologic hemodynamic profiles following the perioperative effects of deep hypothermic circulatory arrest (DHCA) and low-flow cardiopulmonary bypass in neonates and infants. Wernovsky et al. [75] studied patients randomly assigned to either low-flow (50 cm3/kg/min) bypass or circulatory arrest. Cardiac output, mean systemic arterial, pulmonary arterial, and right and left atrial pressures were recorded. Perfusion strategy did not have an impact on the postoperative hemodynamics in the end. However, the patient population was limited to those undergoing the arterial switch opera-

tion and therefore either circulatory arrest or lowflow bypass strategies could be used with equal facility. The authors cautioned the use of low-flow bypass in other types of neonatal and infant surgeries as longer support times may have increased the chances of total body fluid overload. Clearly the decision to balance the technical advantages of facilitating a complete repair under circulatory arrest versus the risks of prolonged low-flow cardiopulmonary bypass must be decided on an individual basis.

Palliation versus early repair Newly developed variations on previous techniques for cardioplegic composition and administration as well as postoperative care have allowed for the complete repair of many congenital heart defects in the neonatal or early infancy period. However, the optimal age for complete repair of most congenital heart defects remains undefined and controversial. Palliative procedures were first introduced when the condition of the child or the congenital morphology of the malformations were such that complete repair of the defect was impossible or unsafe. Since then, palliation has been an accepted mode of therapy in the treatment of these patients with congenital heart disease. However, with the greater number of corrective operations which are now available, the role of palliation versus initial corrective surgery has changed. The surgical literature is filled with numerous successful reports of correction for a variety of complex congenital defects. In fact, complete repairs of such defects as atrioventricular canal, tetralogy of Fallot (with or without pulmonary atresia), truncus arteriosus, and transposition of the great arteries are considered routine, and postoperative evaluation of the quality of life of these children often surpasses those who have undergone staged procedures. With the advent of new options for not only myocardial protection but also protection of the brain and other organs as well, more importance is being given to primary repair of congenital lesions. Therefore, primary anatomic and physiologic repair in early life, in order to avoid the chronic volume and pressure overload and persistent cyanosis associated with palliative procedures, may actually provide the best strategy of myocardial protection.

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References 1 Jarmakani JM, Nakazawa M, Nagatomo T. Effect of hypoxia on mechanical function in the neonatal mammalian heart. Am} Physiol 1978; 224: H469-74. 2 Yamamoto F, Takaichi S, Ishikawa T et al. Pediatric myocardial protection. From the aspect of the developmental status of the myocardium. Ann NYAcad Sci 1996; 793:355-65. 3 Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 1972; 15:87-111. 4 Coles JG, Watanabe T, Wilson GJ. Age-related differences in the response to myocardial ischemic stress. 7 Thome Cardiovasc Surg 1987; 94:526-34. 5 Sheldon CA, Friedman WF, Sybers HD. Scanning electron microscopy of fetal and neonatal lamb cardiac cells. JMol Cell Cardiol 1976; 8: 853-62. 6 Magovern JA, Pae WE Jr, Miller CA et al The mature and immature heart: response to normothermic ischemia. JSurgRes 1989; 46: 366-9. 7 Page E, Barley J, Power B. Normal growth of ultrastructures in rat left ventricular myocardial cells. Circ Res 1974; (2)supplII:12-16. 8 Boudreaux JP, Schieber RA, Cook DR. Hemodynamic effects of halothane in the newborn piglet. Anesth Analg 1984;63:731-7. 9 Krane EJ, Su JY. Comparison of the effects of halothane on skinned myocardial fibers from newborn and adult rabbit. 1. Effects on contractile proteins. Anesthesiology 1989; 71:103-9. 10 Anderson PAW. Immature myocardium. In: Moller JH, Neal WA, eds. Fetal Neonatal and Infant Cardiac Disease. Norwalk, CT: Appleton & Lange, 1990. 11 Hoerter J, Mazet F, Vassort G. Perinatal growth of the rabbit cardiac cell: possible implications for the mechanism of relaxation. JMol Cell Cardiol 1981; 13:725-40. 12 Abd-Elfattah A, Murphy C, Salter D et al. Age-related and species-related differences in adenine nucleotide degradation during myocardial global ischemia. Fed Proc 1986; 45:1039. 13 del Nido PJ, Nakamura H, Mickle DAG et al Maturational difference in functional/metabolic sequelae of free radical formation of reperfusion. / Surg Res 1989; 46: 532-6. 14 del Nido PJ, Mickle DAG, Wilson GJ et al. Evidence of myocardial free radical injury during elective repair of tetraology of Fallot. Circulation 1987; 76 (Suppl 5 Part 2): VI74-9. 15 Kohman LJ, Veit LJ. Neonatal myocardium resists reperfusion injury. JSurgRes 1991; 51:133-7. 16 Stammers AH. Advances in myocardial protection: the role of mechanical devices in providing cardioprotective strategies. Int Anesthesiol Clinic 1996; 34:61-84. 17 Kempsford RD, Hearse DJ. Protection of the immature myocardium during global ischemia. A comparison of four clinical cardioplegic solutions in the rabbit heart. 7 Thorac Cardiovasc Surg 1989; 97:856-63. 18 Diaco M, DiSesa VJ, Sun S-C et al. Cardioplegia for the immature myocardium: a comparative study in the

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51 Chiu JS, Lin SF, Sin CY et al Direct delivery of cardioplegia to the coronary arteries during arterial switch operation. Thorac Cardiovasc Surg 1995; 43:215-16. 52 Palanzo DA, O'Neill MJ, Harrison LH. An effective oxygen micron filter for the administration of cardioplegia. ProcAnn Acad Cardiovasc Perf 1987; 8:182-5. 53 Hayashi Y, Sawa Y, Nishimura M et al. Clinical evaluation of leukocyte-depleted blood cardioplegia for pediatric open heart operation. Ann Thorac Surg 2000; 69: 191419. 54 Zhang JI, Jamieson WR, Sadeghi H et al. Strategies of myocardial protection for operation in chronic model of cyanotic heart disease. Ann Thorac Surg 1998; 66: 1507-13. 55 Qayumi AK, Jamieson WRE, Poostizadeh A. Effects of platelet-activating factor antagonist CV-3988 in preservation of heart and lung for transplantation. Ann Thorac Surg 1991; 52:1026-32. 56 Sawa Y, Schaper J, Roth M et al. Platelet-activating factor plays an important role in reperfusion myocardium. Efficacy of platelet-activating factor receptor antagonist (CV-3988) as compared with leukocyte-depleted reperfusion. 7 Thorac Cardiovasc Surg 1994; 108:953-9. 57 Allen BS, Rahman S, Ilbaur MN et al. Detrimental effects of cardiopulmonary bypass in cyanotic infants. Preventing the reoxygenation injury. Ann Thorac Surg 1997; 64: 1381-8. 58 Shum-Tim D, Tchervenkov CI, Chiu R-CJ. Oral vitamin E prophylaxis in the protection of newborn myocardium from global ischemia. Surgery 1992; 112:441-9. 59 Boiling KS, Halldorsson A, Allen BS et al Prevention of the hypoxic/reoxygenation injury using a leukocyte depleting filter. J Thorac Cardiovasc Surg 1997; 113: 1081-9. 60 Morita K, Ihnken K, Buckberg G et al Studies of hypoxemic/reoxygenation injury: without aortic cross-clamping. Importance of avoiding preoperative hyperoxemia in the setting of previous cyanosis. J Thorac Cardiovasc Surg 1995; 110:1235-44. 61 Elliott MJ. Ultrafiltration and modified ultrafiltration in pediatric open heart operations. Ann Thorac Surg 1993; 56:1518-22. 62 Montenegro LM, Greeley WJ. Pro: the use of modified ultrafiltration during pediatric cardiac surgery is a benefit. 7 Cardiothoracic Vascular Anesthesia 1998; 12: 480-2. 63 Watanabe T, Miura M, Orita H et al Brain tissue pH, oxygen tension, and carbon dioxide tension in profoundly hypothermic cardiopulmonary bypass: pulsatile assistance for circulatory arrest, low-flow perfusion, and moderate-flow perfusion. 7 Thorac Cardiovasc Surg 1990; 100:274-80. 64 Naik SK, Knight A, Elliott M. A prospective randomized study of a modified technique of ultrafiltration during pediatric open-heart surgery. Circulation 1991; 84 (Suppl III): 422-31. 65 Naik SK, Knight A, Elliott MJ. A successful modification of ultrafiltration for cardiopulmonary bypass in children. Perfusion 1991; 6:41-50.

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66 Journois D, Puopard P, Greeley WJ et al. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Anesthesiology 1998; 81:1181-9. 67 Darling EM, Shearer IR, Nanry K et al Modified ultrafiltration in pediatric cardiopulmonary bypass. / Extracorpor Technol 1994; 26:295-9. 68 Davies MJ, Nguyen K, Gaynor JW et al. Modified ultrafiltration improves left ventricular systolic function in infants after cardiopulmonary bypass. / Thome CardiovascSurg 1998; 115: 361-70. 69 Corno AF, von Segesser LK. Is hypothermia necessary in pediatric cardiac surgery? Eur ] Cardiothoracic Surg 1999; 15:110-11. 70 Corno AF, Hurni M, von Segesser LK. Normothermic high flow in pediatric cardiac surgery. Thome Cardiovasc Surg2QQQ; 48 (Suppl I): 34-5. 71 Watanabe T, Miura M, Orita H et al. Brain tissue pH, oxygen tension, and carbon dioxide tension in pro-

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Extracardiac Fontan: the importance of avoiding cardioplegic arrest Carlo F. Marcelletti, MD & Raul F. Abella, MD

Single ventricle repair resulting in right heart bypass may be applicable in the management of a variety of complex congenital cardiac anomalies. Over the years, a number of modifications of the original Fontan procedure have been proposed in an effort to improve outcome. During the past 10 years, we have focused our attention on two main issues: the concept of staging toward the Fontan procedure, which has proven to reduce the number and impact of risk factors present when such a procedure is performed, and the development of a surgical technique that is simple and easy to teach, the total extracardiac Fontan repair. The Fontan procedure by means of an extracardiac conduit was initially proposed for patients presenting with anomalies of intra-atrial anatomy, such as pulmonary and systemic venous return, auricular juxtaposition hypoplasia, or atresia of the atrioventricular left valve or common atrioventricular valve [1]. In addition to this preliminary experience and because of the uneventful outcome of these patients, we extended this technique to all patients, with a functional anatomic single ventricle. In our early experience we were quite concerned about this novel procedure based on the implementation of an artificial conduit into the systemic venous pathway because of the possible risks of late stenosis and thrombus formation. The extracardiac modified Fontan has a number of theoretical advantages. Because the conduit is constructed outside the heart, the operation may be performed with the patient supported on cardiopulmonary bypass (CPB) without arresting the heart. In

selected patients, the extracardiac Fontan may be accomplished without the use of CBP. A close and careful follow-up including examinations was conducted in 231 patients; the first 64 patients had been operated using the initial technique of cardiocirculatory arrest and the remaining 167 patients underwent the new approach without cardiac arrest.

Myocardial protection and management in patients with a functional single ventricle No single method of myocardial management is unequivocally the best. Many different methods are in use by surgeons obtaining good results. We used two principal approaches: 1 Staging towards the Fontan procedure. 2 Fontan procedure without cardioplegic arrest in moderate hypothermic perfusion. Ventricular hypertrophy is a widely known risk factor of the Fontan operation for complex cardiac anomalies. Ventricular hypertrophy alters both diastolic function [2] and threshold sensitivity to ischemic damage of the systemic ventricles [3], thereby affecting its crucial role of negative pump mechanism in the Fontan circulation. It is worth noting that this myocardial lesion has been reported in patients who have complex cardiac anomalies. Even after a Fontan operation problems can manifest as one of two acute complications. One is a relative increase in ventricular mass after sudden

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normalization of volume overload [4], and the second is a result of inadequate myocardial protection during the operation.

Staging toward the Fontan procedure Surgical management of children with single ventricular physiology has continued to evolve. Many institutions have adopted various approaches with improved early clinical outcome. Staging the Fontan operation with the bidirectional Glenn anastomosis, and the deliberate creation of a residual right-to-left atrial shunt, have undoubtedly contributed significantly to an improved early outcome in these patients and permitted the extracardiac approach of the Fontan procedure. The ideal candidates for the Fontan procedure should have a normal pulmonary vascular bed with low pulmonary artery pressure, low pulmonary vascular resistance, absence of distortions of pulmonary arteries, absence of anomalous pulmonary venous connections, and normal or near-normal function of the single ventricle (i.e. without severe ventricular hypertrophy or dilatation related to pressure or volume overload) [2]. Many of these patients undergo the Fontan procedure after one or more surgical palliations. The potential effects of previous surgery must be considered, such as chronic volume overload secondary to systemic to pulmonary artery shunt and/or atrioventricular valve regurgitation, and chronic pressure overload secondary to pulmonary artery banding and/or subaortic obstruction. These hemodynamic changes may cause ventricular hypertrophy with early compromise of cardiac function. It is clear that correct timing in patients with a univentricular heart (UVH) is paramount in both the early and late outcome of surgical treatment. No matter which type of UVH the patient has, the goal is to keep the patient alive until approximately 2 years of age, at that time a total cavopulmonary connection can be accomplished since the systolic and diastolic function of the single ventricle has been preserved. First stage and associated procedures Bidirectional cavopulmonary anastomosis (BCPA) brings the advantage of dramatically reducing the volume load of the systemic ventricle to normal values,

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and diverting desaturated blood only to the lungs, increasing the effective pulmonary blood flow. Considering the persistence of systemic venous drainage from the inferior vena cava (IVC) directly into the atrial cavity provides an adequate filling pressure for the single ventricle, independent from any restriction, and from the passage of blood through the pulmonary vascular bed [5,6]. The first stage can be performed primarily in cyanotic patients older than 3 months who have single ventricle physiology and are either extremely cyanotic or have an excessive volume load. This usually results in signs of congestive heart failure. For the child who has an ideal balance of pulmonary and systemic blood flow, we generally wait until at least 9 months of age. The objective of this first stage is to treat or eliminate all the possible risk factors to allow the Fontan circulation. The first stage of the bidirectional Glenn procedure increases the effective pulmonary blood flow and eliminates ventricular volume [5]. Patch enlargement of the pulmonary arteries The most frequent site of pulmonary artery stenosis is the origin of the left pulmonary artery in correspondence to the insertion of a formerly patent ductus arteriosus whose retraction causes a true coarctation of the pulmonary artery. Less frequently, a stenosis or distortion is found involving the right (or left) pulmonary artery due to a previous systemic to pulmonary artery shunt. The anastomotic site of the superior vena cava (SVC) can be used for resolution in many of the latter stenoses, but if the stenoses are peripheral and involve the branches, a patch is required. Atrioseptectomy can either be performed from the opening of the cavoatrial junction after division of the SVC, or from the opening of the pursestring suture of atrial cannulation, when circulatory arrest is used, and the cannula is removed. The opening is pushed down toward the atrial septum and the septum primum is grasped, pulled up, and resected. Complete resection of the septum primum is generally an adequate atrioseptectomy [7]. Main pulmonary artery (MPA) to aorta anastomosis Patients with previous pulmonary artery banding are prone to develop subaortic obstruction; therefore, since 1986, our policy has been to associate

Extracardiac Fontan an MPA to an aorta anastomosis at the time of a BCPA[8].

Second stage Fontan extracardiac Extracardiac Fontan with cardioplegia and cardiocirculatory arrest Our group described the technique of a total right bypass by means of interposition of an extracardiac conduit in 1990 [1]. In the last 10 years many modifications have been made to the original approach. We used deep hypothermia and circulatory arrest in 64 patients. After median sternotomy CPB was instituted by means of aortic cannulation and a single right atrial cannula. Cardiac standstill occurred under deep hypothermia, and circulatory arrest was achieved. The IVC was transected, and care was taken to avoid damage to the right coronary artery, and the atrial stump of the IVC was oversewn with a running suture. Preclotted Dacron conduit was anastomosed end-toend to the stump of the transected IVC with a running suture. The distal end of the conduit was anastomosed end-to-side to the inferior aspect of the right pulmonary artery which was opened with a longitudinal incision. The conduit connecting the IVC to the pulmonary artery (PA) remained completely extracardiac. Atrial septectomy, when required, was performed through the atrial stump of the transected IVC. Cardiopulmonary bypass was reinstituted with the atrial cannula now draining the pulmonary venous return plus the coronary sinus return. No particular difficulties in venous drainage relating to use of a single left atrial cannula during rewarming were observed. Thirty-six patients received crystalloid cardioplegia and 28 patients received blood cardioplegia. The mean aortic cross-clamp time was 34 min (range 15-80 min).

Results Seven hospital deaths occurred (10.9%) in this initial period, the principal cause being myocardial damage in five patients all of whom had a combination of ventricular pressure or volume overload with myocardial hypertrophy before total extracardiac cavopulmonary connection (TECC).

Postoperative treatment Mean pulmonary artery pressure was 12 ± 4 mmHg (range 4-24 mmHg), the mean arterial oxygen saturation 82% ± 7.5% (range 51-95%), and the mean end-

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diastolic ventricular pressure 8 ± 3 mmHg (range 2-16 mmHg). The mean duration of mechanical ventilation was 28.3 h (1-96 h) excluding seven patients in whom ventilatory support was prolonged (100 h). Prolonged pleural and peritoneal effusions, defined as more than 10 days of drainage, or the need for multiple drainage procedures, occurred in 22 patients (33%). All patients received inotropic agents for 72 h.

Modification of the extracardiac Fontan without cardioplegic arrest Tolerance of the hypertrophied ventricle to ischemia Damage from a period of ischemia may result from a prolonged period (many days) of both systolic and diastolic dysfunction without muscle necrosis [9,10]. This condition is now termed myocardial stunning or myocardial hibernation [11,12]. Ischemic damage involves the myocardial cells, the vascular endothelium, and the specialized conduction cells. Overall reviews of the damage from myocardial ischemia and of the potentially damaging effect of reperfusion are available [13,14]. The switch from aerobic to anerobic glycolysis occurs within seconds of the onset of ischemia, and clearly reduces the level of high-energy phosphates in the myocardial cell [15-18]. Calcium plays a key role in reperfusion injury [14]. The stiffness of cardiac muscle resulting from uncontrolled reperfusion after a period of ischemia results from the massive influx of calcium into mitochondria and the cytoplasm of myocytes, as well as from edema and capillary disruption [19-21]. The observation is that of highly reactive oxygen species (free radicals) having destructive effects on cellular membranes that are generated during reperfusion after the ischemia period. All these events of ischemic damage have bigger repercussions in hypertrophied ventricles. For these reasons we avoid the use of cardioplegia in patients withUVH. The Fontan procedure is frequently performed in patients who have undergone at least one median sternotomy and therefore have large mediastinal adhesions found at resternotomy. We used this procedure without cardioplegic arrest in 167 patients. Cardiopulmonary bypass is initiated using femoral vein cannulation and single arterial cannulation. The venous cannulas should be kept as far away from the

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Figure 29.2 The anastomosis between the PTFE stretch and the inferior surface of the right pulmonary artery.

Figure 29.1 The SVC cannulation site should be high. Cannulation of the femoral vein is obligatory in order to carry out this technique.

heart as possible. This is important to allow for sufficient room in placing the extracardiac conduit. The inferior cannulation should invariably be in the femoral vein, to permit inferior anastomosis to the conduit and IVC. The SVC cannulation site should also be high at the SVC-innominate vein junction (Figure 29.1). It is important to encircle the SVC following cannulation. This cannulation allows decreasing cerebral venous pressure and increasing cerebral perfusion pressure. We use continuous perfusion without aortic cross-clamping; the surgical procedure is totally extracardiac since the atrioseptectomy had

been already performed at the BCPA stage. The operation is preformed in either moderate hypothermia or on a beating heart. The left ventricle is vented with a cannula placed in the right atrium. The border of the right pulmonary artery is incised along its entire length (Figure 29.2). The incision must reach the confluence of the pulmonary artery and the left pulmonary artery origin must be seen. The PTFE stretch conduit (we have never used a diameter less than 18 mm or greater than 22 mm) is cut slightly oblique to direct the IVC blood flow toward the confluence of the pulmonary arteries and sutured in place using a monofilament running suture. The PTFE stretch conduit is pulled down toward the IVC and cut slightly short to put the IVC and right pulmonary artery under gentle traction. The correct length of the conduit varies between 3 and 5 cm according to the patient's anatomy. The anastomosis with the IVC is performed with a running 6-0 prolene suture (Figure 29.3). If the IVC is not present, as is the case in patients with left isomerism and azygos continuation, the surgery is the same because the hepatic veins usually join together before reaching the atrium. A separate vein is sometimes present; in such cases, the vein should be "unifocalized" with the others to create a common single vein. When good staging is performed for single ventricular repair, the last step (extracardiac conduit) becomes a relatively simple procedure. The mean bypass time was 25 min (range 15-50 min). The shorter period on bypass certainly played a positive role in early success.

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Figure 29.4 Duration of mechanical ventilatory support. Improvement in cardiorespiratory function in patients without cardioplegic arrest.

artery distortion or hypoplasia appeared to be the cause of death in two patients, and heart failure in the other three patients. Figure 29.3 End-to-end anastomosis between the extracardiac conduit and the IVC. This surgical technique is totally extracardiac.

Ultrafiltration After bypass, significant accumulation of total body water may occur. This edema is distributed not only in the periphery, but also in vital areas such as brain, heart, gut, and lung. This increase in total body water can be partially controlled by limiting the excess amount of crystalloid given with the pump prime, and also by removing fluid using various means during or after CPB. The technique of ultrafiltration is performed in the immediate postbypass period. Most commonly, blood is removed from the aortic cannula, passed through a hemofilter, and returned as oxygenated, hemoconcentrated, and ultrafiltered blood to the cannula in the right atrium. Ultrafiltration improves intrinsic ventricular systolic function, improves diastolic compliance, increases blood pressure, and decreases inotropic drug use in the early postoperative period [22]. Ultrafiltration was performed in all patients after CBP as an important form of myocardial protection. Results Eight hospital deaths occurred (4.7%). The principal cause was myocardial in three patients, pulmonary

Postoperative treatment Mean pulmonary artery pressure was 11 ± 4 mmHg (range 5-20 mmHg), mean arterial oxygen saturation 90% ± 6.7% (range 67-97%), and mean end-diastolic ventricular pressure 5 ± 2 mmHg (range 3-11 mmHg). The mean duration of mechanical ventilation was 9.9 h (1-54 h) (Figure 29.4). Prolonged pleural and peritoneal effusions, defined as more than 10 days of drainage or a need for multiple drainage procedures occurred in 33 patients (20%). In this group of patients only 5% underwent the fenestration procedure (Figure 29.5). All patients received inotropic agents (mean 35.4 h) (Figure 29.6).

Extracardiac Fontan operation without cardiopulmonary bypass Cardiopulmonary bypass is known to activate inflammatory mediators, increase lung water, and decrease right ventricular compliance. These unfavorable effects of cardiopulmonary bypass can increase pulmonary vascular resistance and decrease pulmonary blood flow after cavopulmonary connection. If intracardiac repair is not necessary, the extracardiac total cavopulmonary connection could be performed without cardiopulmonary bypass. Several centers have begun to use this technique [23-25], which is one that should be in the pediatric cardiac surgeon's armamentarium.

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for cardiopulmonary bypass without the need for cardioplegia.

Summary

Figure 29.5 Decrease of the effusion in 13% of patients in whom the surgical technique was performed without cardioplegic arrest. In 5% of the patients it was necessary to carry out the fenestration procedure.

Figure 29.6 Duration of inotropic support. Improvement of ventricular function in the group of patients operated on without cardioplegic arrest.

Patients with a functional anatomic single ventricle undergo the Fontan procedure after one or more surgical palliations. Chronic volume overload secondary to systemic to pulmonary artery shunt and chronic pressure overload secondary to pulmonary artery banding result in an increase in ventricular cavity size followed by a proportional increase in eccentric hypertrophy, altering both systolic and diastolic function [5]. Myocardial protection begins with staging toward the Fontan procedure. The aim of this first stage is to prepare the myocardium and eliminate all possible risk factors to allow the Fontan circulation. In the first stage we performed BCPA, with all the associated procedures (patch enlargement of the pulmonary arteries, main pulmonary artery to aorta anastomosis) and intracardiac surgery (atrioseptectomy). This approach reduces the volume load of the systemic ventricle to normal values and diverts desaturated blood to the lung, thus increasing effective pulmonary blood flow. The second important form of myocardial protection is performance of the Fontan procedure using an extracardiac conduit. This technique has several theoretical and practical advantages. In our experience, one of the most important benefits of the extracardiac conduit approach has been the ability to complete the Fontan circulation without cardioplegic arrest. This technique is easy to reproduce and enables cardiopulmonary bypass time to be reduced, while preserving systolic and diastolic ventricular function. With this technique substantial improvements in early postoperative outcome are achieved.

References The ability to perform the extracardiac conduit Fontan procedure without cardiopulmonary bypass depends on a number of variables. The indications for performing this technique are not well established [23]. With this technique, it was found that time to extubation, length of ICU stay, and hospital stay were not statistically different in comparison with patients in whom cardiopulmonary bypass was used [25]. We prefer the approach which employs a short duration

1 Marcelletti C, Corno A, Ginnico S et al. Inferior vena cava—pulmonary artery extracardiac conduit. A new form of right heart bypass. / Thorac Cardiovascular Surg 1990; 100:228-32. 2 Giannico S, lorio FS, Carotti A et al. Staging toward the Fontan operation. Semin Thorac Cardiovascular Surg 1994; 6:13-16. 3 Di Donato R, Amodeo A, Di Carlo DD et al. Staged Fontan operation for complex cardiac anomalies with subaortic obstruction. / Thorac Cardiovasc Surg 1993; 105: 398-405.

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4 Martelletti CF, lorio FS, Abella RF. Late results of extracardiac Fontan repair. In: Pediatric Cardiac Surgery Annual of Seminars in Thoracic and Cardiovascular Surgery, Vol 2. Philadelphia, PA: Saunders, 1999: 31-141. 5 Albanese S, Carotti A, Di Donato R et al. Bidirectional cavopulmonary anastomosis in patients under two years of age. / Thorac Cardiovasc Surg 1992; 104:904-9. 6 Mazzera E, Corno A, Picardo S et al. Bidirectional cavopulmonary shunts: clinical applications as staged or definitive palliation. Ann Thorac Surg 1989; 47: 41520. 7 lorio FS, Marcelletti C, Hanley FL et al. Current approach for cavopulmonary conection. In: Operative Techniques in Cardiac and Thoracic Surgery. A Comparative Atlas, Vol 2. Philadelphia, PA: Saunders, 1997:196-204. 8 Di Carlo DD, Di Donato RM, Carotti A et al. Evaluation of the Damus-Kaye-Stansel operation in infancy. Ann Thorac Surg 1991; 52:1148-53. 9 Ellis SG, Henschke CI, Sandor T, Wynne J et al. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. / Am Coll Cardiol 1983; 1:1047-55. 10 Heyndrickx GR, Millard RW, McRitchie RJ et al. Regional myocardial function and electrophysiological alterations after brief coronary artery occlusion in dogs. JClin Invest 1975; 56:978-85. 11 Braunwald E. The stunned myocardium. Newer insights into mechanisms and clinical implications [letter]. / Thorac Cardiovasc Surg 1990; 100: 310-11. 12 Braunwald E, Kloner RA. The stunned myocardium: prolonged postischemic ventricular dysfunction. Circulation 1982;66:1146-49. 13 Hearse DJ, Braimbrige MV, Jynge P. Ischemia and reperfusion: the progression and prevention of tissue injury. In: Protection of the Ischemic Myocardium: Cardioplegia. New York: Raven Press, 1981: 21. 14 Nayler W, Elz JS. Reperfusion injury: Laboratory artifact or clinical dilemma? Circulation 1986; 74:215-21.

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15 Clark BJ III, Woodford EJ, Malec EJ et al. Effects of potasium cardioplegia on high-energy phosphate kinetics during circulatory arrest with deep hypothermia in the newborn piglet heart. / Thorac Cardiovasc Surg 1991; 101: 342-49. 16 Jarmakani JM, Nakazawa M, Nagatomo T et al. Effect of hypoxia on mechanical function in the neonatal mammalian heart. Am JPhysiol 1978; 235: H469. 17 Murphy CE, Salter DR, Morris JJ et al. Age-related differences in adenine nucleotide metabolism during in vivo global ischemia. SurgForum 1986; 37:288. 18 Starnes VA, Hammon JW Jr, Lupinetti FM et al. Function and metabolic preservation of immature myocardium with Verapamil following global ischemia. Ann Thorac Surg 1982; 34:58-65. 19 Beyersdorf F, Okamoto F, Buckberg GD etal. Studies on prolonged acute regional ischemia. II. Implications of progression from dyskinesia to akinesia in the ischemic segment. / Thorac Cardiovasc Surg 1989; 98:224-33. 20 Buja LM, Chien KR, Burton KP et al. Membrane damage in ischemia. AdvExpMed Biol 1982; 161:421-31. 21 Castaneda AR, Jonas RA, Mayer JE, Hanley FL. Cardiac Surgery of the Neonate and Infant. Philadelphia, PA: Saunders, 1994:41-64. 22 Davies MJ, Nguyen K, Gaynor JW et al. Modified ultrafiltration improves left ventricular systolic function in infants after cardiopulmonary bypass. / Thorac Cardiovasc Surg 1998; 115:361-70. 23 McElhinney DB, Petrossian E, Reddy VM et al. Extracardiac conduit Fontan procedure without cardiopulmonary bypass. Ann Thorac Surg 1998; 66:1826-8. 24 Okabe H, Nagata N, Kaneko Y et al. Extracardiac cavopulmonary connection of Fontan procedure with autologous pedkled pericardium without cardiopulmonary bypass. / Thorac Cardiovasc Surg 1998; 116:1073-5. 25 Tarn VKH, Miller BE, Murphy K. Modified Fontan without use of cardiopulmonary bypass. Ann Thorac Surg 1999;68:1698-703.

CHAPTER 30

Preservative cardioplegic solutions in cardiac transplantation: recent advances RomualdoJ. Segurolajr, MD & Rosemary F. Kelly, MD

Introduction This chapter considers the current advances in preservation solutions used for cardiac transplantation. Poor tolerance of the myocardium to prolonged cold ischemia remains a major concern in heart transplantation. There is a known correlation between early patient survival and duration of cold ischemic times. One-year mortality rates increase after transplantation of hearts subjected to more than 3.5 h of ischemia, and clinical graft viability is still limited to 4—6 h of heart preservation [1]. Clinical methods of myocardial preservation for cardiac transplantation are discussed in detail in Chapter 31. Although methods of improving graft function include methods of continuous hypothermic perfusion, effective cardioplegic solutions for myocardial protection are the first step in any successful preservation protocol, and will be the focus of this chapter.

Perf usate composition There is considerable variability in the type of heart preservation solutions used in the United States, with no consensus regarding the optimal preservation solution [2]. Cardioplegia is used to stop the heart safely, it diminishes the myocardial energy requirements, creates an environment for continued energy production, and counteracts the deleterious effects of ischemia. The active components found in nearly all preservation solutions include potassium to arrest the heart, sodium and chloride for ion exchange, glucose to provide a substrate for anerobic metabolism, and

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bicarbonate to buffer the ischemic acidosis [3]. Although glucose has been used in preservation solutions as the metabolic substrate, documentation is lacking that hypothermic hearts consume exogenous glucose during cardioplegic conditions [4]. Indeed, the dominant protective effects of hypothermia and mechanical cardiac arrest may mask the suboptimal composition of solutions used for cardiac preservation. Even with the most advanced methods of myocardial protection, ischemic tissue injury progresses exponentially with time, thus emphasizing the importance of an expeditiously performed operation. An increase in donor organ myocardial ischemia is known to affect early graft function and patient survival [5]. Diastolic function has been reported to be more sensitive to ischemic damage, and its deterioration occurs earlier than systolic dysfunction [6]. During cardiac surgery or cardiac transplantation the heart must be protected against ischemic and reperfusion injury in order to preserve postoperative function. Ischemic effect on the myocardium appears to be minimal if kept under 4 h [7]. The optimal preservation solution for donor cardiac allograft procurement would minimize, or even eliminate, any structural or functional damage to the myocardium due to ischemia and reperfusion. It is a solution that has yet to be developed. There are currently more than 160 preservation solutions used clinically in cardiac transplantation [2]. The most common preservation solutions are Plegisol, University of Wisconsin, Stanford, Roe, Collins, Krebs, and St Thomas. The most common additives in

Cardioplegia in cardiac transplantation customized solutions are gluconate, acetate, lidocaine (lignocaine), albumin, and insulin. Demmy et al. analyzed the pattern of usage and related survival of these commonly used solutions [2]. In their retrospective study, they reported that among 167 solutions used in 137 different transplant centers between June 1994 and February 1995, the most common solutions were the traditionally cited ones (55%), and the remainder were customized. Univariate analysis of this data regarding survival suggests that survival rates are not equal for all commonly used solutions, but no difference was noted in customized solutions. Krebs' solution fared the best and the clinical advantage of the Stanford solution previously shown was not evident [8]. Intracellular solutions were defined as having sodium content of less than 70 mmol/L. These solutions with intracellular composition had a 1-month survival benefit but did not have a 1-year survival over extracellular solutions. Logistic regression to adjust for the effects of donor and recipient risk factors upon cardiac transplantation only confirmed a significantly lower odds of mortality at 1 month when comparing intra- versus extracellular solutions. This difference was lost thereafter. One of the important factors involved in the decline of diastolic function after ischemia is interstitial edema, which may occur especially with the extracellular type of crystalloid cardioplegic solutions [9]. However, this decline in diastolic function with extracellular solutions found in the animal model has not been evident in the clinical situation. In fact, as follow-up to the clinical survey, Demmy et al. further studied the impact of intra- versus extracellular preservation solutions on a rat heart model [10]. Again, the data supported the superiority of certain intracellular formulations, but that the evidence of optimal organ preservation is difficult to judge clinically using hemodynamic values routinely available. Obviously, such considerations as technical problems, patient selection, variation in donor heart quality, program volume, and patient comorbid conditions dramatically affect outcome, making it difficult to clearly establish solution-related problems [2]. There are several common cardioplegic additives currently used clinically that offer additional protection to the myocardium. Mannitol is an osmotic agent used to prevent cellular edema. Lidocaine (lignocaine) and procaine stabilize cell membranes, induce arrest, and suppress arrhythmias. Calcium

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maintains cell membrane integrity and prevents calcium paradox. Magnesium induces arrest and stabilizes membranes. Glutamate and aspartate provide substrate for the Krebs' cycle. Nitroglycerine acts as a nitric oxide donor and promotes coronary vasodilatation. Methylprednisolone reduces cellular edema. Calcium channel blockers stabilize membranes. Highenergy phosphates provide energy to the myocardium. Experimentally, these agents have demonstrated a reduction in the degree of ischemia-reperfusion injury, and improved myocardial recovery. Though additives should clearly demonstrate their clinical benefit, few formulas have been so studied in the clinical arena. Other additives incorporated into cardioplegic solutions include amino acids that can be metabolized to citric acid cycle intermediates [11]. Segel et al. studied the addition of pyruvate to preservation solution in a rabbit model [12]. The hearts preserved with pyruvate-containing crystalloid had better posttransplantation function, although there was slight loss in compliance and decreased contractile function compared to controls. Other experimental work on long-term preservation has incorporated substrates for oxidative metabolism into cardioplegic solutions [13,14]. Overall the results remain somewhat equivocal as to benefits and depend on the animal model utilized. Histidine-tryptophan-ketoglutarate (HTK) solution is a preservation solution that relies heavily on amino acid substrates. It may be an effective preservation solution due to the high buffering capacity provided by histidine/histidine-hydrochloride that suppresses ischemia-induced acidosis [15]. The decrease in acidosis inhibits ATP degradation during hypothermic storage. In addition, the ketoglutarate and tryptophan in HTK solution are effective additives in protecting the myocardium during ischemia [16]. In an animal model, the myocardial tissue level of ATP was significantly higher in hearts preserved with the HTK compared to University of Wisconsin solution [17]. In addition, the solution has been modified by the addition of hyaluronidase that resulted in superior cardioprotective qualities compared to HTK solution with cold storage up to 24 h in the rat and rabbit hearts [ 18]. As with other solutions, however, prospective clinical studies are unavailable that clearly demonstrate the advantage of HTK solution over other solutions.

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Mechanism of ischemiareperfusion injury Understanding the mechanisms of ischemia-reperfusion injury during organ procurement is critical to the improvement of future preservation techniques. Even under hypothermic conditions used during transportation of the donor organ, myocardial cells maintain a level of metabolic activity. The initial phase of organ procurement involves a prolonged ischemic event requiring anerobic metabolism to support any myocardial metabolic activity during storage. During this phase, intracellular acidosis occurs, which is poorly tolerated by myocardial cells. Resultant edema formation during ischemia and upon reperfusion is a morphologic sign of severe myocyte membrane damage and is associated with a disturbance of the ionic balance of cell membranes [19]. Clearly, myocardial edema impairs both coronary circulation and systolic performance [20]. The ability to preserve graft function following prolonged ischemia is critical to improving cardiac transplantation outcomes. Though current preservation strategies do employ antioxidant additives, optimization of the preservation solutions involves understanding and alteration of the various mechanisms of tissue injury that can occur with transplantation. Ischemia-reperfusion injury is an important mechanism of organ injury in heart transplantation. Cell damage from ischemia primes the tissue for the subsequent damage from reperfusion, with reperfusion resulting in even greater injury than ischemia alone. The mechanism of ischemia-reperfusion injury in heart transplantation is a complex series of events. Prolonged ischemia results in the activation of proteases, particularly lysosomal enzymes, which lead to biological and morphological damage to the myocardium. This is then associated with a decrease in glycogen stores, depletion of high-energy phosphate compounds, ionic imbalances, local release of catecholamine, accumulation of lactic acid, and deterioration of cellular function. Reperfusion after ischemia causes additional damage to the myocardium through the production of free radicals and activation of enzymes, which causes cellular damage and depression of the left ventricular function. The ischemic phase of heart transplantation leads to anaerobic metabolism that results in depletion of ATP. Depletion of ATP alters membrane ionic

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ATP-dependent pumps, thereby increasing the entry of calcium, sodium and water into the cell [21]. This massive calcium overload leads to: (i) activation of proteases, lipase, and phospholipases; (ii) ATP usage by activation of ATPases; and (iii) inhibition of mitochondrial oxidative phosphorylation. Ischemia also causes the catabolism of adenine nucleotides resulting in an accumulation of hypoxanthine within the cells [22]. At the same time, ischemia is associated with the proteolytic conversion of xanthine/hypoxanthine dehydrogenase to xanthine/hypoxanthine oxidase, which primes the cell for free radical production upon reperfusion with oxygenated blood [23]. Upon reperfusion, xanthine oxidase metabolizes hypoxanthine and xanthine to uric acid, and in the process generates superoxide radical and hydrogen peroxide. The superoxide radical may then react in the ion-catalyzed Fenton reaction to form highly reactive hydroxyl radicals [24]. Studies of reoxygenated human and bovine endothelial cells show release of superoxide anion and hydroxyl radical. These free radicals cause lipid peroxidation, protein sulfhydryl oxidation, and cross-linking, which leads to enzyme activation and subsequent extravasation of intravascular components, signifying alteration of barrier function [25]. Membrane injury then results in release of intracellular enzymes from the myocytes, causing cell injury and death. Vulnerability to oxidant damage increases as the burst of reactive oxygen species during ischemiareperfusion overwhelms endogenous antioxidants. Normally, organs contain ubiquitous endogenous oxygen radical scavengers such as superoxide dismutase, reduced glutathione, catalase, and vitamins C and E, which counteract the effects of such toxic oxygen species as superoxide, hydrogen peroxide, and hydroxyl radical. Ischemia depletes tissue levels of these naturally occurring barriers to oxidant injury and increases vulnerability to reoxygenation injury, especially as reoxygenation further reduces antioxidant availability [26,27]. Following the initial injury of ischemiareperfusion, the activation of neutrophils significantly amplifies tissue injury. There are several well-defined pathways of neutrophil activation. Early endothelial cell membrane injury promotes neutrophil adherence and activation, leading to capillary plugging, reduced flow, and release of oxidants. This neutrophil activation may then contribute to myocardial stunning,

Cardioplegia in cardiac transplantation resulting in low-output syndrome following transplantation [28]. One particularly important pathway of neutrophil activation is through platelet activating factor (PAF) formation. This PAF formation is a result of the increased intracellular calcium concentration that occurs with ischemia-reperfusion injury, causing phospholipase A2 activation. Activated phospholipase A2 hydrolyzes arachidonic-containing phospholipids, including a PAF precursor. Formation of PAF results in activated endothelial cell presenting PAF to the neutrophil receptor, which causes neutrophil aggregation. In addition, oxygen free radicals generated during ischemia-reperfusion cause prolonged and inappropriate expression of P-selectin on the surface of endothelial cells. The coexpression of P-selectin and PAF mediates a joint process of neutrophil tethering and activation [29]. Neutrophils attached to the endothelial cells become polarized and able to release proteolytic enzymes as well as reactive oxygen species, both of which induce cell damage. Another pathway of neutrophil activation includes reactive oxygen intermediates stimulating interleukin 8 (IL-8), which in turn induces the transmigration and aggregation of neutrophils [30,31]. At the same time, complement activation by ischemic tissue generates C3a and C5a, which causes vascular leakage and enhances activation and infiltration of leukocytes. The complement activation disrupts vascular endothelial cell function and leads to tissue injury. Thus, amplification of organ injury continues during reperfusion through activation of neutrophils and the complement system. All these pathways are potential points of intervention for eliminating organ injury following procurement and transplantation.

Interventions to reduce ischemiareperfusion injury Cardiac preservation solutions have included additives that attenuate tissue injury from ischemiareperfusion. Yet despite the additives and improved understanding of various mechanisms of ischemiareperfusion injury, the clinical limitation of 4-6 h of ischemic time persists. Although the different steps involved in the ischemia-reperfusion cascade permit distinct points of intervention, no critical step has been defined that results in the elimination of such injury. Many interventions are in the experimental

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stage and require further refinement before clinical application is possible. Free radical scavengers or inhibitors are important additives. Several additives have been included in experimental and clinical preservation solutions with varying success in experimental animal models. Extrapolation of experimental findings to clinical events requires a reasonable perspective of the limitations of laboratory methods. Inhibitors of reactive oxygen species production include superoxide dismutase and allopurinol. AUopurinol has been used clinically in University of Wisconsin solution, though improved outcomes have not been directly linked to this additive in cardiac transplantation. Free radical scavengers include glutathione, nitric oxide, lazaroids, and vitamin E. Inhibition of the Fenton reaction with iron chelators may reduce the formation of the highly reactive hydroxyl radical. All of these additives have shown improved graft function in experimental studies, but have not yet been incorporated into a clinical preservation strategy. What may be even more important to limiting ischemia-reperfusion injury is inhibition or deactivation of neutrophils. In a rabbit model, neutrophils were sequestered in transplanted hearts within 4 h after transplantation, but not in hearts transplanted within 1 h of ischemic time [32]. This suggests that neutrophil-mediated reperfusion injury may be an important component in heart graft failure when ischemic times are prolonged. Neutrophils play a central role in tissue injury through amplification of the reperfusion injury. Targeting the adhesion molecules using monoclonal antibodies inhibits the cellular interaction between neutrophils and endothelial cells, and limits reperfusion injury. Similarly, a monoclonal antibody against IL-8 prevents neutrophil activation and aggregation. In addition, protease inhibitors may inactivate the cytotoxic enzymes released from activated neutrophils. It is also possible to use mechanical filtration of neutrophils during cardiopulmonary bypass [33]. Although each of the methods discussed has experimental merit in reducing graft injury, they have not yet been available clinically. Inhibition of complement activation may also have a potential role in heart transplantation. Soluble complement receptor type 1 inhibits the activation of the classic and alternate pathways. These interventions may limit the amplification of injury that occurs during reperfusion. There is less experimental data

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currently available for this mechanism of intervention, but further study is indicated. The role of nitric oxide remains unclear despite extensive study, as the data are somewhat conflicting. Nitric oxide causes vasodilatation, reduces platelet aggregation, and reduces neutrophil activation. Sodium nitroprusside administered with cardioplegic solution and with reperfusion in a rat heart model was found to improve donor heart preservation. However, the inducible enzymatic pathway of nitric oxide production is associated with tissue injury. The ability to inhibit inducible nitric oxide synthetase can be protective during ischemia. Due to the conflict in information, the clinical application of nitric oxide in heart transplantation remains limited and it is not routinely utilized as an additive in preservation techniques.

Hyperpolarized cardiac arrest A separate area of investigation has focused on the development of cardioplegic solutions directed at prolonging the tolerance of the myocardium to ischemia by maintaining the heart in a state of "reversible injury." It has been suggested that the depolarizing nature of hyperkalemic solutions results in ionic imbalance caused by continuing transmembrane fluxes [34]. This imbalance may increase the impact of ischemiareperfusion injury on the myocardium. An alternative to hyperkalemic cardioplegia is to arrest the heart in a hyperpolarized state, which maintains the membrane of the myocardium near the resting membrane potential [34]. Hyperkalemic cardioplegic solutions are the current clinical standard and have an elevated potassium concentration ranging between 12 and 25 mmol/L. As the resting membrane potential of cardiac cells is around -90 mV, these hyperkalemic solutions lead to a depolarization of the membrane potential to about -50 mV. At this membrane potential the sodium channels are also inactivated and the heart arrested in a flaccid diastolic state [35]. However, at this membrane potential, other ionic mechanisms such as sodium-hydrogen exchange may cause a slow influx of sodium. This sodium influx could lead to calcium overload during reperfusion, which is toxic to the myocardium [36]. Hyperpolarization results in complete arrest of the sinus node. This potassium agonistic property will offer a more complete and persistent arrest of the

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heart. Recognition of this mechanism launched the idea of using hyperpolarizing instead of depolarizing agents for the induction of cardiac arrest with cardioplegia. The resultant hyperpolarized state offers a balanced transmembrane gradient, which will maintain ionic balances during ischemia. Polarized arrest has been associated with reduced ionic imbalance and improved recovery of cardiac function [37]. It is possible to achieve this hyperpolarized state using various drugs. These drugs include adenosine, sodium channel blockers (procaine, tetrodotoxin, and lidocaine (lignocaine)), or potassium channel openers (nicorandil and pinacidil). Multiple animal studies have demonstrated that using adenosine cardioplegic solutions alone or in combination with potassium reduces the time to myocardial arrest and recovery after reperfusion is significantly better [38-40]. Adenosine has been shown to be protective to the ischemia-reperfused myocardium. The addition of adenosine deaminase inhibitor to cardioplegia solution resulted in improved functional recovery following cold storage in a dose-dependent fashion. It appears to inhibit adenosine catabolism via a receptor-mediated mechanism [41]. Potassium channel openers as well have been studied in multiple animal models but results have been conflicting [42]. Potassium channel openers are thought to exert their protective effect by inducing hyperpolarization of the myocardial cells. It is assumed that hyperpolarization represents a resting membrane potential that is more negative, as by opening the potassium channels should move the resting membrane potential toward the potassium equilibrium potential. Alternatively, a hyperpolarized state may be achieved by blocking sodium channels. Studies have suggested that the depolarized arrest induced by tetrodotoxin reduced metabolic demands on ischemic hearts by a larger factor than depolarized arrest by hyperkalemia. Extracellular potassium accumulation was significantly reduced in hearts arrested with tetrodotoxin compared to hyperkalemic arrest [43]. Myocardial protection during cardiac transplantation has been successfully accomplished with potassium-dependent cardioplegia, but this predisposes to ionic imbalances and, hence, reperfusion irritability. Arresting the heart in a hyperpolarized state theoretically reduces these ionic imbalances and therefore decreases the rate of postischemic irritability.

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Another major metabolic consequence of ischemic preconditioning is reduction of intracellular acidosis, which then results in reduced myocardial edema. The sodium (Na+)/hydrogen (H+) exchange is also affected by the reduction in intracellular acidosis, and its activity is reduced with a noted decrease in intracellular sodium [53]. However, the protection afforded to Ischemic preconditioning myocytes by preconditioning does not appear to Brief periods of myocardial ischemia separated by extend to endothelial cells, as endothelium-dependent reperfusion increase myocardial tolerance to infarction coronary responses are unaffected by preconditioning —a phenomenon termed "ischemic preconditioning" [49,54]. Diazoxide is a drug that duplicates the beneficial [44]. Preconditioning has been shown to: (i) cause preservation of myocardial high-energy phosphates; effects of preconditioning on postischemic function (ii) attenuate intramyocardial acidosis; and (iii) by selective opening of the mitochondrial KATP chanreduce the rate of anaerobic glycolysis and subsequent nels. This effect supports the role of KATP channels as accumulation of lactate during prolonged ischemic mediators of the cardioprotective effects of ischemic insult. It has been identified as a successful strategy preconditioning [52]. Subsequently, the beneficial for improving preservation of cardiac allografts and action of diazoxide involves a reduction in intracellumay be an important adjunct to cardiac preserva- lar calcium overload. However, diazoxide administion strategies [45,46]. Single or repeated periods of tered in the postischemic period failed to improve ischemia may have a protective effect during more recovery of the myocardial function and this may be prolonged ischemic episodes by the induction of due to another effect of diazoxide, which includes endogenous antioxidants [47]. In a rat model, precon- reduction in ATP synthesis. By contrast, study of another mitochondrial KATP ditioning was noted to offer additional protection to the myocardium by preventing increase in diastolic channel activator, nicorandil, showed significant stiffness following cardioplegic arrest with St Thomas' beneficial effects in cold-stored hearts [55]. The best Hospital solution [48]. Though the extent of added method of administration for these drugs appears to protection to hypothermic arrest from precondition- be in conjunction with a cardioplegic solution, as the ing may be relatively small compared to protection drugs may exert a hypotensive effect that would be observed after unprotected normothermic ischemia, detrimental if given prior to donor organ procurement. Recently, reduction in calcium overload by inhibitthis conclusion has been challenged [48,49]. Possible mechanisms underlying the endogenous ing the (Na+-H+) exchanger has been investigated protection of ischemic preconditioning are: (i) reduc- [56]. This antiport allows the extrusion of intracellular tion of lactate accumulation; (ii) increase in adenosine protons in exchange for sodium ions. In ischemiarelease; (iii) enhancement of cell salvage of ATP; (iv) reperfusion, the depletion of ATP leads to impaired the opening of ATP-sensitive potassium channels; and efflux of sodium ions through the ATP-driven Na+(v) the inhibition of intracellular calcium overload. potassium (K+) ATPase. The increased intracellular Ischemic preconditioning is thought to cause a pro- sodium results in calcium (Ca2+) overload because of tein kinase C-mediated activation of mitochondrial the increased calcium influx through the Na+-Ca+2 potassium adenosine triphosphate (KATP) channels exchanger. It is possible to blunt the ischemia[ 50 ]. It has been postulated that the entry of potassium reperfusion injury using Na+-H+ exchanger inhibitors through these open channels dissipates the mem- [56]. This has not been used clinically in the transbrane potential normally established across the inner plantation setting, but may become an important mitochondrial membrane by the proton pump. This additive to cardioplegic solutions or upon reperfusion. The choice of a Na+-H+ exchanger inhibitor may be in turn would decrease the calcium uptake into the mitochondria, which is a major determinant of post- better than a potassium channel opener (diazoxide) ischemic function [51,52]. This idea is consistent for improving preservation of cold-stored hearts. with the ability of preconditioning to reduce calcium Cariporide is a Na+-H+ exchange inhibitor that has been studied experimentally in rat hearts [49]. When overload in the myocardium. However, the profibrillatory effects of the hyperpolarizing agents are well established. Therefore, despite promising experimental data, considerable additional studies will be required to make hyperpolarized arrest a clinical standard.

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cariporide was added to the cardioplegia solution as well as the reperfusate, the myocardial protective effects were similar to preconditioning. In addition to limiting sodium-driven calcium overload, Na+-H+ exchanger inhibitors prevent the alkaline overshoot occurring during reperfusion, and the hypercontracture of myofilaments. The improved outcome was noted in both small and large animal models [49,57]. In particular, the combination of ischemic preconditioning with the addition of cariporide to cardioplegia and upon reperfusion had the greatest impact on preservation of postischemic cardiac function [49].

Protease inhibitor As discussed, prolonged ischemia results in activation of proteases, which in turn leads to biological and morphological damage to the myocardium. Aprotinin, a protease inhibitor, may protect the myocardium from ischemia-reperfusion injury by suppressing the release of lysosomal enzymes during ischemia [58]. It may preserve adenine nucleotide and adenosine triphosphate as well as stabilize tissue cyclic adenosine monophosphate levels in hearts preserved at 4°C for 6 h followed by reperfusion [59]. However, in this study, despite better biological and morphological integrity in the aprotinin-preserved hearts, the functional recovery of the left ventricle was slow. This unexpected result suggests that the utilization of aprotinin in preservation solution may be somewhat limited.

Gene therapy Gene transfer techniques are a potential adjunct to cardioplegia and cardiac preservation by allowing the transfer of protective proteins and enzymes to the transplanted heart. The delivery techniques and transfection rates have greatly improved recently. However, gene therapy requires further refinement in experimental models before it is clinically applicable in heart transplantation. Heat shock proteins (HSP) are a family of inducible intracellular proteins that have a protective role for cells exposed to environmental stress and that have been transfected and studied in heart transplantation animal models. Levels of HSP are known to increase in ischemia-reperfusion injury. Mechanisms that increase HSP, induce free radical scavengers, and attenuate

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apoptosis lead to the protection of ventricular and endothelial function after ischemia-reperfusion injury [60—62]. In a clinical study, patients with high initial myocardial levels of inducible HSP 70 had a higher degree of cardioprotection during cardiac surgery [63]. In a rat model, HSP 70 was successfully transfected into donor hearts [64]. There was improved preservation of ventricular and endothelial function in HSP 70 gene-transfected hearts. Therefore it is possible that HSP may have a role in the clinical setting as an adjunct to cardioplegia for myocardial protection. Gene transfer techniques have also been used for transfection of free radical production inhibitors such as manganese-superoxide dismutase. This enzyme can confer a protective effect for ischemia-reperfusion injury. The method of gene transfer uses coronary artery infusion of the hemagglutinating virus of Japan liposome during cardioplegic arrest at the time of organ harvest [65]. The rat hearts transfected with manganese-superoxide dismutase showed a significant improvement in tolerance to ischemia-reperfusion injury. This model may provide a new tool for gene transfer that improves preservation techniques. It is possible that future clinical advances in transfection techniques may allow a more rapid induction of such protein expression as HSP 70 and superoxide dismutase by introduction into the heart by catheter techniques prior to organ donation [66].

Conclusion There continue to be significant advances in myocardial protection for cardiac transplantation. The alterations in cardioplegic ionic composition and solution additives have demonstrated potential improvement in preservation strategies using animal models, and have shown promise in the clinical arena. In particular, reduction in ischemia-reperfusion injury with antioxidant additives has been extensively studied and utilized. In addition, the reduction in neutrophil activation appears to limit the amplification of injury during reperfusion, and is an important area of investigation. As an adjunct to cardioplegia and hypothermia, the use of ischemic preconditioning in cardiac transplantation has intriguing possibilities, especially given the ease with which it can be incorporated clinically both pharmacologically and technically. The same is true for the potential role of gene transfer therapy. Continued investigations in the laboratory and clinical

Cardioplegia in cardiac transplantation arenas remain a vital part of improving preservation strategies and patient outcomes in heart transplantation. These advances in preservation techniques will positively impact cardiac transplantation by prolonging ischemic tolerance during organ procurement as well as improving graft function following implantation.

References 1 Hosenpud JD, Bennett LE, Keck BM et al. The Registry of the International Society for Heart and Lung Transplantation: seventeenth official report—2000. / Heart Lung Transplant 2000; 19:909-31. 2 Demmy TL, Biddle JS, Bennett LE et al. Organ preservation solutions in heart transplantation—patterns of usage and related survival. Transplantation 1997; 63: 262-9. 3 Demmy TL, Haggerty SP, Boley TM, Curtis JJ. Lack of cardioplegia uniformity in clinical myocardial preservation. Ann ThoracSurg 1994; 57:648-51. 4 von Oppell UO, Du Toit EF, King LM et al. St Thomas' Hospital cardioplegic solution. Beneficial effect of glucose and multidose reinfusions of cardioplegic solution. / Thorac Cardiovasc Surg 1991; 102:405-12. 5 Fragomeni LS, Kaye MP. The Registry of the International Society for Heart Transplantation: fifth official report—1988. /Heart Transplant 1988; 7:249-53. 6 Mirsky I. Assessment of diastolic function: suggested methods and future considerations. Circulation 1984; 69: 836-41. 7 Trento A, Hardesty RL, Griffith BP et al. Early function of cardiac homografts: relationship to hemodynamics in the donor and length of the ischemic period. Circulation 1986; 74: III77-9. 8 Gott JP, Pan C, Dorsey LM et al. Cardioplegia for transplantation: failure of extracellular solution compared with Stanford or UW solution. Ann Thorac Surg 1990; 50: 348-54. 9 Chambers DJ, Braimbridge MV. Cardioplegia with an Extracellular Formation. Dor drecht Kleiwer, 1993. 10 Demmy TL, Turpin TA, Wagner-Mann CC. Laboratory confirmation of clinical heart allograft preservation variability. Ann Thorac Surg 2001; 71:1312-9. 11 Rosenkranz ER, Okamoto F, Buckberg GD et al Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. / Thorac Cardiovasc Surg 1986; 91:428 -35. 12 Segel LD, Follette DM, Contino IP et al. Importance of substrate enhancement for long-term heart preservation. /Heart Lung Transplant 1993; 12:613-23. 13 Choong YS, Gavin JB, Buckman J. Long-term preservation of explanted hearts perfused with L-aspartate-enriched cardioplegic solution. Improved function, metabolism, and ultrastructure. / Thorac Cardiovasc Surg 1992; 103: 210-18.

289 14 Lazar HL, Yang XM, Rivers S et al. Superiority of substrate enhancement over oxygen free-radical scavengers during extended periods of cold storage for cardiac transplantation. Surgery 1990; 108:423-9; discussion 429-30. 15 Kallerhoff M, Blech M, Kehrer G et al. Post-ischemic renal function after kidney protection with the HTKsolution of Bretschneider. UrolRes 1986; 14:271-7. 16 Hachida M, Ookado A, Nonoyama M, Koyanagi H. Effect of HTK solution for myocardial preservation. J Cardiovasc Surg (Torino) 1996; 37:269-74. 17 Saitoh Y, Hashimoto M, Ku K et al Heart preservation in HTK solution: role of coronary vasculature in recovery of cardiac function. Ann Thorac Surg 2000; 69:107-12. 18 Kuhn-Regnier F, Fischer 1H, Jeschkeit S et al. Coronary oxygen persufflation combined with HTK cardioplegia prolongs the preservation time in heart transplantation. EurJCardiothoracSurg2QQQ; 17:71-6. 19 Kober IM, Obermayr RP, Spieckermann PG. How beneficial is the reduction of edema formation by polyethylene glycol during cardioplegic arrest? Transplant Proc 1996;28:160-2. 20 Rubboli A, Sobotka PA, Euler DE. Effect of acute edema on left ventricular function and coronary vascular resistance in the isolated rat heart. Am J Physiol 1994; 267: H1054-61. 21 Grinyo JM. Reperfusion injury. Transplant Proc 1997; 29: 59-62. 22 Mandel LJ, Takano T, Soltoff SP, Murdaugh S. Mechanisms whereby exogenous adenine nucleotides improve rabbit renal proximal function during and after anoxia. / Clin Invest 1988; 81:1255-64. 23 Engerson TD, McKelvey TG, Rhyne DB et al. Conversion of xanthine dehydrogenase to oxidase in ischemic rat tissues. J Clin Invest 1987; 79:1564-70. 24 Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest 1982; 47:412-26. 25 Zweier JL, Kuppusamy P, Lutty GA. Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues. ProcNatlAcadSci USA 1988; 85:4046-50. 26 Guarnieri C, Flamigni F, Caldarera CM. Role of oxygen in the cellular damage induced by re-oxygenation of hypoxic heart. JMol Cell Cardiol 1980; 12: 797-808. 27 Ferrari R, Ceconi C, Curello S et al Oxygen-mediated myocardial damage during ischaemia and reperfusion: role of the cellular defences against oxygen toxicity. JMol Cell Cardiol 1985; 17:937-45. 28 Engler RL, Schmid-Schonbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. AmJPathol 1983; 111:98-111. 29 Lorant DE, Patel KD, Mclntyre TM et al. Coexpression of GMP-140 and PAF by endothelium stimulated by histamine or thrombin: a juxtacrine system for adhesion and activation of neutrophils. / CellBiol 1991; 115:223-34. 30 Takahashi M, Masuyama J, Ikeda U et al. Effects of endogenous endothelial interleukin-8 on neutrophil migration across an endothelial monolayer. Cardiovasc Res 1995; 29:670-5.

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31 Windsor AC, Mullen PG, Fowler AA, Sugerman HJ. Role of the neutrophil in adult respiratory distress syndrome. BrJSurg 1993; 80:10-17. 32 Byrne JG, Karavas AN, Elhalabi A, Cohn LH. Myocardial neutrophil sequestration during reperfusion of the transplanted rabbit heart. / Heart Lung Transplant 2000; 19: 786-91. 33 Bando K, Pillai R, Cameron DE etal. Leukocyte depletion ameliorates free radical-mediated lung injury after cardiopulmonary bypass. / Thorac Cardiovasc Surg 1990; 99: 873-7. 34 Chambers DJ, Hearse DJ. Developments in cardioprotection: "polarized" arrest as an alternative to "depolarized" arrest. Ann Thorac Surg 1999; 68:1960-6. 35 Rasgado-Flores H, Blaustein MP. Na/Ca exchange in barnacle muscle cells has a stoichiometry of 3 Na + /l Ca2+. AmJPhysiol 1987; 252: C499-504. 36 Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. JMol CellCardiol 1985; 17:1029-42. 37 Snabaitis AK, Shattock MJ, Chambers DJ. Comparison of polarized and depolarized arrest in the isolated rat heart for long-term preservation. Circulation 1997; 96: 3148-56. 38 Schubert T, Vetter H, Owen P et al. Adenosine cardioplegia. Adenosine versus potassium cardioplegia: effects on cardiac arrest and postischemic recovery in the isolated rat heart. / Thorac Cardiovasc Surg 1989; 98:1057-65. 39 Boehm DH, Human PA, von Oppell U et al. Adenosine cardioplegia: reducing reperfusion injury of the ischaemic myocardium? Eur J Cardiothorac Surg 1991; 5:542-5. 40 Belardinelli L, Giles WR, West A. Ionic mechanisms of adenosine actions in pacemaker cells from rabbit heart. JPhysiol 1988; 405:615-33. 41 Zhu Q, Yang X, Claydon MA et al. Adenosine deaminase inhibitor in cardioplegia enhanced function preservation of the hypothermically stored rat heart. Transplantation 1994; 57:35-40. 42 Hearse DJ. Activation of ATP-sensitive potassium channels: a novel pharmacological approach to myocardial protection? Cardiovasc Res 1995; 30:1-17. 43 Snabaitis AK, Shattock MJ, Chambers DJ. Long-term myocardial preservation, effects of hyperkalemia, sodium channel, and Na/K/2Cl cotransport inhibition on extracellular potassium accumulation during hypothermic storage. / Thorac Cardiovasc Surg 1999; 118:123-34. 44 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74:1124—36. 45 Landymore RW, Bayes AJ, Murphy JT, Fris JH. Preconditioning prevents myocardial stunning after cardiac transplantation. Ann Thorac Surg 1998; 66:1953-7. 46 Karck M, Rahmanian P, Haverich A. Ischemic preconditioning enhances donor heart preservation. Transplantation 1996; 62:17-22. 47 Yamashita N, Nishida M, Hoshida S et al. Induction of

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48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

manganese superoxide dismutase in rat cardiac myocytes increases tolerance to hypoxia 24 hours after preconditioning./C/m Invest 1994; 94:2193-9. Ogino H, Smolensk! RT, Zych M et al. Influence of preconditioning on rat heart subjected to prolonged cardioplegic arrest. Ann Thorac Surg 1996; 62:469-74. Kevelaitis E, Oubenaissa A, Mouas C et al. Ischemic preconditioning with opening of mitochondrial adenosine triphosphate-sensitive potassium channels or Na/H exchange inhibition: which is the best protective strategy for heart transplants? / Thorac Cardiovasc Surg 2001; 121: 155-62. Sato T, O'Rourke B, Marban E. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. CircRes 1998; 83:110-14. Miyamae M, Camacho SA, Weiner MW, Figueredo VM. Attenuation of postischemic reperfusion injury is related to prevention of [Ca2+]m overload in rat hearts. Am JPhysiol 1996; 271: H2145-53. Gross GJ, Fryer RM. Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning. CircRes 1999; 84:973-9. Steenbergen C, Perlman ME, London RE, Murphy E. Mechanism of preconditioning. Ionic alterations. Circ Res 1993; 72:112-25. Shirai T, Rao V, Weisel RD et al. Preconditioning human cardiomyocytes and endothelial cells. / Thorac Cardiovasc Surg 1998; 115:210-19. Sato T, Sasaki N, O'Rourke B, Marban E. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels. J Am Coll Cardiol 2000; 35: 514-18. Karmazyn M. Sodium-hydrogen exchange inhibition—a superior cardioprotective strategy. / Thorac Cardiovasc Surg 1996; 112:776-7. Kim YI, Herijgers P, Laycock SK et al. Na+/H+ exchange inhibition improves long-term myocardial preservation. Ann Thorac Surg 1998; 66:436-42. Sunamori M, Innami R, Amano J et al. Role of protease inhibition in myocardial preservation in prolonged hypothermic cardioplegia followed by reperfusion. Effect of aprotinin in an experimental model. / Thorac Cardiovasc Surg 1988; 96: 314-20. Sunamori M, Sultan I, Suzuki A. Effect of aprotinin to improve myocardial viability in myocardial preservation followed by reperfusion. Ann Thorac Surg 1991; 52:971-8. Benjamin IJ, McMillan DR. Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. CircRes 1998; 83:117-32. Hess ML, Kukreja RC. Free radicals, calcium homeostasis, heat shock proteins, and myocardial stunning. Ann Thorac Surg 1995; 60: 760-6. Samali A, Orrenius S. Heat shock proteins: regulators of stress response and apoptosis. Cell Stress Chaperones 1998; 3:228-36. Demidov ON, Tyrenko W, Svistov AS et al. Heat shock proteins in cardiosurgery patients. Eur J Cardiothorac Surg 1999; 16:444-9.

Cardioplegia in cardiac transplantation

64 Jayakumar J, Suzuki K, Khan M et al. Gene therapy for myocardial protection: transfection of donor hearts with heat shock protein 70 gene protects cardiac function against ischemia-reperfusion injury. Circulation 2000; 102: III302-6. 66 65 Sawa Y, Kadoba K, Suzuki K etal. Efficient gene transfer

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method into the whole heart through the coronary artery with hemagglutinating virus of Japan liposome. / Thome Cardiovasc Surg 1997; 113: 512-18; discussion 518-19. Allen MD. Myocardial protection: is there a role for gene therapy? Ann Thorac Surg 1999; 68:1924-8.

CHAPTER 31

Myocardial preservation in clinical cardiac transplantation: an update Louis B. Louis TV, MD, Xiao-Shi Qi, MD, PHD, & Si M. Pham, MD, FAGS

Advances over the past five decades have made heart transplantation an effective treatment for end-stage heart disease. The 1-year patient and graft survival has approached 90%. However, primary graft failure continues to account for approximately 25% of early recipient death, and is mainly due to inadequate myocardial preservation. Although there have been some recent advances in extending the ischemic time of the donor heart, myocardial preservation for clinical heart transplantation still depends on the use of hypothermic cardiac arrest and static storage. With this technique, acceptable results can be achieved in 4-6 h [ 1-3]. Cases of prolonged preservation up to 8 h have been reported in pediatric hearts [2], however ischemic times greater than 5 h are associated with poor survival [4]. In this chapter, we will review the current techniques of myocardial preservation for clinical heart transplantation, organizing myocardial preservation into the four distinct stages as suggested by Buckberg: preharvest, cardioplegic arrest, storage, and reperfusion [5].

Preharvest donor management It is now clear that brain death results in significant hormonal imbalance in the donor, and suboptimal donor management can result in myocardial injury. Therefore, donor management plays an important role in a successful strategy of myocardial preservation. Myocardial preservation for cardiac transplantation commences as soon as a donor is identified. The primary goal of donor management is to maintain

292

and optimize cardiac function of the donor. Brain dead donors experience severe disruption of the hypothalamic-pituitary-adrenal axis, hypovolemia, and electrolyte abnormalities [6]. Volume replacement, correction of acid-base disturbances, and electrolyte abnormalities, are the initial steps for maintaining proper organ function. However, attention must be paid to the remainder of the disrupted endocrine axis, particularly to antidiuretic hormone (ADH) and thyroid hormone [7]. Loss of ADH, which results in diabetes insipidus, polyuria, dehydration, hypernatremia, hypokalemia, and hyperosmolarity, is a hallmark of brain injury. Administration of synthetic ADH will promptly correct the sequelae of diabetes insipidus. In addition, synthetic arginine vasopressin (1-2 units per hour) will potentiate the effects of epinephrine. When brain dead patients were treated with epinephrine and vasopressin versus epinephrine alone, they survived a mean length of 24 days compared with only 48 h [8]. Currently, synthetic ADH is commonly used in brain dead donors [9]. Another hormone important in the brain dead donor is thyroid hormone. Thyroxine (T4) is normally converted to the metabolically active triiodothyronine (T3). While T3 does not have an intrinsic inotropic effect on the normal heart, it improves ventricular function after ischemia [10]. Using a model of isolated atrial myocardium, Timek et al. demonstrated that T3 reversed the depressed myocardial contractility due to prolonged exposure to catecholamines (as typically occurs in brain dead organ donors) [11]. Additionally, T3 acts at the peripheral

293

Clinical cardiac transplantation level to decrease the breakdown of catecholamines. It has been shown that a majority of brain dead donors are T3 deficient, and that supplementation with T3 (2 |lg; Triostat, SmithKline Beecham Pharmaceuticals, Pittsburgh, PA), cortisol (100 mg), and insulin (20 units) at hourly intervals significantly stabilizes the hemodynamic status of these donors, making them suitable candidates for cardiac donation [6]. Jeevanandam et al. demonstrated that T3 replacement (0.2 |lg/kg bolus every hour for a total of 3 doses) improved cardiac function and stabilized the hemodynamic status of heart donors [12]. Wheeldon et al. demonstrated that an aggressive approach to donor management that includes invasive hemodynamic monitoring, fluid resuscitation, and hormonal replacement (methylprednisolone, insulin, arginine vasopressin, and triiodothyronine) resulted in better cardiac function and increased the rate of cardiac donation in marginal donors [13]. Through this standardized approach, they increased the number of organs available for transplantation by 30% [14,15]. Furthermore, when aggressive treatment was applied to donors who initially fell outside the minimum acceptance criteria on arrival, 44 of 52 initially unacceptable donors were able to provide useful organs [ 13]. Elevated peripheral levels of the cardiac-specific troponins I and T have recently been shown to be risk factors for primary graft failure. A peripheral troponin I greater than 1.6 (ig/L and a peripheral troponin T greater than 0.1 |lg/L is associated with an odds ratio for acute graft failure of 42.7 and 56.9, respectively [ 16]. Caution is indicated with donors who have a documented history of hypertension and ventricular hypertrophy. In a retrospective review of 37 patients who received donor hearts with left ventricular hypertrophy (LVH) compared to a cohort of 221 patients receiving optimal hearts, there was decreased survival in recipients of LVH hearts at 2 months (86.4% compared with 91%) and 12 months (73% vs. 86.9%) [17]. Inferior survival rates were observed when donors had known hypertension, ischemic time greater than 180 min, LVH by EGG, and moderate LVH by echocardiographic criteria [17]. Precise measurement of LV wall thickness by echocardiography should be considered in addition to EGG in all donors to estimate the severity of LVH. Donor hearts with LVH may be used selectively, particularly if there are no EGG criteria and if ischemia time is short.

Cardioplegic arrest The current technique of myocardial preservation for clinical transplantation typically includes infusion of cold cardioplegia to achieve electromechanical arrest, immersion of the heart in cold crystalloid or cardioplegic solution before implantation (static hypothermic storage), infusion of various solutions during the implantation, and reperfusion of the transplanted heart.

Types of cardioplegia A wide variety of cardioplegia solutions have been used to preserve the donor heart in clinical transplantation. A retrospective study of all active cardiac transplant programs in the United States from 1987 to 1992 showed that of 143 programs, there were 167 different preservation solutions in use [18]. Cardioplegia solutions are divided into two types based on their ionic composition of sodium and potassium—intracellular-type or extracellular-type. Intracellular-type solutions, such as University of Wisconsin (UW, ViaSpan, Dupont, Wilmington, DE) and Euro-Collins (EC, Fresenius AG, Bad Hamburg, Germany) solution, have low sodium (below 70 mmol/L), and high potassium contents (between 30 and 125 mmol/L). These solutions mimic the intracellular ionic milieu, inducing rapid cardiac arrest by reducing the potassium gradient. Bretschneider solution (HTK, Custodiol, Koehler Chemie GmbH, Alsbach, Germany) is also considered an intracellular solution based on its sodium concentration; however, cardiac arrest is induced by histidine. Extracellular-type solutions such as Celsior (SangStat Medical Corporation, Fremont, CA) or Plegisol (St Thomas II, Abbott Laboratories, Abbott Park, IL) solutions have sodium concentrations greater than or equal to 70 mmol/L, and a potassium concentration between 5 and 30 mmol/L. Table 31.1 depicts the compositions of commonly used cardioplegia solutions. There is a paucity of large, randomized, controlled trials designed to test the efficacy of cardioplegia solutions. Reported data are either from retrospective studies or from small controlled single center trials; as a result, conclusions are sometimes contradictory. A retrospective study of 9401 patients who received heart transplants between 1987 and 1992 concluded that the adjusted 1 -month odds ratio for mortality was

294

CHAPTER 31

Table 31.1 Compositions of common heart preservation solutions. Cardioplegia Content (mmol/L)*

EC [74]

Na

UW[74]

HTK [74]

Celsior[75]

STH-1 [28]

Plegisol [76]

Roe [2]

Stanford [77]

10

30

15

100

144

110

27

K

115

125

10

15

20

16

20

Mg

-

5

4

13

16

16

6

Ca

-

-

—

Glucose

198

-

Dextrose (g/L)

-

Lactobionate

-

100

-

Raffinose Hydroxyethylstarch (g/L)

-

30 30

_

_

_

_

_

-

-

-

-

50

30

_

80 _

_

_

_

-

50

-

-

-

-

-

-

-

60

-

-

Ketoglutarate Tryptophan

-

-

20 _

_

_

Phosphate Bicarbonate

100

-

-

-

-

-

-

-

10

30

-

-

-

-

3

_

_

—

Manitol Glutamate

0.015

30 1 2

-

10

25 -

Histidine

-

Glutathione

-

3

180

50 g

— 12. 5 g/L

— _

-

Variablet

60

_

_

_

1

_

_

-

-

_

100

-

-

-

-

-

-

16

-

-

-

-

-

-

-

-

-

-

7.2 310

7.3 320

5.5-7.0 300-320

7.8 320

Adenosine

-

5

-

1

Procaine

-

Dexamethasone (mg/L)

1.2

_

Allopurinol Insulin (U/L)

2.2

0.25

— -

Methylprednisolone (mg/L) PH Osmolarity (mosmol)

-

7.4 406

7.4 320

250

7.4 323

7.8 431

EC, Euro-collins; UW, University of Wisconsin; HTK, Bretschneider; STH-1, St Thomas' Hospital. * All measurements mmol/L unless stated otherwise, t Adjust to pH of 7.4.

lower in recipients whose donor hearts were preserved with intracellular-type solutions [18]. However, there was no difference in survival at the 1- or 2-year time points. In another retrospective study, Stringham etal. compared UW and Stanford solutions in 66 heart transplants whose ischemic time was greater than 3 h [19]. Of these 66 hearts, 17 were preserved with Stanford solution and 49 with UW solution. They showed no difference in primary graft failure, hospital stay, or survival rates. However, the time to wean from bypass after cross-clamp removal was nearly twice as long with Stanford solution than with UW (80.6 vs. 44.3 min), and the average need for inotropic support over the first eight post-transplant hours was significantly higher with Stanford solution than UW [ 19].

Wildhirt et al. performed a single-center, prospective, randomized trial, comparing the efficacy of UW solution (n = 20) and Celsior solution (n = 21) heart transplant recipients [20]. The mean ischemic time was 197 ± 13 min and 210 ± 13 min in the Celsior and UW groups, respectively. There was an increased need for vasodilator and catecholamine therapy in the immediate postoperative period in patients who had received Celsior solution, but no difference in myocardial performance, endothelial function, or mortality at 1 month after transplantation. Total ischemic time correlated with impaired endothelial function in the Celsior but not in the UW group. Endothelin and inducible nitric oxide synthase (iNOS) gene expression were significantly higher in

295

Clinical cardiac transplantation the Celsior group. Another single-center clinical trial, conducted in Poland, comparing Celsior (n = 28, mean ischemic time 221 ± 8.6 min), HTK (n - 132, mean ischemic time 109 ± 3.5 min), and UW (n = 64, mean ischemic time 216 ± 5.4 min) solutions, failed to demonstrate any significant difference in mortality, or hemodynamic support required following transplant [21]. In the only multicenter, randomized, controlled trial to date, Celsior (n = 64, mean ischemic time 3.3 ± 1.0 h) proved to be as safe and effective as conventional solutions (n = 67, mean ischemic time 3.1 ± 1.0 h) for myocardial preservation prior to transplantation [22]. There was no difference in primary graft failure rate or inotropic support required in the perioperative period. Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% vs. 25%). Blood cardioplegia has been used to preserve hearts for transplantation with some benefit. A recent prospective, randomized, clinical trial comparing the efficacy of crystalloid (n = 27, ischemic time 176 ± 51 min) versus blood cardioplegia (n — 20, ischemic time 180 ± 58 min) demonstrated that blood cardioplegia was associated with a lower incidence of right heart failure, cardiac rhythm dysfunction, and laboratory evidence of ischemia [23]. However, there were no differences in operative mortality rates, and requirement for inotropic support or mechanical assistance between the two groups. Considering the more complicated logistics and the marginal benefits gained from the use of blood cardioplegia in the transplant setting, it is unlikely that blood cardioplegia will gain wide acceptance for preservation of heart donors. Because endothelial injury accelerates the development of coronary allograft vasculopathy (CAV) [24], the possible deleterious effect of high potassium concentration of UW solution on the coronary endothelium has been a concern. In a retrospective study involving 195 heart transplant recipients (100 received Stanford solution, and 95 UW solution), Drinkwater et al. from the University of California in Los Angeles (UCLA) reported that UW solution is associated with a higher incidence of allograft vasculopathy by multivariate analysis [25]. However, several subsequent studies have not shown this to be the case. Stringham et al. [26] retrospectively reviewed the outcomes of heart recipients who received hearts preserved with either UW solution (n = 94) or Stanford (n = 65) and

demonstrated that the incidence and the severity of allograft vasculopathy were similar between groups at 3 years after transplantation. Furthermore, deaths attributed to CAV were equal in each group. Recently, Marelli etal. from UCLA reported their 17-year experience with 1803 heart transplants at a single institution [27]. These authors reported no difference in freedom from coronary artery disease at 5 years after transplantation in hearts preserved with UW solution (from 1994 to 2002) compared with hearts preserved with Stanford solution (before 1994). However, death due to allograft vasculopathy was significantly higher in the latter group.

Delivery pressure Monitoring of delivery pressure is important, as the cardioplegia solution is often given at high pressure following aortic clamping to ensure rapid diastolic arrest. With standard setup in clinical practice, it is easy to exceed 200 mmHg in the aortic root. It has been demonstrated that high delivery pressure is deleterious to the myocardium. Katayama et al. reported that the mean recovery of cardiac output and coronary endothelial function in rodent hearts decreased with increasing cardioplegic delivery pressure [28]. Delivery pressures higher than 120 cmH2O (88.2 mmHg) cause coronary smooth muscle constriction. Using an adult porcine model, Irtun et al. reported that high cardioplegic delivery pressure (175 mmHg) resulted in a more rapid diastolic arrest, but was associated with poorer myocardial recovery than low pressure (75 mmHg) [29]. Drinkwater et al. demonstrated that delivery pressures greater than 120 mmHg caused marked myocardial dysfunction in a neonatal pig, and recommended that cardioplegia should be administered at less than 80 mmHg for a total volume of 10-15 ml/kg [30].

Storage The current storage stage involves immersion of the donor heart in cold crystalloid or cardioplegia solutions, a technique that is sometimes referred to as static hypothermic storage. Hypothermia preserves organ function by slowing enzymatic reaction rates, and the rate at which intracellular enzymes degrade cellular components [31]. Most euthermic enzymes will show a 1.5-2-fold decrease in enzymatic metabolism for each 10°C decrease in temperature [32]. Hypothermia

296 does not prevent cell death; it merely delays it, and should be considered a double-edged sword. By decreasing enzymatic function, hypothermia also slows down processes that would be considered beneficial, such as the synthesis of ATP. The limitation of static hypothermic storage has prompted the search for alternatives, such as coronary artery perfusion, to prolong myocardial preservation for transplantation. Coronary perfusion with oxygen-carrying solutions has three basic advantages over static hypothermic storage. Firstly, it prevents ischemia, anerobic metabolism, and reperfusion injury. Secondly, nutritional supplementation and provision of substrate can be more effectively delivered to myocardial cells. Lastly, continuous perfusion preservation effects the clearance of metabolic waste products from the coronary circulation [33]. Continuous cold perfusion has been shown to be superior to static hypothermic storage in several studies. Canine hearts perfused with UW solution for 12 h required significantly less inotropic support after transplantation compared with hearts that had been stored in UW solution [34]. After 24 h of continuous cold perfusion, rabbit hearts preserved with UW solution regained 93% of LV developing pressures compared with only 35% in the control (static storage) group [35]. Likewise, porcine hearts demonstrated significantly better function when perfused for 6, 12, and 24 h compared to nonperfused controls. It should be noted that at the 6 h time point, there was no discernible functional difference, but there was metabolic evidence for injury in the nonperfused controls [36]. Continuous coronary perfusion during storage has not been adopted for clinical heart transplantation because of the complexity of the equipment required. However, several recent studies involving simpler equipment have showed promise. Using a simple portable perfusion system, Oshima et al. demonstrated that perfused canine hearts recovered faster and had less damage after 12 h of ischemia than controls (static storage) [37]. These results have been reproduced in canine hearts for up to 24 h of ischemia [38,39].

Reperfusion The role of antioxidants Reperfusion, the final phase of myocardial preservation, is the point at which the heart may sustain

CHAPTER 31

the greatest amount of injury. Ischemia-reperfusion injury involves a complex series of interactions at both the molecular and cellular levels. As ATP is consumed during ischemia, there is a build up of hypoxanthine. Once the graft is reperfused with oxygen rich blood, a burst of oxygen free radicals is produced by the endothelial xanthine oxidase pathway, resulting in lipid peroxidation [40,41]. This cascade of oxygen free radical injury leads to increased permeability of cellular membranes, and intracellular edema. The sarcoplasmic reticulum, and thus calcium transport, is damaged by peroxidation, as is mitochondrial oxidative phosphorylation. Inflammatory mediators such as prostaglandins, leukotrienes, and thromboxanes, produced by the injured cells, and as a result of cardiopulmonary bypass, act as chemotactic factors for leukocytes, amplifying oxygen free radical injury. The protective role of oxygen radical scavengers in myocardial preservation has been well recognized [42-44], and oxygen radical scavengers, such as reduced glutathione, polyethelene glycol, and manitol, either alone or in combination, have been included in several cardioplegic solutions. Among other oxygen radical scavengers that have been studied extensively in recent years are the lazaroid compounds. These compounds act both as antioxidants and calcium antagonists, and protect tissue from lipid peroxidation. It has been reported that lazaroid compounds reduce free radical-mediated injury in various organs [45-49]. Takahashi et al. demonstrated that intravenous administration of the lazaroid compound U-74389G 30 min prior to reperfusion resulted in better cardiac function and less myocardial damage in canine hearts [50]. These data suggesting that novel inhibitors of lipid peroxidation may further reduce the ischemia-reperfusion injury and enhance myocardial protection for clinical cardiac transplantation. Another strategy to minimize oxygen radical injury is to reduce the exposure of the ischemic heart to leukocytes during the initial reperfusion period. The use of a leukocyte filter in the cardiopulmonary bypass circuit has been shown to decrease injury associated with oxygen free radicals, and improve function following bypass [51]. In an animal study with long ischemic time (4 h), leukocyte depletion resulted in improved functional recovery, as well as improved endothelial function [52]. Yamamoto et al. reported that reperfusion with leukocyte-depleted blood

Clinical cardiac transplantation improved coronary endothelial function, and reduced myocardial injury, in a canine heart transplant model [53]. Clinical data from bypass surgery also demonstrated that leukocyte nitration correlated with improved cardiac and lung function following surgery [54]. In a randomized, controlled, clinical trial, reperfusion of transplanted hearts with leukocyte-depleted reperfusate was associated with less release of the creatine kinase MB fraction (CK-MB) (and thromboxane B2), indicating a lesser degree of ischemia-reperfusion injury. There was no difference in the graft survival rate or requirement for inotropic support; however, the ischemic times were rather short in this study (mean 152 min) [55]. Endothelial dysfunction also contributes to reperfusion injury, as impaired endothelial-dependent vascular relaxation via reduced nitric oxide production may significantly reduce coronary blood flow. Administration of nitric oxide, its substrate L-arginine, and various nitric oxide donors to the reperfusate has reduced ischemia-reperfusion injury in animal models [56-59]. However, nitric oxide may have deleterious effects on the ischemic myocardium because of its propensity to convert to peroxynitrite and causes lipid peroxidation. Using a canine model of orthotopic heart transplantation, Tanoue et al. examined whether adding the organic nitric oxide donor nitroglycerin (NTG) to UW solution caused deleterious effects on coronary endothelial and LV function. After 24 h of cold storage in either UW solution alone or UW solution augmented with NTG (0.1 mg/ml), cardiac function was significantly better in the NTG group, but levels of lipid peroxide in the NTG group were significantly higher, implying peroxynitrite formation. The overall effect of NTG was cardioprotective, and seems to outweigh any effect of lipid peroxidation [60]. Newer nitric oxide donors also exhibit a protective effect on the myocardium. Rodent hearts preserved with an extracellular solution augmented with the nitric oxide donor diethylamine NONOate had significantly better coronary artery flow and cardiac function than controls [61]. Another novel nitric oxide donor is FK409. It is the first spontaneous nitric oxide donor that is able to increase plasma guanosine 3':5'-cyclic monophosphate [62,63]. Mohara et al. demonstrated that the administration of FK409 during reperfusion ameliorated ischemia-reperfusion injury in a canine heart transplant model [64,65].

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Post-transplant cardiac function was better in the FK409 group as compared with controls. The FK409 group is associated with a lower endothelin-1 level, and better preservation of the capillary basal lamina, glycogen granules, and mitochondrial structures.

Intraoperative administration of triiodothyronine (T3) during heart transplantation It has been shown that patients with heart failure have a decrease in free T3. The low free T3 state has also been observed during and following cardiac operations that require the use of cardiopulmonary bypass [66,67]. Therefore in the immediate post-transplant period, heart recipients may have significant T3 deficiency. It is recommended that T3 be administered intraoperatively before reperfusion of the donor heart to prevent relapse of the hemodynamic-metabolic abnormality observed in the donor [68]. Although the benefits of intraoperative T3-administration are well documented in adult and pediatric cardiac surgical patients [69,70], there is a paucity of data supporting the beneficial effects of intraoperative T3 in heart transplantation. In a small randomized study in which T3 (0.2 [ig/kg bolus, 0.4 (ig/kg infusion over 6 h) was administered immediately before donor heart reperfusion, Jeevanandam et al. reported that recipients in the T3 groups required less inotropic supports, and had less coronary lactate production than the placebo group [71]. Reperfusion pressure The mechanical aspects of reperfusion have also been shown to play an important role in myocardial preservation. High initial reperfusion pressure (60 mmHg) leads to endothelial damage, possibly due to shear forces inflicted upon vulnerable endothelium [72]. Low initial reperfusion pressures followed by gradual increase have been shown to lead to significant improvement in mechanical and endothelial function in lamb hearts [73]. Low pressure retrograde reperfusion before unclamping of the aorta may also help remove debris and air from the coronary circulation [3]. Because of these potential benefits, it is recommended that there is a short period (3-5 min) of low reperfusion (preferably via the coronary sinus) with substrate-enhanced, leukocyte-depleted blood reperfusate before unclamping the aorta [3].

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Summary For the sake of simplicity myocardial preservation for heart transplantation can be divided into four stages: preharvest donor management, cadioplegic arrest, storage, and reperfusion. In the donor management stage, in addition to correction of fluid and electrolytes, hormonal replacement (with steroids, insulin, T3, and catecholamines) and invasive hemodynamic monitoring have been shown to improve myocardial function, resulting in successful usage of a high percentage (85%) of donors who were initially considered unacceptable. A variety of cardioplegia solutions have been used to arrest the heart during the cardioplegic arrest stage with similar efficacy. This is, in part, due to the relatively short ischemic interval. However, current data indicate a detrimental effect of high cardioplegic delivery pressure. A delivery pressure of 80 mmHg seems to be optimal. In the storage stage, although continuous coronary perfusion with oxygen carrying solutions have been shown to be superior to static hypothermic storage, it has not been adopted widely in clinical heart transplantation because of the complexity of the equipment required. Simpler devices developed in recent years, along with the everincreasing need to maximize the use of donors, have prompted a renewed research interest in this area. In the reperfusion stage, in addition to the use of substrate-enhanced reperfusate, low initial reperfusion pressure with leukocyte-depleted blood and intraoperative administration of T3 before reperfusion of the transplanted heart have been shown to be beneficial. It must be emphasized that not every cardiac recipient or donor requires all the treatments outlined. However, these treatments may help reduce the incidence of primary graft failure, especially in marginal donors.

References 1 Thomas FT, Szentpetery SS, Mammana RE et al. Longdistance transportation of human hearts for transplantation. Awn Thome Surg 1978; 26: 344-50. 2 Kawauchi M, Gundry SR, de Begona JA et al. Prolonged preservation of human pediatric hearts for transplantation: correlation of ischemic time and subsequent function. J Heart Lung Transplant 1993; 12:55-8. 3 Jeevanandam V. Myocardial preservation for pediatric cardiac transplantation. In: Franco KL, ed. Pediatric Cardiopulmonary Transplantation. Armonk, NY: Futura Publishing, 1997:81-95.

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4 Baumgartner WA. Myocardial and pulmonary protection: long-distance transport. Prog Cardiovasc Dis 1990; 33: 85-96. 5 Buckberg GD. Invited letter concerning phases of myocardial protection during transplantation. / Thorac Cardiovasc Surg 1990; 100:461-3. 6 Novitzky D, Cooper DK, Reichart B. Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987; 43: 852-4. 7 Novitzky D, Cooper DK, Human PA et al. Triiodothyronine therapy for heart donor and recipient. J Heart Transplant 1988; 7:370-6. 8 Yoshioka T, Sugimoto H, Uenishi M et al. Prolonged hemodynamic maintenance by the combined administration of vasopressin and epinephrine in brain death: a clinical study. Neurosurgery 1986; 18: 565-7. 9 Pallis C. Brainstem death: the evolution of a concept. Semin Thorac Cardiovasc Surg 1990; 2:135-52. 10 Dyke CM, Yeh T Jr, Lehman JD et al. As originally published 1991: triiodothyronine-enhanced left ventricular function after ischemic injury. Updated in 1998. Ann Thorac Surg 1998; 66:1450-1. 11 Timek T, Bonz A, Dillmann R et al. The effect of triiodothyronine on myocardial contractile performance after epinephrine exposure: implications for donor heart management. / Heart Lung Transplant 1998; 17: 931-40. 12 Jeevanandam V, Todd B, Regillo T et al. Reversal of donor myocardial dysfunction by triiodothyronine replacement therapy./ Heart Lung Transplant 1994; 13:681-7; discussion 685-7. 13 Wheeldon DR, Potter CD, Oduro A et al. Transforming the "unacceptable" donor: outcomes from the adoption of a standardized donor management technique. / Heart Lung Transplant 1995; 14: 734-42. 14 Lloyd-Jones H, Wheeldon DR, Smith JA et al. An approach to the retrieval of thoracic organs for transplantation. AORNJ1996; 63:425-16. 15 Potter CD, Wheeldon DR, Wallwork J. Functional assessment and management of heart donors: a rationale for characterization and a guide to therapy. / Heart Lung Transplant 1995; 14:59-65. 16 Potapov EV, Ivanitskaia EA, Loebe M et al. Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure. Transplantation 2001; 71: 1394-400. 17 Marelli D, Laks H, Fazio D et al. The use of donor hearts with left ventricular hypertrophy. / Heart Lung Transplant 2000; 19:496-503. 18 Demmy TL, Biddle JS, Bennett LE et al. Organ preservation solutions in heart transplantation—patterns of usage and related survival. Transplantation 1997; 63:262-9. 19 Stringham JC, Love RB, Welter D et al. Impact of University of Wisconsin solution on clinical heart transplantation. A comparison with Stanford solution for extended preservation. Circulation 1998; 98: 11157-61; discussion II162. 20 Wildhirt SM, Weis M, Schulze C et al. Effects of Celsior and University of Wisconsin preservation solutions on hemodynamics and endothelial function after cardiac

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transplantation in humans: a single-center, prospective, randomized trial. Transplant Int 2000; 13: S203-11. Garlicki M, Kolcz}, Rudzinski P et al. Myocardial protection for transplantation. Transplant Proc 1999; 31:2079-83. Vega JD, Ochsner JL, Jeevanandam V et al. A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts. Ann Thorac Surg 2001; 71:1442-7. Luciani GB, Faggian G, Montalbano G et al. Blood versus crystalloid cardioplegia for myocardial protection of donor hearts during transplantation: a prospective, randomized clinical trial. / Thorac Cardiovasc Surg 1999; 118:787-95. Davis SF, Yeung AC, Meredith IT et al. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year post-transplant. Circulation 1996:93:457-62. Drinkwater DC, Rudis E, Laks H et al. University of Wisconsin solution versus Stanford cardioplegic solution and the development of cardiac allograft vasculopathy. 7 Heart Lung Transplant 1995; 14: 891-6. Stringham JC, Love RB, Welter D et al Does University of Wisconsin solution harm the transplanted heart? / Heart Lung Transplant 1999; 18: 587-96. Marelli D, Laks H, Kobashigawa JA et al. Seventeen-year experience with 1083 heart transplants at a single institution. Ann Thorac Surg 2002; 74:1558-66. Katayama O, Amrani M, Ledingham S et al. Effect of cardioplegia infusion pressure on coronary artery endothelium and cardiac mechanical function. Eur]Cardiothorac Surg 1997; 11: 751-62. Irtun O, Sorlie D. High cardioplegic perfusion pressure entails reduced myocardial recovery. Eur J Cardiothorac Surg 1997; 11: 358-62. Drinkwater DC, Laks H, Buckberg GD. A new simplified method of optimizing cardioplegic delivery without right heart isolation. Antegrade/retrograde blood cardioplegia. 7 Thorac Cardiovasc Surg 1990; 100: 56-63; discussion 63-54. Buckberg GD. Myocardial temperature management during aortic clamping for cardiac surgery. Protection, preoccupation, and perspective. / Thorac Cardiovasc Surg 1991; 102: 895-903. Belzer FO, Southard JH. Principles of solid-organ preservation by cold storage. Transplantation 1988; 45:673—6. Smulowitz PB, Serna DL, Beckham GE et al Ex vivo cardiac allograft preservation by continuous perfusion techniques. ASAIO /2000; 46: 389-96. Calhoon JH, Bunegin L, Gelineau JF et al Twelve-hour canine heart preservation with a simple, portable hypothermic organ perfusion device. Ann Thorac Surg 1996; 62:91-3. Nutt MP, Fields BL, Belzer FO et al. Comparison of continuous perfusion and simple cold storage for rabbit heart preservation. Transplant Proc 1991; 23:2445-6. Ferrera R, Marcsek P, Larese A et al. Comparison of continuous microperfusion and cold storage for pig heart preservation. / Heart Lung Transplant 1993; 12: 463-9.

299 37 Oshima K, Morishita Y, Yamagishi T et al. Long-term heart preservation using a new portable hypothermic perfusion apparatus. / Heart Lung Transplant 1999; 18: 852-61. 38 Aizaki M, Takeyoshi I, Oshima K et al Effects of Celsior solution on long-term preservation of canine hearts with a new portable hypothermic perfusion apparatus: a preliminary study. Transplant Proc 2000; 32: 2409-10. 39 Tsutsumi H, Oshima K, Mohara J et al. Cardiac transplantation following a 24-h preservation using a perfusion apparatus. / Surg Res 2001; 96:260-7. 40 Mack CP, Brosamer KM, Shlafer M. Ultrastructural demonstration of peroxidative activity and peroxidation in ischaemic and ischaemic-reperfused rabbit hearts. Cardiovasc Res 1993; 27: 371-6. 41 Shlafer M, Gallagher KP, Adkins S. Hydrogen peroxide generation by mitochondria isolated from regionally ischemic and nonischemic dog myocardium. Basic Res Cardiol 1990; 85: 318-29. 42 Wicomb WN, Percy R, Portnoy V et al. The role of reduced glutathione in heart preservation using a polyethylene glycol solution. Cardiosol Transplant 1992; 54:181-2. 43 Wicomb WN, Hill JD, Avery J et al Optimal cardioplegia and 24-hour heart storage with simplified UW solution containing polyethylene glycol. Transplantation 1990; 49:261-4. 44 Menasche P, Grousset C, Gauduel Y et al. A comparative study of free radical scavengers in cardioplegic solutions. Improved protection with peroxidase. / Thorac Cardiovasc Surg 1986; 92:264-71. 45 Moreyra AE, Conway RS, Wilson AC et al Attenuation of myocardial stunning in isolated rat hearts by a 21aminosteroid lazaroid (U74389G). J Cardiovasc Pharmacol 1996; 28:659-64. 46 Ishizaki N, Zhu Y, Zhang S et al. Comparison of various lazaroid compounds for protection against ischemic liver injury. Transplant Proc 1997; 29:1333-4. 47 Nishida T, Morita S, Miyamoto K et al. Lazaroid (U74500A) prevents vascular and myocardial dysfunction after 24-hour heart preservation. A study based on cross-circulated blood-perfused rabbit hearts. Circulation 1996; 94:11326-31. 48 Tanoue Y, Morita S, Ochiai Y et al Successful twentyfour-hour canine lung preservation with lazaroid U74500A.J Heart Lung Transplant 1996; 15:43-50. 49 Sasaki S, Alessandrini F, Lodi R et al. Improvement of pulmonary graft after storage for twenty-four hours by in vivo administration of lazaroid U74389G: functional and morphologic analysis. / Heart Lung Transplant 1996; 15: 35-42. 50 Takahashi T, Takeyoshi I, Hasegawa Y et al Cardioprotective effects of lazaroid U-74389G on ischemiareperfusion injury in canine hearts. / Heart Lung Transplant 1999; 18:285-91. 51 Boiling KS, Halldorsson A, Allen BS et al Prevention of the hypoxic reoxygenation injury with the use of a leukocyte-depleting filter. 7 Thorac Cardiovasc Surg 1997; 113: 1081-9; discussion 1089-90.

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52 Okazaki Y, Cao ZL, Ohtsubo S et al. Leukocyte-depleted reperfusion after long cardioplegic arrest attenuates ischemia-reperfusion injury of the coronary endothelium and myocardium in rabbit hearts. Eur] Cardiothorac Surg 2000; 18:90-7. 53 Yamamoto H, Moriyama Y, Hisatomi K et al. A leukocyte depleting filter reduces endothelial cell dysfunction and improves transplanted canine heart function. / Heart Lung Transplant 2001; 20:670-8. 54 Hachida M, Hanayama N, Okamura T et al. The role of leukocyte depletion in reducing injury to myocardium and lung during cardiopulmonary bypass. ASAIOJ1995; 41:M291-4. 55 Pearl JM, Drinkwater DC, Laks H et al. Leukocytedepleted reperfusion of transplanted human hearts: a randomized, double-blind clinical trial. / Heart Lung Transplant 1992; 11:1082-92. 56 Pinsky DJ, Oz MC, Koga S et al. Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway. / Clin Invest 1994; 93:2291-7. 57 Szabo G, Bahrle S, Batkai S et al. L-arginine: effect on reperfusion injury after heart transplantation. World J Surg 1998; 22: 791-7. 58 Baxter K, Howden B, Saunder A et al. Improved cardiac preservation by the addition of nitroglycerine to colloidfree University of Wisconsin solution (MUW). / Heart Lung Transplant 1999; 18: 769-74. 59 Baxter K, Howden BO, Jablonski P. Heart preservation with celsior solution improved by the addition of nitroglycerine. Transplantation 2001; 71:1380-4. 60 Tanoue Y, Morita S, Ochiai Y et al. Nitroglycerin as a nitric oxide donor accelerates lipid peroxidation but preserves ventricular function in a canine model of orthotopic heart transplantation. / Thorac Cardiovasc Surg 1999; 118: 547-56. 61 Du ZY, Hicks M, Jansz P et al. The nitric oxide donor, diethylamine NONOate, enhances preservation of the donor rat heart. / Heart Lung Transplant 1998; 17: 1113-20. 62 Hino M, Takase S, Itoh Y et al. Structure and synthesis of FK409, a novel vasodilator isolated from Streptomyces as a semiartificial fermentation product. Chem Pharm Bull 1989; 37:2864-6. 63 Yamada H, Yoneyama F, Satoh K et al. Cardiohemodynamic effect of FK409, a novel highly potent nitrovasodilator, in anesthetized dogs. Eur J Pharmacol 1991;205:81-3. 64 Mohara J, Oshima K, Tsutsumi H et al. FK409 enhances post-transplant cardiac function following 12-hour cold preservation. Transplant Proc 2000; 32: 2407-8.

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65 Mohara }, Oshima K, Tsutsumi H et al. FK409 ameliorates ischemia-reperfusion injury in heart transplantation following 12-hour cold preservation. / Heart Lung Transplant 2000; 19:694-700. 66 Reichert MG, Verzino KG. Triiodothyronine supplementation in patients undergoing cardiopulmonary bypass. Pharmacotherapy2001;2l: 1368-74. 67 Reinhardt W, Mocker V, Jockenhovel F et al. Influence of coronary artery bypass surgery on thyroid hormone parameters. Hormone Res 1997; 47:1-8. 68 Novitzky D. Novel actions of thyroid hormone: the role of triiodothyronine in cardiac transplantation. Thyroid 1996; 6:531-6. 69 Mullis-Jansson SL, Argenziano M, Corwin S et al. A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. / Thorac Cardiovasc Surg 1999; 117:1128-34. 70 Bettendorf M, Schmidt KG, Grulich-Henn J et al. Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study. Lancet 2000; 356: 529-34. 71 Jeevanandam V. Triiodothyronine spectrum of use in heart transplantation. Thyroid 1997; 7:139-45. 72 Sawatari K. Myocardial preservation in the immature heart. In: Castaneda A, Jonas R, Myaer J, Hanley F, eds. Cardiac Surgery of the Neonate and Infant. Philadelphia, PA: WB Saunders 1994:41-53. 73 Sawatari K, Kadoba K, Bergner KA et al. Influence of initial reperfusion pressure after hypothermic cardioplegic ischemia on endothelial modulation of coronary tone in neonatal lambs. Impaired coronary vasodilator response to acetylcholine. / Thorac Cardiovasc Surg 1991; 101: 777-82. 74 Muhlbacher F, Langer F, Mittermayer C. Preservation solutions for transplantation. Transplant Proc 1999; 31: 2069-70. 75 Menasche P, Termignon JL, Pradier F et al. Experimental evaluation of Celsior, a new heart preservation solution. Eur J Cardiothorac Surg 1994; 8:207-13. 76 Bernard M, Caus T, Sciaky M et al. Optimized cardiac graft preservation: a comparative experimental study using P-31 magnetic resonance spectroscopy and biochemical analyzes. / Heart Lung Transplant 1999; 18: 572-81. 77 Collins GM, Peterson T, Wicomb WN et al. Experimental observations on the mode of action of "intracellular" flush solution. ] Surg Res 1984; 36:1-8.

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Myocardial protection during left ventricular assist device implantation Aftab R. Kherani, MD, Mehmet C. Oz, MD, & Yoshifumi Naka, MD, PhD

As success with left ventricular assist device (LVAD) implantation has increased, attention now focuses more on the subtle techniques required to make the procedure reproducible with minimal morbidity [1,2]. A major debate over the optimal implantation procedure concerns the risks and benefits of arresting the heart and the subsequent importance of myocardial protection. While the left heart should not be neglected, particularly in those patients who are candidates for bridge to recovery, the focus of protection should be on the right ventricle.

Left ventricular assist device implantation It is important to note that a complete cross-clamp is not routinely applied during LVAD implantation. In these cases, myocardial protection is not an issue as the heart is not arrested. Typically, a coring knife is used to create the apical defect once the patient is on bypass. A Teflon graft is secured on the apex, and the inflow cannula is inserted through it. Next, a partial occluding clamp is applied onto the right lateral surface of the aorta. Then a longitudinal aortotomy is made to fit the diameter of the outflow graft. Following this the anastomosis to the outflow graft is performed. The device is then activated at a fixed rate of 50 beats per minute while weaning off cardiopulmonary bypass. To minimize the risk of air embolism to the right coronary artery and maximize protection of the right

ventricle, deairing plays an important role. To this end, several precautions are taken [3]. First, the LVAD is filled with blood by giving volume to the patient when the outflow is connected, using the device as a vent. Second, a 14-g aortic root cannula, on suction, is placed into the outflow graft to evacuate air. Third, the patient is placed in exaggerated Trendelenburg position and kept volume-loaded while the hand pump is used to deair. Fourth, transesophageal echocardiography is utilized to identify air bubbles, especially in the aortic root, and the outflow graft is sometimes partially clamped distal to the root vent to trap air bubbles. Fifth, when actuating the device, the root vent is kept on suction to further evacuate air until weaning off cardiopulmonary bypass. Finally, the entire surgical field, especially the inflow, is kept under fluid when weaning off cardiopulmonary bypass, thereby minimizing the chance that air enters the device. Slowly weaning off bypass and careful deairing are critical to minimizing the extent of right ventricular damage that may occur during implantation. Preservation of right ventricular function is a major priority during this procedure. To this end, some advocate cannulation of the left atrial appendage to create a right to left side oxygenated shunt. Once on bypass, the cannula is then connected to the cardioplegia system, in line with the oxygenator reservoir. This arrangement can deliver up to 2 L of oxygenated blood per minute to the left atrium [4]. Our concern with this method centers on the risk of air embolus that may arise during left atrial cannulation.

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Our specific technique to maximize right heart protection involves deairing using the hand pump. Even with meticulous deairing small air bubbles may arise. They can embolize to the right coronary artery, causing right ventricular dysfunction. This can lead to a vicious cycle, as right-sided dysfunction will result in decreased left-sided filling, predisposing to increased air being sucked into the system, leading to further embolization. After sufficient deairing, we decrease cardiopulmonary bypass flow to 2 L/min while giving the patient volume. Next, we initiate the LVAD. During this time, we maintain bypass flow at 2 L/min for a few minutes to support the right ventricle as well as maintaining systemic blood pressure for the elimination of air bubbles in the right coronary artery. We then gradually wean the patient off cardiopulmonary bypass as we confirm stable right ventricular function. During these periods, the LVAD is switched to auto mode as LVAD flow reaches 4 L/min. For this procedure, we liberally give volume to achieve our target central venous pressure of 15 mmHg. To maintain a reasonable mean arterial pressure as well as maximal right ventricular support, we routinely use milrinone (Sanofi-Synthelabo, Malvern, PA), dobutamine (Eli Lilly, Indianapolis, IN), arginine vasopressin (Novartis, East Hanover, NJ), norepinephrine (Abbott Laboratories, Abbott Park, IL), and nitric oxide (Cayman Chemical, Ann Arbor, MI).

How and when to arrest The procedure described above delineates a typical LVAD implantation that avoids arresting of the heart. In situations where complete cross-clamping and arrest are necessary during device implantation, it is the practice at our institution to give one dose of cardioplegia antegrade followed by creation of the outflow anastomosis and subsequent release of the clamp on the aorta. We use high-dose cardioplegia containing 126 mEq/L potassium chloride, 15 mEq/L sodium bicarbonate with 5% dextrose and 20% mannitol added, which is mixed one to four with blood. The heart may then be perfused and warmed during the inflow procedure. Rewarming allows the heart to recover from the arrest. In cases where arrest is indicated, the tenants surrounding deairing and right ventricular protection also apply. There are mainly three circumstances in which arresting the heart is necessary. The first is in the pres-

CHAPTER 32

Image Not Available

Figure 32.1 Aortic valve repair with creation of a bicuspid valve. Reprinted from Annals of Thoracic Surgery, Vol. 71, Rao Vet a/. Surgical management of valvular disease in patients requiring left ventricular assist device support, pp. 1448-1453. © 2001, with permission from Society of Thoracic Surgeons.

ence of aortic valvular pathology, which previously was a contraindication to LVAD placement. In cases of aortic insufficiency, cardioplegia is given antegrade until the heart fibrillates. The aortotomy made for the outflow anastomosis is extended longitudinally, and additional cardioplegia is given directly down the coronary ostia. The valve is then repaired by creating a bicuspid orifice (Figure 32.1). Alternatively, the three cusps of the native valve may simply be oversewn. If the LVAD recipient has a mechanical aortic valve, a Dacron patch is sewn to the aortic aspect of the valve (Figure 32.2), preventing leaflet motion and thereby limiting thrombus migration formed on the ventricular aspect of the outflow tract [5]. In these patients, high-dose cardioplegia is also given antegrade (1000 cm3) prior to creation of the aortotomy. The second situation in which arrest of the heart is necessary during LVAD implantation is when there is not enough space on the ascending aorta to

LVAD implantation

Image Not Available

Figure 32.2 Prevention of thromboembolism by Dacron graft closure of mechanical aortic valve prosthesis. Reprinted from Annals of Thoracic Surgery, Vol. 71, Rao Vet a/. Surgical management of valvular disease in patients requiring left ventricular assist device support, pp. 1448-1453. © 2001, with permission from Society of Thoracic Surgeons.

accommodate a partial occluding clamp. This can be true in patients where the ascending aorta is simply too small to accommodate a partial occluding clamp or when the ascending aorta is cluttered with several grafts from previous coronary artery bypass surgery that precludes the placement of such a clamp. In these cases, 1000 cm3 of high-dose cardioplegia is given antegrade. In patients who previously have undergone coronary artery bypass grafting, great care should be taken to preserve the graft to the right coronary artery. If it does not have a graft but has a significant lesion, then it should be bypassed at this time. The third situation requiring attention to myocardial protection is when coronary artery bypass grafting is required during LVAD implantation. This occurs in the setting of acute myocardial infarction and cardiogenic shock even with intra-aortic balloon pump support. These patients experience extremely high mortality with conventional medical and/or surgical therapy [6]; we believe that they can benefit from LVAD implantation. As discussed in the previous paragraph,

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the right coronary artery should be bypassed if it has a significant lesion. In addition, we graft at least one major left coronary artery to avoid postoperative angina and infarction which can lead to ventricular tachyarrhythmia. Proximal anastomoses can be performed on the ascending aorta, leaving enough room for placement of a partial occluding clamp and creation of the LVAD outflow anastomosis. Coronary artery bypass grafting can be completed with a single dose of antegrade cardioplegia. Then the aortic clamp may be released, resuming coronary circulation. During the period of rewarming and reperfusion, the remainder of the implantation procedure can be performed. LVADs have established a well-defined niche in the management of heart failure. Today, devices are found in patients who were not previously candidates for implantation. With some of these patients, the heart must be arrested during implantation. In these situations myocardial protection becomes an issue, especially for the right heart. Various modifications exist but in our experience, a single dose of antegrade cardioplegia is sufficient. By stressing the importance of myocardial protection during LVAD implantation, a broader spectrum of patients is now eligible for the device.

References 1

2

3

4

5

6

Sun BC, Catanese KA, Spanier TB et al. 100 long-term implantable left ventricular assist devices: the Columbia Presbyterian interim experience. Ann Thorac Surg 1997; 68:688-94. Goldstein DJ. Intracorporeal support: Thermo Cardiosystems ventricular assist devices. In: Goldstein DJ, Oz MC, eds. Cardiac Assist Devices. Armonk, NY: Futura, 2000:307-21. Oz MC, Goldstein DJ, Rose EA. Preperitoneal placement of ventricular assist devices: an illustrated stepwise approach./ Card Surg 1995; 10:288-94. Van Meter CH, Robbins RJ, Ochsner JL. Technique of right heart protection and deairing during Heartmate vented electric LVAD implantation. Ann Thorac Surg 1997;63:1191-2. Rao V, Slater JP, Edwards NM et al. Surgical management of valvular disease in patients requiring left ventricular device support. Ann Thorac Surg 2001; 71:1448-53. Hochman JS, Sleeper LA, White HD et al. One-year survival following early revascularization for cardiogenic shock. JAMA 2001; 285:190-2.

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Gene therapy for myocardial protection Said F. Yassin, MD d* Christopher G. McGregor, MD

Introduction Therapeutic gene therapy is likely to dramatically alter medical practice in the coming decades [1]. Multiple clinical applications are possible, as great progress has been made in genomics and molecular medicine. Based on our current knowledge about human genes and cellular communication mechanisms, combined with current and developing abilities to deliver genes, and the development of mechanisms to control subsequent gene expression by promoters, the potential of genetic engineering seems to have no limits. The optimization of vectors and delivery systems, as well as methods of monitoring gene expression, are required to achieve these ends. In cardiac surgery, gene therapy has the potential to deliver prolonged focused localized therapy to the heart without generalized systemic side effects. This is potentially beneficial in heart transplantation where gene therapy to the heart prior to implantation into the recipient could produce organ-specific immunosuppression and eliminate the need for systemic immunosuppression. Another potential application for gene therapy is protection and resuscitation of the myocardium during routine cardiac surgery and after coronary ischemic events. Ischemia-reperfusion injury is the major pathophysiological phenomenon in these circumstances where reoxygenation of the ischemic myocardium results in the formation of reactive oxygen species, leading to activation of the inflammatory cascade, myocyte injury, and endothelial dysfunction. The accumulation of oxygen free radicals during reperfusion may eventually deplete the buffering capabilities of endogenous antioxidant

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systems, leading to impairment of contractile function resulting in circulatory failure. Gene therapy could be applied to limit such free radical-induced myocardial injury.

Gene delivery Direct injection into the myocardial site This is effective and was one of the first methods used for gene delivery. It has been proven that high levels of protein expression can be achieved by this method as far as 1.5 cm from the site of vector administration, and this expression was shown to last for at least 14 days after the myocardial injection of adenovirus vectors without significant transfixion of a distant organ or compromising cardiac function [2].

Perf usion of the vector through the coronary circulation This can be performed percutaneously with a fluoroscopically guided catheter [3], or directly during open-heart or in-heart transplant surgery. A highly efficient gene transfer method was described using hypothermic coronary circulation of the adenoviral vector by means of a peristaltic pump for 5 min [4,5].

Direct exposure of the treated organ to the virus This method was shown to be successful for transfection of saphenous vein grafts with endothelial nitric oxide synthase carried on adenoviral vector before bypass surgery to prevent graft atherosclerosis [6].

Gene therapy for myocardial protection

Indirect transducing cells in vitro that are subsequently implanted into specific sites in vivo [7] Attempts to inject myocytes from Myo-Dtransformed fibroblasts into infarcts to repopulate the areas of damaged myocardium are underway. Other examples are transplanting neonatal myocytes to repopulate infarcts [8], and repopulation of the denuded endothelium with engineered endothelial or smooth muscle cells.

Systemic intravenous injection of viral vector with a myocardial-specif ic promoter (like myosin light chain promoter) to drive the transgene to express mRNA specifically in the heart [9] Systemic intravenous injection of recombinant adenovirus which is extremely efficient and selective to the liver was studied for transferring superoxide dismutase gene, and resulted in expression of superoxide dismutase protein in the liver; the protein was secreted from hepatocytes with relatively modest plasma level activities. However, truly supraphysiological plasma levels (up to 100-fold over baseline) were obtained by displacing the recombinant enzyme from its heparan sulfate proteoglycan binding sites by dextran sulfate or heparin [10]. In theory, recombinant techniques could be used to add the secretory and heparinbinding domain of extracellular superoxide dismutase to any therapeutic protein. Liver-directed gene transfer would then lead to modest resting plasma levels that could be rapidly increased when needed with simple intravenous injection of dextran or heparin. This method also alleviates concerns regarding the possibility of myocardial inflammation and its potential impact on myocardial stunning and preconditioning. This observation provides the basis for a method to control gene therapy at the post-translation level and for simultaneous protection of multiple organs from ischemia-reperfusion injury.

Vectors Liposomes Liposomes were one of the first vectors to be used— they can transfect nondividing cells like myocytes, the transfection is fast which makes them practical for

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intraoperative use without requiring modifications of the current techniques, and they do not incite a host immune response which allows retreatment. In comparison to viral vectors, liposomes have the advantage of freedom from infectious risk or wild-type recombination. The feasibility of liposome transfection has been shown with equivalent gene expression in all distributions in the heart (the vast majority of the coronary arteries cells and the coronary sinus cells), and demonstrated at least 7 days after transfection [5,11-13].

Viral vectors Hemagglutinating virus of Japan inactivated by ultraviolet irradiation and combined with active DNA liposome has been transferred to the nuclei of the endothelial cells and myocytes in all layers of the myocardium, by means of in vivo coronary infusion of the virus during cardioplegic arrest. The nontoxicity and lack of antigenicity of this virus has been proven [14]. Adenovirus vectors are recombinant vectors in which the gene of interest is inserted into the viral chromosome and one or more genes are removed to prevent viral reproduction. Although pathology due to replication is eliminated, the majority of viral genes remain, resulting in expression of viral proteins in the target cells. Adenoviral vectors have been used for gene transfer by direct intramuscular injection and via intracoronary infusion in both small and large mammals [15-17]. Gene transfection by adenovirus is excellent even in nondividing cells; however, in these studies gene expression was often transient and accompanied by cell-mediated immune response and cell toxicity, a significant disadvantage for myocardial protection [18]. This has led to the development of an improved vector, the adeno-associated virus vectors, a defective DNA virus that in nature requires coinfection with adenovirus for efficient replication and spread. Defective viral vectors contain no viral genes but permit packaging of foreign gene into a viral coat. This allows efficient transfer of genes without toxic or immunologic side effects due to the viral genes' expression [3]. In a recent study Phillips et al. demonstrated that a heart-specific promoter MLC-2v incorporated into adeno-associated virus vector can drive a therapeutic (angiotensin type 1 receptor antisense) and reporter

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gene (green fluorescence protein) specifically in the heart after systemic injection. DNA measurement showed that the vector was taken up into multiple tissues; the transgene protein mRNA, however, was only expressed in heart tissue. To switch on the virus transgene during ischemia they inserted a hypoxia response element, which upregulates transcription when oxygen levels are low. By adding additional hypoxia inducible factors and using double plasmid, 400-fold gene amplification in 1% O2 could be achieved. This construct was suggested as a prototype "vigilant vector" to switch on therapeutic genes in specific tissue with physiological signals [9]. Several other on-off switches have been developed, including tetracycline-controlled transcription [19], and viral vectors with expression cassettes containing corticosteroid-response promoters [20], which might allow the physician in the future to regulate the onset and the duration of gene products' expression in previously transfected genes. Retroviral vectors can integrate the gene of interest into the genome of the target cell and provide long gene expression; transfection in these cases, however, is efficient only in actively dividing cells. Also the incidence of T-cell lymphoma as a result of contamination with a wild-type retrovirus has been reported in monkeys transfected with retrovirus [21,22]. Many other viruses including disabled pathogens such as herpes viruses are being studied as potential gene delivery vectors [23]. As these vectors are progressively developed in the future, they give hope that therapeutic genes could be delivered safely and efficiently to cardiac cells. Similarly, if highly efficient liposome preparations suitable for use in man were developed, this would be an equally valid therapeutic approach.

Therapeutic genes Multiple preventive and therapeutic strategies have been trialled experimentally. An approach aimed at potentiating endogenous antioxidant reserves could be used as a preventive measure against myocardial injury induced by ischemia-reperfusion.

Heat shock proteins Heat shock proteins are a family of intracellular proteins which are observed in all organisms studied, from prokaryotic bacteria to mammals including man.

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These proteins are synthesized by normal unstressed cells, with a number of them acting as molecular chaperones (ensuring correct protein folding of other proteins within the cell) and others playing a role in protein degradation [24]. Although initially identified on the basis of their induction by elevation in temperature, these proteins are in fact induced by a wide range of stressful stimuli including a variety of viral infections, ethanol, steroids, heavy metals, anoxia, ischemia, and free radical generators. This association suggests that heat shock proteins have a critical function in the cell's response to stress and in assisting the cell to protect itself from such stress. Heat shock protein 70 (each heat shock protein is named according to its mass in kilodaltons) is induced in dogs' hearts exposed to ischemia, pressure or volume overload, and drugs such as vasopressin, angiotensin, or isoproterenol [25-27]. Moreover, heat shock proteins' expression is elevated in human hearts of patients with unstable angina and dilated cardiomyopathy [27,28]. Several studies demonstrate that heat shock proteins have protective effects on the myocardial cells with decreased reperfusion injury measured by creatine kinase release, improved recovery of contractile function, and reduction in infarct size following ischemia in hearts exposed to these proteins compared to controls, an effect that was shown to correlate with the amount of the heat shock protein induced [27-31]. Subsequent studies reported the generation of transgenie mice which overexpressed heat shock protein 70 in the heart and demonstrated that such overexpression was able to protect the heart against the damaging effects of ischemia [32]. Heat shock protein 32 (hemeoxygenase-1) is one of three identified isoforms, products of three distinct genes. They are the rate-limiting enzymes in the degradation of heme to bilirubin, carbon monoxide, and iron. These catalytic products exert wide-ranging antioxidant and cytoprotective effects [33,34]. Furthermore, hearts from hemeoxygenase-1 knockout mice show enhanced infarct formation following hypoxia [35]; conversely cardiac-specific overexpression of hemeoxygenase-1 leads to attenuated myocardial injury after ischemic perfusion injury in transgenic mice [36], and induction of the enzyme by exogenous heme before an ischemic episode markedly reduces infarct size [37]. The mechanisms mediating the protective effects of heat shock proteins are molecular chaperoning, attenuation of cardiac cells' apoptosis, protection of

Gene therapy for myocardial protection the integrity of the microtubules and the actin cytoskeleton of the myocardial and endothelial cells, and enhancing the production and stimulating the activity of endothelial nitric oxide synthase (eNOS) [38-40]. It has been shown that heat shock protein 70 gene within plasmid vector can be delivered to the heart within a plasmid, or viral vector, via intracoronary perfusion, conferring effective protection against subsequent ischemia-reperfusion injuries [38,41]. Adenoviral-mediated gene delivery of human hemeoxygenase-1 gene to rat hearts has also been shown to prolong transgene expression and, consequently, exert long-term myocardial protection demonstrated by dramatic reduction in infarct size after ischemia [42].

Antioxidant enzymes Considerable experimental evidence suggests that reactive oxygen species, such as superoxide anion O2 and hydrogen peroxide H2O2, are generated during reperfusion of the ischemic myocardium and play an important role in the initiation of the myocardial ischemia-reperfusion injury resulting in myocardial stunning and subsequently myocardial infarction. Under normal conditions the myocardium is equipped with enzyme systems that efficiently metabolize these reactive species. However, when subjected to ischemia and reperfusion, there is excessive production of free radicals that may overwhelm the antioxidant defense mechanism, combined with depletion of these enzymes during ischemia, which also prevents the cellular reconstitution of these systems [43]. The vast majority of animal studies examining the role of antioxidant enzymes in protecting the myocardium from ischemia-reperfusion injury have used superoxide dismutase, either alone or in combination with other antioxidants or antioxidant enzymes. Superoxide dismutase provides antioxidant protection by inactivating O2, sparing nitric oxide from destruction, and preventing O2 from forming more destructive reactive oxygen species, such as peroxynitrite and its reaction products, including hydroxyl radical (OH). Careful examination of the distribution kinetics of superoxide dismutase indicate that the interstitial levels rather than the plasma levels of this enzyme are primarily responsible for protection against ischemiareperfusion injury [44].

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Extracellular superoxide dismutase type C is a secretory isoenzyme that binds to heparan sulfate proteoglycans on cellular surfaces and has, in contrast to the intracellular isoenzyme, natural affinity for the endothelium and interstitial space and a long vascular half life, which provides more consistent cardioprotection than freely soluble isoforms. Gene therapy with extracellular superoxide dismutase gene as single antioxidant enzyme is an efficient and consistent myocardial protection method and was proven to decrease infarct size and regional myocardial dysfunction after ischemic injury in mice, conscious rabbits, and pigs [10,45-47]. Catalase is another antioxidant enzyme that has been studied widely for its potential cardioprotective effects by converting hydrogen peroxide (H2O2, a reactive oxygen) to water and oxygen and preventing the formation of highly reactive hydroxyl radical (OH). Detoxification of hydrogen peroxide in the myocardium is mainly accomplished by the glutathione peroxidase enzyme system, which is depleted during myocardial ischemia and reperfusion. Therefore, the capacity for hydrogen peroxide degradation is greatly diminished in the heart following ischemia. Although catalase levels in the myocardium are low, it is the major antioxidant enzyme in other tissues. Studies have shown that it participates to a significant extent in detoxification of hydrogen peroxide during periods of ischemia. Initial attempts have been made to increase antioxidant supplies by administration intravenously or by addition to the pump perfusate during cardiopulmonary bypass. Exogenous antioxidant enzyme administration, however, is limited by the ability of the myocytes to internalize these large molecules [48]. Gene transfection of catalase DNA into the myocardium via adenovirus vector can achieve high levels of catalase expression and significantly increase catalase activity in the myocardium. This was shown to result in the preservation of the contractile function in rabbit heart during reperfusion after ischemic injury [49].

Nitric oxide synthase Overexpressing nitric oxide synthase with a single intraoperative dose of liposomes was shown to inhibit nuclear factor-KB (NF-KB), a proinflammatory transcriptional activation factor for E-selectin and vascular cell adhesion molecule 1, resulting in inhibition of

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leukocyte infiltration and ischemia-reperfusion injury [11]. Adenoviral transfection of inducible nitric oxide synthase has been effective in inhibiting aortic allograft arteriopathy [50], whereas endothelial nitric oxide synthase has been used to inhibit neointimal formation in balloon injury models [51 ].

Immunosuppressive cytokines and adhesion molecules The activation of NF-KB was implicated in cellular damage after ischemia. NF-KB is a crucial transcriptional activator of many genes whose expression is related to ischemia-reperfusion injury, such as tumor necrosis factor a, interleukin 10, and intracellular adhesion molecule 1 [52]. In vivo transfection of a synthetic double-stranded deoxynucleotide with highaffinity to NF-KB "decoy oligodeoxynucleotides" results in binding of the transcriptional factor and blocking the activation of genes mediating myocardial injury. This effect was shown to provide effective therapy for myocardial injury when given before induction of ischemia or immediately after reperfusion, as hearts of treated rats had significant reduction of neutrophil adherence to endothelial cells, tissue levels of interleukin 8 resulting in significantly higher postischemic coronary flow, a higher percentage of left ventricular functional recovery, and reduction in the extent of myocardial infarction [53,54]. The NF-KB decoy was also shown to have the same protective effect on the brain during circulatory arrest, with evidence of attenuating neuronal damage after global brain ischemia by using in vivo transfection of decoy, which was successfully introduced into the nuclei of the neurons by infusing the carrying vector (hemagglutinating virus of Japan-liposome complex) through the carotid artery and across the bloodbrain barrier. This might have a potential for wide clinical applications, such as retrograde perfusion of cerebroplegia [55].

Apoptosis regulators Apoptosis, the predominant mode of cardiac cell death, is positively and negatively regulated by the Bcl2 family of proteins. Proapoptotic proteins include Bax, Bak, Bcl-XS, Bad, Bid, Bik, Bim, Hrk, and Bok, whereas antiapoptotic proteins include Bcl-2, Bel-XL, Bcl-w, Mcl-1, and Al/Bfl-1. Bcl-2 is a 26-kDa protein localized to the cytoplasmic face of the mitochondrial outer membrane, endoplasmic reticulum, and nuclear

envelope. Bcl-2 has been shown to prevent cytochrome c release, caspase activation, and cell death. Regulation of apoptosis is highly dependent on the ratio of antiapoptotic to proapoptotic proteins. Bcl-2 is capable of preventing p53-induced programmed cell death of neonatal ventricular myocytes. The Hcl-2 protein plays an antiapoptotic role by inhibiting the formation of the mitochondrial permeability transition pores, which promote contact between the inner and the outer membranes of the mitochondria and play a critical role in apoptosis. It was also suggested that Bcl-2 might have a role in maintaining calcium homeostasis and stable mitochondrial membrane potential to offset pathologic insult. Although the exact mechanism is not clear yet, overexpression of Bcl-2 in the hearts of transgenic mice resulted in significantly improved myocardial protection and functional recovery after ischemia-reperfusion injury induced by ligation of the coronary artery; this was demonstrated by a threefold decrease in lactate dehydrogenase released, a decrease in the infarct sizes, and left ventricular developed pressure [56]. The Akt is a proto-oncogene, a serine/threonine protein kinase, with antiapoptotic activity resulting from its ability to inactivate proapoptotic molecules, including Bad and caspase 9, and to activate potential prosurvival molecules, such as IKKa. Rat hearts transfected with the Akt gene were shown to have significantly smaller infarct areas following ischemiareperfusion injury [57]. As further progress is made in understanding the pathophysiology of ischemia-reperfusion heart injury and in developing methods for safe and efficient gene delivery to the heart, we are heading toward developing an effective gene therapy for myocardial protection. Such a therapy would incorporate genetic targets for preventing myocardial injury and restoring the injured myocardium. The development of tissuespecific and regulatable transgene expression, such that the therapeutic enzyme would be produced only where and when needed, will avert potential cytotoxic effects associated with constitutive expression of the therapeutic enzyme.

References 1 Crystal R. Transfer of genes to humans: early lessons and obstacles to success. Science 1995; 270:404-10. 2 Magovern C, Mack C, Rosengart T et al. Direct in vivo gene transfere to canine myocardium using a replication

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309 19 Baron U, Gossen M, Bujard H. Tetracycline-controlled transcription in eukaryotes. Novel transactivators with graded transactivation potential. Nucleic Acids Res 1997; 25:2723-9. 20 Lee Y, Zhou X, Rosengart T et al. Exogenous control of cardiac gene therapy: evidence of regulated myocardial transgene expression after adenovirus and adenoassociated virus transfer of expression cassettes containing corticosteroid response element promoters. / Thorac Cardiovasc Surg 1999; 118:26-5. 21 Kim S, Yu S, Park J et al. Construction of retroviral vectors with improved safety, gene expression, and versatility. J Virol 1998; 72:994-1004. 22 Thompson L. Gene therapy: monkey tests spark safety review. Science 1992; 257:1854. 23 Coffin R, Howard M, Gumming D et al. Gene delivery to the heart in vivo and to cardiac myocytes and vascular smooth muscle cells in vitro using herpes virus vectors. Gene Ther 1996; 3,560-6. 24 Ellis R. Molecular chaperones. Semin Cell Biol 1990; 1: 1-72. 25 Dillmann W, Mehta H, Barrieux A et al. Ischemia of the dog heart induces the appearance of a cardiac mRNA for a protein with migration characteristics similar to heatshock/stress protein 71. CircRes 1986; 59:110-14. 26 Yellon D, Latchman D. Stress proteins and myocardial protection. JMol Cell Cardiol 1992; 24:113-24. 27 Latchman D. Heat shock proteins and cardiac protection. Cardiovasc Res 2001; 51:637-46. 28 Latif N, Taylor P, Khan M, Yacoub M, Dunn M. The expression of heat shock protein 60 in patients with dilated cardiomyopathy. Basic Res Cardiol 1999; 94:112-19. 29 Currie R, Karmazyn M, Kloc M. Heat-shock response is associated with enhanced postischemic ventricular recovery. CircRes 1988; 63: 543-9. 30 Marber M, Latchman D, Walker J, Yellon D. Cardiac stress protein elevation 24 hours after brief ischemia or stress is associated with resistance to myocardial infarction. CircRes 1993; 88:1264-72. 31 Hutter M, Sievers R, Barbosa V, Wolfe C. Heat shock protein induction in rat hearts. A direct correlation between the amount of heat shock protein induced and the degree of myocardial protection. Circulation 1994; 89: 353-60. 32 Plumier J, Ross B, Currie R et al. Transgenic mice expressing the human heat shock protein 70 have improved postischemic myocardial recovery. J Clin Invest 1995;95:1854-60. 33 Otterbein L, Choi A. Heme oxygenase: colors of defense against cellular stress. AmJPhysiol 2000; 279: L1029-37. 34 Brouard S, Otterbein L, Anrather J et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis./£xpMed 2000; 192:1015-25. 35 Yet S, Perrella M, Layne M et al. Hyopoxia induces severe right ventricular dilation and infarction in heme oxygenase- 1 null mice. J Clin Invest 1999; 103: R23-9. 36 Yet S, Tian R, Layne M et al. Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res 2001; 89: 168-73.

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37 Clark J, Foresti R, Sarathchandra P et al. Heme oxygenase1-derived bilirubin ameliorates postischemic myocardial dysfusion. Am} Physiol 2000; 278: H643-51. 38 Brar B, Stephanou A, Wagstaff M et al. Heat shock proteins delivered with a virus vector can protect cardiac cells against apoptosis as well as against thermal or ischaemic stress. ]Mol Cell Cardiol 1999; 31:135-46. 39 Bluhm W, Martin J, Mestril R, Dillmann W. Specific heat shock proteins protect microtubules during simulated ischemia in cardiac myocytes. Am J Physiol 1998; 275: H2243-9. 40 Garcia G, Fan R, Shah V et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 1998; 392:821-4. 41 Jayakumar J, Suzuki K, Khan M et al. Gene therapy for myocardial protection. Transfection of donor hearts with heat shock protein 70 gene protects cardiac function against ischemia-reprofusion injury. Circulation 2000; 102(19suppl3):III302-6. 42 Melo L, Agrawal R, Zhang L et al. Gene therapy strategy for long-term myocardial protection using adeno-associated virus-medicated delivery of heme oxygenase gene. Circulation 2002; 105:602-7. 43 Ferrari R, Ceconi C, Curello S et al. Oxygen-mediated myocardial damage during ischemia and reperfusion: role of the cellular defenses against oxygen toxicity. J Mol Cell Cardiol 1985; 17:937-45. 44 Omar B, McCord J. Interstitial equilibration of superoxide dismutase correlates with its protective effect in the isolated rabbit heart./Mo/ Cell Cardiol 1991; 23:149-59. 45 Hatori N, Sjoquist P, Marklund S et al. Effects of recombinant human extracellular-superoxide dismutase type C on myocardial infarct size in pigs. Free Radic Biol Med 1992; 13: 221-30. 46 Li Q, Bolli R, Qui Y et al. Gene therapy with extracellular superoxide dismutase attenuates myocardial stuning in conscious rabbits. Circulation 1998; 98:1438-48. 47 Chen E, Bittner H, Davis R et al. Physiologic effects of extracellular superoxide dismutase transgene overexpression on myocardial function after ischemia and

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Aortic and mitral valve surgery on the beating heart Marco Ricci, MD, Pierluca Lombardi, MD, Michael O. Sigler, MD, Giuseppe D'Ancona, MD, & TomasA. Salerno, MD

Introduction Coronary artery bypass grafting (CABG) on the beating heart has been recently revived as an alternative to conventional myocardial revascularization performed on cardiopulmonary bypass (CPB) and on the arrested heart [1,2]. Despite its increasing popularity many surgeons, at least initially, accepted this technique with substantial skepticism [3,4]. Among others, their contrary view to beating heart CABG was due to the fact that they felt that a motionless and bloodless field was an indispensable component of coronary artery surgery. Furthermore, as a result of the progressive improvement in perioperative and long-term results of conventional CABG on the arrested heart [5], many surgeons remained reluctant to embrace a new procedure of unproven efficacy [3]. As technical advances have been made in the field of beating heart coronary revascularization, and as the experience with beating heart CABG has accumulated, there has been increasing evidence to suggest that CPB and cardioplegic arrest are not, in reality, indispensable adjuncts to coronary operations [ 1,2 ]. Similarly, the surgical strategies used by the vast majority of surgeons in aortic and mitral valve operations have invariably encompassed the use of some sort of cardioplegic arrest, with only a few recent sporadic exceptions [6,7]. As techniques in cardiac surgery have evolved during the last two or three decades, much attention has focused on experimentation with new strategies of cardioplegic arrest [8], and on the introduction of new techniques of minimally invasive valvular operations on the arrested heart

[9,10]. The introduction and popularization of cardioplegic solutions have replaced the original methods of myocardial protection initially proposed and utilized during the early days of cardiac surgery, in which the heart was arrested by a combination of ischemia and hypothermia [11]. As this technique was found to provide only limited and suboptimal protection of the myocardium during the interruption of coronary blood flow, in recent years a multitude of new strategies of myocardial protection have been introduced and investigated, both clinically and experimentally [8]. While the common denominator for these techniques has remained the induction and maintenance of cardioplegic arrest, much of the debate has focused on many other variables such as composition of the cardioplegia perfusate (i.e. blood vs. crystalloid), concentration of the constituents, route of delivery (antegrade vs. retrograde), and temperature of the perfusate (i.e. warm vs. cold) [ 12]. Data from the literature have shown that many of these techniques have stood the test of time, and that they have proved to provide safe and effective myocardial protection in many diverse cardiac operations. In certain patients, however, the enhancement of myocardial protection and maximal preservation of ventricular function remains a challenge. In fact, in the presence of severely compromised left ventricular (LV) function preoperatively, exposure of the already compromised myocardium to any additional ischemic insult could lead to severe postoperative ventricular dysfunction [ 13]. This may be of particular significance when prolonged periods of aortic cross-clamping are anticipated (i.e. simultaneous aortic and mitral valve

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surgery, valve surgery, and CABG, etc.). In this perspective, the cardioprotective strategy behind beating heart valve operations, which is described in this chapter, was designed to enhance myocardial protection and promote myocardial recovery, especially in patients at risk of developing postoperative myocardial dysfunction.

Rationale for avoiding cardioplegic arrest in aortic and mitral valve operations A large body of clinical and experimental evidence has shown that myocardial ischemic injury during cardiac operations may be effectively prevented by substantially reducing the myocardial oxygen demand during the interruption of coronary blood flow [ 14]. Although with many variants, this has been traditionally accomplished by the vast majority of surgeons by a combination of electromechanical arrest, hypothermia, and avoidance of cardiac distension (or reduction in wall tension) [12], which are used in concert in an attempt to minimize the imbalance between myocardial oxygen supply and demand. As many of the strategies currently used by contemporary surgeons in various valve operations are extensively described in the literature, and are also addressed in other chapters in this book, a thorough description of their rationale, biochemical background, and clinical applications will not be given in this chapter. The elimination of the electrical and mechanical myocardial activity accomplished by using many of the techniques currently available has been shown to consistently reduce myocardial oxygen demand and consumption during aortic cross-clamping. However, myocardial ischemic injury may be less effectively prevented during cardiac procedures requiring, for example, prolonged periods of aortic cross-clamping. In these situations, such as those in which both mitral and aortic valve replacement are undertaken concomitantly, prolonged myocardial ischemia may result in profound metabolic derangement, and ultimately ischemic injury, irrespective of the strategy of myocardial protection used [15]. The susceptibility of the myocardium to ischemic injury may be enhanced by the presence of coexisting adverse variables, such as coronary artery disease, myocardial hypertrophy, and poor LV function [12]. In these situations, preservation of adequate coronary perfusion throughout the

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procedure, and maintenance of the heart in a beatingempty, normothermic state, should be viewed as an attractive alternative, as it could prevent the deleterious effects of a protracted ischemic time on an already compromised myocardial substrate.

"Beating heart" surgery and "warm heart" surgery The theoretical and conceptual framework behind the strategy of performing aortic and mitral valve operations on the beating heart, in many ways, is not entirely new. In fact, the principles supporting this strategy further extend those previously described for warm heart surgery [15—17], in which myocardial protection was accomplished by inducing electromechanical arrest at normothermia, keeping the heart continuously perfused with oxygenated and hyperkalemic blood perfusate throughout the operation [ 16]. As originally conceived, this strategy was designed to enhance protection of the myocardium by reducing substantially myocardial oxygen demand (electromechanical arrest), while maximizing oxygen supply (maintenance of coronary perfusion) [17]. Furthermore, the elimination of any supply—demand mismatch was compounded by the advantages of normothermia [15], and by the avoidance of reperfusion injury [15]. In turn, normothermia was largely responsible for maintaining many of the myocardial enzymatic pathways functioning at a normal, or near-normal, state [ 15], and for optimizing the oxygen dissociation curve and oxygen delivery to the myocardial substrate [15]. This innovative approach stood in sharp contrast to other widely adopted methods of myocardial protection of the 1980s and 1990s, which all shared in common the presence of some degree of supply-demand mismatch, of variable duration and severity, as well as the potential for myocardial anoxia, anaerobic metabolism, reperfusion injury, and ultimately myocardial ischemic injury. In the strategy proposed and described herein (beating heart surgery), myocardial protection is promoted essentially by maintaining the heart in a beatingempty and continuously perfused state, by using either antegrade coronary flow or a combination of antegrade-retrograde flow. As a result, as in warm heart surgery, the principles behind beating heart surgery can be fundamentally simplified to the theoretical and actual elimination of any degree of supply-demand

Beating heart valve surgery mismatch. In warm heart surgery, the amount of oxygen supplied to the myocardium was found to exceed that utilized by the arrested, normothermic heart (approximately 1 cm3/lOO g/min) [14], so that continuous perfusion with oxygenated, normothermic, and hyperkalemic blood perfusate could be advantageously reduced, or even interrupted, for short periods of time as needed [ 18]. In this regard, studies have shown that periods of interruption of myocardial perfusion of up to 10 min were associated with full myocardial metabolic recovery [18]. By contrast, in beating heart surgery the heart remains in a normothermic, beating-empty state, which is associated with oxygen requirements of approximately 5-6 cm3/100 g/min at heart rates of 70-80/min, which are substantially greater than those of the arrested normothermic heart (1 cm3/lOO g/min) [14]. Such oxygen requirements of normothermic, beating-empty hearts may further increase at higher heart rates. Incidentally, for this specific reason we avoid using the misnomer "beating, non-working" heart, as this term would mistakenly describe a situation in which the myocardium is, in fact, contracting and thus working, although without generating any stroke volume. However, in beating heart surgery, despite myocardial oxygen consumption remaining substantial, oxygen supply approximates that of normal physiologic conditions, as the heart remains continuously perfused at rates similar to those of physiologically perfused hearts. As a postulate, coronary blood flow and oxygen supply must be preserved without interruption, in order to meet ongoing demands. Secondly, there is a strict relationship between heart rate and myocardial oxygen consumption at normothermia. As a result, during beating heart operations the heart rate has to be carefully monitored, and faster rates should be controlled either pharmacologically or by slightly drifting down the bypass temperature (34.5-35°C). However, it should also be noted that oxygen consumption of the beating-empty, normothermic heart (5-6 cm3/100 g/ min) is markedly lower than that of the beatingfull, normally working, normothermic heart (8-9 cm3/ 100 g/min) [14]. This further shifts the ratio supply demand upward, and further extends the safely with which operations on beating-empty, normothermic, and continuously perfused hearts can be conducted. As in warm heart surgery, an important consideration in beating heart surgery is the elimination of any reperfusion injury, since the heart remains continu-

313

ously perfused [15]. Furthermore, the beating-empty state may also prevent the occurrence of myocardial edema, often described after cardioplegic arrest, which, in turn, may have detrimental effects on myocardial contractility and postoperative ventricular function based on these considerations. The aim of this chapter is to describe a variety of alternative techniques for performing aortic and mitral valve operations, primary or preoperative, with or without concomitant CABG, which all have in common the strategy of myocardial protection (beating heart surgery).

Aortic valve operations on the beating heart The surgical technique of aortic valve repair or replacement used by our group does not differ from those already described extensively in the literature by others. As a result, they will not be discussed in this section, which will focus exclusively on the strategy of myocardial protection. As previously described, this consists of keeping the heart in a beating-empty and continuously perfused state. Many of the steps of the operation are essentially similar to those of conventional operations. Standard cannulation of the ascending aorta and right atrium ('two-stage' single venous cannula) is performed. The patient is placed on CPB and kept normothermic (35-37°C). A standard catheter with self-inflating balloon is inserted through the coronary sinus for retrograde, high-flow perfusion with normothermic, oxygenated blood. The retrograde catheter is usually secured and stabilized by using a single 4-0 prolene stitch placed around the coronary sinus free wall, as previously described by our group [19]. This effectively prevents catheter dislodgement and, in our experience, is not associated with any notable shortcomings [19]. The retrograde line is connected to a manifold, to which additional perfusion catheters (1 or 2) can be attached. These will be used for simultaneous perfusion through the coronary ostia. Some of the technical details of the operation are illustrated in Figure 34.1. After proper CPB is established, an LV venting catheter is then inserted through the right superior pulmonary vein to both avoid distension of the left ventricle and improve visibility in the surgical field. The aorta is then crossclamped. Retrograde perfusion with normothermic (35-37°C), oxygenated blood is immediately commenced through the coronary sinus catheter.

314

Figure 34.1 Aortic valve surgery on the beating-empty heart. For explanation see the text.

Flows of 300-350 cm3/min are normally delivered. An attempt is made at keeping coronary sinus perfusion pressures at less than 60-70 mmHg. The aortic root is immediately opened in the usual fashion and, after clearing the blood from the field, both coronary ostia are inspected. Cannulation of at least one of the coronary ostia is established (usually the left) by using a self-inflating balloon catheter. The catheter is connected to the manifold along with the CS catheter. Antegrade normothermic oxygenated blood through a single coronary ostia is then delivered simultaneously with retrograde perfusion, at a total rate of 350400 cm3/min. Once simultaneous antegrade/retrograde perfusion is commenced, the right coronary ostia (usually not cannulated) is inspected to ensure that an adequate amount of effluent is coming back from the coronary circulation. In our experience, we favor cannulation of the left coronary ostia to enhance adequate LV perfusion, and also because a perfusion catheter placed in the left ostia tends to dislodge less frequently than one placed in the right ostia. Surgery on the aortic valve is then performed while the heart is kept normothermic and beating-empty. The EGG is monitored throughout the procedure. Normal sinus rhythm (NSR) is frequently preserved, and is often indicative of proper coronary perfusion. Upon completion, the aortic

CHAPTER 34

root is closed. The antegrade left coronary catheter is retrieved, while the heart is supported for a very short period of time solely on retrograde flow. After deairing, the aorta is undamped and retrograde perfusion discontinued. A venting catheter is also inserted in the aortic root to completely deair the left chambers. While this strategy of myocardial protection may seem cumbersome, especially in regard to poor visualization, it presents several distinct advantages. In our experience it may be particularly advantageous in patients with aortic regurgitation and markedly compromised ventricular function. In fact, after establishing CPB, the heart is kept at normothermia and beating, thus avoiding LV distention. Although visualization is somewhat inferior to that obtained on the arrested heart, in our experience it remains certainly adequate to perform valve surgery. The LV venting catheter, as previously described, maintains the left ventricle empty. As a result, much of the blood in the field arises from the coronary ostia that has not been cannulated for antegrade perfusion (normally the right), and can be easily recovered by the LV vent as it falls by gravity into the left ventricle. As previously stated, when using this strategy of myocardial protection, the heart is maintained continuously perfused by simultaneous antegraderetrograde perfusion with normothermic, oxygenated blood. Some of the principles upon which this strategy is based were recently reported in the literature by Tian and Deslauriers [20,21]. In one of their recent experimental studies [21], these investigators established whether simultaneous antegrade-retrograde cardioplegia, with the antegrade component delivered through a single coronary artery, could result in adequate perfusion of the entire myocardium in pig hearts. The distribution of the cardioplegic perfusate was assessed both by magnetic resonance (MR) technique and by analysing the quantity and characteristics of the blood recovered from the nonperfused coronary artery. In this original study, simultaneous antegrade-retrograde cardioplegia delivered through the coronary sinus (CS) and a single coronary artery resulted in adequate and homogeneous perfusion of the entire heart, irrespective of the coronary artery used [21]. This was in sharp contrast to what was observed after isolated perfusion through the CS, or through a single coronary artery, as both techniques failed to provide adequate and homogeneous perfusion of all areas of myocardium, leaving some regions

Beating heart valve surgery underperfused or not perfused at all. Of note, the adequacy of isolated retrograde delivery of cardioplegic perfusate in reaching all areas of myocardium has been previously questioned, based on both experimental and clinical evidence [22,23]. Despite these important findings obtained in the experimental model, and after using cardioplegia as opposed to normothermic blood, it is conceivable that these data could very well be extrapolated and applied to the clinical model described herein. In addition to providing adequate myocardial perfusion in normal hearts, simultaneous antegrade-retrograde perfusion has been shown to also enhance perfusion of areas of myocardium supplied by occluded coronary arteries [20]. This may be of great relevance, especially in elderly patients undergoing valve operations, in whom coexistent coronary artery disease is not infrequent, although in many of these patients we would favor CABG as the first step. As such, the results of this investigation constitute the conceptual framework upon which our strategy of myocardial protection was conceived. As there is evidence to suggest that isolated perfusion through the CS would inadequately support the entire myocardium in a beating-empty heart at normothermia, we do not favor the approach described by others [6] in which myocardial perfusion is supported solely by the retrograde route. Conversely, while coronary perfusion through both coronary ostia would adequately support the myocardium at least in the absence of coronary artery disease, the presence of two coronary catheters in the operative field could make aortic valve surgery cumbersome and more time-consuming. As such, the strategy of maintaining myocardial perfusion through the CS and only one coronary ostia facilitates surgery, as only one coronary catheter crosses the operative field, while it promotes adequate perfusion of all areas of myocardium. In summary, aortic valve operations can be performed on the beating heart. Simultaneous retrograde and antegrade perfusion with normothermic oxygenated blood through the coronary sinus and a single coronary artery provides adequate blood supply of the beating-empty, non-working heart. Myocardial oxygen supply is kept at a normal or near-normal state, while oxygen consumption is reduced to approximately 60-70% of that of a normal, beating-full heart (from 8 to 9 cm3/100 g/min to 5-6 crrvVlOO g/min) [14]. Thus, any supply-demand mismatch is eliminated throughout the procedure.

315

Patients that may particularly benefit from this approach are those requiring aortic valve replacement for aortic insufficiency, those presenting with very poor ventricular function, and those with renal failure requiring hemodialysis. Also, patients in whom prolonged periods of aortic cross-clamping are anticipated (double valve replacement, valve grafting, and CABG) could benefit from this approach. In these patients, however, the strategy described herein is further modified, and it will be described in a following section in this chapter (see "Concomitant valve surgery and coronary artery bypass grafting on the beating heart" below). Patients with renal failure may benefit a great deal from the beating heart approach, as cardioplegia and the risk of hyperkalemia are avoided altogether.

Mitral valve operations on the beating heart Many of the principles of myocardial protection described for beating heart aortic valve procedures apply to mitral valve operations on the beating heart. As in aortic valve surgery, the heart is kept beatingempty at normothermia throughout the procedure. Bicaval cannulation is used and a deairing catheter is placed into the aortic root and kept on very low suction. When the trans-septal approach is chosen, it is necessary to use caval tapes, which must be snared prior to entering the right atrium. In contrast to aortic valve operations coronary blood supply is provided physiologically through the aortic root and coronary ostia, as the aorta is not cross-clamped (Figure 34.2). As a result, our approach differs from that previously described for solely retrograde perfusion through the CS. This contrary view to isolated retrograde perfusion is supported by the fact that—as previously mentioned for aortic valve operations—there is increasing evidence to suggest that this strategy may lead to maldistribution of the perfusate and malperfusion of the myocardium, with the consequential potential for myocardial ischemic injury [22,23]. While avoiding aortic cross-clamping and maintaining the heart continuously perfused through the aortic root are associated with several distinct advantages, the conduct of the operation has been refined to avoid the risk of air embolization. The procedure (Figure 34.2) is routinely commenced by standard aortic cannulation, and suction is used throughout the operation.

316

Figure 34.2 Mitral valve replacement on the beating-empy heart. For explanation see the text.

Cardiopulmonary bypass at normothermia (35-37°C) is then established. When the posterior approach through the interatrial groove is used to expose the mitral valve, the superior vena cava (SVC) and inferior vena cava (IVC) are not encircled with tapes. Therefore blood coming back to the right atrium through the CS is drained and returned to the CPB reservoir; thus keeping the right-sided chamber of the atrium opened, a floppy cardiotomy sucker can be inserted into the CS to collect the coronary effluent and improve visibility. The main concerns of beating heart mitral valve surgery without aortic crossclamping are the avoidance of air embolism, whose significance is obvious, and the avoidance of aortic insufficiency, and which may be induced by the retractor used to expose the mitral valve. The avoidance of air embolism obviously represents a major concern, and to prevent this dreadful complication the operative strategy must be discussed in detail beforehand with both the anesthesiologist and the perfusion technician. In addition, several principles must be followed: (i) the patient is placed and maintained in Trendelenburg position for the entire duration of the operation, until the left atrium is closed; (ii) an aortic root venting catheter is kept on low suction throughout the operation; (iii) during CPB, perfusion pressures must be maintained above 80-90 mmHg; (iv) a very short period of fibrillatory arrest (less than 1 min) is used while the left atrium is entered, but only in patients in whom the mitral valve is competent (i.e. mitral valve surgery for mitral stenosis). In the pres-

CHAPTER 34

ence of severe mitral insufficiency, the left atrium can be entered while the heart is beating, when the recommendations described above are carefully followed. However, it is also important that, as soon as the left atrium is opened, a cardiotomy sucker is placed into the left ventricle through the mitral valve, so as to decompress the left ventricle and further eliminate the risk of air embolism. In our view, as long as the left ventricle is kept beating-empty and properly decompressed, and perfusion pressures are maintained above 80-90 mmHg, air embolization is effectively prevented. Conversely, in patients presenting with a competent mitral valve, air embolism could occur when the left atrium is entered. As a result, this strategy is modified by inducing a very brief period (normally less than a minute) of ventricular fibrillation with a fibrillator, during which access to the left atrium is rapidly gained. A cardiotomy sucker is then placed through the mitral valve into the left ventricle. Once the left ventricle is decompressed, the heart can be safely defibrillated. In our view, such a brief period of ventricular fibrillation is of no consequence in respect to myocardial protection. Also, following this strategy we have not observed any adverse neurologic event which could have been ascribed with certainty to air embolism. Although the clinical results of our series of patients who underwent mitral valve operations on the beating heart are currently under investigation and will not be presented in this chapter, we have observed only one case of adverse neurologic outcome that was unlikely to have been caused by air embolism. This involved a patient in renal failure who underwent double-valve replacement for severe and diffuse calcific degeneration of both mitral and aortic valves. After the left atrium is entered and the LV cavity has been decompressed, a "mitral" retractor is placed to gain adequate exposure of the mitral valve. It is at this point, however, that improper placement of the retractor or excessive traction may alter the geometry of the aortic root, leading to torrential aortic insufficiency. Aortic insufficiency, which may be further enhanced by high perfusion pressures, could also adversely affect coronary perfusion. Importantly, severe aortic regurgitation would inevitably compromise visualization and could preclude the performance of mitral valve surgery on the beating heart. For the same reasons, the presence of moderate or severe aortic insufficiency preoperatively may also preclude

Beating heart valve surgery this approach, unless the strategy of the operation is modified so as to perform aortic valve surgery concomitantly. The technical modifications adopted in the setting of combined aortic and mitral valve surgery will be discussed below (see "Combined aortic and mitral valve operations on the beating heart"). In these situations, when both mitral and aortic valve surgery are contemplated in a patient with aortic insufficiency, it may be preferable to clamp the aorta and establish perfusion of the myocardium through the antegrade (single coronary ostia) and retrograde route simultaneously, in a fashion similar to that previously described for aortic valve surgery on the beating heart. Once the mitral retractor is placed into position and aortic regurgitation is avoided, the mitral valve can be repaired, or replaced, as planned. During the procedure, visualization is improved by using two floppy cardiotomy suckers, one placed in the left ventricle through the mitral orifice, and a second one placed in the left atrium at the bottom of the well. In contrast to mitral valve repair on the arrested heart, repair of the mitral valve on the beating heart is facilitated by the fact that the geometry of the mitral valve apparatus closely resembles that of hearts under normal physiologic conditions. Thus, the quality of the repair can be tested more effectively than in the arrested heart. After the mitral valve is repaired or replaced, a floppy cardiotomy sucker is left through the mitral orifice so as to keep the left ventricle empty and prevent LV ejection, while the left atrium is closed. At last, the LV vent is removed, while the root vent is kept constantly on gentle suction to complete deairing, and the operation is completed in the usual fashion. In patients with concomitant coronary artery disease, this strategy can be modified by using a retrograde catheter in the CS as an adjunct in myocardial perfusion. In reality, we rarely, if ever, use this strategy in the presence of concomitant coronary disease, as we would normally perform CABG on the beating heart (with or without CPB) prior to addressing the mitral valve (see "Concomitant valve surgery and coronary artery bypass grafting on the beating heart" below). As a result, once coronary revascularization is accomplished, the heart is kept perfused through the aortic root (coronary ostia and newly constructed grafts) as mitral valve surgery is performed. However, using an additional source of coronary blood supply through the coronary sinus may be advantageous in patients presenting with coronary disease that, for whatever

317

reason, does not lend itself to coronary revascularization. In fact, studies from the literature have shown that myocardial perfusion of areas of myocardium supported by occluded coronary arteries is superior when simultaneous antegrade-retrograde perfusion is used, in contrast to isolated antegrade perfusion [20]. In summary, mitral valve surgery can be performed using the beating heart technique as the strategy of myocardial protection. Patients who may benefit from this approach include those presenting with very compromised ventricular function, especially when prolonged periods of aortic cross-clamping are anticipated. The presence of moderate or severe aortic insufficiency may preclude this approach for the reasons described above.

Combined aortic and mitral valve operations on the beating heart Although the principles described for aortic and mitral operations on the beating heart also apply to patients requiring combined procedures, a few technical modifications are necessary. When concomitant aortic and mitral valve surgery are contemplated, the theoretical advantages of the beating heart approach are obvious. Prolonged periods of ischemia, which would be the consequence of many of the strategies of cardioplegic arrest, are avoided, and exchanged for prolonged periods during which the heart remains perfused, thus eliminating the potential for ischemic injury. In these situations, after proper CPB at normothermia is established, the "mitral" portion of the operation (repair or replacement) is performed before the "aortic" portion, as is the case in conventional operations on the arrested heart. However, the strategy of myocardial perfusion and the conduct of the operation differ, based on whether the patient presents with or without aortic insufficiency. In patients with moderate or severe aortic insufficiency, in whom mitral and aortic valve replacement are contemplated concomitantly, myocardial perfusion is accomplished in a manner similar to that described for isolated operations on the aortic valve. Cardiopulmonary bypass at normothermia is initiated. An LV vent through the right superior pulmonary vein is inserted. Then the aorta is cross-clamped and retrograde, high-flow perfusion is commenced while the aortic root is opened. The left coronary ostia is cannulated, and simultaneous antegrade-retrograde perfusion is delivered, while

318

the heart is kept beating-empty. At this point, the left atrium is entered, and mitral valve surgery performed. The left atrium is then closed leaving a floppy cardiotomy sucker in it. The attention is directed to the aortic valve, which is excised and replaced, venting the left ventricle through the left ventricular outflow tract. At completion, the aortic root is closed, deairing is performed, and the aorta is undamped, discontinuing retrograde perfusion. Alternatively, in patients without aortic insufficiency, the first portion of the operation (mitral valve surgery) can be performed with the aorta undamped, the patient in Trendelenburg position, high perfusion pressures (above 80-90 mmHg), the aortic root vent on very gentle suction, and the myocardium perfused through the aortic root, as previously described for isolated mitral valve operations. Once the mitral portion of the operation is completed, retrograde perfusion through the CS is begun, the aorta is clamped, the aortic root is opened, and simultaneous antegraderetrograde perfusion is established, as described above. In essence, the presence or absence of aortic regurgitation dictates the strategy of the first part of the operation, during which the mitral valve is dealt with.

Concomitant valve surgery and coronary artery bypass grafting on the beating heart In the presence of coronary artery disease amenable for surgical revascularization, we routinely initiate the operation by performing CABG on the beating heart, without CPB. Various techniques of beating heart coronary surgery are employed, as previously described [1,24]. The next step encompasses the institution of CPB, and performance of valve surgery on CPB, on the beating heart. Only in a minority of patients have we observed deterioration of the hemodynamic parameters during the performance of CABG without CPB. In these situations, we establish CPB and we perform coronary revascularization on bypass, while the heart is perfused and beating. The operation then proceeds as previously described for beating heart aortic and mitral valve procedures. In patients requiring aortic valve replacement concomitantly with CABG, after constructing distal anastomoses we routinely perform the aortic valve procedure while the heart is perfused by a combination of antegrade perfusion (through the grafts and

CHAPTER 34

through one coronary ostia) and retrograde perfusion (catheter in the coronary sinus). When aortic valve replacement is completed and the aortic root is closed, the proximal anastomoses of newly constructed coronary grafts are constructed. In patients necessitating a mitral valve procedure and CABG, distal anastomoses and then proximal anastomoses are performed first, with or without CPB. Subsequently, after establishment of CPB, the operation proceeds as previously described for mitral valve operations on the beating heart, so that the heart is perfused from the aortic root without clamping the aorta (both through the coronary ostia and through the newly constructed coronary grafts).

Conclusions As sicker and older patients are referred for cardiac surgery, surgical techniques evolve and new cardioprotective strategies are proposed. For several decades, cardiac surgeons have focused on refining techniques of myocardial protection during cardioplegic arrest, either by introducing new cardioplegic solutions or by modifying their modalities of delivery. Also, with the recent advent of minimally invasive valve surgery, a great deal of attention has centred on the magnitude of the operative approach, and on the length of the surgical incision. In aortic and mitral valve surgery, more limited and sometimes cumbersome surgical incisions have been advocated. Although many of these techniques have enjoyed the consensus of some patients, their real value should be weighted against their potential disadvantages, such as the risk of longer periods of aortic cross-clamping and cardioplegic arrest. While in many patients the impact of such adverse variables may be difficult to establish, and is perhaps of modest clinical relevance, in others it can unnecessarily increase the risk of both myocardial ischemic injury and postoperative ventricular dysfunction. In this perspective, if it is agreed that maximal preservation of myocardial function should be viewed as one of the main priorities in cardiac operations, then the "minimal invasiveness" of some of these "minimally invasive" valve operations could be questioned, as their use remains associated with a risk of myocardial injury that is equal to, or even greater than, that of conventional operations. In our view, minimally invasive valve operations are most notably those designed to minimize the risks of the operation and to preserve

319

Beating heart valve surgery

maximally myocardial function, rather than those in which cosmetic considerations are prioritized. As a result, beating heart techniques of aortic and mitral

8

valve surgery may play an important role in expanding the armamentarium of cardiac surgeons. In fact, although their efficacy remains to be proven, these

9

techniques have been conceived and designed to maximally preserve ventricular function. This may be of great importance, especially in patients presenting

10

with severe preoperative ventricular dysfunction, or

11

in those requiring procedures in which prolonged periods of aortic cross-clamping are required. To date, there is no conclusive scientific evidence to prove or dispute the superiority of this strategy of myocardial protection over other widely adopted conventional strategies. Nevertheless, the validity of the principles supporting beating heart surgery, the advantages of having the heart beating-empty and continuously per-

12 13

14

fused at normothermia throughout the period of aortic cross-clamping, and the consequential advantages of eliminating any supply-demand mismatch, cannot

15

be disputed. As the clinical data relative to the use of these techniques for both aortic and mitral valve surgery are currently under review, and they will be the object of publications in the future, they will not be presented herein. However, our preliminary experience

16

of beating heart valve surgery, which now consists

17

of well over 100 patients operated on in the context of various clinical conditions, seems to suggest that this

18

approach is associated with early favorable results.

References 1 Ricci M, Karamanoukinan HL, D'Ancona G et al. Exposure and mechanical stabilization in off-pump coronary artery bypass grafting via sternotomy. Ann Thorac Surg2000; 70: 1736-40. 2 Mack MJ. Minimally invasive and robotic surgery. JAMA 2001; 285: 568-72. 3 Cooley DA. Con: beating heart surgery for coronary revascularization: is it the most important development since the introduction of the heart-lung machine? Ann Thorac Surg 2000; 70:1779-81. 4 Cosgrove DM. Is coronary reoperation without the pump an advantage? Ann Thorac Surg 1993; 55:329. 5 Estafanous FG, Loop FD, Higgins TL et al. Increased risk and decreased morbidity of coronary artery bypass grafting between 1986 and 1994. Ann Thorac Surg 1998; 65: 383-9. 6 Gersak B. Mitral valve repair or replacement on the beating heart. Heart Surg Forum 2000; 3:232-7. 7 Downing SW, Herzog WA Jr, McLaughlin JS, Gilbert TP. Beating-heart mitral value surgery: prelimary model and

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20

21

22

23

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methodology. / Thorac Cardiovasc Surg 2002; 123: 1141-46. Buckberg GD. Cardioplegia solutions—unproven herbal approach versus scientific study. Semin Thorac Cardiovasc Surg 2001; 13:52-5. Byrne JG, Mitchell ME, Adams DA et al. Minimally invasive direct access mitral valve surgery. Semin Thorac Cardiovasc Surg 1999:212-22. Gillinov AM, Banbury MK, Cosgrove DM. Hemisternotomy approach for aortic and mitral valve surgery. JCard Surg 2000; 15:15-20. Shumway NE, Lower R. Hypothermia for extended periods of anoxic arrest. Surg Forum 1959; 10: 563. Buckberg GD. Update on current techniques of myocardial protection. Ann Thorac Surg 1995; 60: 805-14. Christakis GT, Weisel RD, Fremes SE et al. Coronary artery bypass grafting in patients with poor ventricular function. Cardiovascular Surgeons of the University of Toronto. / Thorac Cardiovasc Surg 1992; 103:1083-91. Buckberg GD, Brazier JR, Nelson RL et al. Studies on the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart. / Thorac Cardiovasc Surg 1977; 73: 87-94. Salerno TA. Myocardial temperature management during aortic clamping for cardiac surgery-protection, preoccupation, and perspective. / Thorac Cardiovasc Surg 1992; 103:1019-28. Salerno TA. Continuous blood cardioplegia: option for the future or return to the past. /Mo/ Cell Cardiol 1990; 22(supplV):849. Salerno TA, Houck JP, Barrozo CAM et al. Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection. Ann Thorac Surg 1991; 51:245-7. Tiang G, Xiang B, Butler KW et al. A 3 ' P nuclear magnetic resonance study of intermittent warm blood cardioplegia. J Thorac Cardiovasc Surg 1995; 109:1155-63. Lessana A, Pargaonkar S, Hu HQ et al. External stabilization of coronary sinus catheter. / Card Surg 1995; 10: 95-7. Tian G, Shen J, Sun J et al. Does simultaneous antegrade/ retrograde cardioplegia improve myocardial perfusion in the area at risk? A magnetic resonance perfusion imaging study in isolated pig hearts. / Thorac Cardiovasc Surg 1998; 115:913-24. Tian G, Dai G, Xiang B et al. Effect on myocardial perfusion of simultaneous delivery of cardioplegic solution through a single coronary artery and the coronary sinus. I Thorac Cardiovasc Surg 2001; 122:1004-10. Ye J, Sun J, Shell J et al. Does retrograde warm blood cardioplegia provide equal protection to both ventricles? A magnetic resonance spectroscopy study in pigs. Circulation 1997; 96: II210-1 IS. Hoffenberg EF, YeJ, Sun J etal. Antegrade and retrograde continuous warm blood cardioplegia: a 31P magnetic resonance study. Ann Thorac Surg 1995; 60:1203—9. Soltoski P, Bergsland J, Salerno TA et al. Techniques of exposure and stabilization in off-pump coronary artery bypass grafting. / Card Surg 1999:14:392-400.

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Index

N-acetylcysteine 27 adenosine 50,54,99 adenosine receptors 19 adenosine triphosphate (ATP) 33,45 - 6 see also potassium-ATP channels adhesion molecules 308 allopurinol 110 amiloride 27 AMISTADI trial 50 AMISTADII trial 50 anastomosis coronary sinus perfusion 153 left anterior descending coronary artery 138-40 main pulmonary artery to aorta 276-7 anesthetic preconditioning 33-42 cytokine response 36-8,37 inflammatory response to myocardial ischemia 35-6 ischemia-reperfusion injury 34-5,34,35 neutrophilic inflammatory response to myocardial ischemia 38-40,39 oxidants as neutrophilic mediators 40 angioplasty 46-9 angiotensin blockers 46-7 angiotensin converting enzyme 235 anipamil 21 antegrade cardioplegia 82-3 intermittent cold crystalloid 72 intermittent warm blood 75-81 antioxidant enzymes 307 antioxidants 20,27 cardiac transplantation 296-7 antiplatelet Ilb-IIIa inhibitors 49 aortic cross-clamping, intermittent 53-8 operative technique 54,55,56 pathophysiology 54 aortic root surgery 189-92 aortic surgery 193-5 St Antonius method 194-5 aortic valve surgery aortic insufficiency 168 aortic stenosis 167-8 beatingheart 313-15,314 cardioplegia 176-7 cold versus warm 184 - 6,184,185 intermittent warm blood cardioplegia 181-8 minimally invasive 176-8 myocardial protection 182—3 redo operations 177-8 apoptosis regulators 308 L-arginine 106 atrial septal defect 2

beating heart surgery 16,311—19 CABG 119-25,126-33 continuous perfusion through coronary sinus 152-9 myocardial infarction 144 -51 on-pump 141-2 on-pump CABG 141-2 dilated cardiomyopathy 160—6 valvular surgery 311-19 aortic valve 313-15,314 combined aortic/mitral valve 317-18 combined with CABG 318 mitral valve 315-17,376 Beck, Claude 2,5 benidipine 21 Bernard, Claude 1 beta-blockers reduction of myocardial oxygen requirement 47 valvular surgery 167-73 beta-carotene 20 blood cardioplegia see cold blood cardioplegia; warm blood cardioplegia bradykinin activation of nitric oxide 244-6,245 experimental studies 236-7,237 improvement of ischemia tolerance 237 as preconditioning agent 233,235-6 protein kinase C activation 239-41,240,241,242 recovery of ventricular performance and coronary flow 237-9,238,239 translocation of glucose transporter 4 246-9,247,248, 249 tyrosine kinase activation 241,243—4,243,244 bradykinin receptors 19 CABG see coronary artery bypass graft calcium 213-15,214,275 calcium channel blockers 27 in cardioplegia 101-2,102 and ischemia-reperfusion injury 20-1 calcium homeostasis, in myocardial stunning 101 calyculinA 23 cantharidin 23 carbohydrate metabolism 233 cardiac arrest 120 cardiac hypertrophy 181 myocardial metabolic state in 182 susceptibility to ischemia-reperfusion 182 cardiac transplantation 292-300 cardioplegia 293-5,294 preharvest donor management 292 -3

321

322

reperfusion 296-7 antioxidants in 296-7 triiodothyronine administration 297 storage 295-6 cardioplegia 3,120 antegrade 75-81,82-3 avoidance in Fontan procedure 275- 81 CABG reoperation 197-9 calcium channel blockade 101-2,102 calcium and magnesium 213-15,214,215 cardiac transplantation 293-5,294 cold blood 212-13,213,217,267-8 combined antegrade/retrograde 85-6,85,86 continuous 4-5 crystalloid 4,72,205,212-13,213 pediatric surgery 212-13,213,266-7 hyperpolarization 286-7 intermittent warm blood see intermittent warm blood cardioplegia magnetic resonance spectroscopy 59-60 minimally invasive valvular surgery 174-5,174,176-7 pediatric surgery 211-12,212,266-8 distribution 220 induction 215-16,276,267 infusion pressure 220-1,221 maintenance 216-17,217 reintroduction of 3-4 retrograde 5,83-5,152-9 substrate enhancement 94-118 pediatric surgery 268 valvular surgery 169-70,174-5,174,176-7 warm blood 4,59-69,70-4,75-81,168-70,312-13 see also miniplegia cardiopulmonary bypass angioplasty 48 beating heart surgery 120-2,122 low-flow, in pediatric surgery 270-1 reoperative CABG 197 systemic inflammatory syndrome 122 cardiovascular physiology 1-2 cariporide 22,27 CARISA trial 46 L-carnitine 96-7 catalase 20,27 chlorpromazine 22 cinanserin 27 closed heart surgery 2 coenzymeQIO 97 cold blood cardioplegia 4,212-13,213,217,267-8 collateralizing vessels 129 -30 complement cascade 103-11 L-arginine 106 endothelial dysfunction 105 endothelin 107-8,107 neutrophil activation 104 nitric oxide donors 106 nitric oxide pathway 105-6,105 reactive oxygen species 108 -11,109 steroid therapy 104-5 tetrahydrobiopterin 106-7 complement inhibitors 51 continuous cardioplegia 4-5 continuous retrograde warm blood cardioplegia 72 coronary artery bypass graft 16,119-25 adverse effects 122-3

Index

avoidance of myocardial ischemia 134—43 beating heart surgery 120-2,122,126-7,134-43 cardioplegia intermittent antegrade warm blood cardioplegia 78-9, 79 reoperation 197-9 warm versus cold 123,124,183-4 combined with valvular surgery 318 coronary sinus perfusion 152-9 minimally invasive 205-6 with myocardial infarction 144 - 51 myocardial protection 119-20,126-33 off-pump 126-7 on-pump 141-2 perfusion-assisted 127,130-1,131 reoperation 196-201 totally endoscopic 204 coronary sinus perfusion 48-9,152-9 avoidance of ischemia 153-5,756 cardiac wall stabilization 153 conversion to cardiopulmonary bypass 156 distal anastomosis 153 follow-up 155 hemodynamic stability 153 initial assessment 153 intraoperative complications 156 maintenance of normothermia 152-3 operative techniques 153 preoperative preparation 152 results 155-6 revascularization assessment 155 sequence of grafting 155 crystalloid cardioplegia 4,72,205 pediatric surgery 212-13,213,266-7 cyanosis 208 cytokines immunosuppression 308 and ischemia-reperfusion injury 24 myocardial ischemia 36-8,37 deferoxamine 108-9 descending thoracic surgery 195 diazoxide 250,257 dihydropyridines 21 dilated cardiomyopathy 160-6 etiology 161 history 160-1 operative procedures 161—4 endoventricular circular patch plasty 162,163 partial left ventriculectomy 162 septal anterior ventricular exclusion 162,163,164 results 164,165 diltiazem 27 DV-7028 27 elastase 122 endothelial dysfunction 105 endothelin 107-8,707 entoxifylline 23-4,27 esmolol 168-9 excitation-contraction coupling 99-100,700 fatty acid oxidation inhibitors 46 felodipine 21 filters 269-70

Index

Fontan procedure 275-81 cardioplegia and cardiocirculatory arrest 277 main pulmonary artery to aorta anastomosis 276-7 patch enlargement of pulmonary arteries 276 patients with functional single ventricle 275-6 postoperative treatment 277 results 277 staging 276-7 without cardioplegia 277—9 postoperative treatment 279 results 279 tolerance to ischemia 277-9,278,279 ultrafiltration 279 without cardiopulmonary bypass 279-80,280 fostriecin 23,27 free radicals generation in warm blood cardioplegia 77-8,78 ischemic preconditioning 234 production in open-heart surgery 77 G-protein-linked phospholipase C-coupled receptors 19 gene therapy 288,304-10 gene delivery 304-5 therapeutic genes antioxidant enzymes 307 apoptosis regulators 308 cytokines and adhesion molecules 308 heat shock proteins 306-7 nitric oxide synthase 307-8 vectors liposomes 305 perfusion in coronary circulation 304 viral 305-6 Gibbon, John 2 glucose insulin potassium 44-5 glucose transporter 4 246-9 PI3K activity 246-7,248 protein kinase C activation 247-9,248,249 translocation 246-7,247 glutamate-aspartate 96 glutathione 20,27,110 glutathione peroxidase 20 HALT-MI trial 50 heart-lung machine 2 heat shock proteins 306-7 hemodynamic changes during heart manipulation 128-9 histidine-tryptophan-ketoglutarate 97 history 1-12 blood cardioplegia 4 cardioplegia 3 closed heart surgery 2 continuous cardioplegia 4-5 early cardiac physiology 1—2 open heart surgery 2-3 reassessment of myocardial damage 3-4 retrograde cardioplegia 5 HOE 140 244-6,245 hydrogen peroxide 20 hydroxyl radical 20 hyperpolarized cardioplegia 286-7 hypothermia 14,46 pediatric surgery 270-1 see also cold blood cardioplegia hypoxia 208-11,209,210,211

323

ICS 205-930 27 immature myocardium cardioplegia 266-8 administration of 267 blood 267-8 crystalloid 266-7 integrated approach to 268 substrate enhancement 268 hypothermia/circulatory arrest versus low-flow cardiopulmonary bypass 270-1 mechanical devices for cardioprotection 268-70 filters 269-70 modified ultrafiltration 270 ultrafiltration 270 palliation versus early repair 271 response to ischemia 265 tolerance to ischemia 251-8 pinacidil pretreatment 256-8,256,257 potassium-ATP channel opening 255-6,255 upregulation of protein kinase C 252-5,253,254,255 versus adult myocardium 264-5 see also pediatric surgery inflammatory mediators 122 inflammatory response to ischemia 35-6,38-40,39,103 inorganic phosphate, and cardioplegia 65 insulin, and myocardial metabolism 95-6 intercellular adhesion molecule 1 (ICAM-1) 36 interleukin-6 36,122 interleukin-10 122 intermittent antegrade cold crystalloid cardioplegia 72 intermittent antegrade warm blood cardioplegia 75-81 coronary artery bypass grafting 78 -9,79 metabolic studies 77-8,78 surgical technique and delivery protocol 76-7,76,77 valve surgery 79-80,80 intermittent warm blood cardioplegia 59-69 antegrade see intermittent antegrade warm blood cardioplegia aortic valve surgery 181-8 effect on myocardial energy metabolism 60—2,61 heterogeneous ischemic changes during 62-6,63,64,65, 66

minimum perfusion pressure 66—7,67 intra-aortic balloon counterpulsation 199 —200 intra-aortic balloon pump 47-8 intracoronary shunts 128 ischemia cytokines in 36-8,37 inflammatory response to 35-6,38-40,39 intraoperative 134-43 response of immature myocardium to 265 tolerance to by immature myocardium 251—8 improvement by bradykinin 237 ischemia-reperfusion injury 18-32,119-20 cardiac hypertrophy 182 cardiac transplantation 284-6 causes of 26 cell biology of cardiac myocytes in 34-5,34,35 ion exchange during 34 mechanism of 284-5 oxidants as neutrophilic mediators 40 preconditioning see ischemic preconditioning reduction of 49-51,285-6 5-HT receptor antagonists 24—5,27

324

Index

adenosine 50 antioxidants 20,27 antiplatelet Ilb-IIIa inhibitors 49 calcium channel blockers 20-1,27 complement inhibitors 51 leukocyte receptor monoclonal antibody 50 magnesium 49-50 MAP kinase inhibitors 22-3,27 phosphodiesterase inhibitors 23-4,27 phospholipase A2 inhibitors 21-2,27 protein phosphatase inhibitors 23,27 sodium-hydrogen exchanger inhibitors 22,27,49 ischemic preconditioning 19 -20,98 -9,98 anesthetic see anesthetic preconditioning biology of 231 cardiac transplantation 287-8 cellular effects of 233-4 carbohydrate metabolism 233 concurrent stunning 233-4 free radicals and reactive oxygen species 234 genetic mechanisms 234 discovery of 230—1 experimental studies 234-5 off-pump CABG 127-8 preconditioning agents 44-6 adenosine 99 bradykinin 235-51 fatty acid oxidation inhibitors 46 glucose insulin potassium 44-5 hypothermia 46 nicorandil 99 potassium-ATP channel antagonists 45 potassium-ATP channel openers 98-9,249-51,250, 251 signal transduction pathways 231—3,232,233 see also substrate enhancement ketamine 38 ketanserin 27 lacidipine 21 lactate dehydrogenase 38 left anterior descending coronary artery, anastomosis

138-40 left ventricular assist device implantation 301-3 Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) 50 leukocyte receptor monoclonal antibody 50 leukocyte-adhesion molecules 39 LIMA suture 136,137,138 lipopolysaccharide-induced CXC chemokine 38 liposomes 305 LY53857 27 lysophosphatidylcholine 21 magnesium 49-50 pediatric surgery 213-15,214,215 magnetic resonance spectroscopy 59-60 manoalide 21 MAP kinase inhibitors 22-3,27 MAPkinases 35,232 MDL28 27 mechanical objectives of cardiac surgery 13-17 Melrose solution 3 miancerin 27

minimally invasive cardiac surgery 203-6 animal studies 203-4 CABG surgery 205-6 evolution of 203 see also minimally invasive valvular surgery minimally invasive valvular surgery 174 - 80,204 -5 aortic valve 176-8 cardioplegic delivery 174-5,174,176-7 chest incisions 175 - 6,175,176 mitral valve 178-9,178 muscular mass and metabolism 174 reperfusion 175 tricuspid valve 179-80 minimum perfusion pressure in cardioplegia 66-7, 67 miniplegia 88-93 clinical and experimental studies 91-2,91 perfusion technique 89-90,90 rheologic and biologic issues 88-9 see also cardioplegia mitogen-activated protein kinases see MAP kinases mitral regurgitation 168 mitral valve surgery beating heart 315-17,316 limited sternotomy 178 minimally invasive surgery 178-9 mitral stenosis 168 redo operations 179 right anterior thoracotomy 178-9 MR-256 22 myocardial damage 3-4 myocardial infarction 43-52 beating heart surgery 144 -51 increased resistance to fatty acid oxidation inhibitors 46 glucose insulin potassium 43-4 hypothermia 46 ischemic preconditioning 43 potassium-ATP channel agonists 45 indications for CABG 145-6 reduction of oxygen requirements 46—9 angiotensin blockers 46—7 beta-blockers 47 cardiopulmonary bypass support 48 coronary retroperfusion 48-9 intra-aortic balloon pump 47- 8 reduction of reperfusion injury 49—51 adenosine 50 antiplatelet Ilb-IIIa inhibitors 49 complement inhibitors 51 leukocyte receptor monoclonal antibody 50 magnesium 49-50 sodium-hydrogen exchanger 49 timing and mechanism of reperfusion 43-4 myocardial ischemia see ischemia myocardial metabolism 95-7,95 and cardioplegia 60-2,61 objectives of cardiac surgery 13-17 see also substrate enhancement myocardial preconditioning see ischemic preconditioning myocardial shunts 128 myocardial stunning 99-103 disruption of calcium homeostasis 101 excitation-contraction coupling 99-100,100 and ischemic preconditioning 233-4

Index

L-type calcium channel blockade 101-2,102 sodium-hydrogen exchanger inhibitors 103 L-NAME 244-6,245 neutrophil activation 104 nicorandil 99 nifedipine 21,27 nitecapine 110-11 nitric oxide 24,230 activation 244-6,245 and complement activation 105—6,105 nitric oxide donors 106 nitric oxide synthase 307— 8 normothermia 152-3 normoxemia 209 nuclear factor kappa B 38 off-pump CABG 126 continuous perfusion through coronary sinus 152 - 9 distal anastomosis construction 129 - 30 myocardial injury 126-7 perfusion-assisted 127,130-1,131 okadaicacid 23 on-pump beating heart surgery CABG 141-2 dilated cardiomyopathy 160-6 open heart surgery 2-3 opioid receptors 19 oxidants, as neutrophilic mediators 40 pediatric surgery 207-29,264-74 cardioplegia 211-12,212 blood versus crystalloid 212-13,213 calcium and magnesium 213-15,214,215 distribution 220 induction 215-16,216 infusion pressure 220-1,22] maintenance 216-17,217 clinical studies 223-5,225 hypoxia 208-11,209,210,211 modified integrated cardioplegia 221—3,222 preoperative considerations 207 reperfusion 217-18,218 volume and pressure overload 207-8 white blood cell filtration 218 -20,219 see also immature myocardium perfusate composition 282-3 perfusion-assisted CABG 127,130-1,131 pFOX see fatty acid oxidation inhibitors phosphocreatine, and cardioplegia 65 phosphodiesterase inhibitors 23-4,27 phospholipase A2 inhibitors 21-2,27 pinacidil 256-8,256,257 platelet activating factor 39 potassium-ATP channel agonists 98 -9 ischemia tolerance in immature myocardium 255-6,255 potassium-ATP channels 19 in ischemic preconditioning 45—6,249-51,250,251 preservation solutions 282—91 gene therapy 287 hyperpolarized cardiac arrest 286-7 ischemic preconditioning 287-8 perfusate composition 282-3 protease inhibitor 287 reduction of ischemia-reperfusion injury 285-6

325

propofol 37 protease inhibitors 288 protein kinase C 19,230,239-41 activation 239-2040,240,247-9,248,249 translocation 240,241 upregulation in neonatal heart 252-5,253,254,255 ventricular performance and coronary flow 240-1, 242 protein phosphatase inhibitors 23,27 ranolazine 46 reactive oxygen species 234 allopurinol 110 and complement activation 108-11,109 deferoxamine 108-9 glutathione 110 as mediators of ischemia-reperfusion injury 20, 40 nitecapine 110-11 renin-angiotensin system 47 reoperation aortic valve surgery 177-8 CABG 196-201 mitral valve surgery 179 reoxygenation 208-10,209,210 reperfusion 43-4 cardiac transplantation 297 see also ischemia-myocardial perfusion injury retrograde cardioplegia 5,83-5,152-9 retrograde perfusion see retrograde cardioplegia Ringer, Sydney 1 St Antonius method of myocardial protection 194-5 SB-203580 27 septal anterior ventricular exclusion 163 serotonin receptor antagonists 24-5,27 sevoflurane 37 SHOCK trial 48,146 SM-20550 27 sodium-hydrogen exchanger 22,49 sodium-hydrogen exchanger inhibitors 22,27,49 myocardial stunning 103 stenosis see arterial stenosis steroid therapy 104-5 stone heart 3,13 substrate enhancement 94-118 L-carnitine 96-7 coenzymeQIO 97 glutamate-aspartate 96 histidine-tryptophan-ketoglutarate 97 immature myocardium 268 insulin 95-6 in pediatric surgery 268 see also ischemic preconditioning superoxide anion 20 superoxide dismutase 20,27 surgery closed 2 objectives of 13-17 open 2 systemic inflammatory syndrome 122 taurine 20 tetrahydrobiopterin 106-7 thoracoabdominal aortic surgery 195

326

totally endoscopic coronary artery bypass (TECAB) 204, 205 beating heart 205 tricuspid valve surgery 179 - 80 triiodothyronine, administration in cardiac transplantation 297 troponin 121 tumor necrosis factor alpha 19,36 tyrosine kinase 19,230,241,243-4,243,244 ultrafiltration 270 Fontan procedure 279 modified 270 valvular surgery aortic valve see aortic valve surgery avoidance of cardioplegia 312 beating heart 311-19 aortic valve 313-15,314 combined aortic/mitral valve 317-18 combined with CABG 318 mitral valve 315-17,316

Index

beta-blockers in 167-73 cardioplegia 79-80,80,168-70,174-5,174,176-7, 312-13 minimally invasive 174-80,204-5 mitral valve see mitral valve surgery tricuspid valve 179-80 vanadate 27 verpamil 27 viral vectors for gene therapy 305-6 vitamin A 20 vitamin C (ascorbic acid) 20 vitamin E (alpha-tocopherol) 20,27 warm blood cardioplegia 4,70-4,75-81,168-70,312-13 anatomy and physiology 70-1 clinical trials 71-2,71 intermittent see intermittent warm blood cardioplegia valvular surgery 167-73 warm heart surgery see warm blood cardioplegia white blood cell nitration 218-20,219 yohimbine 27