Cardiovascular Disease in the Elderly:Third Edition, Revised and Expanded

We dedicate this third edition to our elderly patients and to the memory of Donald D. Tresch, M.D., who coedited with D...

Author: Wilbert S. Aronow | Jerome L. Fleg

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We dedicate this third edition to our elderly patients and to the memory of Donald D. Tresch, M.D., who coedited with Dr. Aronow the ﬁrst and second editions of this book. At the time of his death, Dr. Tresch was Professor of Medicine (Cardiology and Geriatrics) and Director of the Cardiology Fellowship Training Program at the Medical College of Wisconsin in Milwaukee. Dr. Tresch was an outstanding teacher, clinician, and researcher who made numerous important original research contributions to the ﬁeld of cardiovascular disease in the elderly. Dr. Tresch was also a very compassionate person and perfect gentleman who was very encouraging and supportive to his patients, his students, and his colleagues. The geriatric cardiology community misses him and recognizes his passing as the loss of a valuable mentor, scholar, and friend. All beginnings are joyous. Our elderly patients show us that endings may also be joyous and they never fail to teach us that life, even with the struggles of aging and disease, may be full of meaning and joy.

iii

Series Introduction

Marcel Dekker, Inc., has focused on the development of various series of beautifully produced books in diﬀerent branches of medicine. These series have facilitated the integration of rapidly advancing information for both the clinical specialist and the researcher. My goal as editor-in-chief of the Fundamental and Clinical Cardiology series is to assemble the talents of world-renowned authorities to discuss virtually every area of cardiovascular medicine. In the current monograph, Cardiovascular Disease in the Elderly: Third Edition, Revised and Expanded, Wilbert S. Aronow and Jerome L. Fleg have edited a much-needed and timely book. Future contributions to this series will include books on molecular biology, interventional cardiology, and clinical management of such problems as coronary artery disease and ventricular arrhythmias. Samuel Z. Goldhaber

v

Foreword

Publication of the third edition of Cardiovascular Disease in the Elderly reﬂects increasing appreciation of the close association between aging and cardiovascular disease (CVD), which rises exponentially as a cause of morbidity and mortality through middle and old age, accounting for nearly half of all adult deaths. All of the chapters in this edition reﬂect this sobering reality of increasing importance in our aging society, contributed by authors who are not only acknowledged experts in cardiovascular physiology and disease in general but also possess speciﬁc expertise in the emerging discipline of geriatric cardiology. The opening section on aging changes in the cardiovascular system introduces the subject appropriately. Its chapters document the declining homeostatic reserve of the aging heart and vasculature, whether measured at the cellular and organ system level (Chapter 1), non-invasively in the aging patient (Chapter 2), or at necropsy (Chapter 3). This decrease in physiological resilience, coupled with the myriad of comorbidities that are the norm in elderly patients, makes pharmacological management of CVD in both preventive and therapeutic modes an exercise of excruciating complexity and judgment (Chapter 4). The array of CVD risk factors, notably hypertension (Chapter 5), hyperlipidemia (Chapter 6), and diabetes (Chapter 7), and their increased incidence and prevalence in the elderly converge to place the older patient at exponentially escalating risk with advancing age (Chapter 8). Fortunately, however, each of these risk indices appears amenable to management with a combination of lifestyle and pharmacological interventions. Moreover, the evidence base supporting the eﬃcacy of such strategies grows with each passing year. But to what age, we must now ask? Or, indeed, regardless of age? These age-related processes also demand appreciation of special subtleties in diagnosis (Chapter 10) and management of CVD in the elderly patient: angina (Chapter 11) and acute myocardial infarction (Chapter 12) may present in atypical (e.g., painless) fashion or as frank heart failure (Chapter 22). Thyroid disease, itself increasingly common in aging patients, may mask or aggravate CVD (Chapter 21). Arrhythmias abound in the absence or presence of ASCVD (Chapters 23–25). Stroke (Chapter 26), syncope (Chapter 27), and pulmonary embolism (Chapter 29) are ever-present risks to the health and independence in older persons. Yet bold interventions are increasingly undertaken in these arenas, with remarkable success in even the oldest patients—aortic valve replacement (Chapter 27) being a notable example. vii

viii

Foreword

Thus the third edition documents advances in all dimensions of vascular biology, cardiology, and cardiovascular surgery in elderly patients. Such remarkable progress, however, barely manages to keep pace with the rising age of patients cared for by cardiologists and indeed all physicians who care for older adults. Thus it is also encouraging that the current edition reﬂects increasing acceptance of the content of this book by an expanding readership and the emergence of a new subdiscipline of cardiology—geriatric cardiology. This development takes place as a growing number of clinicians identify themselves as geriatric cardiologists and the membership of the Society of Geriatric Cardiology grows apace. Although this sub-subspecialty has yet to achieve formal recognition through specialized Residency Review Committee (RRC)—accredited training and certiﬁcation by the American Board of Internal Medicine (ABIM) as a domain of Added Qualiﬁcations, as has become the case with Cardiac Electrophysiology and Interventional Cardiology—this, too, may come to pass in the not-too-distant future as the base of knowledge and skills in geriatric cardiology continue to expand. These developments could not be more timely. Not only is the American (and global) population growing older with each passing year but also—in no small part attributable to the triumphs of modern preventive and therapeutic cardiology—the number of persons who do not succumb to premature disease but instead survive with clinical or subclinical CVD into advanced old age is increasing at an even greater pace! While age-adjusted cardiovascular mortality rates have declined over the past four decades, overall cardiovascular deaths have remained relatively constant. However, these deaths have occurred at an increasingly advanced average age. A by-product of this deferral of CVD death into old age has been a narrowing in the age-adjusted sex ratio in CVD mortality, which historically has disproportionately prematurely aﬀected men. As a result, with more and more women surviving into old age (above 75 and 80), the number of women dying of CVD now equals or exceeds that of men, though still at a somewhat higher mean age. On the other hand, the average longevity of men is increasing faster in men than in women, and the gender gap in the surviving elderly has narrowed progressively over the past quarter century. This has translated directly into shorter average duration of widowhood, which exerts a major social and economic impact in an aging society. Thus by escaping CVD death in middle age, men are more likely to accompany their wives into old age, and the mutual support rendered to each other by aging spouses has been a major factor in decreasing utilization of nursing homes, historically populated primarily by widows. While of course this is enormously good news for aging couples and society at large, the implications of these trends for the patient clienteles of practicing physicians—not only cardiologists but all who care for adult patients—underscore the importance of books like this one. Thus as more and more patients survive or escape clinical CVD in middle age, more and more of those in their 80s and 90s will come under the care of both generalists and cardiologists. Perhaps then all (except perhaps pediatric) cardiologists will become (at least part time) geriatric cardiologists, and Cardiovascular Disease in the Elderly will become core reading for every cardiologist and a reference text for all physicians who share in the challenge to provide excellent geriatric medical care. As this upward shift in the average age of patients cared for by cardiologists continues over the next several decades, many of the special skills and insights of geriatricians—physicians who have received specialized additional training in geriatrics—will also become essential to the expert practice of cardiology. Such specialized training appropriately focuses upon comprehensive evaluation and management of the most complex,

Foreword

ix

challenging, and vulnerable patients, most of whom are in their 80s and 90s. What are the goals of such training? First, given the major burden of cardiovascular disease among the elderly patients they care for, geriatricians must acquire sophisticated appreciation of all of the issues presented in this volume at the level of the skilled generalist. However, geriatricians must also come to understand and manage with equivalent expertise all of the diseases, disabilities, and functional impairments that are common in patients of such advanced age, including cancer, renal disease, osteoporosis, osteoarthritis, pulmonary disease, infections, diabetes, dementia, depression; the ‘‘geriatric syndromes’’ of falls, incontinence, immobility, impaired homeostasis, susceptibility to iatrogenesis; and palliative and end-of-life care. In certain cases geriatricians will serve as consultants to other specialists (often cardiologists) in the evaluation and management of their frail elderly patients undergoing diagnostic evaluation or treatment in hospital or oﬃce settings. In other cases geriatricians will serve as primary care clinicians for frail and complicated patients, with consultation and in collaboration with specialists and subspecialists. In yet other cases, as supervisors and administrators, geriatricians will oversee or provide medical input to the care of groups of the most frail and dependent patients, especially those in long-term care settings. However, it cannot be overstated that in the future—as at present and in the past—the vast bulk of the care of elderly patients will be provided by generalists and specialists without specialized geriatric training at the fellowship level. Geriatricians have no monopoly on expert care of elderly patients, nor do they aspire to such. Stated in the most concrete and practical terms, it remains clear that the provision of geriatric medical care will extend well beyond the capacity of those who have received advanced geriatric training. Currently fellowship-trained geriatricians comprise less than 1% of practicing American physicians, a fraction that remains constant even as the numbers and average age of elderly patients continue to grow with every passing year. Moreover, less than 1% of current U.S. medical graduates pursue fellowship training in geriatrics—in spite of its having been compressed into a single year following completion of accredited training in internal medicine, family practice, or a subspecialty of internal medicine. Therefore, given the ‘‘age wave’’ of babyboomers now passing through the American population, certiﬁed geriatricians will be challenged to the maximum to leverage their professional eﬀorts. This will be accomplished by focusing principally in the academic arena in advancing the aging knowledge base through research and broadly disseminating their expertise through the education in geriatrics and gerontology of all physicians, especially the other 99% of medical graduates (including future cardiologists as students, residents, and fellows), physicians who will in turn provide the vast bulk of direct geriatric medical care for the indeﬁnite future. In their own generally limited academic practices, geriatricians will appropriately concentrate upon the care of the most frail and complex patients, those with the panoply of physical, psychological, and social problems enumerated above, including those on their ﬁnal pathway toward death. This brings us back to the principal goal of this book: to prepare all physicians— including but by no means limited to cardiologists—to better prevent, diagnose, and treat CVD in their aging and elderly patients. As required for optimal management, such knowledge can be supplemented by reference to companion textbooks of geriatrics, internal medicine, psychiatry, or other relevant specialty disciplines. Inevitably this demands of the practitioner both command of the expanding relevant knowledge base in each of these domains and also skill in managing their complex interactions in the prototypical frail

x

Foreword

elderly patient. Fortunately the possibility of remaining abreast of the increasing knowledge base is facilitated by the exploding ﬁeld of information technology, the management of which becomes an additional essential skill for all modern practitioners. Likewise fortunately, continuing growth in the diagnostic and therapeutic potential of interventions to deal with problems of their aging patients permits an optimistic, ‘‘can-do’’ attitude in the application of those skills. Thus two medical disciplines, cardiology and geriatrics, approach each another and begin to merge as the patients cared for in each domain become more alike in age, medical morbidity, and complexity. Here a challenge emerges to build bridges of collaboration and mutual education and training between the two disciplines, as well as to identify problems that remain to be solved through clinically informed and creative research. One gap in the essential knowledge base has been a product of the longstanding under-representation of the kinds of patients cared for by geriatricians in the studies that constitute the principal evidence base of the practicing cardiologist. To put this challenge another way, randomized clinical trials have by design generally excluded the kinds of frail patients cared for by geriatricians: the demented, the immobile, the incontinent, the unstable, those with life expectancy limited by competing conditions (e.g., cancer), those in precarious homeostatic balance at grave risk to rapid demise (classically illustrated by the patient with heart failure), and the dying. Furthermore, in clinical trials of cardiovascular interventions, patients with premature CVD have generally been over-represented (typically clinical trials have enrolled patients of average age 65 or below). Hence interpretation of the results of such studies has required signiﬁcant extrapolation to the care of ‘‘truly geriatric’’ patients in their 80s and 90s (though to be fair, to date each such trial has suggested encouraging continued eﬃcacy of interventions in participants above 75 and even beyond 80 years of age). Nevertheless, intervention trials speciﬁcally targeting the frail elderly are indicated with increasing urgency, lest such patients either fail to receive appropriate treatment because of a presumed lack of eﬃcacy (e.g., as in the current under-use of statins) or receive inappropriate treatments of presumed (but speciﬁcally untested) eﬃcacy based on trials of less representative elderly participants. What is the most evident link between cardiology and geriatrics, the point at which the cardiologist exclaims, ‘‘Aha, I get it now?’’ Here I would point to frailty as the deﬁning syndrome that most challenges both ﬁelds. Frailty is becoming better deﬁned—most recently according to the ﬁve criteria of ‘‘shrinking’’ (unintentional weight loss); exhaustion; weakness; slow walking; and low physical activity, as speciﬁcally investigated in the landmark Cardiovascular Health Study (CHS) [1]. Thus frail subjects meeting this deﬁnition can be selectively recruited for targeted CVD intervention studies, which can be designed to capitalize on increasing understanding of this syndrome at the most basic as well as the most practical level. In many studies it appears to be pathophysiologically linked with CVD and other common aﬄictions of the elderly through the process of inﬂammation, which seems ubiquitous among the frail. Can, for instance, anti-inﬂammatory agents (which include the statins) prevent or retard CVD in the frail elderly? Thus conjoint continuing challenges to education and training, research, and practice are shared by cardiologists and geriatricians. We predict with great conﬁdence that gaps of communication and cooperation will progressively narrow with each passing year and that more eﬀective models of collaborative research and training between these disciplines will be documented in each successive edition of Cardiovascular Disease in the Elderly.

Foreword

xi

REFERENCE 1.

Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA. Frailty in older adults: evidence for a phenotype. J Gerontol 2001; 56A:M146–M156.

William R. Hazzard, M.D. Professor, Division of Gerontology and Geriatric Medicine, School of Medicine, University of Washington, Seattle, Washington, U.S.A.

Preface

Although only a few years have elapsed since the publication of the second edition of Cardiovascular Disease in the Elderly, the ever-accelerating pace of advances in the understanding and treatment of heart and vascular disorders dictates an update of that edition. Many important clinical trials addressing disorders common to older patients have been published since then. Approximately 34 million Americans are currently 65 years or older. Because of the ‘‘coming of age’’ of the post–World War II baby boomers, this number is expected to reach 75 million by 2040, representing more than 20% of the U.S. population. The implications of the demographic shift for the prevalence and socioeconomic burden of cardiovascular disease for our society are enormous. Conditions common in the elderly such as acute myocardial infarction, atrial ﬁbrillation, and heart failure can be anticipated to reach epidemic proportions. Hopefully, improvements in prevention and treatment of antecedent risk factors and continued advances in the treatment of these disorders will ameliorate their impact. Because the elderly represent the majority of cardiovascular patients, it is crucial that practitioners be aware of advances in geriatric cardiology, particularly those that reduce morbidity and enhance survival and quality of life. The primary goal of this third edition is to provide clinicians with a comprehensive, easy-to-read information source incorporating the latest knowledge on the epidemiology, pathophysiology, and management of cardiovascular disease in older persons. A recurring theme throughout the new edition is that aging per se lowers the threshold for the development of various cardiac, vascular, and metabolic disorders and alters their clinical manifestations. For example, the marked age-associated increase in hypertension prevalence can be linked to a progressive stiﬀening of the arterial tree that begins in early adulthood. A second example is the striking reduction of early diastolic ﬁlling rate observed with normative aging, which appears to lower the threshold for development of diastolic heart failure. Understanding these interactions between the aging process and development of cardiovascular disease should help practitioners in managing their older cardiac patients. As with the previous editions, the target audience includes all clinicians who treat older cardiovascular patients, not just cardiologists. Indeed, a large proportion of these patients are managed by general internists, geriatricians, or family physicians, who we hope will ﬁnd the current edition useful in their day-to-day decision-making. In this third edition, all of the prior chapters have been revised to incorporate the most current information available. Evidence-based cardiovascular medicine is emphasized, xiii

xiv

Preface

particularly recent multicenter studies with sizeable numbers of older patients. Sixteen of the 32 chapters have new authorship, allowing fresh perspectives on these topics. A chapter on diabetes and cardiovascular disease has been added to emphasize the major importance of this condition as a contributor to cardiovascular morbidity and mortality in the elderly. The prior chapter on electrocardiography has been incorporated into an expanded chapter on normal aging changes; similarly, information on mitral annular calcium is now included in the chapter on mitral valve disease (Chapter 18). Finally, the table of contents has been organized into parts, for easier location of speciﬁc topics. As in the two prior editions, all of the chapter contributors are widely acknowledged experts in geriatric cardiology. Their many years of personal experience allow them to summarize and synthesize their respective topics with unique insights that are highly beneﬁcial to the reader. We greatly appreciate their expertise and diligence. We hope you, the reader, will ﬁnd this third edition useful in your day-to-day care of older cardiovascular patients, helping them to enjoy both longer and fuller lives. Wilbert S. Aronow Jerome L. Fleg

Contents

Series Introduction Samuel Z. Goldhaber Foreword William R. Hazzard Preface Contributors

Part I

v vii xiii xix

Aging Changes in the Cardiovascular System

1. Normal Aging Changes of the Cardiovascular System Jerome L. Fleg and Edward G. Lakatta 2. Echocardiographic Measurements in Elderly Patients Without Clinical Heart Disease Julius M. Gardin and Cheryl K. Nordstrom

1

43

3. Morphological Features of the Elderly Heart William Cliﬀord Roberts

69

4. Cardiovascular Drug Therapy in the Elderly William H. Frishman, Angela Cheng-Lai, and Wilbert S. Aronow

95

Part II Coronary Artery Disease: Risk Factors and Epidemiology 5. Systemic Hypertension in the Elderly William H. Frishman, Mohammed J. Iqbal, and Gregory Yesenski

131

6. Hyperlipidemia in the Elderly: When Is Drug Therapy Justiﬁed? John C. LaRosa

153

7. Diabetes Mellitus and Cardiovascular Disease in the Elderly Gabriel Gregoratos and Gordon Leung

163

8. Epidemiology of Coronary Heart Disease in the Elderly Pantel S. Vokonas and William B. Kannel

189 xv

xvi

Part III

Contents

Coronary Artery Disease

9. Pathophysiology of Coronary Artery Disease in the Elderly Roberto Corti, Antonio Ferna´ndez-Ortiz, and Valentin Fuster

215

10. Diagnosis of Coronary Artery Disease in the Elderly Wilbert S. Aronow and Jerome L. Fleg

251

11. Angina in the Elderly Wilbert S. Aronow and William H. Frishman

273

12. Therapy of Acute Myocardial Infarction Michael W. Rich

297

13. Management of the Older Patient After Myocardial Infarction Wilbert S. Aronow

329

14. Surgical Management of Coronary Artery Disease in the Elderly Edward A. Stemmer and Wilbert S. Aronow

353

15. Percutaneous Coronary Intervention in the Elderly Charles L. Laham, Mandeep Singh, and David R. Holmes, Jr.

389

16. Exercise Training in the Older Cardiac Patients Philip A. Ades

405

Part IV

Valvular Heart Disease

17. Aortic Valve Disease in the Elderly Wilbert S. Aronow and Melvin B. Weiss 18. Mitral Regurgitation, Mitral Stenosis, and Mitral Annular Calciﬁcation in the Elderly Melvin D. Cheitlin and Wilbert S. Aronow 19. Endocarditis in the Elderly Thomas C. Cesario and David A. Cesario

Part V

417

443 477

Cardiomyopathies and Heart Failure

20. Cardiomyopathies in the Elderly John Arthur McClung, Wilbert S. Aronow, Robert Belkin, and Michael Nanna

489

21. Thyroid Heart Disease in the Elderly Steven R. Gambert, Charles R. Albreht, and Myron Miller

511

22. Heart Failure Dalane W. Kitzman and Jerome L. Fleg

529

Contents

Part VI

xvii

Arrhythmias and Conduction Disorders

23. Supraventricular Tachyarrhythmias in the Elderly Wilbert S. Aronow and Carmine Sorbera

559

24. Ventricular Arrhythmias in the Elderly Wilbert S. Aronow and Carmine Sorbera

585

25. Bradyarrhythmias and Cardiac Pacemakers in the Elderly Anthony D. Mercando

607

Part VII

Cerebrovascular Disease

26. Cerebrovascular Disease in the Elderly Patient Jesse Weinberger

625

27. Evaluation of Syncope in the Elderly Patient Scott Hummel and Mathew S. Maurer

653

Part VIII

Miscellaneous Topics

28. Anticoagulation in the Elderly Jonathan L. Halperin

677

29. Acute Pulmonary Embolism in the Elderly Paul D. Stein and Fadi Kayali

695

30. Peripheral Vascular Disease in the Elderly Roy M. Fujitani, Ganesha B. Perera, Ian L. Gordon, and Samuel E. Wilson

707

31. Perioperative Cardiovascular Evaluation and Treatment of Elderly Patients Undergoing Noncardiac Surgery Rita A. Falcone, Roy C. Ziegelstein, and Lee A. Fleisher

765

32. Ethical Decisions and Quality of Life in Older Patients with Cardiovascular Disease Lofty L. Basta and Henry D. McIntosh

811

Index

825

Contributors

Philip A. Ades University of Vermont College of Medicine, Fletcher-Allen Health Care, Burlington, Vermont, U.S.A. Charles R. Albreht Sinai Hospital of Baltimore, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Wilbert S. Aronow Westchester Medical Center/New York Medical College, Valhalla, and Mount Sinai School of Medicine, New York, New York, U.S.A. Lofty L. Basta Clearwater Cardiovascular and Interventional Cardiovascular Consultants and Project GRACE, Clearwater, Florida, U.S.A. Robert Belkin Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A. David A. Cesario University of California, Irvine, Irvine, California, U.S.A. Thomas C. Cesario University of California, Irvine, Irvine, California, U.S.A. Melvin D. Cheitlin University of California, San Francisco, San Francisco, California, U.S.A. Angela Cheng-Lai Monteﬁore Medical Center, Bronx, New York, U.S.A. Roberto Corti University Hospital Zurich, Zurich, Switzerland Rita A. Falcone Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Antonio Ferna´ndez-Ortiz San Carlos University Hospital, Madrid, Spain Jerome L. Fleg National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, U.S.A. xix

xx

Contributors

Lee A. Fleisher Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. William H. Frishman Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A. Roy M. Fujitani University of California–Irvine Medical Center, Orange, California, U.S.A. Valentin Fuster Zena and Michael A. Wiener Cardiovascular Institute, The Mount Sinai School of Medicine, New York, New York, U.S.A. Steven R. Gambert Sinai Hospital of Baltimore, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Julius M. Gardin St. John Hospital and Medical Center, Detroit, Michigan, U.S.A. Ian L. Gordon University of California–Irvine Medical Center, Orange, California, U.S.A. Gabriel Gregoratos University of California, San Francisco, San Francisco, California, U.S.A. Jonathan L. Halperin The Zena and Michael Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, New York, U.S.A. David R. Holmes, Jr. Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A. Scott Hummel College of Physicians & Surgeons, Columbia University, New York, New York, U.S.A. Mohammed J. Iqbal New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A. William B. Kannel Boston University Medical Center, Boston, Massachussettes, U.S.A. Fadi Kayali St. Joseph Mercy Oakland, Pontiac, Michigan, U.S.A. Dalane W. Kitzman Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Charles L. Laham Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A. Edward G. Lakatta National Institute on Aging, National Institutes of Health, Bethesda, Maryland, U.S.A.

Contributors

xxi

John C. LaRosa State University of New York Health Science Center at Brooklyn, Brooklyn, New York, U.S.A. Gordon Leung University of California, San Francisco, California, U.S.A. Mathew S. Maurer College of Physicians & Surgeons, Columbia University, New York, New York, U.S.A. John Arthur McClung Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A. Henry D. McIntosh Lakeland, Florida, U.S.A. Anthony D. Mercando College of Physicians and Surgeons, Columbia University New York, and Albert Einstein College of Medicine and Monteﬁore Medical Center, Bronx, New York, U.S.A. Myron Miller Sinai Hospital of Baltimore, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Michael Nanna Albert Einstein College of Medicine, Bronx, New York, U.S.A. Cheryl K. Nordstrom St. John Hospital and Medical Center, Detroit, Michigan, U.S.A. Ganesha B. Perera University of California–Irvine Medical Center, Orange, California, U.S.A. Michael W. Rich Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri, U.S.A. William Cliﬀord Roberts Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, U.S.A. Mandeep Singh Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A. Carmine Sorbera New York Medical College, Valhalla, New York, U.S.A. Paul D. Stein St. Joseph Mercy Oakland, Pontiac, Michigan, U.S.A. Edward A. Stemmer University of California at Irvine, Irvine, and Veterans Aﬀairs Medical Center, Long Beach, California, U.S.A. Pantel S. Vokonas Boston University Medical Center, Boston, Massachusetts, U.S.A. Jesse Weinberger The Mount Sinai School of Medicine, New York, New York, U.S.A.

xxii

Contributors

Melvin B. Weiss Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A. Samuel E. Wilson University of California–Irvine Medical Center, Orange, California, U.S.A. Gregory Yesenski St. Barnabas Hospital–Cornell Medical School, Bronx, New York, U.S.A. Roy C. Ziegelstein Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

1 Normal Aging of the Cardiovascular System Jerome L. Fleg National Heart, Lung, and Blood Institute Bethesda, Maryland, U.S.A.

Edward G. Lakatta National Institute on Aging Bethesda, Maryland, U.S.A.

INTRODUCTION The dramatic increase in life expectancy that has occurred during the past century in developed countries has markedly altered their population composition. Between 1900 and 1990, the U.S. population increased threefold while the subgroup z65 years increased tenfold. Currently, 13% of Americans are in this age group; by 2035, nearly one in four individuals will be z65 years old. The most rapidly growing segment of elders comprises those aged 85 years or older, whose numbers more than quadrupled between 1960 and 2000 (Table 1) [1]. Accompanying this aging of the population has been an exponential rise in the prevalence of cardiovascular (CV) disease. More than 80% of CV deaths occur in persons z65 years old. Despite these parallel trends, it must be emphasized that aging per se is not synonymous with the development of CV disease. This chapter will delineate those changes in the CV system that are thought to represent the eﬀects of age per se in the absence of CV disease. This is by no means a simple task, given the multiple factors that blur their separation. It is important, however, to develop norms of CV structure and function in the elderly to facilitate the accurate diagnosis of CV disease in this age group. The enhanced CV risk associated with age indicates important interactions between mechanisms that underlie aging and those that underlie diseases. The nature of these interactions is complex and involves not only mechanisms of aging but also multiple deﬁned and undeﬁned (e.g., genetic) risk factors. The role of speciﬁc age-associated changes in CV structure and function has, and largely continues to be, unrecognized by those who shape medical policy and, until recently, not considered in most epidemiological studies of CV disease. Yet quantitative information on age-associated alterations in CV structure and function is essential to deﬁne and target the speciﬁc characteristics of CV aging that render it such a major CV risk factor. Such information is also required to diﬀerentiate between the 1

2 Table 1

Fleg and Lakatta Actual and Projected Growth of the Elderly American Population z65 Years

z85 Years

Year

Total population (all ages)

Number

% of total

Number

% of z65

1960 1980 1990 2000 2020 2040

179,323 226,546 248,710 274,634 322,742 369,980

16,560 25,550 31,079 34,709 53,220 75,233

9.2 11.3 12.5 12.6 16.5 20.6

929 2,240 3,021 4.259 6,460 13,552

5.6 8.8 9.7 12.3 12.1 18.0

Source: From Ref. 1.

limitations of an elderly person that relate to disease and those that are within expected normal limits.

METHODOLOGICAL ISSUES Multiple methodological issues must be addressed in the attempt to deﬁne ‘‘normal’’ aging. Because the population sample from which norms are derived will strongly inﬂuence the results obtained, it should be representative of the general population. For example, neither nursing home residents nor a seniors running club would yield an appropriate estimate of maximal exercise capacity that could be applied to the majority of elders. The degree of screening used to deﬁne a normal population can profoundly inﬂuence the results. In clinically healthy older adults, a resting electrocardiogram (ECG), echocardiogram, or exercise perfusion imaging will often identify silent CV disease, especially coronary artery disease (CAD). If several such screening tests are used, only a small proportion of the older population may qualify as normal, limiting the applicability of ﬁndings to the majority of elderly individuals. In addition, the inclusion limits chosen for body fatness, blood pressure, smoking status, and other constitutional or lifestyle variables will signiﬁcantly inﬂuence the normal values for measuring CV variables. Additional methodological factors can aﬀect the deﬁnitions of normal aging. Crosssectional studies, which study individuals across a wide age range at one time point, may underestimate the magnitude of age-associated changes because, in such studies, older normal persons represent ‘‘survival of the ﬁttest.’’ True age-induced changes are better estimated by longitudinal studies, in which given individuals are examined serially over time. A reality of aging research, however, is that most data are derived from cross-sectional studies because they are easier to perform. Even longitudinal studies have their limitations— changes in methodology or measurement drift over time and development of disease in previously healthy persons. In addition, secular trends such as the downward drift in serum cholesterol or increasing obesity of Americans can alter age-related longitudinal changes. In the current chapter, emphasis will be given to data obtained from communitydwelling samples screened for the absence of clinical and, in some cases, subclinical CV disease and major systemic disorders. A sizeable portion of the data presented derive from the authors’ studies over the past three decades in community-based volunteers from the Baltimore Longitudinal Study of Aging (BLSA).

Normal Aging

3

UNSUCCESSFUL VASCULAR AGING AS THE ‘‘RISKY’’ COMPONENT OF AGING Intimal Medial Thickening Age-associated changes in arterial properties of individuals who are otherwise considered healthy may have relevance to the exponential increase in CV disease. Cross-sectional studies in humans have found that wall thickening and dilatation are prominent structural changes that occur within large elastic arteries during aging [2]. Postmortem studies indicate that aortic wall thickening with aging consists mainly of intimal thickening, even in populations with a low incidence of atherosclerosis [3]. Noninvasive measurements made within the context of several epidemiological studies indicate that the carotid wall intimal medial (IM) thickness increases nearly threefold between 20 and 90 years of age, which is also the case in BLSA individuals rigorously screened to exclude carotid or coronary arterial disease (Fig. 1A). It has been argued that the age-associated increase in IM thickness with aging in humans represents an early stage of atherosclerosis [4]. Indeed, excessive IM thickening at a given age predicts silent CAD (Fig. 1B). Since silent CAD (as deﬁned in Fig. 1B) often progresses to clinical CAD, it is not surprising that increased IM thickness (a vascular endpoint) predicts future clinical CV disease. A plethora of other epidemiological studies of individuals not initially screened to exclude the presence of occult CV disease, have indicated that increased IM thickness is an independent predictor of future CV events. Note in Figure 1C that the degree of risk varies with the degree of vascular thickening, and that the risk gradation among quintiles of IM thickening is nonlinear, with the greatest risk occurring in the upper quintile [5]. Thus, those older persons in the upper quintile of IM thickness may be considered to have aged ‘‘unsuccessfully’’ or to have ‘‘subclinical’’ vascular disease. The potency of IM thickness as a risk factor in older individuals equals or exceeds that of most other, more ‘‘traditional,’’ risk factors. Note, however, in Figure 1B that the diﬀerence in IM thickness between those older and younger persons without evidence of CAD far exceeds the diﬀerence between older persons free of coronary disease, and those with disease. The phenomenon of age-dependent IM thickening has been noted in the absence of atherosclerosis, both in laboratory animals and in humans [3]. In other words, the ‘‘subclinical disease’’ of excessive IM thickening is not necessarily ‘‘early’’ atherosclerosis. Rather, ‘‘subclinical disease’’ is strongly correlated with arterial aging. Interpreted in this way, the increase in IM thickness with aging is analogous to the intimal hyperplasia that develops in aortocoronary saphenous vein grafts, which is independent of atherosclerosis, but predisposes for its later development [6]. Age-associated endothelial dysfunction, arterial stiﬀening, and arterial pulse pressure widening can also be interpreted in the same way. Combinations of these processes occurring to varying degrees determine the overall vascular aging proﬁle of a given individual (i.e., the degree of ‘‘unsuccessful’’ vascular aging). In Western societies, additional risk factors (e.g., hypertension, smoking, dyslipidemia, diabetes, diet, or heretofore unidentiﬁed genetic factors) are required to interact with vascular aging (as described above) to activate a preexisting atherosclerotic plaque. According to this view, atherosclerosis that increases with aging is not a speciﬁc disease, but an interaction between atherosclerotic plaque and intrinsic features related to vascular aging modulated by atherosclerotic risk factors. Evidence in support of this view comes from studies in which an atherogenic diet caused markedly more severe atherosclerotic

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Figure 1 (A) The common carotid intimal-medial thickness in healthy BLSA volunteers as a function of age. (From Ref. 4) (B) Common carotid artery intimal-medial thickness as a function of age, stratified by coronary artery disease (CAD) status. CAD-1: subset with positive exercise ECG but negative thallium scan. CAD-2: subset with concordant positive exercise ECG and thallium scan. (From Ref. 4) (C) Common carotid intimal-medial thickness predicts future cardiovascular events in the Cardiovascular Health Study. (From Ref. 5.)

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Figure 1

5

Continued.

lesions in older versus younger rabbits and nonhuman primates despite similar elevations of serum lipids [7,8]. Hence, it is possible that atherosclerosis occurring at younger ages may be attributable not only to exaggerated traditional CV risk factors, but also to accelerated aging of the vascular wall. Of course, the traditional risk factors may themselves accelerate aging of the vascular wall. Studies in various populations with clinically deﬁned vascular disease have demonstrated that pharmacological F lifestyle (diet, physical activity) interventions can retard the progression of IM thickening [9–14]. Arterial Pressure, Arterial Stiffness, and Endothelial Dysfunction Systolic, Diastolic, and Pulse Pressure Arterial pressure is determined by the interplay of peripheral vascular resistance and arterial stiﬀness; the former raises both systolic and diastolic pressure to a similar degree, whereas the latter raises systolic but lowers diastolic pressure. An age-dependent rise in average systolic blood pressure across adult age has been well documented (Fig. 2, lower right panel). In contrast, average diastolic pressure (Fig. 2, lower left panel) was found to rise until about 50 years of age, level oﬀ from age 50 to 60, and decline thereafter [15]. This decline in diastolic pressure is due to the impaired ability of the stiﬀer aorta to expand in systole and thereby augment diastolic pressure by the release of stored blood during diastole. Thus, pulse pressure (systolic minus diastolic), which is a useful hemodynamic indicator of conduit artery vascular stiﬀness, increases with age (Fig. 2, upper right panel). The age-dependent changes in systolic, diastolic, and pulse pressures are consistent with the notion that in younger people, blood pressure is determined largely by peripheral vascular resistance, while in older individuals it is determined to a greater extent by central conduit vessel stiﬀness.

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Figure 2 Change in blood pressure with age in the Framingham Study, stratified by systolic blood pressure at baseline visit. Thick lines represent entire study cohort; thin lines represent cohort after deaths; nonfatal myocardial infarction and heart failure have been excluded. (From Ref. 15.)

Because of the decline in diastolic pressure in older men and women in whom systolic pressure is increased, isolated systolic hypertension emerges as the most common form of hypertension in individuals over the age of 50 [15]. Isolated systolic hypertension, even when mild in severity, is associated with an appreciable increase in cardiovascular disease risk [16,17]. Based on long-term follow-up of middle-aged and older subjects, however, Framingham researchers have found pulse pressure to be a better predictor of coronary disease risk than systolic or diastolic blood pressures [18]. A subsequent Framingham investigation found that pulse pressure was especially informative of coronary risk in older subjects (Fig. 3) [19]. This is because of the ‘‘J’’- or ‘‘U’’-shaped association between diastolic pressure and coronary risk. Thus, consideration of the systolic and diastolic pressures jointly (which are reﬂected in pulse pressure) are preferable to consideration of either value alone.

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Figure 3 Influence of pulse pressure on risk of coronary heart disease (CHD) for given systolic blood pressure strata in the Framingham study. All estimates are adjusted for age, sex, body mass index, cigarettes smoked per day, glucose intolerance, and total cholesterol/HDL ratio. (From Ref. 19.)

As the deﬁnition of ‘‘disease’’ continues to evolve, we may ﬁnd that many subjects who were formerly thought to be healthy may no longer be considered free from disease. For example, if systolic pressure z140 mmHg is now considered to be hypertension, and if hypertension is considered to be a disease, then individuals with a systolic pressure between 140 and 160 mmHg, who a decade ago were thought to be disease- free, are now identiﬁed as having CV disease. Large studies have shown that individuals who manifest modest elevations in systolic and pulse pressures are more likely to develop clinical disease or die from it [16,17]. There are compensatory mechanisms to normalize blood pressure that fail with advancing age. For example, endothelial dysfunction becomes apparent by about the sixth decade, approximately the time when pulse pressure begins to rise appreciably. Thus, impaired endothelial function with aging may be a mechanism that not only permits arterial pulse pressure to rise but also underlies the importance of pulse pressure as a risk factor for cardiovascular events and death, even after accounting for systolic pressure [15,18–27]. Abnormalities in endothelial function have also been identiﬁed as one of the earliest pathophysiological manifestations of atherosclerosis, diabetes, and hypertension [28]. The age-associated increase in IM thickening and endothelial dysfunction are accompanied by both luminal dilatation and a reduction in arterial compliance or distensibility with an increase in vessel stiﬀness [2]. Pulse-wave velocity (PWV), a relatively convenient and noninvasive index of vascular stiﬀening, increases with age in both men and women (Fig. 4B) in parallel with systolic blood pressure (Fig. 4A). PWV is determined in part by the intrinsic stress/strain relationship (stiﬀness) of the vascular wall, and by the mean arterial pressure. Increased PWV has traditionally been linked to structural alterations in the vascular media, such as increased collagen content, covalent cross-linking of the collagen, reduced elastin content, elastin fracture, and calciﬁcation. Prominent age-

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Figure 4 Bar graphs of systolic blood pressure, aortofemoral pulse wave velocity, and augmentation index in young (mean age 29 years), older (mean age 67 years) sedentary BLSA volunteers, and older (mean 67 years) endurance athletes. The age-associated increase in each of these arterial stiffness indices is attenuated in the athletes. (A) Older sedentary differ from young sedentary at p < 0.01; (B) older sedentary differ both other groups at p<0.0001; (C) all groups differ at p < 0.0001. (From Ref. 55.)

associated increases in PWV have been demonstrated in populations with little or no atherosclerosis, again indicating that these vascular parameters are not necessarily indicative of atherosclerosis [29]. However, more recent data emerging from epidemiological studies indicate that increased large vessel stiﬀening also occurs in the context of atherosclerosis and diabetes [30–32]. The link may be that stiﬀness is governed not only by the structural changes within the matrix, as noted above, but also by endothelial regulation of vascular smooth muscle tone and of other aspects of vascular wall structure/ function. Thus, there is evidence of a vicious cycle: altered mechanical properties of the vessel wall facilitate the development of atherosclerosis, which in turn increases arterial stiﬀness via endothelial cell dysfunction and other mechanisms. For example, a longitudinal study in a large population of older individuals has shown that elevated levels of

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pulse pressure are associated with progression of IM thickening and that IM thickening, in turn, is associated with widening of PP [33]. Numerous studies have concurred that elevated pulse pressure is an independent risk factor for future cardiovascular events [15,18– 27]. Thus, an increased PWV reﬂects three potential risk factors: increased systolic pressure, increased pulse pressure, and altered vascular wall properties. Another consequence of age-associated large artery stiﬀening is a change in the arterial pulse contour. The faster PWV leads to an earlier return of reﬂected waves to the heart, producing a late systolic augmentation of blood pressure (Fig. 4C). Thus, the pressure pulse contour is ampliﬁed and has a later peak, representing an additional load against which the older heart must eject blood (Fig. 5) [34]. Recent studies [31,35–41] indicate that increased vascular stiﬀness, over and above blood pressure, is an independent predictor of hypertension, atherosclerosis, cardiovascular events, and mortality. This suggests that altered structure/function of the stiﬀ arterial wall is a risk factor for future vascular events, independent of the associated increase in systolic and pulse pressures. Liao et al. [36], in fact, have demonstrated that increased vascular stiﬀness precedes the development of hypertension. Thus, while a ‘‘secondary’’ increase in large artery stiﬀness is attributable to an increase in mean arterial pressure that occurs in hypertension, evidence now exists that a ‘‘primary’’ increase in large artery stiﬀness that accompanies aging gives rise to an elevation of arterial pressure. Normotensive individuals who fall within the upper quartile for measures of arterial stiﬀness are more likely to subsequently develop hypertension. Observations such as this reinforce the concept that hypertension is, at least in part, a disease of the arterial wall. The mecha-

Figure 5 Ascending aortic blood flow velocity and pressure wave forms from a young and an older individual. Peak pressure becomes elevated with age and peaks later in the cardiac cycle. (Adapted from Ref. 34.)

10 Table 2

Fleg and Lakatta Relationship of Cardiovascular Human Aging in Health to Cardiovascular Disease

Age-associated changes Cardiovascular structural remodeling * Vascular intimal thickness

Plausible mechanisms

* LV wall thickness

* Migration of and * matrix production by VSMC Possible derivation of intimal cells from other sources Elastin fragmentation * Elastase activity * Collagen production by VSMC and * cross-linking of collagen Altered growth factor regulation/ tissue repair mechanisms * LV myocyte size

* Left atrial size

+ Myocyte number (necrotic and apoptotic death) Altered growth factor regulation Focal collagen deposition * Left atrial pressure/volume

* Vascular stiﬀness

Cardiovascular functional changes Altered regulation of vascular tone

+ Cardiovascular reserve

Reduced physical activity

+ NO production/eﬀects + * + +

bAR responses Vascular load Intrinsic myocardial contractility b- Adrenergic modulation of heart rate, myocardial contractility, and vascular tone

Learned lifestyle

Possible relation to human disease

Early stages of atherosclerosis

Systolic hypertension Stroke Atherosclerosis Retarded early diastolic cardiac ﬁlling * Cardiac ﬁlling pressure Lower threshold for dyspnea * Prevalence of lone atrial ﬁbrillation

Vascular stiﬀening; hypertension Lower threshold for, and increased severity of, heart failure

Exaggerated age Ds in some aspects of cardiovascular structure and function; negative impact on atherosclerotic vascular disease, hypertension, and heart failure

Abbreviations: VSMC, vascular smooth muscle cell; LV, left ventricular; NO, nitric oxide; bAR, b-adrenergic receptor.

nisms of age-associated changes in vascular structure and function and the putative relationship of these changes to development of CV disease are depicted in Table 2. CAN VASCULAR AGING BE PREVENTED OR DELAYED? An emerging concept in the treatment of hypertension recognizes that progressive vascular damage can continue to occur even when arterial pressure is controlled. It is conceivable that drugs that retard or reverse age-associated arterial wall remodeling and increased

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stiﬀness will be preferable to those that lower pressure without aﬀecting the vascular wall properties. For example, angiotensin-converting enzyme inhibitors have been shown to delay remodeling of the arterial wall that occurs during aging in rodents by retarding the age-dependent intimal thickening and medial smooth-muscle-cell hypertrophy [42]. In humans, these agents have been shown to reduce arterial wall thickness [43] and decrease vascular stiﬀness as assessed by arterial distensibility [43], pulse-wave velocity [44,45], and arterial wave reﬂections [46,47]. Similar considerations pertain to treating IM thickening in older persons who are otherwise healthy. Drug/diet interventions have been shown to reduce or retard IM thickening in humans [9–12]. In particular, statins have been shown to signiﬁcantly retard the progression of intima medial thickening in patients with coronary artery disease [13] and in hypercholesterolemic subjects [14]. Importantly, many of the beneﬁcial cardiovascular eﬀects of statins are thought to be non lipid-related, including favorable eﬀects on endothelial function [48], plaque architecture, and stability [49], inﬂammation [49], and inhibition of cellular proliferation [50]. Thus, by targeting the arterial wall, statins deserve further testing as modulators of vascular aging. Whereas angiotensin antagonists and statins predominantly aﬀect vascular function, a new class of thiazolium compounds directly targets vascular structure by altering glycoproteins of the vascular wall. These glycoproteins, also known as advanced glycation end products, increase with age and in diabetes, and are thought to contribute to the ageand disease-related increases in large artery stiﬀening. Recently, thiazolium agents have been shown to reduce indices of arterial stiﬀness measures in dogs, nonhuman primates, and, most recently, humans [51–53]. With respect to lifestyle, performance of regular vigorous exercise declines dramatically with age in otherwise healthy persons [54]. It is noteworthy that pulse pressure, pulse-wave velocity, and carotid augmentation index are lower (Fig. 4) [55, 56] and baroreceptor reﬂex function is better preserved [57] in older persons who are physically conditioned than in their sedentary age peers. Similarly, enhanced endothelial function is observed in older athletes [58]. There is also evidence to indicate that low sodium diets are associated with reduced arterial stiﬀening with aging [59]. Whether lifestyle interventions or pharmacotherapy can prevent or retard unsuccessful aging of the vasculature in younger middle-aged individuals who exhibit excessive subclinical evidence of unsuccessful aging remains unknown.

CARDIAC STRUCTURE Prior to the 1970s, autopsy was essentially the only method for obtaining reliable measurements of cardiac structure in normal persons. Such studies are obviously ﬂawed by their inherent selection bias. A large autopsy series by Linsbach et al. [60] in 7112 patients demonstrated an increase in cardiac mass of 1 to 1.5 g/year between the ages of 30 and 90 years. Because the study included individuals with CV disease, the age-associated increase in heart weight may derive at least in part from the development of cardiac pathology. An autopsy study of 765 normal hearts from persons 20 to 99 years old who were free from both hypertension and CAD showed that heart weight indexed to body surface area was not age-related in men but increased with age in women, primarily between the fourth and seventh decades [61]. In hospitalized patients without evidence of CV disease, Olivetti et al. [62] observed an age-associated reduction of LV mass mediated by a decrease in estimated myocyte number, although myocyte enlargement occurred with

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age. These investigators subsequently found a higher prevalence of apoptotic myocytes in older male than female hearts, which paralleled a decline of LV mass with age in men but not in women [63]. The widespread application of echocardiography, beginning in the 1970s, ﬁnally allowed accurate noninvasive assessment of age changes in cardiac structure and function. In healthy normotensive BLSA men, Gerstenblith et al. [64] observed a 25% increase in echocardiographic LV posterior wall thickness between the third and eighth decades, a ﬁnding replicated by others [65,66]. Because LV diastolic cavity size was not signiﬁcantly age related in the BLSA [64], calculated LV mass also increased substantially with age. Thus, an apparent discrepancy existed between the unchanged or decreased LV mass with age seen at autopsy and the increase in LV wall thickness and calculated LV mass observed by echocardiography. A recent study in BLSA volunteers using cardiac magnetic resonance imaging (MRI) to estimate LV mass helps to resolve these divergent ﬁndings [67]. Unlike standard echocardiography, which provides one- and two-dimensional measurements, MRI assesses LV size in three dimensions. In 136 men and 200 women without CV disease, MRI-derived LV wall thickness increased with age (Fig. 6, upper panels) and short axis diastolic dimension was not age related, similar to prior echocardiographic ﬁndings. In contrast, LV length declined with age in both sexes (i.e., the LV became more spherical) (Fig. 6, middle panels) [67]. Thus, MRI-derived LV mass was unrelated to age in women and demonstrated an age-associated decline in men (due to their lesser age-related increase in wall thickness), similar to recent autopsy ﬁndings (Fig. 6, lower panels) [63]. With advancing age, therefore, the normal LV becomes thicker and more spherical. Although the mechanisms for the age-associated remodeling of the LV and increase in myocyte size are not clear, it is attractive to suggest that they are adaptive to the arterial changes that accompany aging. Putative stimuli for cardiac cell enlargement with age are an increase in vascular load due to arterial stiﬀening and a stretching of cells due to dropout of neighboring apoptotic myocytes [68,69]. Phenotypically, the age-associated increase in LV thickness resembles the LV hypertrophy that develops from hypertension. This ﬁnding, coupled with the increase in systolic blood pressure that occurs over time even in healthy individuals, has led to consideration of aging as a muted form of hypertension. In older rodent hearts, which demonstrate a similar increase in LV mass and myocyte size as observed in humans, stretch of cardiac myocytes and ﬁbroblasts releases growth factors such as angiotension II, a known stimulus for apoptosis [70]. In addition, enhanced secretion of atrial natriuretic [71] and opioid [72] peptides is observed. A modest increase in echocardiographic aortic root diameter occurs with age, approximating 6% in BLSA men between the fourth and eighth decades [64]. Similarly, the aortic knob diameter increased from 3.4 to 3.8 cm on serial chest x-rays over 17 years [73]. Such aortic root dilation provides an additional stimulus for LV hypertrophy because the larger volume of blood in the proximal aorta represents a greater inertial load that must be overcome before LV ejection can begin. As previously noted, resting supine LV short-axis diastolic dimension is not signiﬁcantly related to age; resting LV systolic dimension is similarly unrelated to age. Thus, echocardiographic LV shortening fraction [64] and radionuclide LV ejection fraction [74,75], the two most common measures of global LV systolic performance, are unaﬀected by age in healthy normotensive persons. Because LV stroke volume is the diﬀerence of LV end-diastolic and end-systolic volumes, supine resting LV stroke volume is also unrelated to age [74].

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Figure 6 Effect of age on left ventricular (LV) geometry and mass, derived from 3-dimensional cardiac magnetic resonance imaging in normotensive BLSA volunteers. (A) LV wall thickness increases with age in both sexes, though more steeply in women. (B) The LV long axis dimension declines with age in both sexes, but more steeply in men, whereas minor axis dimension (not shown) is unrelated to age. (C) Calculated LV mass is not age-related in women but declines with age in men. (Adapted from Ref. 67.)

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Continued.

Prolonged contractile activation of the thickened LV wall [76] maintains a normal ejection time in the presence of the late systolic augmentation of aortic impedance, preserving systolic cardiac pump function at rest. However, a ‘‘downside’’ of prolonged contractile activation is that at the time of the mitral valve opening, myocardial relaxation is relatively more incomplete in older than in younger individuals and causes the early LV ﬁlling rate to be reduced in the former. Thus, in contrast to the preservation of resting LV systolic performance across the adult age span, LV diastolic performance is profoundly inﬂuenced by aging. These age changes in diastolic performance were ﬁrst documented by reduced mitral valve E–F closure slope on M-mode echocardiography [64,65]. Pulsed Doppler examination conﬁrmed that the transmitral early diastolic peak ﬁlling rate (peak E-wave velocity) declined f50% between ages 20 and 80 years [77–79]. Conversely, peak A-wave velocity, which represents late LV ﬁlling due to atrial contraction, increases with age. This greater atrial contribution to LV ﬁlling is accomplished via a modest age-associated increase in left atrial size demonstrable on echocardiography. Because resting LV end-diastolic volume is not diminished across adult age, the augmented atrial contribution to LV ﬁlling in older adults can be considered a successful adaptation to the reduced early diastolic ﬁlling rate in the thicker, and presumbably stiﬀer, senescent LV. Thus, the relative importance of early and late diastolic LV ﬁlling is reversed with advanced age. The impairment of early LV ﬁlling with age may derive in part from reduced LV diastolic compliance secondary to the increase in LV wall thickness with age; nevertheless an age-associated reduction in ventricular compliance remains unproven in humans. In support of this hypothesis, animal studies in both intact hearts and isolated cardiac muscle have detected prolonged isovolumic relaxation and increased myocardial diastolic stiﬀness. The slower isovolumic relaxation observed in cardiac muscle from older animals [80] may be secondary to diminished rate of Ca2+ accumulation by the sarcoplasmic reticulum [81]. A conceptual framework for the cardiac adaptations to age-associated arterial stiﬀening is shown in Figure 7.

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Figure 7 Conceptual framework for the cardiovascular adaptations to arterial stiffening that occur with aging. LV = left ventricular.

Although the diminished early diastolic ﬁlling rate with age may not compromise resting end-diastolic volume or stroke volume, an underlying reduction of LV compliance might cause a greater rise in LV diastolic pressure in older persons, especially during stressinduced tachycardia, thus causing a lower threshold for dyspnea than in the young. Furthermore, it might be anticipated that the loss of atrial contribution to LV ﬁlling, as occurs during atrial ﬁbrillation, would eﬀect a greater impairment of diastolic performance in older than in younger individuals. Indeed, it is attractive to speculate that the frequent occurrence of heart failure in the elderly despite preserved LV systolic function derives, at least in part, from the age-associated impairment of early diastolic ﬁlling (Table 2). Cardiovascular Physical Findings in Older Adults Certain age-associated alterations in CV structure and function may manifest themselves during the cardiovascular examination. Due to the stiﬀening of the large arteries, systolic blood pressure is often elevated with a normal or low diastolic blood pressure. Therefore, the carotid artery upstroke is usually brisk in the elderly and may mask signiﬁcant aortic valve stenosis. The apical cardiac impulse may be diﬃcult to palpate secondary to senile emphysema and chest wall deformities. Respiratory splitting of the second heart sound is audible in only f30 to 40% of individuals older than 60 years, perhaps due to reduced compliance of the pulmonary vasculature. In contrast, an S4 gallop is commonly heard in older but not younger persons, due to the age-associated increase in late diastolic ﬁlling mediated by vigorous atrial contraction into a thicker walled LV. A soft basal ejection

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murmur occurs in 30 to 60% of the elderly. This murmur is thought to arise from a dilated, tortuous aorta or from sclerosis of the aortic valve.

Cardiovascular Response to Stress The cardiovascular response to stress (e.g., to increases in arterial pressure or to postural maneuvers or to physical exercise) in older individuals is of considerable interest in clinical medicine. First, physicians are often called upon to provide advice and information concerning the CV potential of the elderly (e.g., the eﬀect or importance of conditioning on the maintenance of function). Second, the CV response to stress is of importance in assessing the ability of older individuals to respond to disease states. Third, the CV response to stress has considerable value in terms of the diagnosis and management of patients with CV disease. Despite the high prevalence of CV disease among older Americans, it is of considerable importance to understand the exercise capabilities of disease-free CV elders. Exercise testing is a diagnostic tool frequently utilized to detect and quantify the severity of CV disease. It is very clear that the value of such diagnostic tests and the validity of their interpretation are dependent upon precise information regarding the normal limits of such stress-testing procedures relative to age.

Orthostatic Stress Cardiovascular reﬂex mechanisms become operative in response to perturbations from the supine, basal state and mediate the utilization of CV reserve functions. The end result of these reﬂex mechanisms is enhanced blood ﬂow to and preservation of arterial pressure within selected body organs. In response to a change from the supine to the upright position, mean arterial pressure is maintained by an increase in systemic vascular resistance. A change in blood ﬂow from the heart depends upon the product of changes in heart rate and stroke volume index (SVI), the latter being determined by the changes in end-diastolic volume index (EDVI) and end-systolic volume index (ESVI). Changes in EDVI are determined, in part, by changes in venous return, which depends upon the ability of the blood to ﬂow through the vascular system, and to changes in ESVI. In healthy, community-dwelling older individuals, arterial pressure changes little with assumption of upright posture, and postural hypotension or acute orthostatic intolerance (i.e., dizziness or fainting when assuming an upright from a supine position or during a passive tilt) is uncommon. Orthostatic hypotension (OH), deﬁned by a decline of systolic blood pressure z20 mmHg or diastolic blood pressure z10 mmHg, occurred in 16% of volunteers aged 65 years and older from the Cardiovascular Health Study [82] and in 7% of men aged 71 to 93 years from the Honolulu Heart Program [83]; in both of these older cohorts the prevalence of OH increased with age. In the latter study, OH was an independent predictor for mortality (RR=1.64), and there was a linear relationship between the magnitude of orthostatic decline in systolic blood pressure and 4-year mortality rate [83]. In contrast to healthy, community-dwelling older volunteers, OH and orthostatic intolerance are common in debilitated institutionalized elders with chronic illnesses. Within such populations, the likelihood for orthostatic intolerance is increased among individuals who exhibit very low LV ﬁlling rates and small EDVI and SVI in the supine position [84]. In such individuals, however, the eﬀects of advanced age cannot be dissociated from those of profound deconditioning and multiple diseases and medications.

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With advancing age, the acute heart rate increase to orthostatic stress decreases in magnitude and takes longer to achieve. The baroreceptor sensitivity (i.e., the slope of the relationship of the change in heart rate versus the change in arterial pressure) is negatively correlated with age and resting arterial pressure [85]. The low-pressure baroreceptor, or cardiopulmonary reﬂex, also decreases with age in normotensives but not in hypertensive persons. Although the heart rate increases to a lesser extent during a postural stress in older than in younger BLSA volunteers, the SVI reduction tends to be less in the older group; thus, the postural change in cardiac output does not vary signiﬁcantly with age because the lesser increase in heart rate in older individuals is balanced by a lesser reduction in SVI [86]. Similarly, in studies that have found cardiac output to be reduced with age in the supine position due to a reduced SVI in older versus younger men, this age eﬀect was abolished in the sitting position, due to lesser reduction in SVI in the older men upon sitting. Responses to gradual tilt or to graded lower body negative pressure in older individuals are similar to responses to change in body position: SVI and cardiac output decrease less in older than in younger individuals, although the heart rate increase is blunted in older individuals [87]. A lesser reduction in SVI in older versus younger individuals following a postural stress implies either a smaller reduction in EDVI or a greater reduction in ESVI in older individuals. Reduced venous compliance in older versus younger individuals, advanced as a mechanism to account for a lesser peripheral ﬂuid shift during orthostatic maneuvers, could preserve cardiac ﬁlling volume and maintain SV in the upright position in healthy elderly individuals. A reduction in the venodilatory response to beta-adrenergic stimulation with preservation of the alpha-adrenergic vasoconstrictor response may contribute to a reduced venous compliance with aging. Pressor Stress The stress of sustained, isometric handgrip increases both arterial pressure and heart rate. The response varies in magnitude in proportion to the relative level and duration of eﬀort. After sustained submaximal or maximal handgrip, heart rate was observed to increase more in younger than in older healthy individuals whereas blood pressure increased more in older persons [88,89]. In BLSA volunteers, 3 min of submaximal sustained handgrip elicited mild increases in echocardiographic LV diastolic and systolic dimensions; these increases correlated positively with age [89]. The application of a pressor stress has also been used to assess the intrinsic myocardial reserve capacity. In healthy BLSA individuals, a 30 mmHg increase in systolic blood pressure induced by phenylephrine infusion in the presence of beta-adrenergic blockade induced signiﬁcant echocardiographic LV dilatation at end diastole in healthy older (60 to 68 years), but not in younger (18 to 34 years) men: the cardiac dilatation occurred in older men despite a smaller reduction in their heart rate [90], analagous to the handgrip response. Thus, because of an apparent age-associated decrease in the intrinsic myocardial contractile reserve in response to an increase in afterload, the senescent heart dilates to preserve SVI via the Frank–Starling mechanism. Exercise Capacity and Aging It might be expected that age-associated changes in the cardiovascular system would be initially manifest or most pronounced during exercise, when cardiorespiratory

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performance must increase substantially above the basal level. The maximum oxygen consumption rate (VO2max) achieved during exhaustive exercise is the product of cardiac output (the central component) and arteriovenous oxygen diﬀerence (the peripheral component). In healthy older adults, VO2max is up to 15-fold greater than the basal VO2. In addition to a 4- to 5-fold increase in cardiac output, oxygen extraction by working tissues increases, causing the arteriovenous oxygen diﬀerence to widen up to 3-fold during strenuous exercise. This results, in part, from a dramatic increase (up to 15-fold) in the relative proportion of cardiac output delivered to working muscles. It has been well documented that treadmill VO2max, adjusted for body weight, declines with age. The extent of the VO2max decline with aging varies among studies, depending upon age ranges, diﬀerences in body weight and composition, and diﬀerences in habitual physical activity among the individuals studied. Longitudinal studies report a more pronounced ageassociated decline in VO2max than do cross-sectional studies. Whether the same factors limit the VO2max in individuals of widely diﬀerent ages is not known with certainty. Maximal aerobic (i.e., oxygen utilizing), exercise is usually limited by dyspnea or muscular fatigue that is thought to be secondary to the level to which cardiac output can increase. However, as the maximum minute ventilation is determined by respiratory muscle function, and leg fatigue is inﬂuenced by muscle conditioning status, dyspnea or leg fatigue during exercise may also relate to peripheral factors. In other words, a reduction in respiratory or peripheral muscle reserve function in older individuals, due to an age-associated reduction in the number of muscle ﬁbers or to a reduction in the utilization of oxygen per muscle unit due to aging or to a sedentary lifestyle, might contribute to the age-associated decline of VO2max. Age-associated changes in body composition and muscle mass also appear to be involved in the reduction in VO2max with aging. In spite of a decline in the skeletal muscle mass with aging, total body mass remains relatively constant because of an increase in body fat, not only subcutaneous but also intraperitoneal and intramuscular. In healthy nonendurance-trained BLSA volunteers, normalization of peak VO2 to creatinine excretion, an index of muscle mass, rather than to body weight, reduced the magnitude of the apparent ‘‘age-associated’’ decline in VO2max from 39% to 18% in men and from 30% to 14% in women between ages 30 and 70 years (Fig. 8) [91]. Both cross-sectional [91] and longitudinal [92] analyses of aerobic capacity in this population indicate that the rate of peak VO2 decline varies among individuals and is inﬂuenced by physical activity habits. During upright cycle ergometry, the peak VO2 of healthy BLSA participants averages about 80% of that during treadmill exercise, regardless of age. The primary factor limiting the duration and intensity of cycle exercise is usually leg fatigue. Peak cycle work rate and VO2 decline f50% between ages 20 and 90 years in healthy, nonathletic BLSA men and women, attributable to declines of approximately 30% in cardiac output and 20% in arteriovenous oxygen diﬀerence [93]. The age-associated decrease in cardiac output at maximal eﬀort during upright cycle exercise (Fig. 9F) is due entirely to a reduction in heart rate (Fig. 9E), as the LV SVI does not decline with age in either gender (Fig. 9D) [94]. However, the manner in which SVI is achieved during maximal exercise varies dramatically with aging. Although older individuals have a blunted capacity to reduce ESVI (Fig. 9B), this is oﬀset by a larger EDVI (Fig. 9A) [94]. Thus, a ‘‘stiﬀ heart’’ that prohibits suﬃcient ﬁlling between beats during exercise does not characterize aging in healthy individuals. The larger EDVI in healthy older versus younger individuals during vigorous exercise is due in part to a longer diastolic interval (i.e., slower heart rate) and to a greater amount of blood remaining in the heart at end systole (Fig. 9B) [94].

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Figure 8 Age-associated decline in VO2max in healthy, non-obese BLSA men, normalized in the conventional manner for body mass (top) and normalized per milligram of urinary creatinine, an index of total muscle mass (bottom). The decline in VO2max attributable to age is markedly attenuated after normalizing for muscle mass. (Adapted from Ref. 91.)

The ejection fraction at maximal exercise and its increase from rest are sometimes used clinically as a diagnostic tool to detect and quantify the severity of cardiac disease, particularly CAD. Exercise ejection fraction is thus of considerable clinical interest. The impaired ability of healthy older men and women to reduce LV ESVI during vigorous exercise accounts for their smaller increase in ejection fraction from rest and their lower maximal value compared to younger individuals (Fig. 9C) [94]. A blunted LV ejection fraction response during exercise is even more prominent in older individuals with exercise-induced silent myocardial ischemia than in those without evident ischemia, due to a more pronounced inability to reduce ESV [95]. Mechanisms that underlie the age-associated reduction in maximum ejection fraction are multifactorial and include (1) a reduction in intrinsic myocardial contractility; (2) an increase in vascular afterload; (3) a diminished eﬀectiveness of the autonomic modulation of both LV contractility and arterial afterload; and (4) arterial-ventricular load mismatching. Although these age-associated changes in cardiovascular reserve, per se, are insuﬃcient to produce clinical heart failure, they appear to lower the threshold for developing

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Figure 9 Scatter plots of left ventricular volumes (A, B), ejection fraction (C), stroke volume (D), heart rate (E), and cardiac index (F) during maximal graded upright cycle exercise in healthy BLSA volunteers, carefully screened to exclude silent coronary artery disease. Note the similar age changes in men and women and the increasing heterogeneity with age in the end-systolic volume index, ejection fraction, and heart rate. (Adapted from Ref. 94.)

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symptoms and signs of heart failure and adversely inﬂuence its clinical severity and prognosis for any level of disease burden (Table 2). Myocardial Contractility In humans, information as to how aging aﬀects factors that regulate intrinsic myocardial contractility is incomplete because the eﬀectiveness of intrinsic myocardial contractility in the intact circulation is diﬃcult to separate from loading and autonomic modulatory inﬂuences on contractility. A deﬁcit in maximal intrinsic contractility of older persons might be expected on the basis of the reduced maximum heart rate, as the heart rate, per se, is a determinant of the myocardial contractile state. The most reliable estimate of myocardial contractility, the slope of the end-systolic pressure (ESP)–ESV relationship measured across a range of EDVs at rest, by deﬁnition cannot be assessed during exercise. However, a single point depicting ESP: ESV as a ‘‘contractility’’ index at maximal cycle exercise work rate demonstrates an age-associated decline of myocardial contractile reserve that is nearly identical to that for ejection fraction [94]. Afterload Augmented LV afterload in older versus younger persons during exercise likely plays a major role in the failure of the acute LV ESV reserve with advancing age. However, the extent to which the age-associated increases in afterload at rest becomes more pronounced during exercise is not known with certainty. Whereas the exaggerated cardiac dilation from the resting level that occurs during vigorous exercise in healthy older individuals suggests an exercise-induced increase in cardiac afterload, it has not been possible to noninvasively assess PWV, AGI, aortic diameter, or impedance during exercise. While some indices of afterload, such as arterial pressure and systemic vascular resistance, have been measured during exercise, their levels vary with the degree of eﬀort achieved and are therefore confounded by the decrease in maximum exercise capacity that occurs with age. One approach to determine the role of age-associated increases in afterload on LV performance is to assess the impact of an acute pharmacological reduction in both cardiac and vascular components of LV afterload on the LV ejection characteristics of older persons. In healthy older BLSA volunteers, intravenous infusion of sodium nitroprusside (SNP) titrated to lower resting mean arterial pressure by about 12% abolished the carotid AGI and lowered PWV at rest, and augmented LV ejection fraction during maximal cycle exercise to levels observed in younger unmedicated individuals [96]. Despite the SNPinduced reduction of systolic and diastolic arterial pressures, exercise SVI was not aﬀected due to parallel reductions in EDVI and ESVI; furthermore, maximum heart rate and exercise capacity were also unaﬀected by SNP. Thus, although the age-associated deﬁcits in aerobic performance and maximum cardiac output in healthy persons were not reduced by SNP, the LV of older persons could deliver the same SV and cardiac output while working at a smaller size. Another recent study in apparently healthy older volunteers showed that acute verapamil infusion, which reduced exercise afterload but not preload, improved LV ejection and oxygen utilization during submaximal exercise [97]. Whether factors other than increased afterload are involved in the age-associated impairment of LV ejection during exercise can be assessed using prolonged submaximal exercise, during which afterload decreases progressively with time rather than increasing as

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it does during traditional protocols employing incremental work loads. When BLSA volunteers exercised at a constant submaximal work rate for prolonged periods (i.e., 60 min or more), both arterial pressure and pulse pressure/SVI, an index of arterial stiﬀness, declined over time to a similar extent in younger and older individuals (Fig. 10 A–C) [98]. However, the concomitant reduction in LVESV and increase in ejection fraction were greater in younger than older persons (Fig. 10 D, E), similar to ﬁndings during graded maximal exercise. The mechanism for the age-associated blunting in the time-dependent improvement in LV ejection during prolonged submaximal exercise cannot be attributed to a lesser reduction of afterload over time; thus, other mechanisms appear to limit the acute LV ejection fraction reserve in these healthy older persons. The parallel blunting of heart rate responses in these older volunteers during prolonged submaximal exercise (Fig. 10F) [98] also resembles the age-associated reduction in acute heart rate reserve observed with graded incremental exercise protocols. Beta-Adrenergic Stimulation Catecholamines have a major modulatory inﬂuence on cardiovascular performance during acute stress. Such situations typically evoke an increase in their plasma levels. The average basal level of norepinephrine has been found to increase with advancing age in many, but not all, studies. In response to acute stress, such as exercise, assumption of upright posture, and glucose ingestion, the average plasma level of norepinephrine increases to a greater extent in elderly than in younger individuals, although there is substantial heterogeneity in these responses among the elderly. Beta-adrenergic stimulation modulates the heart rate, preload, afterload, coronary ﬂow, and myocardial contractility in response to exercise. Both the beta-adrenergicmediated relaxation of arterial smooth muscle and the enhancement of myocardial performance facilitate ejection of blood from the heart. Abundant evidence indicates that both myocardial and vascular responses to beta-adrenergic stimulation decline with age. Numerous studies have documented diminished cardio-acceleration with age in response to bolus infusions of beta-adrenergic agonists, in both experimental animals and humans. In contrast, the maximum heart rate that can be elicited by external electric pacing, which is far in excess of that elicited by isoproterenol infusion, is not age-related. In addition, isoproterenol infusion elicited a lesser increase in ejection fraction in healthy older men compared to young men [99]. The deﬁcits in beta-adrenergic signaling with aging are attributable in part to reduction in beta-receptor numbers, deﬁcient G-protein-coupling of receptors to adenyl cyclase, and, possibly, to age-associated reductions in the amount or activation of adenyl cyclase, leading to a relative reduction in the ability to augment cellular cAMP in response to beta-receptor stimulation in the older heart. One approach for examining whether diﬀerences in response to beta-receptor stimulation mediate age-associated changes in exercise hemodynamics is to have young and older persons perform vigorous exercise after acute beta-adrenergic blockade. In this setting, the age-associated diﬀerences in heart rate and LV contractility, EDVI, and early diastolic ﬁlling rate during maximal cycle exercise in BLSA subjects are attenuated or abolished (Fig. 11) [100]. Furthermore, the exercise hemodynamic proﬁle of unmedicated elderly individuals is strikingly similar to that of younger subjects who exercise in the presence of beta-adrenergic blockade. These observations support the hypothesis that the age-associated decline in heart rate and LV ejection performance and the concomitant LV dilation that all occur during maximal aerobic exercise in healthy, highly motivated

Figure 10 Cardiovascular responses to prolonged submaximal upright cycle exercise in healthy, carefully screened younger and older BLSA volunteers. When individuals exercise at a constant submaximal work rate (f50% of VO2max) for prolonged periods (i.e., 60 min or more) arterial pressure (A, B) and pulse pressure (PP)/stroke volume index (SVI) (C), an index of arterial stiffness, decline progressively over time and to a similar extent in younger and older persons. However, the concomitant reduction in LV end-systolic volume index (D) and increase in ejection fraction (E) and heart rate (F) in the young exceed those in the older group. The mechanism for the age-associated failure in the time-dependent improvement in the LV ejection during fraction prolonged submaximal exercise cannot be attributed to a failure of afterload reduction to occur with time, and thus other mechanisms appear to limit the acute LV systolic reserve in these healthy older persons. (Adapted from Ref. 98.)

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Figure 11 Scatterplots of heart rate (top) and end-diastolic volume index (bottom) at maximal effort during upright cycle exercise in healthy, carefully screened BLSA men, some of whom received 0.15 mg/kg of intravenous propranolol immediately prior to exercise. (Top) Maximal heart rate decreased significantly with age in both groups, but the slope of the decline was significantly steeper in men not receiving propranolol (controls). (Bottom) End-diastolic volume index increased with age in controls (r = 0.31; p < 0.01) but was not significantly age-related in men receiving propranolol. (From Ref. 100.)

volunteers rigorously screened to exclude occult cardiac disease are due to a reduction in the eﬃcacy of beta-adrenergic modulation of CV function. The major eﬀects of age on CV performance during exhaustive upright exercise are summarized in Table 3. Aerobic capacity declines with advancing age in individuals without cardiac disease. This can be attributed, in part, to a decrement in cardiac reserve and in part to peripheral factors (i.e., to an increase in body fat and a decrease in muscle mass with age). Although maximal heart rate is lower in healthy older versus younger individuals during exercise, maximal stroke volume is preserved across age via cardiac dilatation at end-diastole in older subjects. Thus, in health, older individuals do not exhibit a compromised EDV due to a ‘‘stiﬀ heart’’ during exercise. While the age-associated increase in EDV preserves SV during exercise in such individuals, the increase in ejection fraction is blunted due to a failure of the healthy older heart to empty as completely as its younger counterpart. This failure to reduce ESV results from a combination of augmented vascular afterload, reduced intrinsic myocardial contractility, and blunted augmentation

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Table 3 Changes in Maximal Aerobic Capacity and Its Determinants Between Ages 20 and 80 Years in Healthy Volunteers Oxygen consumption (A-V)O2 diﬀerence Cardiac index Heart rate Stroke volume Preload EDV Afterload vascular (SVR) cardiac (ESV) cardiac (EDV) Contractility Ejection fraction Plasma catecholamines Cardiac and vascular Responses to h-adrenergic stimulation

+ (50%) + (25%) + (25%) + (25%) no D * * * * * + + * +

(30%) (30%) (275%) (30%) (60%) (15%)

Abbreviations: A-V, arteriovenous; EDV, end-diastolic volume; ESV, end-systolic volume; SVR, systemic vascular resistance.

of contractility by beta-adrenergic stimulation. This same hemodynamic pattern occurring during exhaustive exercise in healthy older humans (i.e., a reduced exercise heart rate and greater cardiac dilatation at end-diastole and end-systole) occurs in individuals of any age who exercise after acute beta-adrenergic blockade. In fact, when perspectives from measurements that range from the stress response in intact humans to subcellular biochemistry in animal models are integrated, a diminished responsiveness to beta-adrenergic modulation is among the most notable changes that occur in the CV system with advancing age. Age-associated alterations in CV function that exceed the identiﬁed limits for healthy elderly individuals most likely represent interactions of aging per se with severe physical deconditioning and/or CV disease, both of which are highly prevalent among older adults. ELECTROCARDIOGRAPHY AND ARRHYTHMIAS Conduction System Aging is accompanied by multiple changes in the cardiac conduction system that aﬀect its electrical properties and, when exaggerated, cause clinical disease. A generalized increase in elastic and collagenous tissue commonly occurs. Fat accumulates around the sinoatrial node, sometimes creating partial or complete separation of the node from the atrial tissue. In extreme cases, this may contribute to development of sick sinus syndrome. A pronounced decline in the number of pacemaker cells generally occurs after age 60; by age 75, less than 10% remain of the number seen in young adults. There is observed a variable degree of calciﬁcation of the left side of the cardiac skeleton, which includes the aortic and mitral annuli, the central ﬁbrous body, and the summit of the interventricular system. Due to their proximity to these structures, the atrioventricular (A-V) node, A-V

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bifurcation, and proximal left and right bundle branches may be damaged or destroyed by this process, resulting in A-V or intraventricular block. ELECTROCARDIOGRAPHY Age-associated alterations in cardiac anatomy and electrophysiology often manifest themselves on the electrocardiogram (ECG). Because the resting ECG remains the most widely used cardiac diagnostic test, a review of these aging changes is relevant to distinguish them from those imposed by disease. Sinus Node Function Although supine resting heart rate is unrelated to age in most studies (Table 4; Fig. 12), the phasic variation in R–R interval known as respiratory sinus arrhythmia declines with age [101,102]. Similarly, a reduced prevalence of sinus bradycardia on resting ECG is evident by the fourth decade [101]. Because both sinus arrhythmia and sinus bradycardia are indices of cardiac parasympathetic activity, the age-associated reduction in parasympathetic function [102] may mediate both ﬁndings. Spectral analysis of heart rate variability has conﬁrmed an age-related reduction of high frequency (0.15–0.45 Hz) oscillations indicative of vagal eﬀerent activity (Fig. 12) [103,104]. Although physical conditioning status inﬂuences autonomic tone, a cross-sectional study in BLSA volunteers demonstrated that the deconditioning that usually accompanies the aging process plays only a minor role in the age-associated blunting of these high-frequency oscillation [104]. Patients with organic heart disease demonstrate a reduced respiratory sinus arrhythmia compared to age-matched normal individuals. A blunting of high-frequency oscillations in apparently healthy older volunteers is predictive of future coronary events [105] and total mortality [106]. Sinus bradycardia below 50 bpm was found in 4.1% of 1172 healthy, nonendurancetrained, unmedicated participants aged 40 and older from the BLSA; the prevalence was similar in men (3.9%) and women (4.5%) [107]. These subjects (mean age 58 years) with unexplained sinus bradycardia had a signiﬁcantly greater prevalence of associated conduction system abnormalities than nonbradycardic age- and sex-matched controls, but there was no diﬀerence in the incidence of future coronary events (angina pectoris, myocardial infarction, or cardiac death) over a 5.4-year mean follow-up period. Sinus bradycardia due to sick sinus syndrome is seen almost exclusively in the elderly and probably derives in part from the marked decline in the number of pacemaker cells in the

Table 4 Normal Age-Associated Changes in Resting ECG Measurements R–R interval P-wave duration P–R interval QRS duration QRS axis QRS voltage Q–T interval T-wave voltage

No change Minor increase Increase No change Leftward shift Decrease Minor increase Decrease

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Figure 12 Mean R–R interval (RRI) and respiratory sinus arrhythmia (RSA) during 3 min of sitting in healthy BLSA men (closed circles and dashed line) and women (open circles and solid line). Whereas RRI (top) was unrelated to age in either sex, RSA (bottom) declined similarly with age in women (r = 0.61; p < 0.001) and men (r = 0.59; p < 0.001). (From Ref. 104.)

sinoatrial node. In the absence of organic heart disease, such bradycardia is not associated with increased cardiac mortality [108]. P Waves The prevalence of left atrial abnormality, deﬁned by a negative P terminal force in lead V1 of at least 0.04 mm-s, increases with age, paralleling the echocardiographic increase in left atrial size. Among 588 institutionalized elderly, such a P terminal force was only 32% sensitive, although 94% speciﬁc, for echocardiographic left atrial enlargement [109]. A small increment in P-wave duration of about 8 ms from the third to seventh decades has been observed [110], presumably secondary to the modest increase in left atrial size. There does not appear to be any increase in ECG evidence of right atrial enlargement with age when individuals with signiﬁcant chronic obstructive lung disease are excluded. P–R Interval The P–R interval undergoes a slight, but signiﬁcant, age-related prolongation [111,112]. An increase in P–R interval from 159 to 175 ms in men and from 156 to 165 ms in women

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occurred between the ages of 30 and 72 years in BLSA volunteers [112]. By high-resolution signal-averaged surface ECGs, the prolongation of A-V conduction was localized proximal to the His bundle deﬂection, but within the P–R segment, presumably reﬂecting delay within the A-V junction [112]. In seven older men with ﬁrst-degree A-V block, there was a similarly located but more pronounced A-V junctional delay. To reﬂect the age-associated slowing of A-V conduction, a value of 0.22 s has been proposed for the upper limit of normal P–R interval in persons over 50 years of age [111]. Using the conventional upper limit of 0.20 s, the prevalence of ﬁrst-degree A-V block in healthy older men is usually 3 to 4%, a prevalence severalfold greater than in young men [111]. Both cross-sectional and longitudinal studies have generally found no correlation between ﬁrst-degree A-V block and cardiac disease [113] or mortality [114]. QRS Complex Whereas the QRS duration shows no signiﬁcant age relationship, the QRS axis shifts progressively leftward with age. Simonson observed a shift in the mean QRS axis from 62 to 36 degrees in normal persons between the third and sixth decades, with no gender diﬀerence [111]. The corresponding lower normal limits shifted from 3 to 28 degrees. The prevalence of left axis deviation <30 degrees therefore increases dramatically with age, with a prevalence of 20% by the tenth decade [115]. This leftward QRS axis shift may be largely due to the age-related increase in LV wall thickness [64,65]. Longitudinal studies have failed to demonstrate any increase in cardiac morbidity or mortality associated with this isolated ECG ﬁnding [116,117]. In patients with known organic heart disease, however, left or right bundle branch block (BBB) portends a worse cardiovascular prognosis if left axis deviation is present [118]. Both cross-sectional [119] and longitudinal [120] studies have demonstrated a decrease in R- and S-wave amplitudes with advancing age, evident by the fourth decade. At ﬁrst glance, this decrease in QRS amplitude seems paradoxical, given the age-related increase in LV thickness. However, the surface ECG is inﬂuenced by extracardiac as well as cardiac factors. By increasing the distance between the heart and the chest wall, senile kyphosis and pulmonary hyperinﬂation in older individuals may contribute to a decrease of QRS voltage. Despite the age-related decline in mean QRS amplitude, the prevalence of electrocardiographic LV hypertrophy (LVH) increases with age [121], probably secondary to the high prevalence of hypertension, CAD, and degenerative aortic valvular disease in the elderly. Echocardiographic studies have demonstrated that the standard ECG is quite insensitive, although very speciﬁc, for anatomical LVH in older populations [122]. In the Framingham study [121,122] and other older cohorts [123], ECG evidence of LVH was strongly related to the presence of hypertension and was a potent independent risk factor for future CV morbidity and mortality. Thus, the presence of ECG criteria for LVH in an older individual should normally trigger further diagnostic assessment, particularly echocardiography. Both left and right BBB increase in prevalence with age [124–126]; nevertheless, these conduction defects should not be attributed to aging per se. In older populations, left BBB occurs only about half as often as right BBB. In contrast to its right-sided counterpart, left BBB is uncommon in the absence of cardiovascular disease [127]. The prognosis of left BBB therefore reﬂects that of the underlying heart disease. Whereas left BBB portended a more ominous prognosis than right BBB in Framingham men, the two conduction defects had similar prognostic signiﬁcance in women [124,125]. Among 310 predominantly

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middle-aged individuals with BBB and no apparent heart disease, both left BBB and right BBB increased in prevalence with age, but neither was associated with increased total mortality over a 9.5-year mean follow-up [127]. A nonspeciﬁc intraventricular conduction defect exceeding 120 ms occurred in only 1.9% of Framingham participants aged 70 and older and, like left BBB, was strongly associated with clinical heart disease [128]. In the BLSA, complete right BBB was observed in 39 of 1142 men (3.4%) [129]. Among the 24 individuals (mean age 64 years) without evidence of heart disease and for whom follow-up information was available, the incidence of angina, nonfatal MI, heart failure, advanced heart block, or cardiac death did not diﬀer from those in age-matched controls over a mean observation period of 8.4 years. At long-term follow-up, maximal exercise capacity and maximal heart rate were similar to those of controls, although a higher prevalence of left axis deviation was found in the group with right BBB (46% vs. 15%, respectively) [129]. These ﬁndings suggest that right BBB in the absence of clinical heart disease is not rare in older men and reﬂects a primary abnormality of the cardiac conduction system. Women in the Framingham study demonstrated a lower prevalence of right BBB than men, but in women there was a stronger association of this conduction defect with cardiomegaly and congestive heart failure [124]. Q waves in two or more contiguous ECG leads are generally considered evidence of prior myocardial infarction. In older as in younger populations, such Q-waves are usually associated with clinical heart disease and increased cardiac mortality. Indeed, pathological Q-waves may serve as the initial clue to the presence of CAD. Prior studies have shown that 25 to 30% or more of acute infarctions are clinically silent [130–132]. The incidence of such ‘‘silent’’ infarctions increases strikingly with age. Aronow et al. [132] reported that 68% of infarctions were silent in a geriatric chronic care facility. Despite the absence of symptoms, these silent myocardial infarctions portend a long-term risk of mortality similar to their symptomatic counterparts. In the elderly, Q-waves not uncommonly occur in the absence of CAD. A QS complex in leads 3 and a VF may occasionally result from marked left axis deviation. A pattern of poor R-wave progression in leads V1 to V3 is a normal age trend, due to the decrease in the initial 20 ms anterior QRS vector with age [111]. Such a pattern may also result from obesity, chronic obstructive lung disease, and LVH, all of which are common in older populations. Repolarization Probably the most prevalent age-associated ECG ﬁndings are abnormalities involving the ST segment and T-wave. In one study of 671 persons aged 70 years and older, nonspeciﬁc ST-T changes were the most common ECG abnormalities, occurring in 16% of individuals [126]. In this sample and others, repolarization abnormalities were generally associated with clinical heart disease. Such an association may stem in part from the frequent use of digitalis and various antiarrhythmic drugs by elderly cardiac patients. Much of the reported increased risk attached to these nonspeciﬁc repolarization changes is undoubtedly due to the underlying heart disease that necessitated use of these cardiac medications. Even among clinically healthy older persons, however, minor ST-segment sagging or straightening is relatively common, although of questionable prognostic signiﬁcance. An age-associated decrease in the T-wave amplitude begins by the fourth decade [111, 119]. The spatial T-wave vector shifts leftward with age in concert with the leftward shift in ORS axis. Obesity magniﬁes these changes in the T-waves, especially in men [111]. The isolated presence of ﬂattened T-waves, particularly in lead aVL, does not portend

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increased CV risk, at least in middle-aged samples [133]. In contrast, deﬁnite T-wave inversion usually occurs in patients with organic heart disease and is associated with increased mortality. The heart rate-corrected Q–T interval increases by about 10 ms from the third to the sixth decade [134]. Table 4 summarizes those changes in resting ECG measurements thought to be secondary to normative aging.

ARRHYTHMIAS Atrial Arrhythmias An increase in the prevalence and complexity of both supraventricular and ventricular arrhythmias, whether detected by resting ECG, ambulatory monitoring, or exercise testing, is a hallmark of normal human aging. Isolated premature atrial ectopic beats (AEB) appear on the resting ECG in 5 to 10% of individuals older than 60 years and are not generally associated with heart disease. Isolated AEB were detected in 6% of healthy BLSA volunteers older than 60 years at rest, in 39% during exercise testing, and in 88% during ambulatory 24-h monitoring [135]. Such isolated AEB on ambulatory monitoring, even if frequent, were not predictive of increased cardiac risk in this sample over a 10-year mean follow-up period [136]. Atrial Fibrillation Approximately 3 to 4% of subjects over age 60 demonstrate atrial ﬁbrillation (AF), a rate tenfold higher than the general adult population [137,138]; the prevalence in octogenarians approaches 10% [139]. Chronic AF is most commonly due to CAD and hypertensive heart disease, mitral valvular disorders, thyrotoxicosis, and sick sinus syndrome. The association between hyperthyroidism and AF is observed almost exclusively in the elderly [140]; this arrhythmia may be the sole clinical manifestation of so-called ‘‘apathetic’’ hyperthyroidism in geriatric patients. In the Framingham population, AF without identiﬁable cause, socalled ‘‘lone’’ AF, represented 17% of men and 6% of women with AF, with mean ages of 70.6 and 68.1 years, respectively [141]. Individuals with lone AF suﬀered over four times as many strokes as those in sinus rhythm during long-term follow-up, although their rates of coronary events or congestive heart failure were not increased [141]. Atrial ﬂutter is a rare arrhythmia in any age group and is usually associated with organic heart disease. Paroxysmal Supraventricular Tachycardia Short bursts of paroxysmal supraventricular tachycardia (PSVT) on resting ECG are found in 1 to 2% of normal individuals older than 65 years. Twenty-four-hour ambulatory monitoring studies have demonstrated short runs of PSVT (usually 3 to 5 beats) in 13 to 50% of clinically healthy older persons [135,138]. Although the presence of nonsustained PSVT on ambulatory monitoring did not predict an increase in risk of a future coronary events in BLSA participants [136], 2 of 13 individuals with PSVT later developed de novo atrial ﬁbrillation, compared with only 1 of the 85 without PSVT. Exercise-induced PSVT has been observed in 3.5% of over 3000 maximal treadmill tests on apparently healthy BLSA volunteers [142]. The arrhythmia increased sharply with age, from 0% in the twenties to approximately 10% in the eighties (Fig. 13A); similar to PSVT on ambulatory ECG, the vast majority of these episodes were asymptomatic 3- to 5-beat salvos. Coronary

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Figure 13 Increased prevalence of exercise-induced cardiac arrhythmias with age during the initial maximal treadmill exercise test in BLSA volunteers free from clinical cardiac disease. The numbers above each bar represent the number of persons in each age decade by gender. (A) Prevalence of exercise-induced nonsustained supraventricular tachycardia (SVT) as a function of age and sex in 1383 apparently healthy individuals. The age-associated increase in SVT prevalence was more pronounced in men ( p < 0.001) than in women ( p = 0.09). (From Ref. 142.) (B) Prevalence of frequent or repetitive ventricular ectopic beats in 1160 clinically healthy volunteers. A highly significant increase in prevalence was observed in men but not in women. (From Ref. 154.)

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risk factors and ECG or thallium scintigraphic evidence of ischemia occurred with similar prevalence in the 85 volunteers with exercise-induced PSVT as in age- and sex-matched controls. Of importance, the group with PSVT experienced no increase in subsequent coronary events over a 5.5-year mean follow-up period. However, 10% of the individuals with PSVT later developed a spontaneous atrial tachyarrhythmia compared with only 2% of the control group, analogous to the results of the ambulatory 24-h ECG [142]. Ventricular Arrhythmias An exponential increase in the prevalence of ventricular ectopic beats (VEB) with advancing age has been found both in unselected populations and in those clinically free of heart disease. Pooled data from nearly 2500 ECGs from hospitalized patients older than 70 years revealed VEB in 8% [143]. Among apparently healthy BLSA volunteers with a normal ST-segment response to treadmill exercise, isolated VEB occurred at rest in 8.6% of men over age 60 compared to only 0.5% in those 20 to 40 years old [144]. Of note, the prevalence of resting VEB was not age-related in women. The prognostic signiﬁcance of VEB detected on the resting ECG in the general elderly population is controversial. Signiﬁcant increases in cardiac mortality among persons with VEB were observed in studies from Busselton [145] and Manitoba [146], with risk ratios of 3.3 and 2.4, respectively, compared with arrhythmia-free cohorts. The Framingham community, however, demonstrated no increase in the age-adjusted risk ratio for cardiac events [147]. Data from the MRFIT study suggest that the prognostic signiﬁcance of resting VEB may vary according to age; asymptomatic white men under 50 years with frequent or complex VEB on a 2-min resting rhythm strip suﬀered a 14-fold relative risk of sudden cardiac death, while in older men the risk was not signiﬁcantly increased [148]. Twenty-four-hour ambulatory ECG recordings have demonstrated the presence of VEB in 69 to 96% of asymptomatic elderly [136,138,149,150]. Not only the prevalence, but the density and complexity of VEB increase with age. In the Cardiovascular Health Study, VEB were found in 82% of 1372 subjects aged 65 and older, including 7% with short runs of nonsustained ventricular tachycardia (VT). The prevalence of all VEB forms was higher in men than women [138]. Among 50 individuals older than 80 years without clinical heart disease, VEB were observed in 96%, including multifocal VEB in 18%, couplets in 8%, and nonsustained VT in 2% [149]. In 106 predominantly healthy patients aged 75 and above, Camm et al. detected VEB in 69% [150]; VEB were multiform in 22%, paired in 4%, and occurred in short runs in 4%. Among 98 carefully screened asymptomatic BLSA participants older than 60 years, 35% had multiform VEB, 11% VEB couplets, and 4% short runs of VT on 24-h monitoring [135]. The prevalence of simple and complex VEB in all of these studies is much higher than in series of healthy younger volunteers. The prognostic importance of VEB detected on ambulatory monitoring, like those found on the resting ECG, is unclear. Over a 10-year mean follow-up period, 14 of the 98 older carefully screened BLSA participants who underwent ambulatory ECG developed coronary events. The prevalence and complexity of VEB were virtually identical in the group who experienced an event and the group who did not [136]. However, horizontal or slowly upsloping ST-segment depression on the ambulatory ECG predicted an increased risk of such events [136]. In the series of Camm et al. [151], 92% of the 5-year survivors who were initially free of VEB remained without VEB on the 5-year follow-up recording. In contrast to the BLSA results, an almost doubled crude mortality was found among individuals with z10 VEB/h versus those with fewer VEB. It should be pointed out that

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83% of the Camm et al. volunteers were taking medications, including several patients with known heart disease. Exercise testing elicits a striking increase in the prevalence and complexity of VEB with advancing age similar to that seen on the ambulatory ECG. In apparently healthy BLSA volunteers, isolated VEB during or after maximal treadmill exercise increased in prevalence from 11% to 57% between the third and ninth decade [144]. Although left ventricular mass index and peak exercise systolic blood pressure were higher in subjects who developed exercise-induced VEB than in those who did not, by multivariate analysis only older age independently predicted the appearance of VEB [152]. Asymptomatic exercise-induced runs of VT, all V6 beats in duration, were found in 4% of apparently healthy BLSA individuals aged 65 and older, a rate 25 times that of younger persons [153]. Over a mean follow-up of about 2 years, however, none of these older volunteers with nonsustained VT during exercise testing developed angina, myocardial infarction, syncope, or cardiac death. In a subsequent BLSA analysis, 80 of 1160 clinically healthy individuals developed frequent VEB (z10% of beats in any minute) or nonsustained VT during maximal treadmill exercise testing (an average of 2.4 tests per individual were performed [154]. These 80 individuals were older than those free of such arrhythmias (64 vs. 50 years). Interestingly, the striking age-associated increase in the prevalence of these complex exercise-induced VEB was observed only in men (Fig. 13B). The prevalence of coronary risk factors and exerciseinduced ischemia by ECG and thallium scanning did not diﬀer between the 80 cases and a group of 80 age- and sex-matched controls. Most important, the incidence of cardiac events (angina pectoris, nonfatal infarction, cardiac syncope, or cardiac death) was nearly identical in cases and controls over a mean follow-up of 5.6 years without antiarrhythmic drug therapy [154]. Thus, the available data available in older adults without apparent heart disease support a marked age-related increase in the prevalence and complexity of exerciserelated VEB, at least in men; however, even frequent or repetitive VEB induced by exercise do not appear to increase cardiac morbidity or mortality in such individuals. A factor of major importance in determining the prognostic signiﬁcance of VEB in the elderly is the milieu in which they occur. For example, among 467 patients aged 62 to 101 years in a long-term care facility, complex VEB occurred during ambulatory monitoring in 21% [155]. In the subset without clinical heart disease, future coronary events developed in an identical 4% of those individuals with or without complex VEB; among patients with CAD, however, such events developed in 46% with complex VEB but only 23% of patients without them. A similar doubling of risk was seen in patients with hypertension, valvular disease, or cardiomyopathy who demonstrated complex VEB. Table 5 summarizes the eﬀect of age on the prevalence of various cardiac arrhythmias and their relationship to mortality in apparently healthy older adult [156]. Table 5

Relationship of Arrhythmias to Age and Mortality

Arrhythmia Supraventricular ectopic beats Paroxysmal supraventricular tachycardia Atrial ﬁbrillation (chronic) Ventricular ectopic beats Ventricular tachycardia (short runs) a

In healthy elderly.

Eﬀect of age on prevalence

Eﬀect on mortalitya

Increased Increased Increased Increased Increased

None Probably none Increased Probably none Probably none

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In summary, aging is associated with multiple ECG changes in persons without evidence of CV disease. Such changes include a blunted respiratory sinus arrhythmia, a mild P–R interval prolongation, a leftward shift of the QRS axis, and increased prevalence, density, and complexity of ectopic beats, both atrial and ventricular. Other ﬁndings that become more prevalent with age, like increased QRS voltage, Q-waves and ST-T-wave abnormalities, are generally associated with increased CV risk. Abnormalities such as left BBB or AF are strongly predictive of future cardiac morbidity and mortality among older adults, even if asymptomatic. A guiding principle for the practitioner is that the prognosis associated with a given ECG abnormality in the elderly is more strongly related to the presence and severity of underlying CV disease than to the ECG ﬁnding itself.

ACKNOWLEDGMENTS The expert secretarial assistance of Christina Link and Mardel North is gratefully acknowledged.

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121. Kannel WB, Gordon T, Oﬀutt D. Left ventricular hypertrophy by electrocardiogram: prevalence, incidence and mortality in the Framingham study. Ann Intern Med 1969; 71:89– 105. 122. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Left ventricular mass and incidence of coronary heart disease in an elderly cohort. The Framingham Heart Study. Ann Intern Med 1989; 110:101–107. 123. Sunderstrom J, Lind L, Arnlov J, Zethelius B, Andren B, Lithell HO. Echocardiographic and electrocardiographic diagnoses of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men. Circulation 2001; 103:2346–2351. 124. Schneider JF, Thomas HE Jr, Kreger BE, McNamara PM, Sorlie P, Kannel WB. Newly acquired right bundle branch block: the Framingham study. Ann Intern Med 1980; 92:37–44. 125. Schneider JF, Thomas HE Jr, Kreger BE, McNamara PM, Kannel WB. Newly acquired left bundle branch block: the Framingham study. Ann Intern Med 1979; 90:303–310. 126. Mihalick MU, Fisch C. Electrocardiographic ﬁndings in the aged. Am Heart J 1974; 87:117– 128. 127. Fahy GJ, Pinski SL, Miller DP, McCabe N, Pye C, Walsh MJ, Robinson K. Natural history of isolated bundle branch block. Am J Cardiol 1996; 77:1185–1190. 128. Kreger BE, Anderson KM, Kannel WB. Prevalence of intraventricular block in the general population: the Framingham Study. Am Heart J 1989; 117:903–910. 129. Fleg JL, Das DN, Lakatta EG. Right bundle block: long-term prognosis in apparently healthy men. J Am Coll Cardiol 1983; 1:887–892. 130. Kannel WB, Abbott RD. Incidence and prognosis of unrecognized myocardial infarction. An update on the Framingham study. N Engl J Med 1984; 311:1144–1147. 131. Yano K, Mac Lean CJ. The incidence and prognosis of unrecognized myocardial infarction in the Honolulu Hawaii Heart Program. Arch Intern Med 1989; 149:1528–1532. 132. Aronow WS, Starling L, Etienne F, D’Alba P, Edwards M, Lee NH, Parungao RF. Unrecognized Q-wave myocardial infarction in patients older than 64 years in a long-term healthcare facility. Am J Cardiol 1985; 56:483. 133. Higgins ITT, Kannel WB, Dawber TR. The electrocardiogram in epidemiological studies. Reproducibility, validity and international comparison. Br J Prev Soc Med 1965; 19:53–68. 134. Simonson E, Cady L, Woodbury M. The normal Q-T interval. Am Heart J 1962; 63:747– 753. 135. Fleg JL, Kennedy HL. Cardiac arrhythmias in a healthy elderly population: detection by 24hour ambulatory electrocardiography. Chest 1982; 81:302–307. 136. Fleg JL, Kennedy HL. Long-term prognostic signiﬁcance of ambulatory electrocardiographic ﬁndings in apparently healthy subjects z60 years of age. Am J Cardiol 1992; 70:748–751. 137. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial ﬁbrillation. N Engl J Med 1982; 306:1018–1022. 138. Manolio TA, Furberg CD, Rautaharju PM, Siscovick D, Newman AB, Borhani NO, Gardin JM, Tabatznik B. Cardiac arrhythmias on 24-hour ambulatory electrocardiography in older women and men: The Cardiovascular Health Study. J Am Coll Cardiol 1994; 23:916–925. 139. Wolf PA, Benjamin EJ. Belanger Secular trends in the prevalence of atrial ﬁbrillation: The Framingham Study. Am Heart J 1996; 131:790–795. 140. Staﬀurth JS, Gibberd MC, Ng TF. Arterial embolism in thyrotoxicosis with atrial ﬁbrillation. Br Med J 1977; 2:688–690. 141. Brand FN, Abbott RD, Kannel WB, Wolf PA. Characteristics and prognosis of lone atrial ﬁbrillation. 30-year follow-up in the Framingham Study. JAMA 1985; 254:3449–3453. 142. Maurer MS, Shefrin EA, Fleg JL. Prevalence and prognostic signiﬁcance of exercise-induced supraventricular tachycardia in apparently healthy volunteers. Am J Cardiol 1995; 75:788– 792. 143. Fisch C. Electrocardiogram in the aged. An independent marker of heart disease? Am J Med 1981; 70:4–6.

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144. Fleg JL. Epidemiology of ventricular arrhythmias in the elderly. In: Paciaroni E, ed. Proceedings of the 13th National Congress of Cardiology (Aging and Cardiac Arrhythmias) I.N.R.C.A. Ancona, Italy: Istituto a Carattere Scientiﬁco, 1991:26–30. 145. Cullen KJ, Stenhouse NS, Wearne KL, Cumpston GN. Electrocardiograms and thirteen year cardiovascular mortality in Busselton study. Br Heart J 1982; 47:209–212. 146. Rabkin SW, Mathewson FAL, Tate RB. Relationship of ventricular ectopy in men without apparent heart disease to occurrence of ischemic heart disease and sudden death. Am Heart J 1981; 101:135–142. 147. Kannel WB, Doyle JT, McNamara PM, Quickenton P, Gordon T. Precursors of sudden death: Factors related to the incidence of sudden death. Circulation 1975; 57:606–613. 148. Abdalla ISH, Prineas RJ, Neaton JD, Jacobs DR, Crow RS. Relations between ventricular premature complexes and sudden cardiac death in apparently healthy men. Am J Cardiol 1987; 60:1036–1042. 149. Kantelip JP, Sage E, Duchene-Marullaz P. Findings on ambulatory electrocardiologic monitoring in subjects older than 80 years. Am J Cardiol 1986; 57:398–401. 150. Camm AJ, Evans KE, Ward DE, Martin A. The rhythm of the heart in active elderly subjects. Am Heart J 1980; 99:598–603. 151. Martin A, Benbow LJ, Butrous GS, Leach C, Camm AJ. Five-year follow-up of 106 elderly subjects by means of long-term ambulatory cardiac monitoring. Eur Heart J 1984; 5:592–596. 152. Mayuga R, Arrington CT, O’Connor FC, Fleg JL. Why do exercise-induced ventricular arrhythmias increase with age? Role of M-mode echocardiographic aging changes. J Gerontol Med Sci 1996; 51A:M23–M28. 153. Fleg JL, Lakatta EG. Prevalence and prognosis of exercise-induced nonsustained ventricular tachycardia in apparently healthy volunteers. Am J Cardiol 1984; 54:762–764. 154. Busby MJ, Shefrin EA, Fleg JL. Signiﬁcance of exercise-induced frequent or repetitive ventricular ectopic beats in apparently healthy volunteers. J Am Coll Cardiol 1989; 14:1659– 1665. 155. Aronow WS, Epstein S, Koenigsberg M, Schwartz KS. Usefulness of echocardiographic abnormal left ventricular ejection fraction, paroxysmal ventricular tachycardia, and complex ventricular arrhythmias in predicting new coronary events in patients over 62 years of age. Am J Cardiol 1988; 61:1349–1351. 156. Fleg JL. Arrhythmias and conduction disorders. In: Beers MH, Berkow R, eds. The Merck Manual of Geriatrics. 3rd ed. Whitehouse Station, NJ: Merck Research Laboratories, 2000: 885–900.

2 Echocardiographic Measurements in Elderly Patients Without Clinical Heart Disease Julius M. Gardin and Cheryl K. Nordstrom St. John Hospital and Medical Center, Detroit, Michigan, U.S.A.

INTRODUCTION The ability to image cardiac structures and to evaluate left ventricular function noninvasively has made echocardiography extremely useful in the evaluation of individuals with known or suspected heart disease. The noninvasive character of the ultrasound technique has made it particularly applicable to an older population [1,2]. The goals of this chapter are to (1) discuss the eﬀect of aging on left ventricular (LV) systolic and diastolic function by M-mode and Doppler echocardiography and (2) present normative M-mode and Doppler echocardiographic measurement data that can serve as a basis for evaluating cardiac structure and function in elderly individuals. In this chapter we present data derived from (1) Doppler measurements of aortic ﬂow velocity, used to evaluate LV systolic performance at rest and during exercise, and (2) transmitral ﬂow-velocity measurements, used to assess LV diastolic function at rest.

RELATIONSHIP OF AGE TO NORMAL M-MODE ECHOCARDIOGRAPHIC MEASUREMENTS To determine the relationship between age and M-mode echocardiographic measurements in normal subjects, we studied 136 adults (78 men and 58 women), 20 to 97 years of age, without evidence of cardiovascular disease [3]. These subjects all underwent history taking and physical examination, chest roentgenography, electrocardiography, and M-mode echocardiography. In no subject did this evaluation reveal the presence of heart disease, hypertension, other serious illness, or obesity. Furthermore, all subjects had a normal electrocardiogram (ECG), normal chest ﬁlm, and no evidence of mitral valve prolapse or pericardial eﬀusion on M-mode echocardiogram. M-mode echocardiography was performed in the left lateral decubitus position, and the following measurements were made: LV internal dimensions at end-diastole (LVIDd) and end-systole (LVIDs); ventricular septal (VSd) and posterobasal LV free-wall thickness 43

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(LVPWd) at end diastole; aortic root and left atrial dimensions; and mitral valve E–F slope, which corresponds to the rate of early diastolic closure of the anterior mitral valve leaﬂet (see Fig. 1). In addition, LV mass, ejection fraction, and fractional shortening were derived from the following formulas [4]: LV mass ¼ ð1:05ÞðLVIDd þ VSd þ LVPWd Þ3 ðLVIDd Þ3 LV ejection fraction ¼

ðLVIDd Þ3 ðLVIDs Þ3 ðLVIDd Þ3

100

ð1Þ ð2Þ

Figure 1 Echocardiographic recording of the left ventricle indicating measurements of parameters of left ventricular muscle mass and percentage fractional shortening. VSD = interventricular septal thickness measured during diastole, VSS = ventricular septal thickness measured during systole, LVWTD = left ventricle posterior wall thickness measured during diastole, LVWTS = left ventricular posterior wall thickness measured during systole, LVTDD = left ventricular transverse dimension measured during diastole, LVTDS = left ventricular transverse dimension measured during systole. (Reprinted from Drayer J, Gardin JM, Weber MA, Aronow WS. Changes in cardiac anatomy and function during therapy with alpha-methyldopa: An echocardiographic study. Curr Ther Res 1982; 32:856–865, with permission.)

Echocardiographic Measurements

LV % fractional shortening ¼

45

ðLVIDd Þ ðLVIDs Þ 100% ðLVIDd Þ

ð3Þ

In the absence of localized disorders of LV function like those that may be present in coronary artery disease, M-mode echocardiographic estimates have been reported to correlate well with two-dimensional echocardiographic and angiographic measurements of LV volume and ejection fraction [4]. Also, under these conditions, LV percentage fractional shortening gives information similar to that obtained from LV ejection fraction. Although ejection fraction does not perfectly characterize the functional state of the left ventricle, this measurement is accepted as providing an overall assessment of pump performance. Furthermore, ejection fraction is thought to be a more sensitive measurement of myocardial contractile state than either cardiac output or LV end-diastolic pressure. Echocardiographic measurements were analyzed for the inﬂuence of age, sex, and body surface area. When the data for each echocardiographic parameter were analyzed separately for men and women as a function of body surface area, statistically signiﬁcant diﬀerences between men and women were found for three parameters: (1) ventricular septal thickness; (2) posterobasal free-wall thickness; and (3) estimated LV mass. However, since the sex diﬀerences for these three parameters were relatively small (range 6.2 to 7.2%), we chose for the sake of simplicity to combine data for men and women in our calculation of regression equations and prediction intervals [3,5,6]. When patients were subdivided into six age groups, progressive changes were found in mean normal values for various M-mode echocardiographic parameters (Fig. 2). Specifically, when the older group (over 70 years) was compared with the youngest group (21–30

Figure 2 Percentage change in M-mode echocardiographic measurements in the five older age groups compared with the 21–30 year age group. Data are displayed for aortic root dimension (AO), left atrial dimension (LA), LV posterobasal free-wall thickness in diastole (LVWT), LV ejection fraction (EJ FRACT), left ventricle internal dimension in diastole (LVIDd), and mitral E–F SLOPE.

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years), signiﬁcant ( p < 0.01) increases in aortic root (22%) and left atrial (16%) dimensions, ventricular septal (20%) and LV free-wall (18%) thicknesses, and estimated LV mass (15%) were noted [3,5,6]. In addition, a signiﬁcant ( p < 0.01) decrease in mean mitral E–F slope (43%) and slight decreases in mean LV systolic and diastolic internal dimensions (5 and 6%, respectively; p < 0.05) were noted. LV ejection fraction and percentage fractional shortening were found to be independent of age. These data were used to derive regression equations related to both age and body surface area (BSA). The regression equations can be used to calculate mean normal values and 95% prediction intervals for echocardiographic measurements in adults. We analyzed our data according to the general regression equation, Echo parameter ¼ BðBSAÞ þ A F C; where A represents the intercept, B represents a slope unique for each parameter, and C represents the width of the 95% prediction interval; that is, the interval into which, with 95% conﬁdence, a new normal observation would fall [3]. When subjects were grouped into six age groups, the slope of the regression relationship was found to be independent of age for every parameter ( p > 0.05), whereas the intercept showed signiﬁcant variation with age for every parameter ( p < 0.05). Therefore, we assumed that the intercept A, but not the slope B, was inﬂuenced by age and that the width of the 95% prediction interval C was constant and not appreciably inﬂuenced by age or BSA. The values of A derived from our data for each age group are give in Table 1, which also includes the values of B and C for each parameter [3]. Figures 3 through 7 depict the relationships between age and aortic root dimension, left atrial dimension, LV diastolic and systolic dimension, LV posterior wall thickness, and LV mass. For each ﬁgure, the regression equations in Table 1 have been utilized to adjust the values to three common body surface area values (1.4, 1.8, and 2.2 m2) [3]. Our echocardiographic ﬁndings are compatible with information derived from previous studies using other methods. Roberts and Perloﬀ noted that hearts of older individuals studied at necropsy appear to have small ventricular chambers and thicker walls than those of their younger counterparts [7]. Although the magnitude of the decrease was small, we also noted that the internal dimensions of the LV decreased as age increased. We also noted progressive increases in the thickness of the ventricular septum and the LV free wall with increasing age. The magnitudes and rates of increase were similar for septum and free wall, so that there was no change in the septum–free-wall ratio with increasing age. Estimated LV mass showed a small, but progressive, increase from the 21 to 30 age group to the over-70 age group. This increase reﬂected an increase in wall thickness that was relatively greater than the decrease in LV diastolic dimension. Since the mean systolic and diastolic blood pressures varied by less than 15 mmHg among the six age groups, we could not ascribe the increased wall thickness or mass observed in our subjects to a change in basal arterial blood pressure with aging. Krovetz reviewed a number of published reports of measurements of aortic valve annulus size made at necropsy [8]. When aortic annulus size was corrected for body surface area, progressive increases with age were noted in both men and women over 20 years of age. We noted similar increases in aortic root dimensions as measured by echocardiography, a ﬁnding conﬁrmed by Demir and Acarturk [9]. These workers found that men had greater aortic root dimensions than women ( p < 0.001). Interestingly, they also noted correlations of aortic root dimension with LV mass in both men and women, but no correlation with LV internal dimensions or ejection fraction.

36.2 22.6 5.47 6.02 1.98 13.1 16.7 90.2

31–40 34.4 21.5 6.27 6.94 8.56 14.7 17.6 78.3

41–50 34.1 21.1 6.53 6.97 10.8 15.6 18.0 66.6

51–60 34.8 21.7 6.84 7.34 26.8 16.4 19.3 62.2

61–70

Intercepts (age dependent)

32.7 20.8 7.20 7.81 22.2 18.5 21.7 43.5

z70

F5.60 F5.81 F1.75 F1.43 F57.6 F5.76 F7.01 F62.2

Prediction interval

Abbreviations: Ao = aortic root dimension; BSA = body surface area; LA = left atrial dimension; LVID = left ventricular internal dimension; d = diastolic; s = systolic. Source: Reprinted from Ref. 3, with permission.

+ + + + + + + +

35.5 22.4 5.27 6.11 9.87 12.3 16.3 99.9

(BSA) (BSA) (BSA) (BSA) (BSA) (BSA) (BSA) (BSA)

LVIDd LVIDs Septum LVPW LV mass Ao LA E-F slope

= 6.94 = 4.24 = 2.53 = 2.18 = 124 = 8.31 = 9.98 = 20.1

21–30

Equation

Table 1 Regression Equations of Echocardiography Measurements Versus Age

Echocardiographic Measurements 47

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Figure 3 Aortic root dimension in late diastole is plotted in millimeters versus age in years. In Figures 3 through 7, the mean value for each age group is depicted by a circle plotted at the mean age in the age group. The bracketed and shaded area on either side of the circle represents the 95% prediction interval for normal values for a subject with a BSA of 1.8 m2. The 95% prediction intervals are also shown for subjects with BSA values of 1.4 m2 (dotted lines) and 2.2 m2 (solid lines). (Reprinted from Ref. 3. Copyright 1979 John Wiley & Sons, Inc., with permission.)

Figure 4 Left atrial dimensions in late diastole in millimeters versus age in years. For each age group, the mean and 95% prediction interval for normal values are depicted. (Reprinted from Ref. 3. Copyright 1979 John Wiley & Sons, Inc., with permission.)

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49

Figure 5 Left ventricular end-diastolic and end-systolic dimensions in millimeters versus age in years. For each age group, the mean and 95% prediction interval for normal values are depicted. (Reprinted from Ref. 3. Copyright 1979 John Wiley & Sons, Inc., with permission.)

Figure 6 Left ventricular posterior wall thickness in late diastole in millimeters versus age in years. For each age group, the mean and 95% prediction interval for normal values are depicted. (Reprinted from Ref. 3. Copyright 1979 John Wiley & Sons, Inc., with permission.)

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Figure 7 Estimated left ventricular mass in grams versus age in years. The mean and 95% prediction interval are depicted for each age group. (Reprinted from Ref. 6, with permission.)

The progressive increase in left atrial dimension with increasing age noted in our normal adult subjects was previously noted by Roberts and Perloﬀ at necropsy [7]. It is important to take this age-related change into account when using echocardiographic measurements of left atrial dimension to make quantitative statements about the eﬀects of various disease states (e.g., hypertension or valvular or coronary disease). Various investigators have reported functional changes with age in the mitral valve echocardiogram consistent with our ﬁndings of decreased E–F slope (10). Factors postulated to explain this decrease in the rate of early diastolic closure of the anterior mitral valve leaﬂet have included sclerosis of the mitral leaﬂets and/or decreased compliance of the left ventricle [10]. In our studies, LV ejection fraction and percentage fractional shortening did not change appreciably as age increased from 20 to 97 years. These ﬁndings are consistent with several previous studies [11,12], including one in which LV function was assessed with radionuclide cineangiography (11). If the LV internal dimension at end diastole is mildly reduced in older subjects, while ejection fraction and heart rate are unchanged, stroke volume and cardiac output are expected to diminish slightly with advancing age. Data indicating that this is so have been reported using a dye-dilution technique [13,14]. Our ﬁndings relating changes in echocardiographic parameters to increasing age are generally in agreement with ﬁndings reported by Gerstenblith, et al. [15]. The major diﬀerence is that we found a slight, but signiﬁcant, decrease in LV systolic and diastolic internal dimensions with increasing age, whereas Gerstenblith and associates found no change. Furthermore, women were not included in their study population, nor did they report measurements of left atrial dimension or LV mass. More recently, Shub, et al. found LV mass to

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51

be associated with increasing age among women, but not among men [16]. This may have been due to increasing body mass index with age among women only. Findings from the Framingham Heart Study showed that age, height, systolic blood pressure, and body mass index were signiﬁcant independent predictors of LV mass in 2226 men and 2746 women aged 17 to 90 years [17]. However, when persons with (1) evidence of cardiopulmonary disease by history, physical examination, electrocardiogram, chest x-ray, or echocardiogram; (2) systemic arterial blood pressure at least 140/90 mmHg at the time of echocardiography; (3) use of prescription medications for cardiopulmonary disease; and (4) body weight z 20% above or below the midpoint of recommended weight for height were excluded from the analyses, age was no longer a signiﬁcant correlate of LV mass/ height among 345 men and 517 women aged 20 to 79 years [18]. These disparate ﬁndings suggest that increases in LV mass associated with age are likely confounded by risk factors that are associated with age, speciﬁcally obesity, hypertension, and clinically manifest cardiopulmonary disease. Although it is highly likely that these echocardiographic changes reported in the diﬀerent age groups are related to the aging process, one cannot be certain that this explanation is correct until these changes are documented during serial studies in the same patient. Nonetheless, this analysis makes it clear that it is important to use normal echocardiographic values corrected for both age and body surface area (or another measure of body size) when evaluating adult patients suspected of having heart disease.

RELATIONSHIP OF AGE TO LEFT VENTRICULAR SYSTOLIC PERFORMANCE AS MEASURED BY DOPPLER AORTIC FLOW VELOCITY PARAMETERS Doppler ﬂow velocity measurements in the aorta have been shown to be useful in diﬀerentiating normal subjects from those with LV dysfunction [19,20]. For example, patients with dilated cardiomyopathy demonstrate aortic peak ﬂow velocity, ﬂow-velocity integral, and average acceleration that are markedly reduced compared with those in normal subjects (Fig. 8) [19]. Furthermore, in patients with congestive heart failure undergoing vasodilator therapy, changes in Doppler aortic peak ﬂow velocity and ﬂow-velocity integral have been shown to be useful in estimating changes in systemic vascular resistance and stroke volume, respectively [20]. We evaluated the relationship between age and Doppler aortic ﬂow-velocity measurements in 97 adults (45 men and 52 women, aged 21–78 years) without clinical evidence of cardiac disease [21]. No subject had a history of hypertension or cardiovascular disease, and all had a normal cardiac examination, electrocardiogram, chest x-ray, and M-mode and two-dimensional echocardiogram. Figure 8 demonstrates an aortic ﬂow-velocity recording from a normal subject [21,22]. Peak ﬂow velocity was measured in centimeters per second at the midpoint of the darkest area of the spectrum at the time of maximum ﬂow velocity. Ejection time (ET) was measured in milliseconds from the onset of the systolic ﬂow-velocity curve to the time the curve crossed the zero-ﬂow line at end systole. Aortic ﬂow-velocity integral (centimeters), which represents the area under the ﬂow-velocity curve, was estimated by the following formula: ﬂow-velocity integral = 0.5 peak ﬂow velocity ET [20]. Multiple linear regression analysis revealed that age was signiﬁcantly correlated with aortic peak ﬂow velocity, average acceleration, and ﬂow-velocity integral (all p < 0.001)

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Figure 8 Doppler aortic and pulmonary flow velocity recording from a normal subject. Measurements made included peak flow velocity (PFV) in cm/s; ejection time (ET) in ms; acceleration time (AT), in ms; and average acceleration in cm/s2 (calculated by dividing PFV by AT). In addition, the aortic flow velocity integral, or area under the flow velocity curve in cm, was estimated. (See text for details.) (Reprinted with permission from Ref. 17.)

(22). Figure 9 depicts the relationship between aortic peak ﬂow velocity and age. The two parameters were related by the following regression equation: aortic peak ﬂow velocity = 0.6 (age) + 110 (r = 0.54; p = 0.001). Aortic peak ﬂow velocity was signiﬁcantly lower in the 61- to 70-year age decade (mean F SD = 93 F 11 cm/s) [22]. The correlation of aortic peak ﬂow velocity with age remained signiﬁcant ( p < 0.001) after division of peak ﬂow velocity by the square root of the R–R interval. More recently, Turkish investigators have also noted that aortic blood ﬂow velocity was related to age ( p < 0.001) in both men and women [9]. Figure 10 depicts the relationship between aortic ﬂow-velocity integral and age. Note the signiﬁcantly lower ( p < 0.001) aortic ﬂow-velocity integral in the 61- to 70-year age decade (mean F SD = 9.5 F 2.3 cm) compared with the 21- to 30-year age decade (13.8 F 2.1 cm). Aortic ﬂow-velocity integral and age are related by the following regression equation: aortic ﬂow-velocity integral = 0.09 (age) + 16.5 (r = 0.44; p < 0.001) [22]. This correlation with age remained signiﬁcant ( p < 0.01) after correction of aortic ﬂow-velocity integral for the square root of the R–R interval. The decrease in aortic peak ﬂow velocity and ﬂow-velocity integral noted with increasing age are probably due, at least in part, to the increases in aortic root diameter noted with aging (3,5,8,15). It was previously shown that resting stroke volume (3,5) and cardiac output [23] do not change signiﬁcantly with aging. Since Doppler stroke volume

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53

Figure 9 Relationship between aortic peak flow velocity (cm/s) and age (years) in 80 subjects. The solid line represents the line of regression. Note the negative slope of the relationship between the two parameters (r = 0.54). Aortic PFV is significantly lower in the 60- to 70-year age group than in the 21–30 year age group ( p < 0.001). (Reprinted with permission from Ref. 18.)

Figure 10 Relationship between aortic flow velocity integral (cm) and age (years). Note the significantly lower flow velocity integral in the 61- to 70-year age group than in the 21- to 30-year age group ( p < 0.001). (Reprinted with permission from Ref. 18.)

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can be estimated by multiplying the aortic ﬂow-velocity integral by the aortic root area, it follows that a decrease in ﬂow-velocity integral must be accompanied by an increase in aortic root area (and diameter) to maintain a constant stroke volume. Furthermore, since aortic ﬂow-velocity integral is approximately equal to 1/2 peak ﬂow velocity ejection time [20], and since we did not ﬁnd any changes in aortic ejection time with aging in this study, it follows that aortic peak ﬂow velocity is expected to decrease with aging. There were no signiﬁcant diﬀerences in Doppler aortic ﬂow-velocity measurements between men and women of the same age. Furthermore, there was no signiﬁcant relationship between body surface area or blood pressure and any of the aortic ﬂow-velocity parameters in this group of normal subjects [22].

RELATIONSHIP OF AGE TO LEFT VENTRICULAR SYSTOLIC PERFORMANCE WITH UPRIGHT EXERCISE AS MEASURED BY DOPPLER AORTIC FLOW-VELOCITY RECORDING DURING TREADMILL TESTING To evaluate the eﬀect of upright exercise on aortic peak ﬂow velocity and acceleration, 60 normal subjects, aged 15 to 74 years, were evaluated by continuous-wave Doppler during treadmill stress testing using the Bruce protocol (24). Subjects were divided into three age groups, each with 20 subjects: group I, 21 F 4 years of age (mean F standard deviation); group II, 36 F 5 years; and group III, 58 F 7 years. Periodic measurements of heart rate,

Figure 11 Doppler peak aortic blood flow velocity measurements before, during, and immediately after exercise. Su = supine, St = standing, PO = immediate postexercise, P5 = 5 min after exercise. Data are shown as the mean for 20 subjects in each of the three groups, except as noted by n value in exercise stages III and IV. (Reprinted with permission from Ref. 20.)

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55

blood pressure, and Doppler blood ﬂow velocity and acceleration were made before, during, and after exercise. Continuous-wave Doppler measurements were recorded from the suprasternal notch. The relationship between Doppler aortic measurements and age, gender, heart rate, and blood pressure responses during exercise were evaluated. Age alone was signiﬁcantly related (inversely) to immediate postexercise Doppler aortic peak blood ﬂow velocity (group I, 1.1 F 0.2; group II, 1.0 F 0.2; and group III, 0.8 F 0.2 m/s, respectively; p < 0.01) and peak acceleration (group I, 55 F 15; group II, 46 F 11; and group III, 36 F 9 m/s2; p < 0.05) (Figs. 11,12). Gender, heart rate, and blood pressure changes during exercise, as well as exercise preconditioning, had no signiﬁcant eﬀect on these aortic ﬂow characteristics. These ﬁndings suggest that age is an important factor inﬂuencing aortic peak blood ﬂow velocity and acceleration with exercise, as well as at rest. These changes in peak velocity and acceleration with exercise may reﬂect, in part, changes in exercise LV function with age. Earlier studies [25–27] showed close correlations between these ﬂow parameters and muscle contractility. However, alterations in aortic conﬁguration, size, and compliance, as well as in impedance (afterload), probably aﬀect these Doppler parameters to an important degree. Importantly, these age-dependent changes must be kept in mind when using Dopplerdetermined peak velocity and acceleration in evaluating LV performance.

Figure 12 Doppler peak acceleration measurements before, during, and immediately after exercise. Abbreviations and data display are as in Figure 14. (Reprinted with permission from Ref. 20.)

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RELATIONSHIP OF AGE TO LEFT VENTRICULAR DIASTOLIC FUNCTION AT REST AS EVALUATED BY DOPPLER TRANSMITRAL FLOW-VELOCITY MEASUREMENTS Although LV systolic function is generally maintained with aging in healthy subjects [23], alterations in diastolic function are known to occur with ‘‘normal’’ aging [28,29]. We evaluated the relationship between age and pulsed Doppler transmitral ﬂow-velocity measurements in 66 adult men and women, aged 21 to 78 years, without a history of hypertension or cardiovascular disease [29]. Measurements of early and late diastolic transmitral peak ﬂow (ﬁlling) velocities, ﬂow times, and ﬂow-velocity integrals, and early diastolic ﬂow acceleration and deceleration were made at the level of the mitral leaﬂet tips. As shown in Figure 13, transmitral peak ﬂow velocities in centimeters per second were measured in early and late diastole (i.e., at the time of atrial systole) at the midpoint of the darkest portion of the spectrum at the time of peak ﬂow velocity. Diﬀerences in Doppler transmitral ﬂow-velocity patterns between 30-year-old and 63-year-old normal adults are depicted in Figure 14 [29]. Mitral peak ﬂow velocity in early diastole (PFVE) was signiﬁcantly lower ( p < 0.01) in the 61- to 70-year age decade (45 F 10 cm/s) than in the 21- to 30-year age decade (66 F 11 cm/s) (Fig. 15). Mitral peak ﬂow velocity in late diastole (PFVA) was signiﬁcantly higher ( p < 0.05) in the 61- to 70-year age decade (55 F 11 cm/s) than in the 21- to 30-year age group (41 F 7 cm/s) (Fig 16). Mitral A/E ratio (i.e., PFVA/PFVE) was signiﬁcantly higher ( p < 0.01) in the oldest (1.2 F 0.3) compared to the youngest (0.6 F 0.1) age group (Fig. 17). Early diastolic ﬂow time increased with age (r = 0.36; p < 0.001), whereas early diastolic deceleration decreased with age (r = 0.59; p < 0.001). The combination of a diminished early diastolic peak ﬂow velocity divided by a prolonged deceleration time resulted in a signiﬁcant ( p < 0.001) decrease in the rate of early diastolic deceleration with increasing age. The results of this study demonstrated that aging is associated with progressive decreases in early diastolic transmitral peak ﬂow velocity and early diastolic deceleration and progressive increases in late diastolic transmitral peak ﬂow velocity and the ratio of lateto-early diastolic peak ﬂow velocity. The ﬁndings are similar to those reported by Miyatake and associates [28]. Evidence that the decrease in early diastolic transmitral peak ﬂow velocity is related to impaired early diastolic LV ﬁlling has been provided by a number of studies. Dabestani et al. [30] showed in 10 patients who underwent both Doppler mitral ﬂow-velocity recording and videoensitometric analysis of LV ﬁlling from digital subtraction left ventriculograms that the percentage of total ﬁlling completed by mid-diastole was directly related to the early diastolic peak ﬂow velocity measured by Doppler. These ﬁndings suggest that Doppler measurements of peak ﬂow velocity in early diastole are related to the rate of ventricular ﬁlling. Rokey et al. [31] also reported a signiﬁcant correlation between early diastolic transmitral peak ﬂow velocity and angiographic peak ﬁlling rate (r = 0.64). They noted even better correlations between Doppler echocardiographic and angiographic peak ﬁlling rates (r = 0.87). Miyatake et al. [28] postulated that the increase in late diastolic peak transmitral ﬂow velocity with aging reﬂects an augmentation of ventricular ﬁlling by atrial contraction that compensates for decreased early diastolic ventricular ﬁlling. Our study demonstrated not only age-related increases in late diastolic peak ﬂow velocity, but also in late diastolic ﬂow time and ﬂow velocity integral [29]. These ﬁndings are further evidence for an age-related increase in the contribution of atrial systole to ventricular ﬁlling.

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Figure 13 Normal flow velocity recording at the level of the mitral valve from the apical fourchamber view depicting the method for making Doppler measurements. Mitral peak flow velocity in early diastole (PFVE) and in late diastole (PFVA) were measured (cm/s) at the midpoint of the darkest portion of the spectrum at the time of the maximal flow velocity in early and late diastole, respectively. Early diastolic flow time (EDFT), late diastolic flow time (ADFT), and early diastolic deceleration time (EFDFT) were measured as noted. (Reprinted from Ref. 25, with permission.)

It may be that the position of the sample volume (tips of the leaﬂets or at the annulus) aﬀects the relationship between age and diastolic function. Mantero et al. showed the Ewave peak velocity at the mitral annulus was more strongly correlated with age than at the tips of the mitral leaﬂets among 288 normal subjects aged 20 to 80 years [32]. However, Awave peak velocity at the leaﬂet tips was more strongly related to age than at the annulus. Similar results were found for the partial integrals of the E- and A-waves. We have pre-

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Figure 14 Doppler mitral valve flow velocity recordings from a younger normal subject, age 30 (left), and from an older normal subject, age 63 (right). Note that the peak flow velocity at early diastole in the older subject is lower and the late diastolic peak flow velocity is higher than in the younger normal subject. (Reprinted from Ref. 25, with permission.)

Figure 15 Data for mitral peak flow velocity in early diastole, PFV(E) (cm/s) is displayed on the vertical axis versus age in years on the horizontal axis (n = 66). Note the negative slope of the regression equation mitral, PFVE = 0.52 (age) + 79. The correlation coefficient r = 0.55. (Reprinted from Ref. 25, with permission.)

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Figure 16 Data for mitral flow velocity in late diastole, PFV(A) (cm/s) is displayed versus age in years (n = 66). Note the positive slope of the relationship, mitral PFVA = 0.39 (age) + 27. (Reprinted from Ref. 25, with permission.)

viously shown that both peak E- and A-wave velocities were signiﬁcantly higher (by about 20%) when measured at the leaﬂet tips than at the annulus [33]. It is now well-established that pulsed Doppler recordings of pulmonary venous ﬂow patterns can be very useful in evaluating LV diastolic function and in classifying LV diastolic dysfunction into stages (e.g., abnormal relaxation, ‘‘pseudonormal,’’ and ‘‘restrictive ﬁlling,’’ or decreased compliance). However, in using pulmonary venous ﬂow patterns, it is important to appreciate that these ﬂow patterns may also be dependent on age in healthy subjects (Fig. 18) [34]. Gentile, et al. reported signiﬁcant correlations between age and peak systolic ﬂow velocity (r = 0.5; p < 0.001) and its integral (r = 0.5; p < 0.001), peak diastolic ﬂow velocity (r = 0.6; p < 0.001) and its integral (r = 0.44; p < 0.001), but not the atrial reversal wave (r = 0.1; p > 0.05) among 143 normal subjects aged 20 to 80 [35]. Among 85 of 117 healthy volunteers with adequate tracings, Klein et al. found that those aged 50 years and older had increased pulmonary venous peak systolic ﬂow velocity (71 F 9 vs. 48 F 9 cm/s; p < 0.01), decreased diastolic ﬂow velocity (38 F 9 vs. 50 F 10 cm/s; p < 0.01), and increased peak atrial reversal ﬂow velocity (23 F 4 vs. 19 F 4 cm/s; p < 0.01) compared with those younger than 50 years (36). Klein et al. later reported the diﬀerence in duration of pulmonary venous atrial reversal ﬂow and transmitral A-wave ﬂow, previously related to LV end-diastolic pressures among patients with heart disease [37], to be unrelated to aging in 72 healthy volunteers aged 23 to 84 years (r = 0.16) [38].

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Figure 17 Data for mitral A/E ratio is depicted versus age in years. Note the positive slope of the relationship, mitral A/E ratio = 0.016 (age) + 0.13. (Reprinted from Ref. 25, with permission.)

EPIDEMIOLOGICAL STUDIES IN THE ELDERLY The Framingham study has shown by M-mode echocardiography that (1) LV hypertrophy is a powerful, independent predictor for mortality and morbidity from coronary heart disease, and (2) increased left atrial dimension is associated with an increased risk of stroke [39–41]. However, no previous multicenter population-based study has evaluated speciﬁcally in the elderly predictive value for coronary heart disease and stroke of echocardiographic imaging and Doppler techniques.

Figure 18

Natural history of LV filling. (Reprinted from Ref. 34, with permission.)

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The Cardiovascular Health Study (CHS) is a multiyear prospective epidemiological study of 5201 men and women older than 65 years recruited from four U.S. ﬁeld centers: Davis, California; Hagerstown, Maryland; Winston-Salem, North Carolina; and Pittsburgh, Pennsylvania [42]. The main objectives of incorporating echocardiography were to determine whether echocardiographic measurements, or changes in these measurements, are (1) correlated with traditional risk factors for coronary heart disease and stroke and (2) independent predictors of morbidity and mortality from coronary heart disease and stroke. Echocardiographic measurements obtained include those related to global and segmental LV systolic and diastolic structure and function and left atrial and aortic root dimension [43]. For each subject, a baseline two-dimensional (2-D), M-mode (2-D directed), and Doppler echocardiogram was recorded on super-VHS tape using a standard protocol and equipment. All studies were sent to a reading center (University of California, Irvine), where images were digitized and measurements made using customized computer algorithms. M-mode measurements were made according to American Society of Echocardiography convention [44]. LV mass was derived from the formula described by Devereux et al. LV mass ðgÞ ¼ 0:80 1:04½ðVSTd þ LVIDd þ PWTdÞ3 ðLVIDdÞ3 þ 0:6; where VSTd is ventricular septal thickness at end-diastole, LVIDd is LV internal dimension at end-diastole, and PWTd is LV posterior wall thickness at end-diastole [45]. Calculated data and images were stored on optical disks to facilitate retrieval and future comparisons in longitudinal studies. Quality-control measures included standardized training of echocardiography technicians and readers, technician observation by a trained echocardiographer, periodic blind duplicate readings with reader review sessions, phantom studies, and quality-control audits (43).

Left Ventricular Mass A number of initial cross-sectional associations with baseline echocardiographic data have been described in the Cardiovascular Health Study. M-mode measurements (2-D directed) of LV mass could not be made in 34% of CHS participants, and this was highly related to age (29% in the 65- to 69-year vs. 50% in the 85+ age group; p < 0.001), white race, male gender, and history of hypertension, diabetes, or CHD. LV mass was found to be signiﬁcantly higher in men than women, even after multivariate adjustments, and modestly increased with aging [46,47]. LV mass increased less than 1 g per year increase in age for both men and women. Of interest, across all CHS age subgroups, the diﬀerence in weightadjusted LV mass by sex was greater in magnitude than the diﬀerence related to clinical CHD (Fig. 19). This may relate to the well-known relatively high prevalence of subclinical manifestations of cardiac disease (e.g., coronary disease) in elderly individuals without clinical disease. After adjustment for traditional CVD risk factors, baseline LV mass was also related to 6- to 7-year incidence of CHD, CHF, and stroke among CHS participants initially free of prevalent disease (48). The highest quartile of LV mass conferred a hazards ratio of 3.36 for incident CHF, compared with the lowest quartile. Further, eccentric and concentric LV hypertrophy conferred higher hazards ratios compared with normal LV geometry for both incident CHF (2.95 and 3.32, respectively) and CHD (2.05 and 1.61, respectively). In comparison, the Framingham study, in a 4-year follow-up of its original cohort (mean age

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Figure 19 Cardiovascular Health Study data: Bar graph shows weight-adjusted mean left ventricular (LV) mass displayed by sex and disease status group across 5-year age intervals. Data are computed using the lower age end point and the mean weight for each age category (65 to 69, 70 to 74, 75 to 79, 80 to 84, 85+ years). Weight-adjusted LV mass was significantly associated with sex, disease status, and age. Of interest, within each age group, the magnitude of the sex effect exceeded that of the effect of the disease (e.g., clinical coronary heart disease [CHD]). HTN indicates hypertension.

69 years) found even higher relative risks (7.8 in men and 3.4 in women) for CHD events in the highest versus the lowest quartile of risk factor-adjusted LV mass [40]. Left Ventricular Wall Motion In this regard, 4.3% of participants with hypertension but no clinical heart disease, and 1.9% of participants with neither clinical heart disease nor hypertension had LV segmental wall motion abnormalities, suggesting silent coronary disease [47]. Multivariate analyses revealed male sex and presence of clinical CHD (both p < 0.001) to be independent predictors of LV akinesis or dyskinesis. Subclinical Disease A new method of classifying subclinical disease at the baseline examination in the Cardiovascular Health Study included measures of ankle–brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire (see Table 2) [49]. Participants were followed for an average of 2.4 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a signiﬁcantly increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes. Consequently, the measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.

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Table 2 Criteria for Clinical and Subclinical Disease in the Cardiovascular Health Study Clinical disease criteria Atrial ﬁbrillation or pacemaker History of intermittent claudication or peripheral vascular surgery History of congestive heart failure History of stroke, transient ischemic attack, or carotid surgery History of coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty History of angina or use of nitroglycerin History of myocardial infarction

Subclinical disease criteria Ankle-arm index l 0.9 mmHg Internal carotid wall thickness >80th percentile Common carotid wall thickness >80th percentile Carotid stenosis >25% Major ECG abnormalitiesa Abnormal ejection fraction on echocardiogram Abnormal wall motion on echocardiogram Rose questionnaire claudication positive Rose questionnaire angina positive

a

According to Minnesota Code, ventricular conduction defects (7-1, 7-2, 7-4); major Q/QS wave abnormalities (11, 1-2); left ventricular hypertrophy (high-amplitude R waves with major or minor ST-T abnormalities) (3-1, 3-3, and 4-1 to 4-3 or 5-1 to 5-3); isolated major ST/T wave abnormalities (4-1, 4-2, 5-1, 5-2). Source: From Ref. 37, with permission of the author and the American Heart Association.

‘‘Healthy’’ Subgroup By excluding CHS participants with either LV ejection fraction or wall motion abnormalities from the group of participants with neither clinical heart disease (including CHD) nor hypertension, a subgroup that was apparently free of clinical heart disease and hypertension was deﬁned. The ‘‘healthy’’ subgroup consisted of 516 men and 773 women, with 339 and 569, respectively, having available echo measurements of LV mass. Preliminary analysis indicated that after adjustment for weight, no adjustment for height was necessary. Likewise, after adjustment for weight, age had only a modest eﬀect on LV mass. Therefore, for simplicity, the reference equations were not expressed as a function of age. There was no evidence of an interaction between sex and weight. Since the baseline CHS cohort race was not a signiﬁcantly independent predictor of LV mass, the reference equations are not race-speciﬁc. The expected LV mass (g) derived from the CHS healthy subgroup can be calculated from the following equations: Men: 16:6 ½Weight ðkgÞ0:51 Women: 13:9 ½Weight ðkgÞ0:51 If the ratio of observed-to-expected LV mass is between 0.69 and 1.47, the patient’s LV mass should not be considered larger than expected given his or her weight. This prediction procedure classiﬁed 28% of the men and 18% of the women with clinical CHD as outside the range of expected LV mass measurements. Exclusions of obese (n = 220) participants from this healthy group had a negligible eﬀect on the reference equations. Left Ventricular Diastolic Filling Pulsed Doppler transmitral ﬂow velocities were analyzed as part of the baseline examination in the Cardiovascular Health Study [43]. Early diastolic LV Doppler (transmitral)

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peak ﬁlling velocity decreased, and peak late diastolic (atrial) velocity increased with increasing age in multivariate analyses (all p < 0.001) [50]. Early and late diastolic peak ﬁlling velocities were both signiﬁcantly higher in women than in men, even after adjustment for body surface area (or height and weight). In multivariate models in the entire cohort and a healthy subgroup (n = 703), gender, age, heart rate, and blood pressure were most strongly related to early and late diastolic transmitral peak velocities. Early and late diastolic peak velocities both increased with increases in systolic blood pressure, and decreased with increases in diastolic blood pressure ( p < 0.001). Doppler transmitral velocities were compared among health status subgroups. In multiple regression models adjusted for other covariates, and in analysis-of-variance models examining diﬀerences across subgroups adjusted only for age, the subgroup with CHF had the highest early diastolic peak velocities (50). All clinical disease subgroups had higher late diastolic peak velocities than did the healthy subgroup, with CHF and hypertensive subgroups having the highest age-adjusted means. The hypertensive subgroup had the lowest ratio of early-to-late diastolic peak velocity, and men with CHF had the highest ratio. Borderline and deﬁnite isolated systolic hypertension were positively associated with LV mass ( p < 0.001) and with increases in transmitral late peak ﬂow velocity and decreases in the ratio of early-to-late diastolic peak ﬂow velocity (51). These ﬁndings are consistent with previous reports that hypertensive subjects exhibit an abnormal relaxation pattern, whereas CHF patients develop a pattern suggestive of an increased early diastolic LA–LV pressure gradient. In summary, echocardiographic imaging and Doppler ﬂow recording have provided convincing evidence of structural and functional cardiac changes related to aging. These noninvasive ultrasound techniques have provided important insights into the cardiovascular epidemiology of aging, as well as the clinical evaluation of elderly patients with suspected cardiovascular disease.

ACKNOWLEDGMENT The authors acknowledge the expert assistance of Kathleen Steiner in the preparation of this manuscript.

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44. Sahn DJ, DeMaria A, Kisslo J, Weyman A, for the Committee on M-mode Standardization of the American Society of Echocardiography. Recommendations regarding quantitation in Mmode echocardiography: results of a survey of echocardiographic methods. Circulation 1978; 58:1072–1083. 45. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison with necropsy ﬁndings. Am J Cardiol 1986; 57:450–458. 46. Gardin JM, Siscovick D, Anton-Culver H, Smith V-E, Klopfenstein S, Bommer W, Fried LP, O’Leary D, Manolio TA. Age and gender relations of left ventricular mass and wall motion in elderly subjects with no clinical heart disease: The Cardiovascular Health Study (CHS) [abstr]. Circulation 1992; 84(4):I–672. 47. Gardin JM, Siscovick D, Anton-Culver H, Lynch JC, Smith V-E, Klopfenstein HS, Bommer WJ, Fried L, O’Leary D, Manolio TA. Sex, age and disease aﬀect echocardiographic left ventricular mass and systolic function in the free-living elderly: The Cardiovascular Health Study. Circulation 1995; 91:1739–1748. 48. Gardin JM, McClelland R, Kitzman D, Lima JA, Bommer W, Klopfenstein HS, Wong ND, Smith VE, Gottdiener J. M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the Cardiovascular Health Study). Am J Cardiol 2001; 87:1051–1057. 49. Kuller LH, Shemanski L, Psaty BM, Borhani NO, Gardin JM, Haan MN, O’Leary DH, Savage PJ, Tell GS, Tracy R. Subclinical disease as an independent risk factor of cardiovascular disease. Circulation 1995; 92:720–726. 50. Gardin JM, Arnold AM, Bild DE, Smith V-E, Lima JAC, Klopfenstein HS, Kitzman DW. Left ventricular diastolic ﬁlling in the elderly: The Cardiovascular Health Study. Am J Cardiol 1998; 82(3):345–351. 51. Psaty BM, Furbert CD, Kuller LH, Borhani NO, Rautaharju PM, O’Leary DH, Bild DE, Robbins J, Fried LP, Reid CL. Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial ﬁndings from the Cardiovascular Health Study. JAMA 1992; 268:1287–12913.

3 Morphological Features of the Elderly Heart William Clifford Roberts Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, U.S.A.

INTRODUCTION As in any body tissue or organ, changes take place in the cardiovascular system as life progresses. Some of these changes allow easy identiﬁcation of the very elderly heart when examining autopsy cardiac specimens as unknowns. The ‘‘normal’’ elderly heart has relatively small ventricular cavities and relatively large atria and great arteries. The ascending aorta and left atrium, in comparison with the relatively small left ventricular cavity, appear particularly large. The coronary arteries increase in both length and width; the former, particularly in association with the decreasing size of the cardiac ventricles, results in arterial tortuosity. (The young river is straight and the old one winding.) The leaﬂets of each of the four cardiac valves thicken with age, particularly the atrioventricular valves; these have a smaller area to occupy in the ventricles because of the diminished size of the latter. Histological examination discloses large quantities of lipofuscin pigment in myocardial cells; some contain mucoid deposits (‘‘mucoid degeneration’’). These changes appear to aﬀect all population groups of elderly individuals regardless of where they reside on the earth or their level of serum lipids. An elevated systemic arterial pressure appears to both accelerate and amplify these normal expected cardiac changes of aging. Both the aorta and its branches and the major pulmonary arteries and their branches enlarge with age. Because the enlargement is in both the longitudinal and the transverse dimensions, the aorta, as the coronary arteries, tends to become tortuous. This process is further ampliﬁed as the vertebral bodies become smaller and the height becomes somewhat shorter. The major pulmonary arteries appear to be too short and have too low a pressure to dilate longitudinally. The amount of information at necropsy in very elderly persons is relatively sparse. In 1983, Waller and Roberts [1] described some clinical and necropsy ﬁndings in 40 American patients aged 90 years and over. In 1988, Lie and Hammond [2] reported ﬁndings at necropsy in 237 patients aged 90 and older. In 1991, Gertz and associates [3] described composition of coronary atherosclerotic plaques in 18 persons z90 years of age. In 1993, Roberts [4] described cardiac necropsy ﬁndings in an additional 53 patients z90 years of age. In 1995, Shirani et al. [5] described cardiac ﬁndings at necropsy in 366 Americans aged 69

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80 to 89 years, and in 1998 Roberts [6] described cardiac ﬁndings at necropsy in six centenarians. Also, in 1998 Roberts and Shirani [7] compared cardiovascular ﬁndings in 490 patients studied at necropsy in three age categories: 80–89; 90–99; and z100 years. This chapter expands on that previous comparative study.

METHODS Patients The ﬁles of the Pathology Branch, National Heart, Lung, and Blood Institutes, National Institutes of Health, Bethesda, Maryland, from 1959 to 1993, and those of the Baylor University Medical Center, Dallas, Texas, beginning January 1993, were searched for all accessioned cases of patients aged z80 years of age. Of 511 such cases found, adequate clinical information was available in 490 necropsy patients and they are the subject of this chapter. The clinical and cardiac morphological records, photographs, and postmortem radiographs, histological slides, and the initial gross description of the heart were reviewed. All 490 hearts were originally examined by WCR, who recorded gross morphological abnormalities in each case. Sources of Patients Of the 490 cases, the hearts in 412 were obtained from 12 Washington, DC, area hospitals, and the hearts in the other 78 cases, from hospitals outside that area, including 25 from Baylor University Medical Center. Of the 490 hearts, 37 (8%) were examined in 1970 or before; 153 (31%), from 1971 through 1980; 244 (50%), from 1981 through 1990; and 56 (11%) from 1991 through 1997. Definitions Sudden coronary death was deﬁned as death within 6 h from the onset of new symptoms of myocardial ischemia in the presence of morphological evidence of signiﬁcant atherosclerotic coronary artery disease (z1 major epicardial coronary artery narrowed >75% in cross-sectional area by atherosclerotic plaque). Most patients who died suddenly did so outside a hospital; a few, however, died shortly after admission to an emergency room. Sudden, out-of-hospital death also occurred in some patients with cardiac disease other than atherosclerotic coronary artery disease. In each case, an underlying cardiac disease generally accepted to cause sudden death was present at necropsy. Acute myocardial infarction was deﬁned as a grossly visible left ventricular wall lesion conﬁrmed histologically to represent coagulation-type myocardial necrosis. Ischemic cardiomyopathy was deﬁned as chronic congestive heart failure associated with a transmural healed myocardial infarct and a dilated left ventricular cavity. Cardiac Morphological Data Hearts were ﬁxed in 10% phosphate-buﬀered formalin for 3 to 15 days before examination. They were ‘‘cleaned’’ of parietal pericardium and postmortem intracavity clot, and the pulmonary trunk and ascending aorta were incised approximately 2 cm cephalad to the

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sinotubular junction. Heart weight was then measured on accurate scales by WCR (Lipsaw scale before 1971, accurate to 10 g, and Mettler P1210 scale after 1971, accurate to 0.1 g). Heart weight was considered increased if it was z350 g in women and >400 g in men. Most hearts were studied by cutting the ventricles transversely at approximately 1-cm-thick intervals from apex to base parallel to the atrioventricular groove posteriorly. In each heart, the sizes of cardiac ventricular cavities (determined by gross inspection), presence of left ventricular necrosis (acute myocardial infarct) and ﬁbrosis (healed myocardial infarct), status of the four cardiac valves, and the maximal degree of cross-sectional luminal narrowing in each of the three major (left anterior descending, left circumﬂex, and right) epicardial coronary arteries were recorded.

RESULTS Number of Patients in Each of the Three Groups Certain clinical and necropsy cardiac ﬁndings in the 490 cases are summarized in Table 1 and illustrated in Figures 1 through 19. The 490 patients were divided into three groups: the octogenarians (80–89 years) (n = 391[80%]); the nonagenarians (90–99 years) (n = 93[19%]); and the centenarians (z100 years) (n = 6[1%]); 248 (51%) were women and 242 (49%) were men.

CLINICAL FINDINGS The clinical manifestations of the various cardiac disorders probably represent minimal numbers: many patients apparently were unable to provide much clinical information, many came to the hospital from nursing homes, and many had varying degrees of dementia. Nevertheless, angina pectoris was noted in the records of 137 (35%) of the 391 octogenarians, in 5 (5%) of the 93 nonagenarians, and in none of the centenarians. A history of a hospitalization for an illness compatible with acute myocardial infarction was present in 78 (20%) of the 391 octogenarians; in 18(19%) ofthe 93 nonagenarians; and innone ofthe 6 octogenarians. Chronic congestive heart failure was present in 36% (140/391) of the octogenarians; in 25% (23/93) of the nonagenarians; and in none of the 6 centenarians. A history of systemic hypertension was present in 44% (174/391) of the octogenarians; in 54% (50/93) of the nonagenarians; and in none of the centenarians. Diabetes mellitus was present in 14% (56/391) of the octogenarians; in 9% (8/93) of the nonagenarians; and in none of the centenarians.

CAUSES OF DEATH The causes of death in the 490 patients are summarized in Table 2. A cardiac condition was the cause of death in 51% (198/391) of the octogenarians; in 32% (30/99) of the nonagenarians; and in none of the centenarians. A noncardiac but vascular condition was responsible for death in 13% (52/391) of the octogenarians and in 20% (19/93) of the nonagenarians. A noncardiac and a nonvascular condition was responsible for death in 36% (141/391) of the octogenarians; in 47% (44/93) of the nonagenarians; and in all of the centenarians.

72 Table 1

Roberts Certain Clinical and Necropsy Findings in 490 Patients Aged 80 to 103 Years Age group (years)

Variable 1. 2. 3. 4. 5. 6. 7. 8. 9.

Mean age (Years) Male: female Angina pectoris Acute myocardial infarction Chronic congestive heart failure Systemic hypertension (history) Diabetes mellitus Atrial ﬁbrillation Heart weight (g): range(mean) Men Women 10. Cardiomegaly Men > 400 g Women > 350 g 11. Cardiac calciﬁc deposits None Present Coronary arteries Aortic valve cusps Heavy (stenosis) Mitral annulus Heavy Papillary muscle 12. Numbers of patients with 0,1,2, or 3 major (right, left anterior descending, left circumﬂex) coronary arteries # >75% in cross-sectional area 0 1 2 3 Mean 13. Number of major coronary arteries (3/patient) # >75% in cross-sectional area by plaque 0 1 2 3 Totals 14. Left ventricular necrosis and/or ﬁbrosis Necrosis only Fibrosis only Both 15. Ventricular cavity dilatation Neither One Right ventricle Left ventricle Both 16. Cardiac amyloidosis (massive)

80–89 (n = 391)

90–99 (n = 93)

z100 (n = 6)

84 F 4 194(50%): 97(50%) 137(35%) 78(20%) 140(36%) 174(44%) 56(14%) 57(15%) 185–900(449) 230–830(493) 185–900(409)

93 F 4 52(56%): 41(44%) 5(5%) 18(18%) 23(25%) 50(54%) 8(9%) 35(38%) 220–660(420) 285–660(436) 220–630(406)

102 2/4 0 0 0 0 0 0 240–410(328) 335&410(372) 240–385(306)

103/154(67%) 133/165(81%)

27/49(55%) 23/42(55%)

43(11%) 348(89%) 304(78%) 164(42%) 43(11%) 146(37%) 52(13%) 37(9%)

3(3%) 90(97%) 89(96%) 59(63%) 8(9%) 42(45%) 11(12%) 42(45%)

159(41%) 9 67 = 71 232ð59%Þ ; 94 1.7

33(35%) 9 20 = 32 60ð65%Þ ; 8 1.5

0/477 67/201 142/213 282/282 491/1173(42%)

0/99 20/60 64/96 24/24 108/279(39%)

1/2 1/4 0 6(100%) 5 5 0 2 0 6

29 2= 2 4 ; 0 1.5

0/6 2/6 4/6 0 6/18(33%)

54/(14%) 101(26%) 37(9%)

10(11%) 20(21%) 5(5%)

0 2 0

222(57%) 84(21%) 42 42 85(22%) 14(4%)

58(62%) 4(4%) 2 2 31(34%) 8(9%)

4 2 2 2 0 0

Figure 1 Tortuous and heavily calciﬁed coronary arteries in a 95-year-old woman (SH #A80-74) who never had symptoms of cardiac dysfunction and who died from a perforated gastric ulcer. Top left: postmortem radiogram of the excised right (R), left main (LM), left anterior descending (LAD), and left circumﬂex (LC) coronary arteries. Top center: radiogram of a portion of the heart after removing the walls of the atria and most of the walls of the ventricles. MVA = mitral valve annulus. Top right and lower panels: photomicrographs of coronary arteries at sites of maximal narrowing by calciﬁed atherosclerotic plaques. (Movat stains; magniﬁcation 17, reduced 40%). This case illustrates extensive calciﬁc deposits in the coronary arteries without signiﬁcant luminal narrowing.

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Figure 2 Coronary arteries in a 95-year-old man (SH #A79-77) who never had symptoms of cardiac dysfunction and who died from cancer. Top: aorta and coronary arteries from above. Bottom: radiograms of aortic root (Ao) and excised coronary arteries that contain calciﬁc deposits. FD = ﬁrst diagonal, LAD = left anterior descending, LC = left circumﬂex, LM = left main, R = right.

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Figure 3 Heart and coronary arteries in a 93-year-old woman who was hospitalized with worsening chronic congestive heart failure. Top left: postmortem radiogram showing calciﬁc deposits in the right (R), left anterior descending (LAD), and left circumﬂex (LC) coronary arteries and in the mitral valve annulus (MVA) and aortic valve. Top right: view of right (RV) and left (LV) ventricles and ventricular septum (VS) showing a transmural scar (arrows). Bottom: coronary arteries at sites of maximal narrowing. LM = left main. (Movat stains; magniﬁcation F 17, reduced 40%.)

Figure 4 This 91-year-old woman (LRC #3) had a ‘‘typical’’ clinical acute myocardial infarct, which was fatal. Left: postmortem radiogram showing calciﬁc deposits in the right (R), left main (LM), left anterior descending (LAD), and left circumﬂex (LC) coronary arteries. Right, view of the left and right (RV) ventricles showing transmural necrosis and ﬁbrosis (arrows) and dilated ventricles. VS = ventricular septum.

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Figure 5 This 90-year-old woman (SH #A82-1) had no symptoms of cardiac dysfunction and died from a ruptured fusiform abdominal aortic aneurysm. Left: postmortem radiogram of the entire heart showing calciﬁc deposits in the left anterior descending (LAD), left circumﬂex (LC), and left main (LM) coronary arteries. Right: view of heart cut in an anteroposterior fashion (Mmode or long-axis two-dimensional echocardiographic view) showing a dilated left atrium (LA) and left ventricle (LV). A and P = anterior and posterior mitral valve leaﬂets; Ao = aorta; RV = right ventricle; VS = ventricular septum.

CARDIAC NECROPSY FINDINGS Cardiac ﬁndings at necropsy are tabulated in Table 1. Heart Weight The mean heart weights were largest in the octogenarians and smallest in the centenarians (449 g vs. 420 g vs. 328 g). Heart weight was increased (>400 g in men; >350 g in women) in 131 (64%) of the 205 men and in 157(74%) of the women, and the percent was highest in the octogenarians. Calcific Deposits in the Heart Calciﬁc deposits were present in the heart at necropsy in 444 (91%) of the 490 patients and were most common in the coronary arteries—in all cases being located in atherosclerotic plaques and not in the media—81% (398/490); in the aortic valve cusps in 47% (228/490)— heavy enough to result in aortic stenosis in 10% (51/490); mitral valve annulus in 39% (190/ 490)—very heavy deposits in 13% (63/490), and in the apices of 1 or both left ventricular papillary muscles in 17% (85/490). The cardiac calciﬁc deposits were more frequent and heavier in the nonagenarians than in the octogenarians.

Figure 6 This 97-year-old man (GT # 69A-585) had complete heart block and had a pacemaker inserted when he was 91 years old. Left: radiogram of heart at necropsy showing calciﬁc deposits in the left anterior descending (LAD), left circumﬂex (LC), and right (R) coronary arteries and a pacemaker wire in the right ventricle (RV). LV = left ventricle. Right: electrocardiogram.

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Figure 7 This 96-year-old woman (DCGH #68A80) had chronic congestive heart failure from dilated cardiomyopathy. Her total serum cholesterol level was 108 mg/dl. Left: postmortem radiogram of the right (R), left main (LM), left anterior descending (LAD), left circumﬂex (LC), ﬁrst diagonal (FD), and left obtuse marginal (OM) coronary arteries showing no calciﬁc deposits. Right: right coronary artery section devoid of calcium or narrowing. (Movat stain; magniﬁcation 16, reduced 23%.)

Numbers of Patients with Narrowing of 1 or More Major Epicardial Coronary Arteries Among the 490 patients, 194 (40%) had none of the three major (right, left anterior descending, and left circumﬂex) epicardial coronary arteries narrowed by plaque >75% in cross-sectional area; 89 (18%) had one artery so narrowed; 105 (21%) had two arteries so narrowed; and 94 (19%) had all three arteries so narrowed. The percent of patients in each of the three groups with no arteries and 1, 2, and 3 arteries narrowed >75% was similar. Numbers of Major Coronary Arteries (Three/Patient) Narrowed >75% in Cross-Sectional Area by Plaque Among the 490 patients, a total of 1470 major epicardial coronary arteries were examined: 865 (59%) arteries had insigniﬁcant (<75% in cross-sectional area) narrowing and 605 (41%) had narrowing by plaque >75% in cross-sectional area. The percent of arteries signiﬁcantly narrowed was similar in each of the three groups (42% vs. 39% vs. 33%). Acute and Healed Myocardial Infarcts Grossly visible foci of left ventricular wall (includes ventricular septum) necrosis (acute infarcts) without associated left ventricular scars (healed infarcts) were found in 64 (13%)

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Figure 8 Right (R), left main (LM), left anterior descending (LAD), and left circumﬂex (LC) coronary arteries at sites of maximal narrowing in a 103-year-old woman (GT #70A301). She never had evidence of cardiac dysfunction and died from complications of a duodenal ulcer. The coronary arteries are devoid of calcium and of signiﬁcant narrowing. (Elastic-van Gieson’s stain; magniﬁcation 16, reduced 31%.)

patients; foci of left ventricular ﬁbrosis without associated necrosis were observed in 123 patients (25%); and foci of both necrosis and ﬁbrosis were found in 42 patients (9%). Thus, a total of 229 (47%) of the 490 patients had grossly visible evidence of acute or healed myocardial infarcts or both. The percents of patients with myocardial lesions of ischemia were similar among the octogenarians and nonagenarians. Ventricular Cavity Dilatation One or both ventricular cavities were dilated (by gross inspection) in 218 (44%) of the 490 patients and no signiﬁcant diﬀerences were observed in the three groups. Cardiac Amyloidosis Grossly visible amyloid (conﬁrmed histologically) in ventricular and atrial myocardium as well as in atrial mural endocardium was present in 22 patients (4%). In these 22 patients, the amyloidosis was symptomatic and fatal. A number of other patients who had no gross

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Figure 9 Mean percentage cross-sectional area narrowing by atherosclerotic plaques in 1789 segments (5 mm) of the four major epicardial coronary arteries in 36 necropsy patients aged 90 years and older, 10 of whom had angina pectoris or acute myocardial infarction, or both, and 26 of whom did not. The mean percentage of narrowing for each 5-mm segment differs significantly in the group with clinical evidence of myocardial ischemia (55%) and the group without such evidence.

evidence of cardiac amyloidosis had small foci in the heart on histological study. These minute deposits did not cause symptoms of cardiac dysfunction. In the 22 patients with fatal cardiac amyloidosis, deposits of amyloid also were present in several other body organs at necropsy.

ELECTROCARDIOGRAPHIC FINDINGS Information on electrocardiograms was available on 30 of the 99 patients aged z90 years. Of the 30 patients, three had electrocardiograms recorded during acute myocardial infarction. The electrocardiograms in all three, however, disclosed only atrial ﬁbrillation and complete left bundle branch block, and these ﬁndings in these patients were known to be present before the fatal acute myocardial infarction. The electrocardiograms in the other 27 patients were not recorded during periods of acute myocardial infarction. Of the 30 patients on whom electrocardiographic information was available, 8 had clinical evidence of heart disease and 22 did not; the ﬁndings are summarized in Table 2. The total 12-lead QRS voltage ranged from 82 to 251 mm (mean 151; 10 mm = 1 mV). In the 19 women, the total voltage ranged from 82 to 251 mm (mean 158) and, in the 5 men, from

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Figure 10 Mean percentage cross-sectional area (XSA) narrowing by atherosclerotic plaques in the 5-mm segments of the right, left main, left anterior descending, and left circumﬂex coronary arteries in the 36 patients in whom the four major coronary arteries in their entirety were available for examination. The 36 patients were classiﬁed into 10 with and 26 without clinical evidence of myocardial ischemia. For each of the four categories of narrowing, a highly signiﬁcant difference in the amount of narrowing was observed.

105 to 154 mm (mean 101; p<0.05). The total 12-lead QRS voltage did not correlate with either heart or body weight. The 24 patients in whom the total 12-lead QRS voltage was measured were separated into two groups: eight patients in whom clinical evidence of cardiac dysfunction was present (coronary heart disease in ﬁve, massive cardiac amyloid in two, and aortic valve stenosis in one) and 16 patients without such evidence (Table 3). Comparison of the total QRS voltage in the eight patients with and in the 16 patients without clinical evidence of heart disease disclosed no signiﬁcant diﬀerence (mean 147 mm vs. 152 mm). Breakdown on the eight patients with cardiac dysfunction did show some diﬀerences: the total 12-lead QRS voltage in the ﬁve patients with angina pectoris or acute myocardial infarction ranged from 123 to 163 mm (mean 143); in the two patients with massive cardiac amyloidosis it was 102 and 117 mm (mean 109); and in the one patient with aortic valve stenosis was 238 mm. Of 29 patients on whom information was available, 18 (62%) received digitalis and only two appeared to have evidence of digitalis toxicity.

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Figure 11 A 92-year-old woman (GT #78A58) with clinicaly recognized and eventually fatal aortic valve stenosis. Top left: stenotic aortic valve from above. PV = pulmonic valve; R = right; LM = left main; LAD = left anterior descending coronary arteries. Top right: postmortem radiogram showing heavy calciﬁc deposits in the aortic valve (AV) and in the mitral valve annular (MVA) region. Bottom left: radiogram of the heart at necropsy showing calciﬁc deposits in the coronary arteries, in the aortic valve, and in the mitral annular region. Bottom right: long-axis view of heart (M-mode or twodimensional long-axis view) showing a small left ventricular (LV) cavity, a thickened and ‘‘sigmoidshaped’’ ventricular septum (VS), and the stenotic aortic valve just above the right ventricular (RV) outﬂow tract. LA = left atrium.

COMMENTS This study describes ﬁndings in a large group (n = 490) of patients z80 years of age studied at necropsy, and it compares certain clinical and necropsy ﬁndings in the octogenarians, nonagenarians, and centenarians. Despite study of nearly 500 patients, only 6 (1%) lived 100 years or longer, and only 93 (19%) lived into the tenth decade of life. Nevertheless, the ratio of one centenarian for every 65 octogenarians is much higher than

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Figure 12 (a) A 90-year-old woman (GT #80A126) with heavy mitral valve annular calciﬁc deposits that reduced the mitral valve oriﬁce to <1 cm in diameter. The unusual feature of the mitral calcium in this patient was that it not only was located behind the posterior mitral leaﬂet (mitral annular region) but it also extended across the anterior mitral leaﬂet, nearly producing a letter O), as has been described previously. She died from rupture of a descending thoracic aortic aneurysm. VS = ventricular septum. (b) View of the left ventricle at the level of the tips of the mitral leaﬂets, showing a very small cavity.

might be expected. In general, it takes 10,000 persons to reach age 85 before one reaches age 100 [8]. Another ﬁnding was the high frequency of men: 248 men (51%) and 242 (49%) women. A higher than expected percent of men may have resulted in part from receiving a number of these cases from a Veterans Administration Hospital and from a retirement home ﬁlled almost entirely by men. The causes of death were divided into three major types: cardiac = 228/490 (47%); vascular but noncardiac = 71/490 (14%); and noncardiac and nonvascular = 191/490 (39%). The frequency of a cardiac condition causing death decreased with increasing age groups (51% vs. 32% vs. 0), and the frequency of a noncardiac and nonvascular condition causing death increased with increasing age groups (36% vs. 47% vs. 100%). Among the cardiac conditions, coronary artery disease was the problem in 62% (141/228), and the other cardiac conditions, mainly aortic valve stenosis (36/228[16%]) and cardiac amyloidosis (22/228[10%]), in the other 38%. Stroke, rupture of an abdominal aortic aneurysm, and complications of peripheral arterial atherosclerosis were the major vascular (noncardiac) conditions causing death. Of the noncardiac and nonvascular causes of death, cancer and infection, mainly pneumonia, were the major conditions, 35% (65/185) and 29% (54/185), respectively, among the octogenarians and nonagenarians. The cardiac necropsy ﬁndings focused primarily on calciﬁc deposits in the coronary arteries, aortic valve cusps, and mitral valve annulus and their consequences, and, to a

Figure 13 A 97-year-old woman (SH #A81-62) who never had clinical evidence of cardiac dysfunction and who died from cancer. (a) External view of anterior surface of the heart showing and increased amount of subepicardial fat. Ao = aorta, LV = left ventricle, PT = pulmonary trunk, RV = right ventricle. (b) Postmortem radiogram showing calciﬁc deposits in the mitral valve annulus (MVA) an aortic valve (AV). LA = left atrium, RA = right atrium. (c) Radiogram of the excised coronary arteries showing a few calciﬁc deposits. LAD = left anterior descending, LC = left circumﬂex, LM = left main, R = right. (d) View of aortic valve (AV) and pulmonic valve (PV) from above. (e) View of left ventricle showing claciﬁc deposits (arrows) in the papillary muscles. (f) Calciﬁc deposits in the mitral annular region (arrows).

84 Roberts

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Figure 14 M-mode echocardiogram obtained 10 months before death (SH #80-18). The ascending aorta (Ao) has a larger diameter than the left atrium (LA). The left ventricular (LV) cavity is small. Calcium is present in the mitral annular region. (I thank Dr. Robert Montgomery, Bethesda, Maryland, for allowing me to show this echocardiogram from his patient.)

lesser extent, on heavy amyloid deposits in the heart. Calciﬁc deposits were present in the atherosclerotic plaques of one or more epicardial coronary arteries in 81% (398/490) of the patients, on the aortic aspects of the aortic valve cusps in 47% (228/490), in the mitral annular regional in 39% (190/490), and in one or both left ventricular papillary in 25% (122/490). The calciﬁc deposits tended to be less frequent in the octogenarians. The frequent presence of calciﬁc deposits in the coronary arteries, aortic valve cusps, and mitral annular region in the same patient suggests that the cause of the calciﬁc deposits in each of these three locations is the same. The calciﬁc deposits in the coronary arteries indicate the presence of atherosclerosis because calcium occurs in the coronary arteries, with one exception [9], only in the plaques and not in the media. It is reasonable to believe that the calciﬁc deposits in and on the aortic cusps, at least when this valve is three-cuspid, are another manifestation of atherosclerosis. Because mitral annular calcium in this older population is nearly always associated with calcium in the coronary arteries, it is also reasonable to believe that mitral annular calcium in persons z80 years of age also is a manifestation of atherosclerosis. Calcium in a papillary muscle appears to be a consequence of aging and not a direct manifestation of atherosclerosis. When the deposits of calcium on the aortic aspects of the aortic valve cusps are extensive, the cusps may become relatively or absolutely immobile, resulting in aortic valve stenosis. These valves usually lack commissural fusion (i.e., adherence of two cusps together near the lateral attachments) and, therefore, aortic regurgitation is usually absent. Although it is most often associated with some degree of mitral regurgitation, mitral annular calcium, if ‘‘massive,’’ and if the left ventricular cavity is also small and the wall quite thickened, may result in mitral stenosis [10]. Although the calciﬁc deposits in the epicardial coronary arteries were located entirely in atherosclerotic plaques, which are located in the intima, the presence of calciﬁc deposits in the coronary arteries in this older population did not necessarily indicate the presence of signiﬁcant (>75% cross-sectional area) luminal narrowing. In contrast, the presence of calciﬁc deposits in epicardial coronary arteries in persons aged<65 years generally

Figure 15 A 95-year-old man (SH #79-77) who never had symptoms of cardiac dysfunction and died from sarcoma. The coronary arteries are shown in Figure 2. Left: radiogram of heart at necropsy showing considerable enlargement of the aorta in comparison to the ventricles. LV = left ventricle, RV = right ventricle, R = right, L = left, and P = posterior sinuses of Valsalva. Right: aortic valve from above. The coronary arteries were excised before the radiogram and photographs were taken.

86 Roberts

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87

Figure 16 A 90-year-old man (DCGH #69A391) with chronic, eventually fatal, congestive heart failure from clinically unrecognized cardiac amyloidosis. (a) External view of the heart showing prominent left ventricle (LV) and left atrial appendage (LAA). PT = pulmonary trunk, RAA = right atrial appendage, RV = right ventricle. (b) Right-to-left longitudinal cut of the heart (four-chamber, two-dimensional echocardiographic view) showing thickened ventricular walls and dilated right (RA) and left (LA) atria. VS = ventricular septum. (c) Photomicrograph of a portion of the left ventricle showing extensive amyloid deposits. (d) Photomicrograph of LA wall showing amyloid deposits in endocardium (E) and in myocardium (M). (Hematoxylin and eosin; magniﬁcation 100 (c) and 25 (d), both reduced 35%.)

Roberts

Figure 17

88

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89

Figure 18 Various QRS complexes, and how each was measured. (Reproduced with permission from Siegel RJ, Roberts WC. Electrocardiographic observations in severe aortic valve stenosis: Correlative necropsy study to clinical, hemodynamic, and ECG variables demonstrating relation of 12-lead QRS amplitude to peak systolic transaortic pressure gradient. Am Heart J 1982; 103: 210–221.)

Figure 17 Electrocardiograms in four patients, each recorded at age 90 years or older. None ever had symptoms of cardiac dysfunction, and each died from noncardiac conditions. Top left: The electrocardiogram was recorded 43 days before death (A66-13), and it is normal (heart weight 270 g). Top right: The electrocardiogram was recorded 11 days before death (GT #68A325), and it shows left QRS axis deviation and a slightly prolonged P-R interval (heart weight 400 g). Bottom left: This electrocardiogram was recorded 28 days before death (A64-62), and it shows left axis deviation and complete left bundle branch block (heart weight 320 g). Bottom right: This electrocardiogram was recorded 128 days before death (SH #A80-74), and it shows atrial ﬁbrillation, left axis deviation, and complete right bundle branch block (heart weight 440 g).

90

Roberts

Figure 19 Cardiac changes in the very elderly. The left atrial (LA) cavity enlarges, and the left ventricular (LV) cavity becomes smaller. The amount of space available for the mitral leaﬂets decreases with aging, and consequently the number of scallops in the leaﬂets appears to increase. (Reproduced from Roberts WC, Perloff JK. Mitral valvular disease. A clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 1972; 77:939–975.)

indicates the presence of signiﬁcant luminal narrowing. The calciﬁc deposits tended to occur in each of the four major (right, left main, left anterior descending, and left circumﬂex) epicardial arteries and were always larger in the proximal than in the distal halves of the right, left anterior descending, and left circumﬂex arteries or, if small, limited to their proximal halves. The plaques consisted mainly (87 F 8%) of ﬁbrous tissue with calciﬁc deposits forming 7 F 6% of the plaques [3]. The percent of patients with narrowing >75% in cross-sectional area by plaque of one or more major epicardial coronary arteries was similar in all three age groups, as was the percent of major coronary arteries narrowed signiﬁcantly. In 36 patients (all z90 years of age), each of the four major coronary arteries were divided into 5-mm-long segments and the degree of cross-sectional area narrowing by atherosclerotic plaque was determined for each segment. Of the 1789 5-mm segments in the 36 patients, the average amount of cross-section area narrowing by atherosclerotic plaques per segment was 42% (range 19 to 69). Of the 467 5-mm segments in the 10 patients with clinical evidence of coronary artery disease, the average amount of cross-sectional area narrowing per segment was 55% (range 43 to 69); and, of 1322 5-mm segments in the 26

Morphological Features Table 2

91

Causes of Death in the 490 Necropsy Patients Aged 80–103 Years Age group (Years)

I. Cardiac A. Coronary artery disease 1. Acute myocardial infarction 2. Chronic congestive heart failure 3. Sudden 4. Coronary bypass B. Valvular heart disease 1. Aortic stenosis 2. Aortic regurgitation 3. Mitral regurgitation 4. Mitral stenosis C. Primary cardiomyopathy 1. Hypertrophic 2. Idiopathic dilated D. Secondary cardiomyopathy 1. Amyloidosis 2. Hemosiderosis 3. Myocarditis E. Pericardial heart disease II. Vascular, noncardiac A. Stroke B. Abdominal aortic aneurysm C. Peripheral arterial disease D. Aortic dissection E. Pulmonary embolism III. Noncardiac, nonvascular A. Cancer B. Infection C. Fall complication D. Other

80–89 (n = 391)

90–99 (n = 93)

z100 (n = 6)

198.(51%) 129./198(65%) 90 15 19 7 41./198(21%) 33 2 5 1 7./198(4%) 4 3 16./198(8%) 14 1 1 3./198(2%) 52.(13%) 17./52(33%) 14./52(33%) 11./52(21%) 4./52(8%) 6.*/52(11%) 141.(36%) 52./141(37%) 37./141(26%) 10./141(7%) 42./141(30%)

30.(32%) 12./30(40%) 12 3 3 0 3./30(10%) 3 0 0 0 1./30(3%) 0 1 8./30(27%) 8 0 0 0 19.(20%) 6./19(32%) 5./19(26%) 5./19(26%) 0./19(0) 3./19*(16%) 44.(47%) 13./44(29%) 17./44(39%) 3./44(7%) 11./44(25%)

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6.(100%) 0./6 0./6 3./6 3./6

All had underlying chronic obstructive pulmonary disease.

patients without clinical evidence of coronary artery disease, 38% (range 19 to 40; p<0.01). Among 129 patients aged 22 to 85 years (mean 56), the amount of crosssectional area narrowing by atherosclerotic plaques per segment averaged 67%; in the control subjects, that is, those without symptomatic coronary artery disease, crosssectional area narrowing averaged 32%. The mean percentage of 5-mm coronary segments narrowed 76 to 100% in cross-sectional area in the 36 patients was 13% (range 2 to 89); of the 10 patients with symptomatic coronary artery disease, the mean was 19% (range 10 to 34); and of the 26 patients without symptomatic coronary artery disease, the mean was 7% (range 2 to 28) ( p < 0.05). The mean of 19% in patients with symptomatic coronary artery disease aged z90 was half that observed in patients <85 years (mean 56) with fatal coronary artery disease, and the mean of 7% was nearly three times that observed in the younger patients without fatal coronary artery disease [11].

92

Roberts

These detailed morphological studies of the coronary arteries in these very elderly persons suggest that the degree of severe coronary narrowing necessary to have a fatal or nearly fatal coronary event is considerably less than that necessary to have a coronary event in younger patients. Moreover, these studies indicate that these very elderly patients without symptoms of coronary artery disease have distinctly more coronary luminal narrowing by atherosclerotic plaque than control subjects who are younger (mean age 52 years) [11]. The latter observation suggests that coronary artery disease may be underdiagnosed clinically in the very elderly. Clinical diagnosis of cardiac and other conditions in patients aged 80 years and over, particularly those z90 years of age, appears more diﬃcult than in younger persons. Historical information may be diﬃcult to obtain because of impaired intellect on the part of the patient and an impaired diagnostic pursuit on the part of the physician. Physicians caring for these very elderly persons may focus primarily on the prevention of suﬀering and only secondarily on accurate diagnosis or longer term therapy. Patients aged 90 years and over generally have outlived their spouses and private physicians and are often ‘‘inherited’’ by nursing home physicians, who may have limited access to earlier medical records. Angina pectoris appears particularly diﬃcult to diagnose in the very elderly because they may not be able to describe this symptom. Acute myocardial infarction is also diﬃcult to diagnose clinically, but it is often fatal in the very elderly. Furthermore, the electrocardiogram is not as useful in diagnosis of acute myocardial infarction in the very elderly because left bundle branch block is frequent and, of course, it prevents the appearance of typical changes. Serial recordings of electrocardiograms also appear to be quite infrequent in the very elderly. Physical examination in the very elderly may be both diﬃcult and misleading. The lack of mobility may prevent proper positioning of the elderly patient for proper examining. Precordial murmurs, although common, infrequently indicate signiﬁcant functional abnormality. Although calciﬁc deposits in the aortic valve are common, actual aortic valve stenosis is not nearly as frequent. Likewise, although mitral annular calciﬁc deposits are common, these calciﬁc deposits rarely narrow the mitral oriﬁce or produce signiﬁcant mitral regurgitation. Electrocardiographic abnormalities are common in elderly persons. Of my patients for whom electrocardiograms were available, all had one or more abnormalities recorded, the most frequent being abnormal axis, atrial ﬁbrillation, and complete bundle branch block. Although 15 of the 30 patients had cardiomegaly (>350 g in women; >400 g in men) at necropsy, only one had voltage criteria for left ventricular hypertrophy. Likewise, only one had low voltage. Measurement of the QRS amplitude in each of the 12 leads was performed in 24 patients. The total QRS voltage was similar in the eight patients with and in the 16 patients without clinical evidence of cardiac disease (mean 147 vs. 152 mm; 10 mm = 1 m V).

SUMMARY Certain clinical and necropsy cardiac ﬁndings are described and compared in 391 octogenarians (80%), 93 nonagenarians (19%), and 6 centenarians (1%). The numbers of men and women were similar (248[51%]) and 242[49%]). The cause of death was cardiac in 228 patients (47%), vascular but noncardiac in 71 (14%), and noncardiac and nonvascular in 191 (39%). The frequency of a cardiac condition causing death decreased

Morphological Features

93

with increasing age groups (51% vs. 32% vs. 0), and the frequency of a noncardiac, nonvascular condition causing death increased with increasing age groups (36% vs. 47% vs. 100%). Among the cardiac conditions causing death, coronary artery disease was the problem in 61% (141/228) followed by aortic valve stenosis in 16% (36/228) and cardiac amyloidosis in 10% (22/228). Calciﬁc deposits were found at necropsy in the coronary arteries in 81% (398/490) of the patients, in the aortic valve in 47% (228/490), in the mitral annular area in 39% (190/490), and in one or both left ventricular papillary muscles in 25% (122/490). The calciﬁc deposits tended to be less frequent in the octogenarians. Three hundred (61%) of the 490 patients had one or more major coronary arteries narrowed >75% in cross-sectional area by plaque and the percent of patients in each of the three age groups and the percent of coronary arteries signiﬁcantly narrowed in each of the three age groups was similar.

REFERENCES 1.

Waller BF, Roberts WC. Cardiovascular disease in the very elderly. Analysis of 40 necropsy patients aged 90 years or over. Am J Cardiol 1983; 51:403–421. 2. Lie JT, Hammond Pl. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clinic Proc 1988; 63:552–564. 3. Gertz SD, Malekzadeh S, Dollar AL, Kragel AH, Roberts WC. Composition of atherosclerotic plaques in the four major epicardial coronary arteries in patients z90 years of age. Am J Cardiol 1991; 67:1228–1233. 4. Roberts WC. Ninety-three hearts z90 years of age. Am J Cardiol 1993; 71:599–602. 5. Shirani J, Youseﬁ J, Roberts WC. Major cardiac ﬁndings at necropsy in 366 American octogenarians. Am J Cardiol 1995; 75:151–156. 6. Roberts WC. The heart at necropsy in centenarians. Am J Cardiol 1998; 81:1224–1225. 7. Roberts WC, Shirani J. Comparison of cardiac ﬁndings at necropsy in octogenarians, nonagenarians, and centenarians. Am J Cardiol 1998; 82:627–631. 8. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med 1980; 303:, 130– 135. 9. Lachman AS, Spray TL, Kerwin DM, Shugoll GI, Roberts WC. Medial calcinosis of Monckeberg. A review of the problem and a description of a patient with involvement of peripheral, visceral, and coronary arteries. Am J Cardiol 1977; 63:615–622. 10. Hammer WJ, Roberts WC, deLeon AC Jr, ‘‘Mitral stenosis’’ secondary to combined ‘‘massive’’ mitral annular calciﬁc deposits and small, hypertrophied left ventricles. Am J Med 1978; 64:371– 376. 11. Roberts WC. Qualitative and quantitative comparison of amounts of narrowing by atherosclerotic plaques in the major epicardial coronary arteries at necropsy in sudden coronary death, transmural acute myocardial infarction, transmural healed myocardial infarction and unstable angina pectoris. Am J Cardiol 1989; 4:324–328.

4 Cardiovascular Drug Therapy in the Elderly William H. Frishman Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A.

Wilbert S. Aronow Westchester Medical Center/New York Medical College, Valhalla, and Mount Sinai School of Medicine, New York, New York, U.S.A.

Angela Cheng-Lai Montefiore Medical Center, Bronx, New York, U.S.A.

Cardiovascular disease is the greatest cause of morbidity and mortality in the elderly, and cardiovascular drugs are the most widely prescribed drugs in this population. Since many cardiovascular drugs have narrow therapeutic windows in the elderly, the incidence of adverse eﬀects from using these drugs is also highest in the elderly. The appropriate use of cardiovascular drugs in the elderly requires knowledge of age-related physiological changes, the eﬀects of concomitant diseases that alter the pharmacokinetic and pharmacodynamic eﬀects of cardiovascular drugs, and drug interactions. PHARMACOKINETIC CONSIDERATIONS IN THE ELDERLY Absorption Age-related physiological changes that may aﬀect absorption include reduced gastric secretion of acid, decreased gastric emptying rate, reduced splanchnic blood ﬂow, and decreased mucosal absorptive surface area (Table 1). Despite these physiological changes, the oral absorption of cardiovascular drugs is not signiﬁcantly aﬀected by aging, probably because most drugs are absorbed passively [1]. Bioavailability There are almost no data available for age-related changes in drug bioavailability for routes of administration other than the oral route [2]. The bioavailability of cardiovascular drugs depends on the extent of drug absorption and on ﬁrst-pass metabolism by the liver and/or 95

Reduced glomerular ﬁltration, renal tubular function, and renal blood ﬂow

Result

Accumulation of renally cleared drugs

Accumulation of metabolized drugs

Increased Vd of highly lipid-soluble drugs Decreased Vd of hydrophilic drugs Changed % of free drug, Vd, and measured levels of bound drugs

Reduced tablet dissolution and decreased solubility of basic drugs Decreased absorption for acidic drugs Less opportunity for drug absorption

Abbreviations: GI, gastrointestinal; ACE, angiotensin converting enzyme. Source: Adapted from Ref. 157.

Excretion

Metabolism

Distribution

Reduced gastric emptying rate Reduced GI mobility, GI blood ﬂow, absorptive surface Decreased total body mass. Increased proportion of body fat Decreased proportion of body water Decreased plasma albumin, disease-related increased a1-acid glycoprotein, altered relative tissue perfusion Reduced liver mass, liver blood ﬂow, and hepatic metabolic capacity

Reduced gastric acid production

Physiological change

Physiological Changes with Aging Potentially Affecting Cardiovascular Drug

Absorption

Process

Table 1

" propranolol, nitrates, lidocaine, diltiazem, warfarin, labetalol, verapamil, mexiletine digoxin, ACE inhibitors, antiarrhythmic drugs, atenolol, sotalol, nadolol

" digoxin and ACE inhibitors " disopyramide and warfarin, lidocaine, propranolol

# h-blockers, central a-agonists

Drugs aﬀected

96 Frishman et al.

Cardiovascular Drug Therapy

97

the wall of the gastrointestinal (GI) tract. In the elderly, the absolute bioavailability of drugs such as propranolol, verapamil, and labetalol is increased because of reduced ﬁrst-pass hepatic extraction [3]. However, the absolute bioavailability of prazosin in the elderly is reduced [4]. Drug Distribution With aging there is a reduction in lean body mass [5] and in total body water [6], causing a decrease in volume of distribution (Vd) of hydrophilic drugs. This leads to higher plasma concentrations of hydrophilic drugs such as digoxin and angiotensin converting enzyme (ACE) inhibitors with ﬁrst dose in the elderly [7]. The increased proportion of body fat that occurs with aging also causes an increased Vd for lipophilic drugs. This leads to lower initial plasma concentrations for lipophilic drugs such as most beta-blockers, antihypertensive drugs, and central alpha-agonists. The level of alpha1-acid glycoprotein increases in the elderly [8]. Weak bases such as disopyramide, lidocaine, and propranolol bind to alpha1-acid glycoprotein. This may cause a reduction in the free fraction of these drugs in the circulation, a decreased Vd, and a higher initial plasma concentration [9]. In the elderly, there is also a tendency for plasma albumin concentration to be reduced [10]. Weak acids, such as salicylates and warfarin, bind extensively to albumin. Decreased binding of drugs such as warfarin to plasma albumin may result in increased free-drug concentrations, resulting in more intense drug eﬀects [11]. Half-Life The half-life of a drug (or of its major metabolite) is the length of time in hours that it takes for the serum concentration of that drug to decrease to one-half of its peak level. This can be described by the kinetic equation: t1/2 = 0.693Vd/Cl, where t1/2 is directly related to drug distribution and inversely to clearance. Therefore, changes in Vd and/or Cl due to aging, as previously mentioned, can aﬀect the half-life of a drug. In elderly patients, an increased halflife of a drug means a longer time until steady-state conditions are achieved. With a prolonged half-life of a drug, there may be an initial delay in maximum eﬀects of the drug and prolonged adverse eﬀects. Table 2 lists the pharmacokinetic changes, routes of elimination, and dosage adjustment for common cardiovascular drugs used in the elderly. Drug Metabolism Decreased hepatic blood ﬂow, liver mass, liver volume, and hepatic metabolic capacity occur in the elderly [12]. There is a reduction in the rate of many drug oxidation reactions (phase 1) and little change in drug conjugation reactions (phase 2). These changes in the elderly may result in higher serum concentrations of cardiovascular drugs metabolized in the liver, including propranolol, lidocaine, labetalol, verapamil, diltiazem, nitrates, warfarin, and mexiletine. Drug Excretion With aging there is a reduction in the total numbers of functioning nephrons and thereby a parallel decline in both glomerular ﬁltration rate and renal plasma ﬂow [13,14]. The age-

98

Frishman et al.

Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly Drug

T 1/2

Primary route(s) of elimination

VD

CI

Alpha-Adrenergic Agonists Centrally Acting Clonidine -

-

-

Hepatic/renal

Guanabenz

-

-

-

Hepatic

Guanfacine

"

-

#

Hepatic/renal

Methyldopa

-

-

-

Hepatic

"

"*

Hepatic

Alpha1-Selective Adrenergic Antagonists Peripherally Acting Doxazosin "

Dosage adjustment

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Prazosin

"

-

-

Hepatic

Terazosin

"

-

-

Hepatic

" NS

-

# #

Renal Renal

Enalapril

-

-

-

Renal

Fosinopril Lisinopril

"

NS

#

Hepatic/renal Renal

Moexipril

-

-

-

Hepatic/renal

Perindopril

-

-

#

Renal

Quinapril

-

-

-

Renal

Ramipril

-

-

-

Renal

Trandolapril

-

-

-

Hepatic/renal

No adjustment needed Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment needed Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment needed

NS "

-

# -

Hepatic/renal Hepatic/fecal/renal Hepatic Hepatic Renal/biliary Hepatic/biliary Hepatic

No No No No No No No

Angiotensin Converting Enzyme Inhibitors Benazepril Captopril

Angiotensin-II Receptor Blockers Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan

adjustment adjustment adjustment adjustment adjustment adjustment adjustment

needed needed needed needed needed needed needed

Cardiovascular Drug Therapy

99

Table 2 Continued Drug

Primary route(s) of elimination

T 1/2

VD

CI

Class I Disopyramide

"

-

#

Renal

Flecainide

"

"

#

Hepatic/renal

Lidocaine

"

"

NS

Hepatic

Mexilitine

-

-

-

Hepatic

Moricizine

-

-

-

Hepatic

Procainamide

-

-

#

Renal

Propafenone

-

-

-

Hepatic

Quinidine

"

NS

#

Hepatic

Tocainide

"

-

#

Hepatic/renal

Class III Amiodarone

-

-

-

Hepatic/biliary

Bretylium

-

-

-

Renal

Dofetilide

-

-

-

Hepatic/renal

Ibutilide Sotalol

-

-

-

Hepatic Renal

Dosage adjustment

Antiarrhythmic Agents Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Class II (see b-Blockers) Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment needed Adjust dose based on renal function

Class IV (see Calcium Channel Blockers) Other Antiarrhythmics Adenosine

-

-

-

Atropine

-

-

-

Anticoagulants Heparin

-

-

-

Ardeparin Argatroban Bivalirudin

-

-

-

Erythrocytes/vascular endothelial cells Hepatic/renal

No adjustment needed Use usual dose with caution

Antithrombotics Hepatic/reticuloendothelial system Renal Hepatic/biliary Renal/proteolytic cleavage

Use usual dose with caution Use usual dose with caution Use usual dose with caution Adjust dose based on renal function

100

Frishman et al.

Table 2 Continued Drug

Primary route(s) of elimination

Dosage adjustment

T 1/2

VD

CI

NS " "

NS -

NS # #

Renal Renal Renal Renal Renal

-

-

-

Renal

NS

NS

NS

Antiplatelets Aspirin Abciximab Anagrelide Clopidogrel Dipyridamole Eptiﬁbatide Ticlopidine Tiroﬁban

NS "

-

# # #

Hepatic/renal Unknown Hepatic/renal Hepatic Hepatic/biliary Renal/plasma Hepatic Hepatic

Use Use Use Use Use Use Use Use

usual usual usual usual usual usual usual usual

dose dose dose dose dose dose dose dose

with with with with with with with with

caution caution caution caution caution caution caution caution

Thrombolytics Alteplase Anistreplase Reteplase Streptokinase

-

-

-

Use Use Use Use

usual usual usual usual

dose dose dose dose

with with with with

caution caution caution caution

Tenecteplase Urokinase Chlorothiazide

-

-

-

Hepatic Unknown Hepatic Circulating antibodies/ reticuloendothelial system Hepatic Hepatic Renal

Chlorthalidone

-

-

-

Renal

Hydrochlorothiazide

-

-

#

Renal

Hydroﬂumethiazide

-

-

-

Unknown

Indapamide

-

-

-

Hepatic

Methyclothiazide

-

-

-

Renal

Metolazone

-

-

-

Renal

Polythiazide

-

-

-

Unknown

Quinethazone

-

-

-

Unknown

Trichlormethiazide

-

-

-

Unknown

Dalteparin Danaparoid Enoxaparin Fondaparinux Lepirudin Tinzaparin Warfarin

Hepatic

Use usual dose with caution Use usual dose with caution Use usual dose with caution Use usual dose with caution Adjust dose based on renal function Use usual dose with caution Initiate at lowest dose; titrate to response

Use usual dose with caution Use usual dose with caution Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Cardiovascular Drug Therapy

101

Table 2 Continued Drug

Primary route(s) of elimination

Dosage adjustment

T 1/2

VD

CI

Potassium-Sparing Amiloride

-

-

#

Renal

Initiate at lowest dose; titrate to response

Eplerenone Spironolactone

-

-

-

Hepatic/renal

Triamterene

"

-

-

Hepatic/renal

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

-

-

Hepatic/biliary

Use usual dose with caution

Human B-Type Natriuretic Peptide Nesiritide -

-

Cellular internalization and lysosomal proteolysis/proteolytic cleavage/renal ﬁltration

Use usual dose with caution

Inotropic and Vasopressor Agents Inamrinone -

-

Hepatic/renal

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment necessary Adjust based on renal function Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Endothelin Receptor Antagonist Bosentan -

Digoxin

"

#

#

Renal

Dobutamine

-

-

-

Hepatic/tissue

Dopamine

-

-

-

Renal/hepatic/plasma

Epinephine

-

-

-

Isoproterenol

-

-

-

Sympathetic nerve endings/plasma Renal

Metaraminol

-

-

-

Unknown

Methoxamine

-

-

-

Unknown

Midodrine Milrinone

-

-

-

Tissue/hepatic/renal Renal

Norepinephrine

-

-

-

Sympathetic nerve endings/plasma Hepatic/intestinal

BAS Cholestyramine

-

-

-

Colestipol

-

-

-

Not absorbed from GI tract Not absorbed from GI tract

Phenylephrine Lipid-Lowering Agents

No adjustment needed No adjustment needed

102

Frishman et al.

Table 2 Continued Drug Colesevelam

Primary route(s) of elimination

Dosage adjustment

T 1/2

VD

CI

-

-

-

Not absorbed from GI tract

No adjustment needed

-

-

Renal

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

SCAI Ezetimibe b-Adrenergic Blockers Nonselective without ISA Nadolol NS Propranolol

"

NS

#

Hepatic

Timolol

-

-

-

Hepatic

NS

#

Renal

b1 Selective without ISA Atenolol "

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use at usual dose with caution Initiate at lowest dose; titrate to response

Betaxolol

-

-

-

Hepatic

Bisoprolol

-

-

-

Hepatic/renal

Esmolol

-

-

-

Erythrocytes

NS

NS

NS

Nonselective with ISA Carteolol

-

-

-

Renal

Penbutolol Pindolol

-

-

-

Hepatic Hepatic/renal

Selective with ISA Acebutolol

"

#

-

Hepatic/biliary

Initiate at lowest dose; titrate to response

Dual Acting Carvedilol

-

-

-

Hepatic/biliary

Labetalol

-

-

NS

Hepatic

Initiate at lowest dose; titrate to response No adjustment needed

Calcium Channel Blockers Amlodipine "

-

#

Hepatic

Metoprolol

Hepatic

Bepridil Diltiazem

"

NS

#

Hepatic Hepatic

Felodipine

-

NS

#

Hepatic

Isradipine

-

-

-

Hepatic

NS

-

-

Hepatic

Nicardipine

Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response

Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment needed

Cardiovascular Drug Therapy

103

Table 2 Continued Drug

Primary route(s) of elimination

T 1/2

VD

CI

Nifedipine

"

NS

#

Hepatic

Nimodipine

-

-

-

Hepatic

Nisoldipine

-

-

-

Hepatic

Verapamil

"

NS

#

Hepatic

Loop Bumetanide

-

NS

-

Renal/hepatic

Ethacrynic Acid

-

-

-

Hepatic

Furosemide

"

NS

#

Renal/hepatic

Torsemide

-

-

-

Hepatic

Thiazides Bendroﬂumethiazide

-

-

-

Renal

Benzthiazide

-

-

-

Renal

FADS Cloﬁbrate

-

-

-

Hepatic/renal

Fenoﬁbrate Gemﬁbrozil Nicotinic Acid

-

-

-

Renal Hepatic/renal Hepatic/renal

" -

– -

-

Hepatic/biliary Hepatic Hepatic/fecal Hepatic

-

-

-

Hepatic/fecal

-

-

-

Hepatic/renal

Guanethidine

-

-

-

Hepatic/renal

Mecamylamine

-

-

-

Renal

Reserpine

-

-

-

Hepatic/fecal

Dosage adjustment Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Diuretics

HMG CoA Reductase Inhibitors Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin Neuronal and Ganglionic Blockers Guanadrel

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Adjust based on renal function No adjustment necessary No adjustment necessary No adjustment necessary

No adjustment necessary No adjustment necessary No adjustment necessary Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

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Table 2 Continued Drug

Primary route(s) of elimination

Dosage adjustment

T 1/2

VD

CI

-

-

-

Hepatic/renal

Initiate at lowest dose; titrate to response

Vasodilators Alprostadil

-

-

-

Pulmonary/renal

Cilostazol Diazoxide

-

-

-

Hepatic/renal Hepatic/renal

Epoprostenol

-

-

-

Hepatic/renal

Fenoldopam Hydralazine

-

-

-

Hepatic Hepatic

ISDN

-

-

-

Hepatic

NS -

-

NS -

Hepatic Renal

Minoxidil

-

-

-

Hepatic

Nitroglycerin

-

-

-

Hepatic

Nitroprusside

-

-

-

Papaverine

-

-

-

Hepatic/renal/ erythrocytes Hepatic

Initiate at lowest dose; titrate to response No adjustment necessary Initiate at lowest dose; titrate to response Initiate at usual dose with caution No adjustment necessary Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment necessary Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use usual dose with caution

Pentoxifylline Sildenaﬁl

-

-

# -

Hepatic/renal Hepatic/fecal

Trimethaphan

ISMN Isoxsuprine

Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response

* Increase in Cl is small compared to increase in VD; T 1/2, half-life; VD, volume of distribution; Cl, clearance; ", increase; #, decrease; -, no information or not relevant; NS, no signiﬁcant change; LMWH, low-molecular-weight heparin; ISA, intrinsic sympathomimetic activity; GI, gastrointestinal; BAS, bile acid sequestrants; SCAI, selective cholesterol absorption inhibitors; FADS, ﬁbric acid derivatives; HMG CoA, hydroxymethylglutaryl coenzyme A; ISDN, isosorbide dinitrate; ISMN, isosorbide mononitrate. Source: From Ref. 158.

related decline in renal function is likely the single most important physiological change causing pharmacokinetic alterations in the elderly. The change in renal function with aging is insidious and poorly characterized by serum creatinine determinations, although serum creatinine measurements remain one of the most widely used tests for gauging renal function. To estimate renal function from a serum creatinine value requires its being indexed for muscle mass, which is diﬃcult in even the most skilled hands. Creatinine is a byproduct of creatine metabolism in muscle and its daily production correlates closely with muscle mass. Thus, the greater the muscle mass, the higher the ‘‘normal serum creatinine.’’ For example, in a heavily muscled male, a serum creatinine value of 1.4 mg/dL might be considered normal, although such a value may be considered grossly abnormal in an individual with

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less muscle, such as an aged individual. A safer way to estimate renal function in the elderly is by use of a urine-free formula such as the Cockcroft–Gault formula [15]: Creatinine clearance ðmL=minÞ ¼

ð140 ageÞ body weight ðkgÞ 72 Screat ðmg=dLÞ

For females, the results of this equation can be multiplied by 0.85 to account for the small muscle mass in most females. It should be appreacited that creatinine clearance is reciprocally related to serum creatinine concentrations, such that a doubling of serum creatinine represents an approximate halving of renal function. The axiom that glomerular ﬁltration rate is reciprocally related to serum creatinine is most important with the ﬁrst doubling of serum creatinine. For example, a serum creatinine value of 0.6 mg/dL in an elderly subject doubles to 1.2 mg/dL and with this doubling creatinine clearance falls from 80 cc/min to about 40 cc/min. The reduced clearance of many drugs primarily excreted by the kidneys causes their half-life to be increased in the elderly. Cardiovascular drugs known to be excreted by the kidney, via various degrees of ﬁltration and tubular secretion, include digoxin, diuretics, ACE inhibitors, antiarrhythmic medications (bretylium, disopyramide, ﬂecainide, procainamide, tocainide) and the beta-blockers (atenolol, bisoprolol, carteolol, nadolol, and sotalol). Typically, a renally cleared compound begins to accumulate when creatinine clearance values drop below 60 cc/min. An example of this phenomenon can be seen with ACE inhibitors [16] wherein accumulation begins early in the course of renal functional decline. Moreover, ACE inhibitor accumulation in the elderly is poorly studied in the case of many of the ACE inhibitors, particularly as relates to the ‘‘true level of renal function’’ when an otherwise healthy elderly subject undergoes formal pharmacokinetic testing. Thus, it has not been uncommon for elderly subjects with serum creatinine values as high as 2.0 mg/dL to be allowed entry into a study whose primary purpose is to determine the diﬀerence in drug handling of a renally cleared compound in young versus elderly subjects.

PHARMACODYNAMICS There are numerous physiological changes with aging that aﬀect pharmacodynamics with alterations in end-organ responsiveness (Table 3). Increased peripheral vascular resistance is the cause of systolic and diastolic hypertension in the elderly [17]. Inappropriate sodium intake and retention may contribute to increased arteriolar resistance and/or plasma volume. Cardiac output, heart rate, renal blood ﬂow, glomerular ﬁltration rate, and renin levels decline with aging. Increased arterial stiﬀness, resulting from changes in the arterial media and an increase in arterial tonus and arterial impedance, increases systolic blood pressure, and contributes to a widened pulse pressure. Maintenance of alpha-adrenergic vasoconstriction with impaired beta-adrenergic-mediated vasodilation may be an additional contributory factor to increased peripheral vascular resistance. The cardiovascular response to catecholamines as well as carotid arterial baroreﬂex sensitivity are both decreased in the elderly. Left ventricular (LV) mass and left atrial dimension are increased, and there is a reduction in both the LV early diastolic ﬁlling rate and volume [17]. The pharmacodynamic, chronotropic, and inotropic eﬀects of beta-agonists and betablockers on beta1-adrenergic receptors are diminished in the elderly [18–20]. The density of beta-receptors in the heart is unchanged in the elderly, but there is a decrease in the ability of

106 Table 3

Frishman et al. Characteristics of the Elderly Relative to Drug Response

Physiological changes Decreased cardiac reserve Decreased LV compliance due to thickened ventricular wall, increased blood viscosity, decreased aortic compliance, increased total and peripheral resistance Decreased baroreceptor sensitivity Diminished cardiac and vascular responsiveness to h-agonists and antagonists Suppressed renin-angiotensin-aldosterone system Increased sensitivity to anticoagulant agents Concurrent illnesses Multiple drugs Sinus and AV node dysfunction

Changes in response Potential for heart failure Decrease of cardiac output

Tendency to orthostatic hypotension Decreased sensitivity to h-agonists and antagonists Theoretically decreased response to ACE inhibitors, but not observed Increased eﬀects of warfarin Increased drug–disease interactions Increased drug–drug interactions Potential for heart block

Abbreviations: LV, left ventricular; ACE, angiotensin converting enzyme; AV, atrioventricular. Source: Adapted from Ref. 157.

beta-receptor agonists to stimulate cyclic adenosine monophosphate production [21]. There are also age-related changes in the cardiac conduction system, as well as an increase in arrhythmias in the elderly. In the Framingham Study, the prevalence of atrial ﬁbrillation was 1.8% in persons 60 to 69 years old, 4.8% in those 70 to 79 years old, and 8.8% in those 80 to 89 years old [22]. In a study of 1153 elderly patients (mean age 82 years), the prevalence of atrial ﬁbrillation was 13% [23]. In elderly patients with unexplained syncope, a 24-h ambulatory electrocardiogram (ECG) should be obtained to rule out the presence of second- or third-degree atrioventricular block or sinus node dysfunction with pauses >3 not seen on the resting ECG. These phenomena were observed in 21 of 148 patients (14%) with unexplained syncope [24]. These 21 patients included 8 with sinus arrest, 7 with advanced second-degree atrioventricular block, and 6 with atrial ﬁbrillation with a slow ventricular rate not drug induced. Unrecognized sinus node or atrioventricular node dysfunction may become evident in elderly persons after drugs such as amiodarone, beta-blockers, digoxin, diltiazem, procainamide, quinidine, or verapamil are administered. Clinical use of these drugs in the elderly, therefore, must be carefully monitored. USE OF CARDIOVASCULAR DRUGS IN THE ELDERLY Digoxin Digoxin has a narrow toxic–therapeutic ratio, especially in the elderly [25]. Decreased renal function and lean body mass may increase serum digoxin levels in this population. Serum creatinine may be normal in elderly persons despite a marked reduction in creatinine clearance, thereby decreasing digoxin clearance and increasing serum digoxin levels. Older persons are also more likely to take drugs that interact with digoxin by interfering with bioavailability and/or elimination. Quinidine, cyclosporin, itraconazole, calcium preparations, verapamil, amiodarone, diltiazem, triamterene, spironolactone, tetracycline, erythromycin, propafenone, and propantheline can increase serum digoxin levels. Hypokalemia,

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hypomagnesemia, hypercalcemia, hypoxia, acidosis, acute and chronic lung disease, hypothyroidism, and myocardial ischemia may also cause digitialis toxicity despite normal serum digoxin levels. Digoxin may also cause visual disturbances [26], depression, and confusional states in older persons, even with therapeutic blood levels. Indications for using digoxin are slowing a rapid ventricular rate in patients with supraventricular tachyarrhythmias such as atrial ﬁbrillation, and treating patients with congestive heart failure (CHF) in sinus rhythm associated with abnormal LV ejection fraction that does not respond to diuretics and ACE inhibitors, or in patients unable to tolerate ACE inhibitors or other vasodilator therapy. Digoxin should not be used to treat patients with CHF in sinus rhythm associated with normal LV ejection fraction. By increasing contractility through increasing intracellular calcium ion concentration, digoxin may increase LV stiﬀness and increase LV ﬁlling pressures, adversely aﬀecting LV diastolic dysfunction. Since almost half the elderly patients with CHF have normal LV ejection fractions [27,28], LV ejection fraction should be measured in all older patients with CHF, so that appropriate therapy may be given [29]. Many older patients with compensated CHF who are in sinus rhythm and are on digoxin may have digoxin withdrawn without decompensation in cardiac function [30,31]. Therapeutic levels of digoxin do not reduce the frequency or duration of episodes of paroxysmal atrial ﬁbrillation detected by 24-h ambulatory ECGs [32]. In addition, therapeutic concentrations of digoxin do not prevent the occurrence of a rapid ventricular rate in patients with paroxysmal atrial ﬁbrillation [32,33]. Many elderly patients are able to tolerate atrial ﬁbrillation without the need for digoxin therapy because the ventricular rate is slow as a result of concomitant atrioventricular nodal disease. Some studies have suggested that digoxin may decrease survival after acute myocardial infarction (MI) in patients with LV dysfunction [34,35]. Leor et al. [36] showed that digoxin may exert a dose-dependent deleterious eﬀect on survival in patients after acute MI, although other studies have not conﬁrmed this ﬁnding [37,38]. Eberhardt et al. [39] demonstrated in the Bronx Longitudinal Aging Study that digoxin use in the elderly without evidence of CHF was an independent predictor of mortality. The results of the Digitalis Investigators Group Trial demonstrated that digoxin could be used in older subjects with CHF, but in lower doses than that previously employed in clinical practice [40]. Diuretics The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommended as initial drug treatment of hypertension thiazidelike diuretics or beta-blockers because these drugs had been demonstrated to reduce cardiovascular morbidity and mortality in controlled clinical trials [41]. Moreover, the results of the Systolic Hypertension in the Elderly (SHEP) trial speciﬁcally show the safety and eﬃcacy of a diuretic and beta-blocker in the treatment of isolated systolic hypertension in the elderly [42]. In the elderly, a blanket recommendation for the starting medication in the treatment of hypertension is ill-advised, in part because of the presence of comorbid conditions. For example, older hypertensive patients with systolic heart failure and a reduced LV ejection fraction [43–45] or in those elderly with a normal LV ejection fraction [46], therapy should include both a diuretic and an ACE inhibitor. Loop diuretics remain ﬁrst-line drug therapy in the treatment of patients with decompensated CHF. Diuretics are multifaceted in their eﬀect in CHF. First, they eﬀect a reduction in plasma volume by triggering a time-dependent natriuretic response. This drop in plasma volume reduces venous return and thereby decreases ventricular ﬁlling pressures.

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These volume changes facilitate relief of congestive symptomatology, such as peripheral and/or pulmonary edema. Intravenous loop-diuretic therapy has also been shown to increase central venous capacitance, which may further contribute to improvement in congestive symptomatology. Both loop and thiazidelike diuretics undergo a mixed pattern of renal/hepatic elimination with the component of renal clearance being responsible for diuresis [47]. Age-related decreases in renal function may reduce the eﬃcacy of conventional doses of diuretics in elderly patients. This ‘‘renal function-related resistance’’ can be easily overcome, if recognized, by careful upward titration of the diuretic dose. Resistance to diuretic eﬀect in CHF may also derive from a pattern of variable and unpredictable absorption, particularly with the loop diuretic furosemide. This issue is resolvable with the use of a predictably absorbed loop diuretic, such as torsemide [48]. A thiazidelike diuretic, such as hydrochlorothiazide, may be used in the occasional older patient with mild CHF. However, thiazidelike diuretics have diminished eﬀectiveness at conventional doses when the glomerular ﬁltration rate falls below 30 mL/min; accordingly, older patients with moderate-to-severe CHF should be treated with a loop diuretic, such as furosemide. Older patients with severe CHF or concomitant signiﬁcant renal insuﬃciency may need combination diuretic therapy employing a loop diuretic together with the thiazidelike diuretic metolazone [47]. The slowly and erratically absorbed form of metolazone (ZaroxylynR) is the preferred form when combination therapy is being considered. Nonsteroidal anti-inﬂammatory drugs (NSAIDs) may decrease both the antihypertensive and natriuretic eﬀect of loop diuretics [47]. This is a particular problem when loop diuretics are being employed t manage CHF-related congestive symptomatology [49]. A ﬁnal consideration is the sometimes insidious manner by which NSAIDs can interact with diuretics in that several commonly used NSAIDs are now available over-the-counter. Serum electrolytes need to be closely monitored in older patients treated with diuretics. Hypokalemia and/or hypomagnesemia, both of which may precipitate ventricular arrhythmias and/or digitalis toxicity, can occur with diuretic therapy [50]. Hyponatremia is not uncommon in the elderly treated with diuretics, particularly when thiazidelike diuretics are being employed [51]. Older patients with CHF are especially sensitive to volume depletion with dehydration, hypotension, and prerenal azotemia occurring in the face of excessive diuretic eﬀect. Older patients with CHF and normal LV ejection fraction should receive diuretics more cautiously. Beta-Adrenergic Blockers Beta-blockers are used in various cardiovascular disorders, with resultant beneﬁcial and adverse eﬀects [52]. Beta-blockers are very eﬀective antianginal agents in older, as well as younger, patients. Combined therapy with beta-blockers and nitrates may be more beneﬁcial in the treatment of angina pectoris than either drug alone [52]. Diuretics or beta-blockers have been recommended as initial drug therapy for hypertension in older persons because these drugs have been shown to decrease cardiovascular morbidity and mortality in controlled clinical trials [41,53]. Beta-blockers are especially useful in the treatment of hypertension in older patients who have had a prior MI, angina pectoris, silent myocardial ischemia, complex ventricular arrhythmias, supraventricular tachyarrhythmias, or hypertrophic cardiomyopathy. Teo et al. [54] analyzed 55 randomized controlled trials that investigated the use of beta-blockers in patients after MI. Mortality was signiﬁcantly decreased (19%) in patients receiving beta-blockers compared with control patients. In the Beta-Blocker Heart Attack Trial (BHAT), propranolol signiﬁcantly decreased total mortality by 34% in patients aged

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60 to 69 years, and insigniﬁcantly reduced total mortality by 19% in patients aged 30 to 59 years [55]. In the Norwegian Timolol Study, timolol signiﬁcantly decreased total mortality by 43% in postinfarction patients aged 65 to 75 years, and signiﬁcantly reduced total mortality by 34% in postinfarction patients<65 years of age [56]. Despite the utility of betablockers in post-myocardial-infarction patients, they are still being underutilized in older patients [57,58]. Beta-blockers decrease complex ventricular arrhythmias including ventricular tachycardia (59–62). Beta-blockers also increase the ventricular ﬁbrillation threshold in animal models, and have been shown to reduce the incidence of ventricular ﬁbrillation in patients with acute MI (63). A randomized, double-blind, placebo-controlled study of propranolol in high-risk survivors of acute MI at 12 Norwegian hospitals demonstrated that patients treated with propranolol for 1 year had a statistical signiﬁcant 52% decrease in sudden cardiac death [60]. In addition, beta-blockers decrease myocardial ischemia [61,62,64] which may reduce the likelihood of ventricular ﬁbrillation. Stone et al. [64] demonstrated by 48-h ambulatory ECGs in 50 patients with stable angina pectoris that propranolol, not diltiazem or nifedipine, caused a signiﬁcant decrease in the mean number of episodes of myocardial ischemia and in the mean duration of myocardial ischemia compared with placebo. Furthermore, beta-blockers reduce sympathetic tone. Studies have demonstrated that beta-blockers reduce mortality in older and younger patients with complex ventricular arrhythmias and heart disease (Table 4) [55,61,62,65–67]. In the BHAT of 3290 patients comparing propranolol with placebo, propranolol reduced sudden cardiac death by 28% in patients with complex ventricular arrhythmias and by 16% in patients without ventricular arrhythmias [55]. Hallstrom et al. [65] did a retrospective analysis of the eﬀect of antiarrhythmic drug use in 941 patients resuscitated from prehospital cardiac arrest due to ventricular ﬁbrillation between 1970 and 1985. Beta-blockers were administered to 28% of the patients, and no antiarrhythmic drug to 39%. There was a reduced incidence of death or recurrent cardiac arrest in patients treated with beta-blockers versus no antiarrhythmic drug (relative risk 0.47; adjusted relative risk 0.62). Aronow et al. [61] performed a prospective study in 245 elderly patients (mean age 81 years) with heart disease (64% with prior MI and 36% with hypertensive heart disease), complex ventricular arrhythmias diagnosed by 24-h ambulatory ECGs, and LV ejection fraction z40%. Nonsustained ventricular tachycardia occurred in 32% of patients. Myocardial ischemia occurred in 33% of patients. Mean follow-up was 30 months in patients randomized to propranolol and 28 months in patients randomized to no antiarrhythmic drug. Propranolol was discontinued because of adverse eﬀects in 11% of patients. Follow-up 24-h ambulatory ECGs showed that propranolol was signiﬁcantly more eﬀective than no antiarrhythmic drug in reducing ventricular tachycardia (>90%), in decreasing the average number of ventricular premature complexes per hour (>70%), and in abolishing silent ischemia. Multivariate Cox regression analysis showed that propranolol caused a signiﬁcant 47% decrease in sudden cardiac death, a signiﬁcant 37% reduction in total cardiac death, and an insigniﬁcant 20% decrease in total death [61]. Univariate Cox regression analysis showed that the reduction in mortality and complex ventricular arrhythmias in elderly patients with heart disease taking propranolol was due more to an anti-ischemic eﬀect than to an antiarrhythmic eﬀect [62]. Table 4 also shows that there was a circadian distribution of sudden cardiac death or fatal MI, with the peak incidence occurring from 6 a.m. to 12 a.m. (peak hour 8 a.m. and secondary peak around 7 p.m.) in patients treated with no

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Table 4 Effect of h-Blockers on Mortality in Elderly Patients with Complex Ventricular Arrhythmias and Heart Disease Age (yrs)

Mean follow-up (mos)

BHAT (55)

60-69 (33%)

25

Hallstrom (65)

62 (mean)

Aronow et al. (61)

62-96 (mean 81)

29

Aronow et al. (62)

62-96 (mean 81)

29

Aronow et al. (66)

62-96 (mean 81)

29

CAST (67)

66-79 (40%)

12

Study

108

Results Compared with placebo, propranolol reduced sudden cardiac death by 28% in patients with complex VA and 16% in patients without VA. Reduced incidence of death or recurrent cardiac arrest in patients treated with h-blockers vs. no antiarrhythmic drug (adjusted relative risk 0.62). Compared with no antiarrhythmic drug, propranolol caused a 47% signiﬁcant decrease in sudden cardiac death, a 37% signiﬁcant reduction in total cardiac death, and a 20% insigniﬁcant decrease in total death. Among patients taking propranolol, suppression of complex VA caused a 33% reduction in sudden cardiac death, a 27% decrease in total cardiac death, and a 30% reduction in total death; abolition of silent ischemia caused a 70% decrease in sudden cardiac death, a 72% reduction in total cardiac death, and a 69% decrease in total death. Incidence of sudden cardiac death or fatal myocardial infarction was signiﬁcantly increased between 6 A.M. and 12 A.M. with peak hour at 8 A.M. and secondary peak at 7 P.M. in patients with no antiarrhythmic drug; propranolol abolished the circadian distribution of sudden cardiac death or fatal myocardial infarction. Patients on h blockers (30% of study group) had a signiﬁcant reduction in all-cause mortality of 43% at 30 days, 46% at 1 year, and 33% at 2 years: in patients on h-blockers, arrhythmic death or cardiac arrest was signiﬁcantly reduced by 66% at 30 days, 53% at 1 year, and 36% at 2 years; multivariate analysis showed h-blockers to be an independent factor for reduced arrhythmic death or cardiac arrest by 40% and for all-cause mortality by 33%.

Abbreviations: BHAT, Beta Blocker Heart Attack Trial; VA, ventricular arrhythmias; CAST, Cardiac Arrhythmia Suppression Trial. Source: Reproduced from Ref. 159.

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antiarrhythmic drug [66]. Propranolol abolished this circadian distribution of sudden cardiac death or fatal MI [66]. In a retrospective analysis of data from the Cardiac Arrhythmia Suppression Trial (CAST), Kennedy et al. [67] found that 30% of patients with an LV ejection fraction V40% were receiving beta-blockers. Forty percent of these 1735 patients were between 66 and 79 years of age. Patients on beta-blockers had a signiﬁcant reduction in all-cause mortality of 43% within 30 days, 46% at 1 year, and 33% at 2 years. Patients receiving beta-blockers also had a signiﬁcant decrease in arrhythmic death or cardiac arrest of 66% at 30 days, 53% at 1 year, and 36% at 2 years. Multivariate analysis showed that beta-blockers were an independent factor for reducing arrhythmic death or cardiac arrest by 40%, for decreasing all-cause mortality by 33%, and for reducing the occurrence of new or worsening CHF by 32%. On the basis of these data (55,61,62,65–67), beta-blockers can be utilized in the treatment of older and younger patients with ventricular tachycardia or complex ventricular arrhythmias associated with ischemic or nonischemic heart disease, and with normal or abnormal LV ejection fraction, if there are no absolute contraindications to the drugs. Beta-blockers are also useful in the treatment of supraventricular tachyarrhythmias in older and younger patients [68,69]. If a rapid ventricular rate associated with atrial ﬁbrillation persists at rest or during exercise despite digoxin therapy, then verapamil [70], diltiazem [71], or a beta-blocker [72] should be added to the therapeutic regimen. These drugs act synergistically with digoxin to depress conduction through the atrioventricular junction. The initial oral dose of propranolol is 10 mg q6h, which can be increased to a maximum of 80 mg q6h if necessary. Beta-blockers have been demonstrated to reduce mortality in older persons with New York Heart Association Class II–IV CHF and abnormal LV ejection fraction treated with diuretics and ACE inhibitors with or without digoxin [73–77]. Beta-blockers have also been shown to reduce mortality in older persons with New York Heart Association Class II–III CHF and normal LV ejection fraction treated with diuretics plus ACE inhibitors [78]. Numerous drug interactions have been reported with beta-blockers in the elderly [52]. Recently, quinidine, a known inhibitor of CYP2D6, was shown to decrease the hepatic metabolism of topically applied ophthalmic timolol, with resultant exaggeration of the betablocking eﬀect of timolol [79]. ACE Inhibitors ACE inhibitors are eﬀective antihypertensive agents. A meta-analysis of 109 treatment studies showed that ACE inhibitors are more eﬀective than other antihypertensive drugs in decreasing LV mass [80]. Older hypertensive patients with CHF associated with abnormal [43–45] or normal [46] LV ejection fraction, LV hypertrophy, or diabetes mellitus, should initially be treated with an ACE inhibitor. ACE inhibitors reduce mortality in patients with CHF associated with abnormal LV ejection fraction [43–45]. The Survival and Ventricular Enlargement (SAVE) trial [81] and the combined Studies of Left Ventricular Dysfunction (SOLVD) treatment and prevention trials [82] also demonstrated that ACE inhibitors such as captopril or enalapril should be standard therapy for most patients with signiﬁcant LV systolic dysfunction with or without CHF. In addition, ACE inhibitor therapy has been shown to be beneﬁcial in the treatment of elderly patients (mean age 80 years) with CHF caused by prior MI associated with normal LV ejection fraction [46]. High-dose ACE inhibitor therapy remains standard-of-care in the management of CHF. Low-dose ACE inhibitor therapy has been studied in CHF, but with

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less favorable results. For example, a recent trial compared low (2.5–5.0 mg/day) with highdose lisinopril (32.5–35.0 mg/day), with the latter being associated with a more signiﬁcant reduction in mortality and all-cause hospitalization rate [83]. Treatment with ACE inhibitors should be initiated in elderly patients in low doses after correction of hyponatremia or volume depletion. It is important to avoid overdiuresis before beginning therapy with ACE inhibitors since volume depletion may cause hypotension or renal insuﬃciency when ACE inhibitors are begun or when the dose of these drugs is increased to full therapeutic levels. After the maintenance dose of ACE inhibitor is reached, it may be necessary to increase the dose of diuretics. The initial dose of enalapril is 2.5 mg daily and of captopril is 6.25 mg TID. The maintenance doses are 5 to 20 mg daily and 25 to 50 mg TID, and the maximum doses are 20 mg BID and 150 mg TID, respectively. Older patients at risk for excessive hypotension should have their blood pressure monitored closely fo the ﬁrst 2 weeks of ACE inhibitor or angiotensin II receptor blocking therapy, and thereafter whenever the dose of ACE inhibitor or diuretic is increased. Renal function should be monitored in patients on ACE inhibitors to detect increases in blood urea nitrogen and serum creatinine, especially in older patients with renal artery stenosis. A rise in serum creatinine in an ACE inhibitor–treated congestive heart failure patient is not uncommonly the result of ACE inhibitor–induced alterations in renal hemodynamics. There is no speciﬁc rise in serum creatinine where corrective actions need be taken although logic would suggest the greater the increment in serum creatinine the more important the intervention. Typically, reducing or temporarily discontinuing diuretics and/or liberalizing sodium intake are suﬃcient measures to return renal function to baseline. Not uncommonly, though, the administered ACE inhibitor is either stopped or the dose reduced. In most instances, ACE inhibitor therapy can be safely resumed as long as careful attention is paid to patient volume status [84]. Potassium-sparing diuretics or potassium supplements should be carefully administered to patients receiving ACE inhibitor therapy because of the attendant risk of hyperkalemia. In this regard, the recently concluded Randomized Aldactone Evaluation Study (RALES) showed that in persons with severe CHF treated with diuretics, ACE inhibitors, and digoxin compared with placebo, spironolactone 25 mg/ day did not carry an excessive risk of hyperkalemia, while resulting in a signiﬁcant reduction in mortality and hospitalization for CHF [85]. Angiotensin-II Receptor Blockers Angiotensin-II receptor blockers (ARBs) are the newest class of antihypertensive drugs to be approved. They have been studied fairly extensively in hypertension [86–88], diabetic nephropathy [89], and CHF [90], with results comparable to those seen when these disease states are treated with ACE inhibitors. Although the published experience with these drugs in the elderly is limited, the drugs appear to be safe if used with similar precautions as those recommended for ACE inhibitors, as described above [86,88]. These drugs are noteworthy in that they have a much more favorable side-eﬀect proﬁle and, in particular, are not associated with cough, a fairly common side eﬀect with ACE inhibitor therapy [87]. Likewise, in the Losartan Heart Failure Survival Study (ELITE II), losartan was associated with fewer adverse eﬀects than was captopril [91]. Outcomes studies are supportive of ARBs, such as losartan and irbesartan, being superior to conventional non-ACE-inhibitor– based therapy in decreasing end-stage renal failure event rates in patients with type II diabetic nephropathy [92,93]. In CHF the hope that ARBs are more eﬀective therapy than ACE inhibitors has not been realized, as of yet, although additional studies are underway to establish the positioning of ARB in current heart failure regimens.

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Nitrates Nitrates are eﬀective therapies for older individuals; however, caution should always be used because of the associated dangers of orthostatic hypotension, syncope, and falls, especially if the treatment is combined with diuretics and other vasodilators. Recently, it was shown that nitrate headaches are less frequent in older patients and in individuals with renal dysfunction [94]. Calcium Channel Blockers Calcium channel blockers are eﬀective antihypertensive and antianginal drugs in older patients. Verapamil [70] and diltiazem [71] are especially valuable in treating hypertensive patients who also have supraventricular tachyarrhythmias. However, recent reports have suggested an increased mortality risk with calcium channel blockers, especially with the use of short-acting dihydropyridines in older subjects [95–97]. With the use of longer-acting calcium blockers, such as the dihydropyridine nitrendipine, a strong mortality beneﬁt was seen in patients with isolated systolic hypertension [98], although many were receiving concurrent beta-blocker therapy. In contrast, nisoldipine was shown to be less eﬀective in protecting against cardiovascular mortality in diabetic patients with hypertension when compared to an enalapril-treated group [99]. Verapamil improved exercise capacity, peak LV ﬁlling rate, and a clinicoradiographic heart failure score in patients with CHF, normal LV ejection fraction, and impaired LV diastolic ﬁlling [100]. However, calcium channel blockers such as verapamil, diltiazem, and nifedipine may exacerbate CHF in patients with associated abnormal LV ejection fraction [101]. In addition, some calcium channel blockers have been shown to increase mortality in patients with CHF and abnormal LV ejection fraction after myocardial infraction [102]. Therefore, calcium channel blockers such as verapamil, diltiazem and nifedipine may be used to treat older patients with CHF associated with normal LV ejection fraction, but are contraindicated in treating older patients with CHF associated with abnormal LV ejection fraction. Amlodipine and felodipine are two vasculospeciﬁc dihydropyridine agents that appear to be safer in patients having CHF, although neither of these drugs should be used to exclusion of ACE inhibitors in the CHF patient. The age-associated decrease in hepatic blood ﬂow and hepatic metabolic capacity may result in higher serum concentrations of verapamil, diltiazem, and nifedipine [103]. Therefore, these drugs should be given to older persons in lower starting doses and titrated carefully. Alpha-Adrenergic Blockers Alpha-adrenergic blockers are eﬀective treatments for patients with hypertension and have become ﬁrst-line treatments for males with symptomatic prostatism. Caution should be exercised when using these agents because of a signiﬁcant incidence of postural hypotension, especially in patients receiving diuretics or other vasodilator drugs [104,105]. A more selective alpha-blocker, tamsulosin, has become available, which improves prostatism symptoms without having vasodilator eﬀects [106]. Recently, the National Heart, Lung and Blood Institute announced that doxazosin was being withdrawn from the ALLHAT trial after an interim analysis showed a 25% greater rate of a secondary endpoint, combined cardiovascular disease, in patients on doxazosin than in those on chlorthalidone, largely

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driven by the increased risk of CHF [107]. These ﬁndings have cast a shroud over the use of doxazosin in the elderly, particularly if it is being contemplated as monotherapy in an elderly hypertensive. Lidocaine I.V. lidocaine may be used to treat complex ventricular arrhythmias during acute myocardial infarction [68]. Lidocaine toxicity is more common in the elderly and older patients should be monitored for dose-related confusion, tinnitus, paresthesias, slurred speech, tremors, seizures, delirium, respiratory depression, and hypotension. Older patients with CHF or impaired liver function are at increased risk for developing central nervous system adverse eﬀects from lidocaine [108]. In these patients, the loading dose should be decreased by 25 to 50%, and any maintenance infusion should be initiated at a rate of 0.5 to 2.5 mg/ min, with the patient monitored closely for adverse eﬀects. The dose of lidocaine should also be reduced if the patient is receiving beta-blockers [109] or cimetidine, since these drugs reduce the metabolism of lidocaine. Other Antiarrhythmic Drugs The use of antiarrhythmic drugs in the elderly is extensively discussed elsewhere [69,110]. In the CAST I trial, encainide and ﬂecainide signiﬁcantly increased mortality in survivors of myocardial infarction with asymptomatic or mildly symptomatic ventricular arrhythmias, when compared to placebo [111]. In the CAST II trial, moricizine insigniﬁcantly increased mortality when compared to placebo [112]. Akiyama et al. [113] found that older age increased the likelihood of adverse events, including death, in patients treated with encainide, ﬂecainide, or moricizine in these two studies. In a retrospective analysis of the eﬀect of empirical antiarrhythmic treatment in 209 cardiac arrest patients who were resuscitated out of hospital, Moosvi et al. [114] found that the 2-year mortality was signiﬁcantly lower for patients treated with no antiarrhythmic drug than for patients treated with quinidine or procainamide. Hallstrom et al. [65] showed an increased incidence of death or recurrent cardiac arrest in patients treated with quinidine or procainamide versus no antiarrhythmic drug. In a prospective study of 406 elderly subjects (mean age 82 years) with heart disease (58% with prior myocardial infarction) and asymptomatic complex ventricular arrhythmias, the incidence of sudden cardiac death, total cardiac death, and total mortality were not signiﬁcantly diﬀerent in patients treated with quinidine or procainamide or with no antiarrhythmic drug [115]. In this study, quinidine or procainamide did not reduce mortality in comparison with no antiarrhythmic drug in elderly patients with presence versus absence of ventricular tachycardia, ischemic or nonischemic heart disease, and abnormal or normal LV ejection fraction. The incidence of adverse events causing drug cessation in elderly patients in this study was 48% for quinidine and 55% for procainamide. A meta-analysis of six double-blind studies of 808 patients with chronic atrial ﬁbrillation who underwent direct current cardioversion to sinus rhythm demonstrated that the 1-year mortality was signiﬁcantly higher in patients treated with quinidine than in patients treated with no antiarrhythmic drug [116]. In the Stroke Prevention in Atrial Fibrillation Study, arrhythmic death and cardiac mortality were also signiﬁcantly increased in patients receiving antiarrhythmic drugs compared with patients not receiving antiarrhythmic drugs, especially in patients with a history of CHF [117].

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Teo et al. [54] analyzed 59 randomized controlled trials comprising 23,229 patients which investigated the use of class I antiarrhythmic drugs after MI. Patients receiving class I antiarrhythmic drugs had a signiﬁcantly higher mortality than patients receiving no antiarrhythmic drugs. None of the 59 trials demonstrated that a class I antiarrhythmic drug decreased mortality in postinfarction patients. Therefore, it is currently not recommended that class I antiarrhythmic drugs be used for the treatment of ventricular tachycardia or complex ventricular arrhythmias associated with heart disease. Amiodarone is very eﬀective in suppressing ventricular tachycardia and complex ventricular arrhythmias. However, there are conﬂicting data about the eﬀect of amiodarone on mortality [118–124]. The Veterans Administration Cooperative Study comparing amiodarone versus placebo in heart failure patients with malignant ventricular arrhythmias was recently completed and showed that amiodarone was very eﬀective in decreasing ventricular tachycardia and complex ventricular arrhythmias, but it did not aﬀect mortality [124]. The incidence of adverse eﬀects from amiodarone has been reported to approach 90% after 5 years of treatment [125]. In the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation Study, the incidence of pulmonary toxicity was 10% at 2 years in patients receiving an amiodarone dose of 158 mg daily [126]. On the basis of these data, one should reserve the use of amiodarone for the treatment of life-threatening ventricular tachyarrhythmias or in patients who cannot tolerate or who do not respond to beta-blocker therapy. Amiodarone is also the most eﬀective drug for treating refractory atrial ﬁbrillation in terms of converting atrial ﬁbrillation to sinus rhythm and slowing a rapid ventricular rate. However, because of the high incidence of adverse eﬀects caused by amiodarone, amiodarone should be used in low doses in patients with atrial ﬁbrillation when life-threatening atrial ﬁbrillation is refractory to other therapy [127]. Lipid-Lowering Drugs The safety of lipid-lowering drugs, speciﬁcally 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, was demonstrated in the Cholesterol Reduction in Seniors Program (CRISP) [128]. Based on CRISP, the Antihypertensive Lipid Lowering Heart Attack Trial (ALLHAT), a large primary prevention trial is now in progress using pravastatin in older subjects to determine whether it reduces morbidity and mortality [129]. In the Scandinavian Simvastatin Survival Study [130], 4444 men and women with coronary artery disease were treated with double-blind simvastatin or placebo. At 5.4 years follow-up, patients treated with simvastatin had a 35% decrease in serum low-density lipoprotein cholesterol, a 25% reduction in serum total cholesterol, an 8% increase in serum high-density lipoprotein cholesterol, a 34% decrease in major coronary events, a 42% reduction in coronary deaths, and a 30% decrease in total mortality. In patients aged 65 to 70 years, simvastatin reduced all-cause mortality 35%, coronary artery disease mortality 43%, major coronary events 34%, nonfatal MI 33%, any atherosclerosis-related endpoint 34%, and coronary revascularization 41% [131]. The absolute risk reduction for both allcause mortality and coronary artery disease mortality was approximately twice as great in persons aged 65 to 70 years compared to persons younger than 65 years [131]. In the Cholesterol and Recurrent Events Trial [132], 4159 men and women aged 21 to 75 years (1283 aged 65–75 years) with MI, serum total cholesterol levels<250 mg/dL, and serum low-density lipoprotein (LDL)-cholesterol levels z115 mg/dL were treated with double-blind pravastatin and placebo. At 5-year follow-up, patients treated with pravas-

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tatin had a 32% reduction in serum LDL-cholesterol, a 20% decrease in serum total cholesterol, and a 5% increase in serum high-density lipoprotein (HDL) cholesterol. Pravastatin reduced coronary artery disease death or nonfatal MI signiﬁcantly by 39% in persons aged 65 to 75 years, and insigniﬁcantly by 13% in persons younger than 65 years [132]. Pravastatin decreased major coronary events signiﬁcantly by 32% in persons aged 65 to 75 years, and signiﬁcantly by 19% in persons younger than 65 years. It also reduced stroke signiﬁcantly by 40% in persons aged 65 to 75 years, and insigniﬁcantly by 20% in persons younger than 65 years. Pravastatin decreased coronary revascularization signiﬁcantly by 32% in persons aged 65 to 75 years, and signiﬁcantly by 25% in persons younger than 65 years. For every 1000 persons treated with pravastatin for 5 years, 225 cardiovascular events would be prevented in persons aged 65 to 75 years and 121 cardiovascular events would be prevented in persons younger than 65 years [132]. In the PROSPER trial, a randomized, placebo-controlled study of 5804 men and 3000 women, pravastatin 40 mg/day was shown to lower LDL concentrations by 34% in subjects 70 to 82 years of age. In this study, drug treatment reduced coronary heart disease death and nonfatal MI. No beneﬁt on stroke prevention was seen, and there were more cancer diagnoses with pravastatin. However, incorporation of this latter ﬁnding in a meta-analysis showed no overall increase in cancer risk [133]. On the basis of the available data showing increased risk of cardiovascular disease from abnormal lipoprotein patterns [134], dietary therapy for older patients with dyslipidemia, regardless of age, in the absence of other serious life-limiting illnesses such as cancer, dementia, or malnutrition, is recommended [135]. If hyperlipidemia persists after 3 months of dietary therapy, hypolipidemic drugs should be considered, depending on serum lipid levels, presence or absence of coronary artery disease, presence or absence of other coronary risk factors, and the patient’s overall clinical status. This approach is consistent with the recent National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults recommendations in males z65 years and females z75 years [136]. In older women, the use of estrogen plus cyclic micronized progesterone, as used in the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial [137], might be considered an adjunctive hypolipidemic approach for treating high serum LDL cholesterol levels [138,139]. This is being analyzed in the Womens Health Initiative Study, where estrogen alone or in combination with progesterone is being looked at to reduce coronary artery disease risks in postmenopausal women, 20% of whom are 70 to 80 years of age. In older men and women, the HMG-CoA reductase inhibitors would be the drugs of choice for treating a high serum LDL cholesterol levels. Recently, the Heart and Estrogen/Progestin Replacement Study (HERS) showed that there was no beneﬁt in using adjunctive hormonal replacement therapy in postmenopausal women with known coronary artery disease [140]. Anticoagulants Anticoagulant therapy in the elderly is discussed extensively elsewhere [69,141]. Anticoagulants are eﬀective in the prevention and treatment of many thromboembolic disorders, including venous thromboembolism and pulmonary embolism, acute MI, and embolism associated with prosthetic heart valves or atrial ﬁbrillation. These conditions, which necessitate the use of anticoagulants, are more common in elderly than in younger patients. In the report from the Sixty Plus Reinfarction Group who evaluated the eﬀects of oral anticoagulant therapy on total mortality after MI in patients older than 60 years, it was

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shown that active therapy lowered both mortality and reinfarction compared with placebo [142]. However, the treatmment group also had more major bleeding complications. The anticoagulant response to warfarin is increased with age [143]. Chronic diseases that increase the risk for bleeding during anticoagulant therapy are also more common in elderly patients than in younger patients. In addition, elderly patients are at higher risk for bleeding during anticoagulant therapy because of increase vascular or endothelial fragility [144]. Furthermore, older patients may be at increased risk for bleeding due to anticoagulant therapy because they may be taking other drugs that potentiate the anticoagulant eﬀect. Drugs such as aspirin, cephalosporins, and penicillins increase the risk of bleeding in patients treated with heparin. Drugs such as allopurinol, amiodarone, aspirin, cimetidine, ciproﬂoxacin, cloﬁbrate, cotrimoxazole, dextroproproxyphene, disulﬁram, erythromycin, ﬂuconazole, isoniazid, ketoconazole, meclofenamic acid, metronidazole, miconazole, norﬂoxacin, phenylbutazone, phenytoin, quinidine, sulﬁnpyrazone, sulindac, thyroxine and trimethoprimsulfamethoxazole potentiate the eﬀect of warfarin, causing an increased prothrombin time and risk of bleeding. ADVERSE EFFECTS OF DRUGS IN THE ELDERLY Cardiovascular drugs are often associated with adverse eﬀects that simulate common disorders of the elderly (Table 5). In addition, important drug–disease interactions (Table 6), drug–drug interactions (Table 7), and drug–alcohol interactions [145] (Table 8) occur in older patients. MEDICATIONS BEST TO AVOID IN THE ELDERLY Careful selection of drugs and dosages of drugs in the elderly can minimize adverse outcomes while maximizing clinical improvement. In their ﬁrst attempt to identify medications and doses of medication that may be best to avoid in the elderly, Beers and colleagues developed a set of explicit criteria after an extensive review of the literature and assistance from 13 well-recognized experts in geriatric medicine and pharmacology [146]. These criteria included 30 statements that described medications that should generally be

Table 5 Cardiovascular Drugs Regularly Detected as the Culprit in Some Common Disorders of the Elderly Disorder Confusion states Tinnitus, vertigo Depression Falls Postural hypotension Constipation Urinary retention Urinary incontinence Source: Adapted from Ref. 157.

Drugs h-blockers, digoxin, methyldopa and related drugs, quinidine Aspirin, furosemide, ethacrynic acid h-blockers, methyldopa, reserpine All drugs liable to produce postural hypotension, glycerol trinitrates All antihypertensives, antianginal drugs, h-blockers, diuretics Anticholinergics, clonidine, diltiazem, diuretics, verapamil Disopyramide, midodrine h-blockers, diuretics, labetalol, prazosin

118 Table 6

Frishman et al. Important Drug-Disease Interactions in Geriatric Patients

Underling disease Congestive heart failure Cardiac conduction disorders Hypertension Peripheral vascular disease Chronic obstructive pulmonary disease Chronic renal impairment

Diabetes mellitus Prostatic hypertrophy Depression Hypokalemia Peptic ulcer disease

Drugs

Adverse eﬀect

h-blockers, verapamil Tricyclic antidepressants

Acute cardiac decompensation Heart block

NSAIDs h-blockers h-blockers

Increased blood pressure Intermittent claudication Bronchoconstriction

NSAIDs, contrast agents, aminoglycosides, ACE inhibitors Diuretics Drugs with antimuscarinic side eﬀects h-blockers, centrally acting antihypertensives Digoxin Anticoagulants, salicylates

Acute renal failure

Hyperglycemia Urinary retention Precipitation or exacerbation of depression Cardiac arrhythmias GI hemorrhage

Abbreviations: NSAIDs, nonsteroidal anti-inﬂammatory drugs; GI, gastrointestinal. Source: Ref. 160. Adapted from Parker BM, Cusack BJ: Pharmacology and appropriate prescribing. In, Reuben DB, Yoshikawa TT, Besdine RW (eds): Geriatric Review Syllabus: A Core Curriculum in Geriatric Medicine, 3rd ed. Iowa: Kendall/Hunt Publishers, Am Geriatric Soc, 1966: 33.

avoided in nursing home residents as well as statements that described doses, frequencies, and duration of medications that generally should not be exceeded. Since the publication of the explict criteria, several research studies have utilized these criteria to evaluate the appropriateness of medication prescribing in the elderly [147–150]. The most striking study of this type was performed by Willcox and colleagues [150], who reported a potentially inappropriate medication prescription in 23.5% of elderly in the community. Willcox and colleagues were criticized, however, for applying criteria that were designed for frail elderly patients in nursing homes to healthier elderly residents in the community, along with criteria that need to be updated [151]. Acknowledging the limitation of this ﬁrst set of criteria, Beers updated and expanded it to encompass elderly patients who are in the ambulatory setting, as well as medications that should be avoided in elderly known to have certain conditions [152]. With the assistance of six nationally recognized experts in geriatric medicine and pharmacology, a set of 63 criteria were developed using the ﬁrst set of criteria plus a more recent literature review. Out of the 63 criteria, 28 criteria described medications or categories of medication that were considered to be potentially inappropriate when used by all older patients, 35 criteria described medications or categories of medications that were considered to be potentially inappropriate when used by elderly patients with any of 15 known medical conditions such as heart failure, diabetes, hypertension, asthma, and arrhythmias. These criteria were further rated by the six panelists regarding their importance. The panelists considered a criterion to be severe when an adverse outcome was both likely to occur and, if it did occur, would likely lead to a clinically signiﬁcant event [152]. Table 9 lists the cardiac medications that were recognized by the expert panel as having the highest severity of potential problems

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Selected Clinically Significant Drug-Drug Interactions in Geriatric Patients

Primary drugs Augmented Drug Eﬀects Antidiabetic sulfonylureas (tolbutamide, chlorpropamide) Azathioprine

Interacting drugs

Chloramphenicol, Warfarin Phenylbutazone Quinidine Allopurinol

Mechanism of interaction

IM IM, DP, IE OM IM

Carbamazepine

Diltiazem, Verapamil

IM

Cyclosporine

Diltiazem, Verapamil

IM

Digoxin

Amiodarone, Diuretics, Quinidine, Verapamil

OM

Disopyramide

Diltiazem, Verapamil h-blockers, cimetidine

OM

Lidocaine

Methotrexate

Procainamide Propranolol Phenytoin

Quinidine

Warfarin

Decreased Drug Eﬀects All medications

Aspirin, Indomethacin, Phenylbutazone Probenecid Sulﬁsoxazole Diltiazem, Verapamil Cimetidine Diltiazem, Verapamil Amidarone, Chloramphenicol, Cimetidine, Fluconazole, Isoniazid, Phenylbutazone Valproic acid, Warfarin Diltiazem, Verapamil

HBF

Possible eﬀects

Hypoglycemia

Bone marrow suppression Increase serum carbamazepine concentration and risk of toxicity (e.g., nausea, ataxia, nystagmus) Increase serum cyclosporine concentratio and risk of toxicity (e.g., hepato- and nephrotoxicity) Increase serum digoxin concentration and risk of toxicity (e.g., nausea, confusion, cardiotoxicity) Bradycardia

DP, IE

Increase serum lidocaine concentration and risk of toxicity (e.g., sedation, seizures, cardiotoxicity) Bone marrow suppression

IE DP OM

Bradycardia

HBF OM IM

DP, IM IM

Aspirin, Indomethacin Amiodarone, Cimetidine, Metronidazole Phenylbutazone, Sulfonamides

DP IM

Cholestyramine

IA

Bradycardia Bradycardia, hypotension Increase serum phenytoin concentration and risk of toxicity (e.g., nystagmus, sedation)

Increase serum quinidine concentration and risk of toxicity (e.g., nausea, cinchonism, arrhythmias) Hemorrhage

DP, IM

Delay or reduce absorption of other drugs. Administer other drugs 1-2 h before or 4-6 h after cholestyramine

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Table 7 Continued Primary drugs

Interacting drugs

Mechanism of interaction

Possible eﬀects

h blockers (nonselective) Corticosteroids, thiazide diuretics

IIS, MCM, IIR OM

Decrease hypoglycemic eﬀects

Sucralfate

IA

Lincomycin Phenytoin

Kaolin-pectin Calcium, Sucralfate Rifampin

IA IA SM

Prednisone Quinidine Tetracycline Warfarin

Barbiturates Barbiturates, Rifampin Antacids-Iron Barbiturates, Carbamazepine, Glutethimide, Rifampin VitaminK

SM SM IA SM

Reduce absorption of digoxin. Administer sucralfate at least 2 h apart from digoxin. Decrease drug bioavailability Decrease serum phenytoin concentration and anticonvulsant eﬀect Decreased steroid eﬀects Decrease antiarrhythmic eﬀect Decrease drug bioavailability Loss of anticoagulant control

Potassium-sparing diuretics, potassiumcontaining medications Cyclosporine, Gemﬁbrozil, and Niacin Erythromycin

RAP

Hyperkalemia

Unknown

Rhabdomyolysis, acute renal failure

Antidiabetic sulfonylureas (tolbutamide, chlorpropamide) Digoxin

Other Drug Eﬀects ACE Inhibitors

HMG-CoA Reductase Inhibitors

SP

IM

Abbreviations: IM, inhibition of drug metabolism; DP, displacement of protein binding; IE, inhibition of renal excretion; OM, other mechanisms (pharmacodynamic eﬀects of drugs on tissue responses); HBF, decreased hepatic blood ﬂow; IA, inhibition of drug absorption; IIS, inhibition of insulin secretion; MCM, modiﬁcation of carbohydrate metabolism; IIR, increased peripheral insulin resistance; SM, stimulation of drug metabolism; SP, increased hepatic synthesis ofprocoagulant factors; RAP, reduction of aldosterone production; HMG-CoA, 3hydroxy-3-methylglutaryl-coenzyme A. Source: Adapted from Ref. 161. Bressler R: Adversed drug reactions. In, Bressler R, Katz MD (eds): Geriatric Pharmacology. New York: McGraw Hill, 1993: 54.

occurring from their use and the reasons for their avoidance. Table 10 lists medications that were identiﬁed by the expert panel as having the highest severity of potential problems and the reasons for their avoidance in the elderly when certain cardiac-related conditions exist. Although these criteria serve as useful tools for assessing the quality of prescribing to the elderly, they do not identify all cases of potentially inappropriate prescribing. In fact, these criteria may identify appropriate prescribing as inappropriate at times. The latter case may be likely particularly when physicians and pharmacists carefully adjust medication regimens for speciﬁc needs of individual patients [152]. PRUDENT USE OF MEDICATION IN THE ELDERLY Although the elderly make up only 14% of our population, they receive more than 30% of all prescribed medication [153]. The increased exposure of medications in the elderly may

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Selected Clinically Significant Drug-Alcohol Interactions in Geriatric Patients

Primary drugs

Interacting drug

Possible eﬀects

Antidiabetic sulfonylureas ACE inhibitors Isoniazid

Alcohol Alcohol Alcohol

Nitrates Phenytoin

Alcohol Alcohol

Rifampin

Alcohol

Sedatives-hypnotics Vitamins

Alcohol Alcohol

Warfarin

Alcohol

Disulﬁram-like reactions (especially with chlorpropamide) Hypotension Decreased therapeutic eﬀect of isoniazid, increased riskof hepatic toxicity Hypotension Decreased serum phenytoin concentration and eﬀectiveness (chronic use of alcohol); increased serum phenytoin concentration and risk of toxicity (acute intake of alcohol) Decreased therapeutic eﬀect of rifampin, increased risk of hepatic toxicity Excessive sedation Decreased absorption and storage of folic acid and thiamine Increased anticoagulant activity (acute intoxication); decreased anticoagulant activity (chronic abuse)

Abbreviations: ACE, angiotensin converting enzyme. Source: Reproduced from Ref. 162.

Table 9

Medications to Avoid in Older Patients

Medications Disopyramide

Digoxina

Methyldopaa and methyldopa/HCTZa Ticlopidine

a

Prescribing concerns Of all antiarrhythmics, disopyramide is the most potent negative inotrope and therefore may induce heart failure in the elderly. It is also strongly anticholinergic. When appropriate, other antiarrhythmic drugs should be used. Because of decreased renal clearance of digoxin, doses in the elderly should rarely exceed 0.125 mg daily, except when treating atrial arrhythmias. Methyldopa may cause bradycardia and exacerbate depression in the elderly. Alternate treatments for hypertension are generally preferred. Ticlopidine has been shown to be no better than aspirin in preventing clotting and is considerably more toxic. Avoid in the elderly.

Panelists believed that the severity of adverse reaction would be substantially greater when these drugs were recently started. In general, the greatest risk would be within about a 1-month period. Abbreviation: HCTZ hydrochlorothiazide. Source: Adapted from Ref. 146.

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Table 10

Medication to Avoid in Older Patients with Specific Diseases and Conditions

Diseases/ conditions

Medications

Heart Failure

Disopyramide

Hypertension Blood-clotting disorders, limited to those receiving anticoagulant Syncope or falls

Diet pills; amphetamines Aspirin, NSAIDS, dipyridamole, and ticlopidine

Arrhythmias

Long-acting benzodiazepine drugs Tricyclic antidepressant drugsa

Prescribing concerns Negative inotrope; may worsen heart failure May elevate blood pressure May cause bleeding in those using anti-coagulant therapy May contribute to falls May induce arrhythmias

a

Panelists believed that the severity of adverse reaction would be substantially greater when these drugs were recently started. In general, the greatest risk would be within about a 1 month period. Abbreviations: NSAIDS, non-steroidal anti-inﬂammatory drugs. Source: Adapted from Ref. 146.

lead to higher incidence of adverse drug reactions and drug–drug interactions in this population [154]. Physiological changes with aging may also alter the elimination of drugs that can contribute to adverse outcomes with medication usage. With these concerns in mind, several authors have suggested some steps that clinicians may employ to ensure safe prescribing [153,155,156]. These suggestions include: Acquire a full history of the patient’s habits and medication use. Evaluate the need for drug therapy; consider alternative nondrug approaches when appropriate. Know the pharmacology of the drugs prescribed. Start with low dose of medication and titrate up slowly. Titrate medication dosage according to the patient’s response. Minimize the number of medications used. Educate patients regarding proper usage of medications. Be aware of medication cost, which may have an impact on compliance. Provide patient with a portable prescription record. Review the treatment plan regularly and discontinue medications no longer needed. With proper monitoring and adequate understanding of the eﬀects of medications in the elderly, the use of medication can be a positive experience for both the elderly patient and the clinician.

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Frishman et al. estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605–613. Sebastian JL, Tresch D. Anticoagulation therapy in the elderly. In: Tresch DD, Aronow WS, eds. Cardiovascular Disease in the Elderly Patient. New York: Marcel Dekker Inc., 1994:213– 261. The Sixty Plus Reinfarction Study Research GroupA double-blind trial to assess long-term anticoagulation therapy in elderly patients after myocardial infarction: report of the Sixty Plus Reinfarction Study Research Group. Lancet 1980; 2:989–994. Shepherd AMM, Hewick DS, Moreland TA, Stevenson TH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 4:315–320. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients takin warfarin. Ann Intern Med 1994; 120:897–902. Fraser AG. Pharmacokinetic interactions between alcohol and other drugs. Clin Pharmacokinet 1997; 33:79–90. Beers MH, Ouslander JG, Rollingher I, Reuben DB, Brooks J, Beck JC. Explicit criteria for determining inappropriate medication use in nursing home residents. Arch Intern Med 1991; 151:1825–1832. Beers MH, Ouslander JG, Fingold SF, Morgenstern H, Reuben DB, Rogers W, et al. Inappropriate medication prescribing in skilled-nursing facilities. Ann Intern Med 1992; 117:684–689. Beers MH, Fingold SF, Ouslander JG, Reuben DB, Morgenstern H, Beck JC. Characteristics and quality of prescribing by doctors practicing in nursing homes. J Am Geriatr Soc 1993; 41:802–807. Stuck AE, Beers MH, Steiner A, Aronow HU, Rubenstein LZ, Beck JC. Inappropriate medication use in community-residing older persons. Arch Intern Med 1994; 154:2195–2200. Willcox SM, Himmelstein DU, Woolhandler S. Inappropriate drug prescribing for the community-dwelling elderly. JAMA 1994; 272:292–296. Gurwitz JH. Suboptimal medication use in the elderly: the tip of the iceberg. JAMA 1994; 272:316–317. Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly: an update. Arch Intern Med 1997; 157:1531–1536. Johnson JF. Considerations in prescribing for the older patient. PCS Health Systems, Inc. Eli Lilly & Co., 1/98. Abrams WB. Cardiovascular drugs in the elderly. Chest 1990; 98:980–986. Stein BE. Avoiding drug reactions: seven steps to writing safe prescriptions. Geriatrics 1994; 49:28–36. Nagle BA, Erwin WG. Geriatrics. In: DiPiro JT, et al. ed. Pharmacotherapy. A Pathophysiologic Approach 3d ed. Stamford: Appleton and Lange, 1997:87–100. Hui KK. Gerontologic considerations in cardiovascular pharmacology and therapeutics. In: Singh BN, Dzau VJ, Vanhoutte PM, Woosley RL, eds. Cardiovascular Pharmacology and Therapeutics. New York: Churchill-Livingstone, 1994:1130. Frishman WH, Sonnenblick E. Cardiovascular Pharmacotherapeutics. 2nd ed. New York: McGraw-Hill, 2003:1033–1036. Aronow WS. Cardiovascular drug therapy in the elderly. In: Frishman WH, Sonnenblick EH, eds. Cardiovascular Pharmacotherapeutics. New York: McGraw-Hill, 1997:1273. Parker BM, Cusack BJ. Pharmacology and appropriate prescribing. In: Reuben DB, Yoshikawa TT, Besdine RW, eds. Geriatric Review Syllabus: A Core Curriculum in Geriatric Medicine. 3d ed. Iowa: Kendall/Hunt Publishers, 1966:33. Bressler R. Adverse drug reactions. In: Bressler R, Katz MD, eds. Geriatric Pharmacology. New York: McGraw-Hill, 1993:54. Frishman WH, Cheng A, Aronow WS. Cardiovascular drug therapy in the elderly. In: Tresch DD, Aronow WS, eds. Cardiovascular Disease in the Elderly Patient. 2d ed. New York: Marcel Dekker Inc., 1999:761.

5 Systemic Hypertension in the Elderly William H. Frishman and Mohammed J. Iqbal New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A.

Gregory Yesenski St. Barnabas Hospital–Cornell Medical School, Bronx, New York, U.S.A.

Strong evidence from large, well-controlled clinical trials indicates that elderly patients with either combined systolic and diastolic hypertension or isolated systolic hypertension beneﬁt from pharmacological blood pressure reduction [1]. These studies reveal the beneﬁt of treatment in reducing the risk of both cardiovascular and cerebrovascular morbidity. This chapter ﬁrst reviews the pathophysiology of hypertension in the elderly and the rationale for nonpharmacological and pharmacological treatment.

HYPERTENSION IN THE ELDERLY Elderly hypertensive patients diﬀer from young hypertensive patients in several respects. It is important to be aware of these diﬀerences in planning therapeutic interventions. The aging process is associated with multiple anatomical and physiological alterations in the cardiovascular system that can inﬂuence blood pressure regulation. Young hypertensive patients tend to be characterized by a hyperkinetic circulatory state, evidently resulting from increased sensitivity to circulating catecholamines [2]. This state is expressed as an increase in heart rate, contractility, and cardiac output with no signiﬁcant change in systemic vascular resistance. In contrast, systemic hypertension in elderly patients appears to be a consequence of structural cardiovascular changes. Decreased vascular compliance and increased resistance predominate and are associated with narrowing of the vascular radius and increases in wall-to-lumen ratios [3]. Histologically, the changes are apparent in the vascular subendothelial and media layers, which thicken with age and demonstrate increased connective tissue inﬁltration as well as calciﬁcation and lipid deposition [4]. With age, this process results in a progressive increase in wall stiﬀness and tortuosity of the aorta and large arteries, often reﬂected by a rise in systolic pressure and a wide pulse pressure [5]. The decreased vascular compliance seen in elderly patients also may result in reduced sensitivity of volume and baroreceptor function. Aging also aﬀects the vascular endothelium, the cells of which become smaller and less uniformly aligned. This change may result in decreased production of endogenous 131

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vasodilating substances (e.g., nitric oxide) and a decline in local control of vascular tone [6,7]. The myocardium of elderly hypertensive patients is also altered by the aging process. Although total heart size generally remains unchanged, mild-to-moderate left ventricular hypertrophy often develops in response to increased afterload. This hypertrophy tends to oﬀset the decline in myocardial contractile speed and strength seen with aging [8]. The elderly heart demonstrates microscopic foci of calciﬁcation and ﬁbrosis as well as macroscopic calciﬁcation of the mitral and aortic valves and conduction system [9,10]. Thus the stiﬀened and hypertrophied left ventricle shows decreased diastolic ﬁlling and greater dependence on atrial contraction. Renal function also shows an age-dependent decline, which is further accelerated by chronically elevated blood pressure. The decline in renal function often manifests as a decline in glomerular ﬁltration rate [11]. Postglomerular increases in vascular resistance have been described as a possible compensatory mechanism and may further increase vascular pressure in the glomerulus [12]. Despite the fact that elderly patients (including those with hypertension) tend to have lower plasma volumes than younger patients, their plasma renin levels are usually normal or low [13]. Plasma levels of angiotensin-II, natriuretic peptides, and aldosterone are also decreased, and the response to antidiuretic hormone is blunted. In theory, these hormonal changes should help to lower or maintain arterial pressure in the elderly. Nonetheless, arterial blood pressure (usually systolic) appears to rise progressively with increasing age [14–16]. It has been estimated that 80% of elderly hypertensive patients present with concomitant medical conditions, which must be taken into consideration in planning therapeutic intervention [17]. Examples include coronary artery disease, diastolic and systolic dysfunction, diabetes mellitus, hyperlipidemia, renal impairment, and chronic obstructive pulmonary disease. Elderly patients often take nonsteroidal anti-inﬂammatory drugs for arthritic conditions, which can cause an increase in blood pressure. Elderly patients also frequently suﬀer from left ventricular hypertrophy, insulin resistance, obesity, mental depression, and cognitive dysfunction. Therapy for hypertensive elderly patients needs to account for these and other concomitant diseases.

RATIONALE FOR TREATMENT It has been estimated that 50 to 70% of elderly Americans have hypertension, which is deﬁned by the National Institutes of Health as blood pressure >140/90 mmHg [1,18]. Higher levels of either systolic or diastolic blood pressure are associated with an increased risk of cardiovascular morbidity or mortality. Examples include coronary artery disease, congestive heart failure, renal insuﬃciency, peripheral vascular disease, and stroke. Hypertension in the elderly poses an important problem for two reasons: (1) the proportion of elderly in the population is steadily increasing, and (2) the incidence of hypertension—and therefore the risk of cardiovascular disease—increases with age [19]. In the past, there was a tendency to deemphasize elevated blood pressure readings in the elderly and to downplay the need for therapeutic intervention. Increasing blood pressure was viewed as part of the normal aging process, and blood pressure measurements that would dictate treatment in young adults were often considered satisfactory or borderline in elderly patients. It was believed that the beneﬁts of antihypertensive therapy might not be realized in patients with

Randomized placebo-controlled double-blind Randomized placebo-controlled single-blind Randomized placebo-controlled single-blind

Randomized placebo-controlled double-blind Randomized non-blind

Study Design

4396

4736

1627

884

840

39

43

z60 65–74

37

70–84

31

30

z60 60–79

Males (yr)

Age (yr)

5.8

4.5

2.1

4.4

4.7

Duration (yr)

160–209

160–219

<115

<90

90–120

z105

z170 180–230

90–119

DBP Range

160–239

SBP Range

BP at entry (mmHg)

18/8

15/6

9/6

10/10

16/11

Control

16/7

11/4

22/9

16/10

21/7

Treatment

BP Reductiona (mmHg)

Diﬀerences between blood pressure in control and active treatment groups. Abbreviations: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; EWPHE, European Working Party Study on High Blood Pressure in the Elderly; STOP, Swedish Trial in Old Patients with Hypertension; SHEP, Systolic Hypertension in the Elderly Program; MRC, Medical Research Trial on Treatment of Hypertension in Older Adults. Source: Adapted from with permission Ref. 19.

a

MRC Working Group

SHEP 1991

Coppe & Warrender 1986 STOP 1991

EWPHE 1985

Study

# of Pts (yrs)

Table 1 Characteristics of Some Long-Term Trials in Elderly Hypertensive Patients

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a limited life expectancy. It was also thought that elderly patients would be more susceptible to adverse drug reactions (e.g., orthostatic hypotension, cerebral hypoperfusion) [12,20]. Several large, randomized, well-controlled trials were designed to investigate whether elderly hypertensives respond positively and receive beneﬁts from pharmacological intervention (Table 1). Examples include the European Working Party Study on High Blood Pressure in the Elderly (EWPHE), the Swedish Trial in Old Patients with Hypertension (STOP), the Medical Research Trial on Treatment of Hypertension in Older Adults (MRC II), and the Systolic Hypertension in the Elderly Program Study (SHEP) [21–25]. The combined data reported from these trials demonstrated a reduction in both cerebrovascular and cardiovascular morbidity and mortality in treatment groups. A metaanalysis by Holzgreve [19] describes a 40% reduction in stroke incidence and 30% reduction in cardiovascular events with antihypertensive therapy. The SHEP study was particularly interesting because it investigated whether antihypertensive therapy can decrease cardiovascular risk in elderly patients with isolated systolic hypertension (study entry criteria being systolic blood pressure 160–219 mmHg and diastolic pressure <90 mmHg), the most typical type of hypertension in the elderly [25]. In the United States, the prevalence of diastolic hypertension tends to plateau around the age of 55, whereas the prevalence of systolic hypertension continues to rise, even after 80 years of age. Before the results of SHEP were published, many physicians held the belief that isolated systolic hypertension, reﬂecting an increase in rigidity of the arterial system, was only an index of bad cardiovascular state and did not play a direct role in the development of cardiovascular complications [26]. This view persisted despite data from the Multiple Risk Factor Intervention Trial (MRFIT), which demonstrated that systolic blood pressure >160 mmHg is a more signiﬁcant risk factor, regardless of age, than diastolic pressure >95 mmHg [27]. The results of the SHEP trial showed conclusively that reduction or correction of hypertension strongly diminished the risk. Antihypertensive therapy was associated not only with a decrease in the number of cerebrovascular events but also with a 25% reduction in fatal and nonfatal coronary events and an even greater beneﬁt in reducing episodes of congestive heart failure (Table 2). The greatest beneﬁt of therapy was seen in patients with severe underlying disease. Even patients over 80 years of age beneﬁt from treatment [28,29]. However, hypertension might not be a risk factor for cardiovascular disease among very old hypertensive patients with advanced atherosclerosis [30].

Table 2 Five-Year Absolute Beneﬁts Found in Placebo-Controlled Endpoint Studies in ISH Number of Events Prevented/1000 Patientsa

Stroke events Major CV events Deaths Dementia

SHEP [25]

Syst-Eur [58–60]

Syst-China [61]

30 55 — —

29 53 — 19

39 59 55 —

a With the therapy/regimen used in this study. Source: Reproduced with permission from Ref. 88.

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NONPHARMACOLOGICAL TREATMENT OF HYPERTENSION Lifestyle modiﬁcations in the elderly may be the only treatment modality necessary for preventing and managing milder forms of hypertension [30a]. Reduction is excess body weight and mental stress, modiﬁcation of alcohol intake, and increased physical activity can also reduce the doses of antihypertensive drugs used for blood pressure control. In the Trial of Non-Pharmacologic Intervention in the Elderly (TONE), it was shown that the combination of dietary sodium restriction and regular moderate physical activity [30–45 min of brisk walking on most days) can prevent hypertension in older subjects, and help to control blood pressure in known hypertensives [31]. The Dietary Approaches to Stop Hypertension (DASH) trial showed that a diet rich in fruits and vegetables and low in saturated and total fat content can lower blood pressure without the need for additional drug treatment [32]. Elderly patients with hypertension should be vigorously screened and treated for any additional cardiovascular risk factors that might be present, including cigarette smoking, hypercholesterolemia, hyperhomocysteinemia, diabetes mellitus, and excessive alcohol intake.

PHARMACOLOGICAL TREATMENT OF HYPERTENSION Diuretics Diuretics such as hydrocholorothiazide (HCTZ) and chlorthalidone have been the mainstay of antihypertensive drug treatment in the elderly for over 40 years. The JNC VII report recommends diuretics as a medication of choice for initiating drug therapy of hypertension [1]. Diuretic use will cause an initial reduction in intravascular volume, and will lower peripheral vascular resistance [33–35]. These drugs will reduce an elevated blood pressure in over 50% of patients, and they are well tolerated and relatively inexpensive. Several clinical trials have assessed the eﬃcacy of diuretics in hypertension and their ability to also reduce the complications of hypertension in the elderly, especially cardiovascular, cerebrovascular, and renal diseases. The European Working Party trial was a double-blinded, randomized, placebocontrolled study that evaluated 840 patients above 60 years of age with blood pressure ranging from 160 to 239 mmHg/ 90 to 119 mmHg [22]. The subjects received in an increasing stepwise fashion HCTZ 25 to 50 mg and triamterene 50 to 100 mg to achieve blood pressure control, or placebo. Methyldopa 500 mg was added if the blood pressure remained elevated. The subjects were followed for 7 years and the outcomes of cardiovascular mortality and all-cause mortality were reported on. With active treatment blood pressure was lowered 19 mmHg/5 mmHg compared to placebo with less than 35% requiring the addition of methyldopa. It was found that 29 fewer cardiovascular events occurred per 1000 patientyears and 14 fewer deaths per 1000 patient-years, which was about a 38% decrease in total cardiovascular death compared to placebo. The National Heart Foundation of Australia studied 582 patients aged 60 to 69 years with diastolic blood pressures of 95 to 110 mmHg and started them on chlorothiazide 500 to 1000 mg to obtain blood pressure control or placebo [36]. If blood pressure did not reach goal levels, a beta-blocker or methyldopa was added. Subsequently, hydralazine or clonidine was given, if necessary. Patients were followed for over 5 years looking at the endpoints of fatal and nonfatal cardiovascular events. Seventy percent of the actively treated patients had

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diastolic blood pressure <90 mmHg, and of those actively treated, only 15% required more than two drugs. Most importantly, there was a decrease of 38% in total fatal and nonfatal cardiovascular events with active treatment compared to placebo. A third multicenter, randomized, double-blind, placebo-controlled trial, SHEP, looked at 4736 patients age >60 years with systolic blood pressure 160 to 219 mmHg and diastolic pressures of <90 mmHg (isolated systolic hypertension) [25]. Patients were started on placebo or chlorthalidone 12.5 mg and then the dose was doubled if the systolic blood pressure goal was not achieved. If at subsequent visits the blood pressure goal was not attained, then atenolol 25 to 50 mg was added. If atenolol was contraindicated, reserpine was given. After 5 years of treatment, the actively treated group had a reduced incidence of stroke, myocardial infarction, and heart failure. Further analyses of the data show that the development of fatal and nonfatal heart failure was 55 of 2365 in the actively treated group compared to 105 of 2371 in the placebo group [37]. Additionally, there were 583 non-insulindependent diabetics at baseline and their absolute risk reduction was twice as great in developing cardiovascular events [38]. A randomized, single-blinded, placebo-controlled trial done by the Medical Research Council studied 4396 patients aged 65 to 74 years with a systolic blood pressure of 160 to 209 mmHg and a diastolic blood pressure of <115 mmHg. Subjects received HCTZ 25 to 50 mg plus amiloride 2.5 to 5 mg, atenolol 50 to 100 mg, or placebo, and were followed for 5 years for incidence of stroke and coronary events as well as all cardiovascular events [24]. The results showed that both active treatments reduced blood pressure and the incidence of stroke equally, but the diuretic group experienced a more rapid and greater control of blood pressure compared to the beta-blocker group, especially within the ﬁrst 3 months of treatment, and the patients on the HCTZ regimen had 44% fewer coronary events and 29% fewer cardiovascular events than the atenolol treatment group. More recently, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) studied 33,357 patients with a mean age of 67 who had stage I or II hypertension and at least one risk factor for coronary heart disease, and looked at fatal and nonfatal coronary heart disease or myocardial infarction, stroke, and all coronary and cardiovascular events [39]. Patients were randomized to receive chlorthalidone 12.5 to 25 mg, amlodipine 2.5 to 10 mg or lisinopril 10 to 40 mg, and followed for 5 years. If blood pressure goal was not achieved, step 2 drugs were added: atenolol 25 to 100 mg, reserpine 0.05 to 0.2 mg, clonidine 0.1 to 0.3 mg, twice a day. If necessary, step 3 treatment with hydralazine 25 to 100 mg twice a day was added. All treatment groups showed a similar decrease in the number of fatal and nonfatal coronary heart disease events or myocardial infarction. All treatments reduced blood pressure eﬀectively, but the systolic blood pressure was lower in the diuretic group, and the lisinopril group had a 15% higher risk of stroke, a 10% higher risk of cardiovascular disease, and a 19% higher risk of heart failure compared to the chlorthalidone group. Furthermore, the amlodipine group had a 38% higher rate of heart failure when compared to chlorthalidone group. Given the data from all these studies, it is reasonable to start antihypertensive therapy with diuretic agents in the elderly unless there are concomitant conditions such as angina pectoris or diabetes mellitus that might warrant treatment with other agents. Why Not Use a Diuretic? As mentioned previously, with aging, physiological changes occur that can be exacerbated with diuretic use. The elderly typically have contracted intravascular volumes and impaired baroreﬂexes, and diuretics cause sodium and water depletion (hypovolemia) and orthostatic

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hypotension. Older people have a high prevalence of left ventricular hypertrophy, which predisposes to ventricular ectopy and sudden death. Diuretics can cause hypokalemia and hypomagnesemia, which can increase ventricular ectopy and other arrhythmias. Typically, hypokalemia and hypomagnesemia which can develop in the ﬁrst few days of treatment. But, after that, the body can achieve a new homeostatic balance and loss of these ions is lessened. Nevertheless, these agents are not advised in patients with baseline abnormalities, and when using them, potassium levels should be monitored and supplementation should be given as needed [40]. Also, as we age, there is a lower renal blood ﬂow and glomerular ﬁltration rate. Diuretic use causes a decrease in renal blood ﬂow, decreased creatine clearance, and glomerular ﬁltration rate. The elderly have a tendency toward hyperuricemia and glucose intolerance. Diuretics cause increases in uric acid and glucose intolerance. Diuretic use can cause dyslipidemia. Cholesterol levels have been shown to increase in the ﬁrst year of treatment with thiazides [41]. However, long-term use has been associated with an overall decrease in baseline cholesterol. Of the clinical trials mentioned, about 160 patients withdrew from the MRC trial because of side eﬀects (less than the beta-blocker group) and 15% withdrew from the ALLHAT trial because of side eﬀects all comparable to the other treatment groups. In the SHEP trial, the most frequent event seen was abnormal electrolyte levels.

Beta-Adrenergic Blockers Although beta-blockers have been used for the treatment of hypertension in the elderly for several years, evidence of their beneﬁt has not been convincing. The major studies of their eﬃcacy, safety, and tolerability for the treatment of elderly hypertensives include the MRC, STOP, STOP-2, SHEP, and LIFE (Losartan Intervention for Endpoint Reduction in Hypertension Study) trials. The MRC trial assessed whether treatment with a diuretic or beta-blocker in hypertensive older adults reduced the risk of stroke, coronary artery disease, and death [24]. As described earlier, both treatments reduced blood pressure below the level of the the placebo group, but only diuretic therapy showed a signiﬁcant reduction in stroke, coronary events, and all cardiovascular events. The beta-blocker group showed no signiﬁcant reductions in these endpoints from placebo. Another signiﬁcant ﬁnding of this trial was poor tolerability of beta-blockers, which is illustrated by the drop-out rate of 63% of patients randomized to receive atenolol [24]. The STOP trial was a multicenter, randomized, double-blind trial in subjects aged 70 to 84 years with systolic blood pressures ranging from 180 to 230 mmHg and/or diastolic blood pressure of 105 to 120 mmHg [23]. Patients were initially treated with either a betablocker or a diuretic. However, two-thirds of the active subjects received combination therapy. The primary endpoints of stroke, myocardial infarction, and cardiovascular death were reduced by active treatment compared to placebo. A separate report described no diﬀerences in monotherapy for diastolic blood pressure reduction during the ﬁrst 2 months, but diuretics were more eﬀective for systolic blood pressure reduction in the ﬁrst 2 months of the trial [42]. The beta-blockers included in the trial were 100 mg metoprolol controlledrelease once daily, 50 mg atenolol once daily, or 5 mg pindolol once daily. At 12 months, the placebo-corrected changes in blood pressure were greatest when the beta-blocker was combined with a diuretic. There were no data in this trial to suggest either a beneﬁt or risk of beta-blocker treatment in terms of mortality.

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STOP-2, a prospective, randomized, open-blinded endpoint design trial evaluated 6614 patients aged 70 to 84 years with systolic blood pressure z180 mmHg and diastolic blood pressure z105 mmHg or both [43]. Patients were assigned to receive either an angiotensin converting enzyme (ACE) inhibitor, a calcium antagonist, or conventional drug therapy with a beta-blocker or diuretic or a combination of both. There was no diﬀerence in the proportion of patients reaching a primary endpoint in this trial. Conventional therapy was just as eﬀective as the newer agents in reducing cardiovascular events. Again, there were no ﬁndings in this trial to suggest either a beneﬁt or risk from beta-blocker treatment. As mentioned in the diuretics section of this chapter, the SHEP trial was a multicenter, randomized, double-blind, placebo-controlled trial of persons 60 years of age or older (25). Initial therapy was with 12.5 to 25 mg of chlorthalidone once daily. If blood pressure was not controlled, then 25 to 50 mg of atenolol or 0.05 mg of reserpine was added once daily. Forty-four percent of the subjects required combination drug therapy to achieve blood pressure control. This was a diuretic-based trial, and not a study of betablockers. A post hoc analysis suggested that neither the beta-blocker nor reserpine added to the beneﬁts observed in this trial. The recently completed LIFE Study was a double-blind, randomized, parallel group trial of 9193 participants aged 55 to 80 years, with essential hypertension and LVH ascertained by ECG [44]. Participants were assigned to once-daily losartan-based or atenololbased antihypertensive treatment for at least 4 years. Although both regimens eﬀectively reduced blood pressure, losartan proved to be more eﬀective than atenolol in preventing cardiovascular morbidity and mortality for a similar reduction in blood pressure. Losartan was also better tolerated, since more patients on beta-blockers withdrew due to the side eﬀects of therapy. Messerli et al. published a meta-analysis of 10 studies comparing beta-blockers and diuretics for the treatment of hypertension in the elderly [45]. A total of 16,154 patients aged z60 years as included. Two-thirds of the patients assigned to diuretics were well controlled on monotherapy. Diuretic therapy was superior to beta-blockade with regard to all endpoints, and was eﬀective in preventing cerebrovascular events, fatal stroke, coronary artery disease, cardiovascular mortality, and all-cause mortality. In contrast, beta-blocker therapy only reduced the odds of cerebrovascular events. Therefore, the clinical beneﬁts of beta-blockers as monotherapy in the treatment of systemic hypertension in the elderly are poorly documented, although they may have a role in combination therapy, especially with diuretics. Beta-blockers have an established role in the treatment of certain arrhythmias, migraine headaches, senile tremor, coronary artery disease, and congestive heart failure. Consideration should be given to adding betablockers as a treatment regimen in hypertensive patients with any of these comorbid conditions [46,47]. It was recently shown that in older patients with isolated systolic hypertension, a clinical heart rate >79 bpm was a signiﬁcant predictor of all-cause, cardiovascular, and non-cardiovascular mortality, suggesting a role for beta-blockers and rate-lowering calcium blockers in this population [47a]. Beta-blockers, especially nonselective beta-blockers, should be used carefully in patients with asthma and chronic obstructive pulmonary disease, because they can induce bronchospasm by inhibiting sympathetic signaling at the h2-adrenergic receptors [46]. As glucose metabolism is modulated by the sympathetic nervous system, beta-blockers can exacerbate diabetes by inhibiting this pathway. Although deterioration of glucose tolerance has been associated with nonselective agents such as propranolol, this has not been as frequently observed with h1-selective agents such as metoprolol and atenolol [46]. Also,

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beta-blockers can mask the sympathetic manifestations of hypoglycemia. Beta-blockers probably do not increase the risk of depression, but they can cause erectile dysfunction [46]. ViagraR can be used with concomitant antihypertensive drugs to alleviate erectile dysfunction. Calcium Blockers The calcium antagonists are a heterogeneous group of drugs with widely variable eﬀects on heart muscle, sinus node function, atrioventricular conduction, peripheral blood vessels, and coronary circulation [48–51]. From a chemical standpoint, they can be divided into three main groups: phenylalkylamines (verapamil), benzothiazepines (diltiazem), and dihydropyridines (nifedipine, nicardipine, nimodipine, amlodipine, felodipine, isradipine). Despite their heterogeneity, they all block the inﬂux of calcium ions into the cells of vascular smooth muscle and myocardial tissue [52]. The observation that calcium antagonists are signiﬁcantly more eﬀective in inhibiting contraction in coronary and peripheral arterial smooth muscle than in cardiac and skeletal muscle is of great clinical importance. This diﬀerential eﬀect is explained by the observation that arterial smooth muscle is more dependent on external calcium entry for contraction, whereas cardiac and skeletal muscle rely on a recirculating internal pool of calcium [53]. Because calcium antagonists are membrane-active drugs, they reduce the entry of calcium into cells and therefore exert a much greater eﬀect on vascular wall contraction. This preferential eﬀect allows calcium antagonists to dilate coronary and peripheral arteries in doses that do not severely aﬀect myocardial contractility or have little, if any, eﬀect on skeletal muscle [48]. Based on the above mechanisms of action, the calcium antagonists appear well suited for use in elderly patients whose hypertensive proﬁle is based on increasing arterial stiﬀness, decreased vascular compliance, and diastolic dysfunction secondary to atrial and ventricular stiﬀness [54]. Because they have multiple clinical applications, including treatment of angina pectoris and management of supraventricular arrhythmias, calcium antagonists also hold promise in the treatment of elderly hypertensive patients with comorbid cardiovascular conditions. In general, calcium antagonists appear to be well tolerated by the elderly. Most adverse eﬀects of the dihydropyridines are attributable to vasodilation; examples include headaches and postural hypotension. Postural hypotension is associated with an increased risk of dizziness and falls; thus, it is a serious concern for elderly patients. Peripheral edema also may result and be confused with symptomatic congestive heart failure [55]. Verapamil, which may be particularly useful in elderly patients with diastolic dysfunction of the left ventricle, has been noted to increase constipation [56]. Verapamil and diltiazem can precipitate heart blocks in elderly patients with underlying conduction defects. Agerelated declines in renal or hepatic function alter drug disposition in elderly patients, mostly as a result of declines in ﬁrst-pass metabolism. This decline decreases total body clearance and increases elimination half-life. Individualized dose adjustments or dosing schedules help to decrease adverse eﬀects [57]. The published results of large double-blind, randomized, placebo- and active-controlled trials have demonstrated the safety and eﬃcacy of calcium antagonists in elderly patients with both isolated systolic hypertension and combined systolic and diastolic hypertension (Table 3). Three studies have evaluated two dihydropyridines, long-acting nitrendipine and felodipine, in patients with isolated systolic hypertension. The Systolic Hypertension in

140 Table 3

Frishman et al. Trials of Antihypertensive Therapy with Calcium Antagonists in Elderly Patients

Trial

Entry criteria

ALLHAT 5 years 40,000 pts

Age >55 yr BP: 140/90 or lower if treated Race: 55% AfricanAmerican Other

CONVINCE 5 years 15,000 pts

Age z 55 yr BP: systolic 140–190 or diastolic 90–100 or 175–100 if treated Other

HOT 2.5 years 18,000 pts

Age 50–80 yr BP: diastolic 100–115

INSIGHT 3 years 6321 pts

Age 55–80 yr BP z 150/95 (sitting) or systolic >160 Other Age 50–69 yr BP: diastolic >110 or >100 (sitting) if treated or other risk factors present

NORDIL 5 years 10,881 pts

PREDICT 4–4.5 years 8000–8500 pts

Age z 55 yr BP: 90–109/140–179 Other

SISH 2 years 171 pts

Age >55 yr BP: systolic 140–159

STOP-2 4 years 6600 pts

Age 70–84 yr BP >180/105 (sitting)

Therapy

Endpoints

1st: amlodipine, lisinopril, doxazosin, or chlorthalidone + pravastatin 2nd: reserpine, clonidine, atenolol, or hydralazine at physician’s discretion 1st: verapamil, atenolol, or HCTZ 2nd: HCTZ or beta blocker for achievement of BP goal 3rd: moexipril 1st: felodipine + aspirin or placebo 2nd: captopril, enalapril, ramipril, atenolol, meto prolol, or propranolol, as needed 1st: long-acting nifedipine or HCTZ-amiloride 2nd: atenolol or enalapril

1st: fatal/nonfatal MI 2nd: morbidity, mortality, cost, beneﬁts of cholesterol reduction

1st: diltiazem, diuretic, or beta blocker 2nd: ACE inhibitor, beta blocker, or diuretic 3rd: ACE inhibitor, beta blocker, or diuretic

1st: diltiazem or chlorthalidone 2nd: open-label therapy 3rd: open-label therapy 1st: felodipine or placebo

1st: felodipine, isradipine, atenolol, metoprolol, pindolol, enalapril, lisinopril, or HCTZ-amiloride

1st: fatal/nonfatal MI, stroke; sudden cardiac death 2nd: cardiovascular disease, number and time of deaths 1st: fatal/nonfatal MI, stroke; achievement of BP goal 2nd: beneﬁts of aspirin

1st: fatal/nonfatal MI, stroke; congestive heart failure 2nd: mortality 1st: fatal/nonfatal MI, stroke; sudden cardiac death 2nd: mortality, ischemic heart disease or attack, atrial ﬁbrillation, congestive heart failure, renal disease 1st: fatal/nonfatal cardiovascular disease

1st: compare eﬀects on EKG measurements of ventricular wall thickness and ventricular function 1st: fatal/nonfatal MI, stroke; sudden cardiac arrest 2nd: cardiovascular disease, cost, institutionalization, tolerability of therapy

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Continued

Trial Syst-Eur 5 years 3000 pts Syst-China STONE

Entry criteria

Therapy

Endpoints

Age z 60 yr BP: systolic 160–219 or diastolic <95 (sitting)

1st: nitrendipine or placebo 2nd: enalapril, HCTZ, or placebo

1st: fatal/nonfatal stroke 2nd: MI, congestive heart failure

1st: nitrendipine or placebo 1st: nifedipine

Abbreviations: pts, patients; BP, blood pressure (mmHg); MI, myocardial infarction; EKG, electrocardigraphic; HCTZ, hydrochlorothiazide; ACE, angiotensin-converting enzyme; ALLHAT, Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular Endpoints; HOT, Hypertension Optimal Treatment Study; INSIGHT, International Nifedipine Study: Intervention as a Goal in Hypertension Treatment; NORDIL, Norwegian Diltiazem Intervention Study; PREDICT, Prospective Randomized Evaluation of Diltiazem CD Trial; SISH, Stage 1 Systolic Hypertension; STOP-2, Swedish Trial in Old Patients with Hypertension 2; Syst-Eur, Systolic Hypertension in Europeans Study; Syst-China, Systolic Hypertension in China; STONE, Shanghai Trial of Nifedipine in the Elderly. Source: Adapted from Ref. 89.

Europe Study (SYST-EUR) was limited to patients 60 years of age and older with a resting systolic pressure of 160 to 219 mmHg, and a diastolic pressure <95 mmHg. Patients were randomized to receive nitrendipine or placebo. If additional blood pressure control was necessary, patients received an ACE inhibitor and then a diuretic. Compared to placebo, nitrendipine therapy was associated with signiﬁcant reductions in the rate of stroke, major cardiovascular events, and cognitive disorders [58–60]. Based on this study, the JNV-VII guidelines include the use of dihydropyridine calcium antagonists in addition to thiazide diuretics as ﬁrst-line treatment for ISH in the elderly [1]. The Systolic Hypertension in China (SYST-CHINA) study also looked at nitrendipine as a ﬁrst-line treatment modality compared to placebo in elderly patients with ISH [61]. Compared to placebo, nitrendipine was associated with a reduction in stroke events, major cardiovascular events, and mortality. The Stage I Systolic Hypertension in the Elderly [62] was a pilot trial that enrolled elderly patients (>55 years of age) with mild (stage 1) systolic hypertension (140 to 155 mmHg), a population not studied in SHEP, SYST-EUR, and SYST-CHINA. Felodipine was compared to placebo in an attempt to reduce systolic blood pressure by 10%. Felodipine was shown to be more eﬀective than placebo in reducing blood pressure. In addition, the drug was shown to reduce ventricular wall thickness and improved ventricular function [62,63]. A number of studies have been completed comparing various calcium blockers to other antihypertensive drugs in older subjects with combined systolic and diastolic hypertension (Table 3). STOP-2 enrolled 6,600 patients ranging in age from 70 to 84 years with a supine blood pressure of 180/105 mmHg or higher [43]. The original STOP trial [23] compared the eﬀects of diuretics and beta-blockers in elderly hypertensives in terms of cardiovascular morbidity and mortality. STOP-2 [43] compared these two treatments with a calcium blocker (felodipine or isradipine) or an ACE inhibitor (enalapril or lisinopril). There was no diﬀerence between the three treatment groups with respect to the combined endpoints of fatal stroke, fatal myocardial infarction, and other cardiovascular diseases

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[43,64]. There was a lower incidence of nonfatal myocardial infarction and congestive heart failure in the ACE inhibition group compared to the other treatment modalities. In the International Nifedipine Study Intervention as a Goal in Hypertension Treatment (INSIGHT) [65], 6321 elderly patients aged 55 to 80 years were randomized to double-blind treatment with either long-acting nifedipine (GITS) or the combination drug co-amilozide (HCTZ and amiloride). The study endpoints were overall cardiovascular morbidity and mortality, and both treatments appeared equally eﬀective in preventing vascular events. In the Nordic Diltiazem Study (NORDIL) [66], 10,881 patients aged 50 to 74 years with systemic hypertension were randomized to receive ﬁrst-line therapy with either diltiazem, diuretics, or beta-blockers. Diltiazem was as eﬀective as the other treatments in reducing the incidence of combined study endpoints of stroke, myocardial infarction, and other cardiovascular death. In the Prospective Randomized Evaluation of Diltiazem CD Trial (PREDICT) study, 8000 patients aged z55 years were randomized to receive either diltiazem or chlorthalidone. The results have not been published to date. Other studies have demonstrated the eﬃcacy of calcium-channel blockers used alone or in combination in elderly patients when compared to alternative medications [67–71]. The HOT trial studied 18,000 patients aged 50 to 80 years. The study examined whether maximal reduction of diastolic blood pressure with antihypertensive drugs and aspirin could cause a further reduction in cardiovascular events (myocardial infarction or stroke) or be associated with harm (J-curve hypothesis) [72]. Felodipine, a long-acting dihydropyridine, was used as the ﬁrst-line treatment for all patients and aspirin (75 mg) or placebo was also given. An ACE inhibitor, a beta-blocker, and a thiazide diuretic could be given to achieve the desired diastolic blood pressure goal. The study results showed that maximal protection with antihypertensive therapy was seen when a diastolic blood pressure of 82.6 mmHg was achieved; in diabetic patients, an additional reduction in diastolic blood pressure (below 80 mmHg) was needed to achieve maximal beneﬁt. A J-curve response was not observed despite major reductions in blood pressure. The HOT study had greater success in achieving blood pressure targets among the oldest subjects, with a low incidence of medication side eﬀects. The Controlled-Onset Verapamil Investigation of Cardiovascular Events (CONVINCE) trial [73] (Table 3) was designed to compare a delayed slow-release verapamil delivery system to atenolol or HCTZ in 15,000 hypertensive patients aged z55 years. The study was stopped by the sponsor for cost reasons, and the accumulated data from the trial showed no diﬀerence in the clinical endpoints with either treatment regimen. Calcium antagonists are well suited for treating elderly hypertensive patients who often have concomitant diseases, especially coronary artery disease or heart failure due to diastolic dysfunction (Table 4). In an elderly patient with both hypertension and ischemic heart disease (with or without angina pectoris), calcium antagonists are an appropriate therapy for both conditions [74]. The combination of a calcium antagonist and a betablocker is well tolerated and serves to oﬀset transient increases in the neurohumoral reﬂex [75]. A combination regimen of felodipine and metoprolol is now being evaluated. Combinations of calcium blockers with ACE inhibitors have also been evaluated [76]. The edema seen with the calcium blocker is reduced, while there is greater blood pressure eﬃcacy with combination therapy than with monotherapy. Elderly patients with diastolic dysfunction have impaired myocardial relaxation, which leads to decreased ventricular ﬁlling. Impairment may be related to age or to myocardial ischemia from coronary disease [77]. Calcium antagonists may help to improve left ventricular diastolic function in such patients [78].

14.7 11.1 2.0 3.5 22.9 — —

Cardiovascular Angina

MI CHF Stroke Diabetes Dementia Depression

4.4 1.3 1.3 20.1 — —

8.6

Women

— — 1.4 10.1 0.4 11.1

4.9

SHEP

3.5 — 1.2 10.5 0.8 —

8.8

Syst-Eur

— 1.4 4.0 — —

Angina and/or MI: 9.4

Syst-China

Trial participants (%) (age >60 years)

11.9 3.0 9.5 20.0 — —

12.1

Men

4.6 4.9 4.9 15.2 — —

16.0

Women

Elderly Patients with hypertension (%) (age >65 years)

16 40 36 23 —

Angina and/or MI: 20

Residents of nursing homes (%) (age 65–74 yrs)

Abbreviations: MI, myocardial infarction; CHF, congestive heart failure; SHEP, Systolic Hypertension in the Elderly Program, Syst-Eur, Systolic Hypertension in Europe; Syst-China, Systolic Hypertension in the Elder Chinese, —, data not available. Source: From Ref. 90.

Men

Disease

General population (%)

Table 4 Incidence of Comorbid Conditions Observed in the General Elderly Population, Hypertension Trial Participants, Elderly Patients with Hypertension, and Nursing Home Residents with Hypertension

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Angiotensin Converting Enzyme Inhibitors Angiotensin converting enzyme (ACE) inhibitors block the conversion of angiotensin-I to angiotensin-II both systemically and locally in arterioles to lower total peripheral vascular resistance. Blood pressure is reduced without reﬂex stimulation of heart rate and cardiac output. As aging occurs, angiotensin levels are lower and, theoretically, ACE inhibitors should not be as eﬀective as other therapies. However, multiple studies have shown otherwise. The Captopril Prevention Project (CAPPP) compared captopril to a beta-blocker in 10,925 older patients with diastolic blood pressure >100 mmHg [79]. Patients receiving captopril had a lower rate of cardiovascular death; patients on beta-blockers had a lower stroke rate. Other studies previously mentioned (ALLHAT and STOP-2) [39,43] showed that ACE inhibitors can reduce the risk of stroke and coronary heart disease as well as other antihypertensive drugs, although in ALLHAT there was less of a reduction, especially in Black patients. ACE inhibitors have been shown to reduce mortality in patients who have already had a stroke [80] and have been shown to reduce mortality in patients with heart failure and poor LV function [81]. The drugs appear to reduce the progression of renal disease in type 1 diabetic patients with proteinuria [82]. The HOPE trial evaluated the eﬀects of ramipril in 9297 patients over the age of 55 who were both normotensive and hypertensive in a placebo-controlled trial [83]. Subjects had a previous history of stroke, coronary disease, peripheral vascular disease, and diabetes mellitus without heart failure. After 5 years, the endpoints of MI, stroke, or cardiovascular death were evaluated. Ramipril was associated with a lower blood pressure than placebo, and reduced the risk of the combined primary outcome by 25%, MI by 22%, stroke by 33%, cardiovascular death by 37%. Given all the available data, ACE inhibitors should be considered as drugs of choice in elderly hypertensive patients with heart failure and/or diabetes mellitus. The main adverse eﬀects of ACE inhibitors include excessive hypotension, chronic dry cough, and, rarely, angioedema or rash. Renal failure can develop in those with renal artery stenosis. Hyperkalemia can occur in patients with renal insuﬃciency or those taking potassium supplements. Therefore, these agents must be used carefully in patients with renal impairment. Rarely neutropenia or agranulocytosis can occur; therefore, close monitoring is suggested the ﬁrst few months of therapy.

Angiotensin Receptor Blockers The angiotensin receptor blockers (ARB) are a relatively new class of drugs employed in the treatment of hypertension. These agents work selectively at the AT1-receptor subtype, the receptor that mediates all the known physiological eﬀects of angiotensin-II that are believed to be relevant to cardiovascular and cardiorenal homeostasis. A large-scale open-label clinical experience trial (ACTION study) showed the eﬀectiveness of the ARB candesartan cilexetil alone or in combination with other agents in 6465 patients with a mean age of 58 who had either combined or isolated systolic hypertension [84]. The LIFE study compared losartan to atenolol in 9193 patients aged 55 to 80 years with essential hypertension and LVH [44]. The study showed a substantially reduced rate of stroke in the losartan-treated group despite comparably reduced blood pressure reduction in both the losartan and atenolol treatment groups. A primary composite outcome of death,

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stroke, and cardiovascular mortality showed a signiﬁcant beneﬁt in favor of losartan. There was also a greater eﬀect on LVH regression with losartan compared to atenolol. Overall, safety and eﬃcacy trials have shown that ARBs are similar to other agents in reducing blood pressure and are well tolerated. ARBs have also been found in recently completed clinical trials to be useful in protecting the kidney in the setting of type 2 diabetes [44], both in established diabetic nephropathy with proteinuria and in microalbuminuria diabetic patients [82]. The drugs have also been shown to be useful in reducing mortality and morbidity in patients with congestive heart failure [82]. In elderly patients, ARBs can be considered a ﬁrst-line treatment in hypertensive patients with type 2 diabetes, and as an alternative to ACE inhibitors in hypertensive patients with heart failure who cannot tolerate ACE inhibition. A study is being done to look at the eﬃcacy of the ARB, candesartan, for left ventricular diastolic dysfunction. Alpha-Adrenergic Blocking Agents In large comparative clinical trials, the eﬃcacy and safety of alpha-blockers have been well documented [46]. Doxazosin 2 to 8 mg daily was one of the drugs used in the ALLHAT trial, and that arm of the study was discontinued after an interim analysis showed a 25% greater rate of cardiovascular events compared to chlorthalidone, largely driven by congestive heart failure [85]. Based on this study, alpha-blockers should not be considered as ﬁrst-line monotherapy treatment for hypertension, but as part of a combination regimen to provide maximal blood pressure control. These drugs are a treatment of choice for symptomatic prostate hypertrophy and caution should always be used because of their potent hypotensive actions. Centrally Acting Agents Centrally acting agents (e.g., clonidine) are not ﬁrst-line treatments in the elderly because many patients experience troublesome sedation. They can be used as part of a combination regimen to maximize blood pressure control. Other Antihypertensive Drugs Under consideration for approval in hypertension is eplerenone, a selective aldosterone antagonist. Aldosterone antagonists as diuretics have been combined with thiazides as part of an antihypertensive regimen. Drugs in this class should be used with caution in elderly patients with renal disease. Combination Therapy Treating hypertension with combination therapy provides more opportunity for creative solutions to a number of problems. Five issues in combined therapy—some practical, some speculative—are listed in Table 5 [86]. The most obvious beneﬁt of drug combinations is the enhanced eﬃcacy that fosters their continued widespread use. Theoretically, some drug combinations might produce synergistic eﬀects that are greater than would be predicted by summing the eﬃcacies of the component drugs. More commonly, combination therapy achieves a little less than the sum of its component drug eﬃcacies. In contrast, some combinations of drugs produce

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Table 5 Rationale for Combination Drug Therapy for Hypertension Increased antihypertensive eﬃcacy Additive eﬀects Synergistic eﬀects Reduced adverse events Low-dose strategy Drugs with oﬀsetting actions Enhanced convenience and compliance Prolonged duration of action Potential for additive target organ protection Source: From Ref. 86 with permission.

oﬀsetting interactions that weaken rather than strengthen their antihypertensive eﬀects, as previously seen with agents aﬀecting peripheral-neuronal actions. For instance, guanethidine and reserpine produced this oﬀsetting interaction; but since these agents are used now only rarely, this issue need not be considered further. A second beneﬁt of combination therapy concerns the avoidance of adverse eﬀects. When patients are treated with two drugs, each drug can be administered in a lower dose that does not produce unwanted side eﬀects but still contributes to overall eﬃcacy. A third issue concerns convenience. Obviously, the multiple drugs of a combination regimen could be confusing and distracting to elderly patients, and could lead to poor treatment compliance. On the other hand, a well-designed, combination pill that incorporates logical doses of two agents could enhance convenience and improve compliance. Further potential value of combination treatment may result from the eﬀects that two drugs have on each other’s pharmacokinetics. Although this has not been studied well, there might be situations where the clinical duration of action of the participating drugs becomes longer when used in combination than when they are administered as monotherapies. Finally, it is interesting to consider the attributes of such agents as ACE inhibitors, ARBs, and calcium channel blockers, which exhibit anti-growth or anti-atherosclerotic actions in addition to their blood pressure–lowering properties. Is it possible that combinations of these newer agents may provide even more powerful protective eﬀects on the circulation?

CONCLUSION A meta-analysis of nine trials with more than 15,000 elderly subjects reported that allcause mortality, stroke mortality, and coronary mortality were reduced by lowering blood pressure [87]. Elderly patients with hypertension, especially isolated systolic hypertension, are the demographic group most likely to have uncontrolled hypertension. Despite clear evidence in elderly patients that morbidity can be reduced with antihypertensive drugs, clinicians are less aggressive with pharmacotherapy than they could be. The elderly also have concomitant diseases that often warrant major reductions in systolic blood pressure. Decreasing blood pressure in this age groups may be diﬃcult. It has to be done carefully and although all of the guidelines suggest that the goal of systolic blood pressure should be <140 mg, this is not achievable in all patients. Blood pressure should also be lowered in patients with a previous stroke or transient ischemic attack [80].

Systemic Hypertension Table 6

147

Approach to Blood Pressure Reduction in the Elderly

I. Lifestyle modiﬁciations (exercise, diet) II. Initiate drug treatment with thiazide diuretic in uncomplicated hypertension (combined systolic/diastolic) and isolated systolic hypertension. III. Initiate alternative therapy in hypertensive patients with angina pectoris (beta-blockers, calcium blockers), heart failure (ACE inhibitors or ARBs), type 1 diabetes (ACE inhibitors), type 2 diabetes (ARBs). IV. Use low-dose combination regimens to maximize blood pressure control when goals are not met; thiazides should be part of combination regimen.

Diuretics should probably be considered the ﬁrst-line treatment for hypertension in the elderly unless other conditions exist (angina pectoris, diabetes mellitus, congestive heart failure), which may warrant treatment with other antihypertensive drugs (Table 6). With the stricter blood pressure goals, most patients will require combination antihypertensive regimens especially for control of systolic blood pressure elevations.

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Frishman et al. in young and elderly hypertensive patients: Altered electrocardiographic and hypotensive responses. Ann Intern Med 1986; 105:329–336. Schwartz JB, Abernethy DR. Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension. Am J Cardiol 1987; 59:1111–1117. Staessen JA, Fagard R, Thijs L, et al. Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350:757– 764. Forette F, Seux M-L, Staeseen JA, et al. Prevention of dementia in randomized double-blind, placebo-controlled systolic hypertension in Europe (SYST-EUR). Lancet 1998; 352:1347– 1351. Staessen JA, Thijs L, Fagard RH, et al. Calcium channel blockade and cardiovascular prognosis in the European trial on Isolated Systolic Hypertension. Hypertension 1998; 32:410–416. Wang JG, Staessen JA, Gong L, et al. Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (SYST-CHINA) Collaborative Group. Arch Intern Med 2000; 160:211–220. Black HR, Elliott WJ, Weber MA, et al. For the Stage 1 Systolic Hypertension (SISH) Study Group: One-year study of felodipine or placebo for stage 1 isolated systolic hypertension. Hypertension 2001; 38:1118–1123. Strom JA, Daboin NP, Meisner JS, et al. Left ventricular hypertrophy is a frequent ﬁnding in older patients with stage 1 systolic hypertension [abstr]. Circulation 1997; 96:1–600. Lindholm LH, Hansson L, Ekbon T, et al. Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension-2 (STOP Hypertension-2 Study Group). J Hypertens 2000; 18:1671–1675. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomized to double-blind treatment with long-acting calcium channel blocker or diuretic in the International Nifedipine GITS Study: intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356:366–372. Hansson L, Hedner T, Lund-Johansen P, et al. Randomized trial of eﬀects of calcium antagonists compared with diuretics and beta blockers on cardiovascular morbidity and mortality in hypertension: The Nordic Diltiazem (NORDIL) Study. Lancet 2000; 356:359– 362. Ogihara T. Practitioner’s Trial on the Eﬃcacy of Antihypertensive Treatment in the Elderly Hypertensive (The PATE-Hypertension Study) in Japan. Am J Hypertens 2000; 13:461–467. Chan P, Lin CN, Tomlinson B, et al. Additive eﬀects of diltiazem and lisinopril in the treatment of elderly patients with mild to moderate hypertension. Am J Hypertens 1997; 10 (7 Pt 1):743–749. National Intervention Cooperative Study in Elderly Hypertensives (NICS-EH). Study Group: Randomized double-blind comparison of a calcium channel antagonist and a diuretic in elderly hypertensives. Hypertension 1999; 34:1129–1133. Gong L, Zhang W, Zhu Y, et al. Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 1996; 14:1237–1245. Liu L, Wang JG, Gong L, et al. For the Systolic Hypertension in China (Syst-China) Collaborative Group: Comparison of active treatment and placebo for older Chinese patients with isolated systolic hypertension. J Hypertens 1998; 16:1823–1829. Hansson L, Zanchetti A, Carruthers SG, et al. Eﬀects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results from the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998; 351:1755–1762. Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) Trial. JAMA 2003; 289:2073–2082. Frishman WH, Michaelson MD. Use of calcium antagonists in patients with ischemic heart disease and systemic hypertension. Am J Cardiol 1997; 79:33–38.

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75. Bassan MM. The combined use of calcium-channel blockers and beta blockers in the treatment of angina pectoris: an update. Pract Cardiol 1987; 13:51–54. 76. Frishman WH, Ram CVS, Mc Mahon FG, et al. Comparison of amlodipine and benazepril monotherapy to combination therapy in patients with systemic hypertension: a randomized, double-blind, placebo-controlled parallel group study. J Clin Pharmacol 1995; 35:1060–1066. 77. Setaro SF, Schulmon DS, Zaret BL, Soufer R. Congestive heart failure and intact systolic function: Improvement in clinical status and diastolic ﬁlling with verapamil. Clin Res 1987; 35:325A. 78. Manning WS, Hung G, Parker J, et al. Heart failure in the elderly: Diastolic dysfunction with preserved systolic function and normal coronary arteries [abstr]. J Am Coll Cardiol 1988; 11: 160A. 79. Hansson L, Lindholm L, Niskanen L, et al. Eﬀect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353:611– 616. 80. PROGRESS Collaborative Group. Randomised trial of perindopril-based blood-pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033–1041. 81. SOLVD Investigators. Eﬀects of ACE inhibition with enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991; 325: 293–302. 82. Sica DA, Gehr TWB, Frishman WH. The renin-angiotensin axis: angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers. In: Frishman WH, Sonnenblick EH, Sica DA, eds. Cardiovascular Pharmacotherapeutics. 2d ed. New York: McGraw Hill, 2003:131–156. 83. Yusef S, Sleight P, Pogue J, et al. Eﬀects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. New Engl J Med 2000; 342:145–153. 84. Weir MR, Weber MA, Neutel JM, et al. For the ACTION study investigators. Eﬃcacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy a clinical experience trial. Am J Hypertens 2001; 14:567–572. 85. ALLHAT Oﬃcers and Coordinators. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. JAMA 2000; 283:1967–1975. 86. Weber MA, Neutel JM, Frishman WH. Combination drug therapy. In: Frishman WH, Sonnenblick EH, Sica DA, eds. Cardiovascular Pharmacotherapeutics. 2d ed. New York: McGraw Hill, 2003:355–368. 87. Moser M. Update on the management of hypertension: do recent trial results indicate a change in national recommendations for therapy? J Clin Hypertens 2002; 4(suppl 2):20–31. 88. Frishman WH, Qureshi A. Calcium antagonists in elderly patients with systemic hypertension. In: Epstein M, ed. Calcium Antagonists in Clinical Medicine. 3rd ed. Philadelphia: Hanley & Belfus, 2002:489–504. 89. Townsend RR, Kimmel SE. Calcium channel blockers and hypertension. I: new trials. Hosp Pract 1996; 31:125–136. 90. Messerli FH, Grodzicki T, Feng Z. Antihypertensive therapy in the elderly: evidence-based guidelines and reality. Arch Intern Med 1999; 159:1621.

6 Hyperlipidemia in the Elderly: When Is Drug Therapy Justified? John C. LaRosa State University of New York Health Science Center at Brooklyn, Brooklyn, New York, U.S.A.

INTRODUCTION Over the centuries, gains in lifespan have been related much more to what might broadly be called public health measures than to medical interventions. Such factors as social organization, access to food, protective clothing, and even the introduction of washable linen underwear have reduced human morbidity and mortality. In the twentieth century, dramatic gains in lifespan in western societies were derived mainly from the elimination of childhood diseases and obstetrical complications [1]. However, with increased longevity has come a dramatic increase in mortality and morbidity from the chronic diseases of older individuals, primarily cancer and the complications of vascular atherosclerosis. Because these diseases have, to some extent, been viewed as inevitable consequences of aging, the notion of prevention in the elderly has been regarded almost as a nonsequitur. This is true even though studies indicate that these risk factors are predictive of atherosclerotic clinical disease in older as well as in younger subjects [2]. Most individuals over 65 years of age have one and often more cardiovascular risk factors. Risk factor prevalence does not begin to decline until age 75 and beyond [3]. That decline is probably a result of selective survival, that is, individuals with multiple risk factors have already succumbed. Most risk factors, however, lose some of their predictive potency in older individuals [4]. This may be due to selective survival, the presence of other diseases that may alter risk factor or mortality levels, mistaken diagnoses of atherosclerosis, and the failure to take into account the lifetime dose eﬀect of a risk factor. Because risk is often expressed as relative, not absolute, the importance of a factor in promoting coronary morbidity and mortality may be missed. The absolute risk of morbidity and mortality from coronary disease, for example, increases steeply with age. It is possible, then, that the number of heart attacks eventually prevented in a population by reduction of a given risk factor may actually increase with age, even though the power of the risk factor to predict relative risk declines [5]. 153

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LIPOPROTEIN DISORDERS AS PREDICTORS OF CARDIOVASCULAR RISK Total cholesterol levels gradually increase with age, more prominently in women than in men. After about the age of 55, women consistently have higher levels of total, lowdensity, and high-density lipoprotein cholesterol levels than do men of the same age [6]. The value of total cholesterol as a predictor of relative risk of coronary disease decreases with increasing age in both men and women. The value of total cholesterol as a predictor of risk, however, can be enhanced in older individuals by controlling for other risk factors and particularly for indices of ‘‘frailty,’’ including low serum albumin and iron levels [4]. Put another way, depressed cholesterol levels in the chronically ill or elderly are not reliable indicators of lifetime exposure to increased cholesterol levels or of the potential risk of coronary disease related to cholesterol. Since women make up two-thirds of the population over age 65, gender speciﬁcity is important in discussing risk factor relationships. HDL cholesterol makes up a greater share of the total cholesterol level in women and, as a result, total cholesterol may be a less precise predictor of risk in women than in men [7]. On the other hand, HDL in the elderly may be a more important risk factor both because it is higher in women than in men and because it is a more potent predictor of risk in women than in men. Because HDL and triglyceride levels are strongly and inversely related, it is not surprising that triglycerides continue to be a predictor of coronary risk in older individuals. Although levels of triglycerides are higher in older men than in older women, they are better predictors of coronary risk in women than in men—again, perhaps, because of the inverse relationship with HDL [8]. These observational epidemiological data are somewhat diﬃcult to evaluate in older individuals. As mentioned earlier, it is especially relevant in these populations to examine the eﬀect of risk factors to absolute risk. When that is done, it is apparent that, as a result of the increased numbers of coronary events with increasing age, the risk attributable to increased cholesterol actually increases as individuals age. Looked at in this way, cholesterol is more, not less, important as a predictor of cardiovascular events in the elderly [5]. Epidemiological studies of the relation of lipoprotein levels to atherosclerosis have, in the elderly, concentrated on coronary disease event rates. Little information exists concerning the predictability of cholesterol on stroke rates. In fact, until recently, cholesterol levels were not considered to be related to incidents of stroke either in younger or older individuals. More recently, imaging techniques have allowed the clinical distinction between hemorrhagic and atherothrombotic stroke to be made. As a result, it has become clear that cholesterol levels are directly related to the incidence of atherothrombotic stroke, but inversely related to the incidence of hemorrhagic stroke [9]. In western societies, where the predominant cause of stroke is related to atherothrombosis, this is an observation of particular signiﬁcance in older patients. Consideration of stroke prevention leads to another issue of unique importance in older individuals. Much of the emphasis, both in epidemiological as well as clinical trial studies, has been on the eﬀects of interventions on mortality. While this is appropriate, it does not give proper attention to the very important issue of the beneﬁts of speciﬁc interventions on morbidity. For many older patients, the prospect of a disabling stroke that might leave them dependent and unable to communicate is as great or greater than the threat of mortality. In such patients, interventions that could lead to a decreased risk of stroke are of particular importance.

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Prevention of morbidity is an important issue, even among those who have achieved an advanced age group in which mortality extension is not a reasonable expectation. The ability of risk factors to continue to be predictive in individuals over 75 or 80 has not been well studied, but in cases where such studies have been performed they have indicated that even at these advanced stages risk factors and, in particular, levels of cholesterol and its subfractions continue to predict risk [10]. Since it is this age group that is the most rapidly growing in the United States and other western countries, the impact of prevention is of great importance. In particular, the ability to delay or prevent serious disability is not only of great importance to the individual but also to society, which must otherwise carry the ﬁnancial burden of caring for individuals with serious disabilities. It is not only important to keep people alive as long as possible, but also to keep them functional and free of disability as long as possible and the period of decline to death as brief as possible. All of these issues must be weighed when we consider the value of risk factor intervention in older individuals.

CHOLESTEROL INTERVENTION AND CARDIOVASCULAR DISEASE PREVENTION Until relatively recently, clinical trial data in older individuals has been very limited. The Los Angeles Veterans Administration Study used diet to lower cholesterol and demonstrated a decline in both myocardial infarction and sudden death with cholesterol lowering over an 8-year period of time. This decline, however, reached statistical signiﬁcance only in those under 65 [11]. The Stockholm Secondary Prevention Study, using a combination of niacin and coﬁbrate, showed a decrease in recurrent ischemic heart disease and total mortality both in those over and under 60 years of age. This has particular signiﬁcance because the combination of drugs used provided lowered both cholesterol and triglycerides and it was the latter which seemed to be most closely associated with the decline in event rates [12]. More recently, a series of now almost classic studies utilizing statins have been completed. A meta-analysis of these studies, summarized in Figure 1, demonstrated that the eﬀect of cholesterol lowering was virtually identical in those over 65 compared to those under 65 [13]. In both groups there was roughly a 30% decline in coronary event rates associated with cholesterol lowering of about the same magnitude. These beneﬁts appeared to be independent of the particular statin used and independent of the gender of the patient. LDL cholesterol lowering, then, in individuals over 65 appeared from these studies to be a critically important intervention in the prevention of both morbidity and mortality related to coronary disease. A surprising aspect of these studies was the unexpected ﬁnding that stroke rates were lowered to about the same degree as the decline in coronary event rates [14]. Because of the conventional wisdom that had prevailed for some time that stroke was not related to cholesterol levels, these results were surprising. They were also very encouraging because they oﬀered the hope that severe disability resulting from stroke could be signiﬁcantly prevented or delayed in elderly subjects, thus forming a separate and important rationale for cholesterol intervention. None of the studies included in these meta-analyses, however, were designed speciﬁcally to look at the eﬀect of cholesterol lowering in elderly subjects. Nor did they include suﬃcient numbers of the ‘‘older’’ elderly, that is, those over 75, to be able to conclude any-

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Figure 1

LaRosa

Effect of age on relative risk of coronary events in major statin trials.

thing meaningful about the value of cholesterol lowering in patients in those age categories. Indeed, many physicians felt intuitively that the older elderly were dealing with such a limited lifespan and such a high risk of disabling events that preventive measures had little relevance to their care. A corollary concept that has held great sway was that anyone who survived to these advances ages must be constitutionally resistant to vascular disease and, therefore, interventions could be considered superﬂuous. In the last year, three studies—the Heart Protection Study (HPS) [15], the Prospective Study of Pravastatin in Elderly at Risk (PROSPER) study [16], and the Antihypertensive Lipid Lowering Heart Attack Trial (ALLHAT) study [17]—have all been reported. In the case of HPS, the study was large enough to include a substantial number of individuals over 65 and even over 75 and, in the case of PROSPER and ALLHAT, only individuals over 65 were included in the ﬁrst place. In HPS, using simvastatin, 40 mg/day versus placebo, men and women who began the study at age <65, at 65 to 70 or over 70, all had similar reductions (about 25%) in cardiovascular diseases event rates (Fig. 2). Even among the 1263 subjects in the study

Figure 2

Effect of simvastatin 40 mg/day on 5-year CHD event rate (HPS).

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who were 75 to 80 years old at study entry (and 80 to 85 years old at its end), there was a 29% decline in event rates. There was a signiﬁcant lowering overall of ischemic strokes but no analysis by age has yet been published. In the PROSPER study, individuals over 65 were enrolled and treated with pravastatin, 40 mg/day versus placebo. A signiﬁcant decline in coronary events was noted after 3 years of study with LDL lowering of 34%. Interestingly, however, there was no decrease in stroke rates, although there was a borderline signiﬁcant lowering of transient ischemic attacks. In the ALLHAT study, which did not achieve a substantial LDL-cholesterol difference (about 9%) between the treated and experimental and usual treatment group, cholesterol lowering with pravastatin achieved neither a signiﬁcant decline in coronary or cerebrovascular event rates. The diﬀerent ﬁndings in these studies may relate simply to the degree of cholesterol lowering achieved. Certainly, the HPS study strongly supports the notion that there is no age beyond which cholesterol lowering is unlikely to have beneﬁt. Again, it must be emphasized that that beneﬁt should not be deﬁned in terms of mortality alone. It is also interesting to hypothesize that the stroke beneﬁt might require a greater degree of cholesterol lowering than beneﬁts on coronary disease. The speciﬁc beneﬁt of cholesterol lowering in stroke prevention or total mortality remains unclear, although further analysis of HPS data may provide some answers. None of these studies provide information about the value of triglyceride lowering in older subjects. Indeed, because statins are not the best drugs for triglyceride lowering and particularly not for increasing HDL, the issue of interventions on these two variables will require further study. This is not a minor question, however. As western populations accumulate increasing numbers of older people with metabolic syndromes including diabetes, hypertriglyceridemia, and low HDL levels, information about interventions designed to aﬀect these risk factors is of great importance. Since older patients are likely to have other serious, sometimes life-threatening, diseases, it has been said in the past that preventive interventions such as cholesterol lowering should surely not be engaged in in individuals with other life-limiting illnesses such as, for example, metastatic cancer. The evidence from the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study [18], of almost immediate beneﬁt of statin therapy prescribed in the period immediately after a coronary event, however, is striking. Even elderly patients with life-limiting conditions may beneﬁt from cholesterol lowering to prevent debilitating strokes and serious disability for whatever lifespan remains. It would be premature to make such interventions a recommendation for regular practice, but it is important to remember that the immediate eﬀects of statins, whether mediated through cholesterol lowering or some non-cholesterol-related ‘‘pleiotropic’’ eﬀects [19], may lead to beneﬁts that do not require months or years of treatment to achieve.

SPECIAL CONSIDERATIONS FOR CHOLESTEROL INTERVENTIONS IN THE ELDERLY The most recent iteration of the National Cholesterol Education Program guidelines depend upon estimates of cardiovascular risk derived from Framingham tables relating levels of individual risk factors to coronary risk. These tables clearly demonstrate that age

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is the most potent predictor of risk of any of the factors considered [20]. As a result, older individuals with modest elevations of risk factors are likely to fall into the category in which treatment, not only with diet but also with drugs to lower cholesterol, is indicated. There is little direct clinical trial evidence that diet alone is eﬀective in reducing coronary risk in older people [21]. Although some concern has been expressed about the potential adverse eﬀects of diet restrictions in older people, including the possibility of aggravation of calcium deﬁciencies due to dairy product restriction, wasting secondary to caloric restriction, and constipation resulting from ﬁber overload. Nevertheless, diet is an eﬀective and, sometimes, the sole intervention necessary to lower cholesterol levels in older individuals. Adherence to diet in older as well as younger subjects is problematic. In many instances, older individuals may be more anxious and have more time to take control of their health and might be expected to be better at sticking to a dietary regimen. On the other hand, older individuals, simply as a result of age and habit, may ﬁnd it more diﬃcult to change diet patterns and, indeed, given the loss of other pleasures, may resist dietary change. As with other groups, drug interventions are reserved for those at highest risk but, because of the impact of age on risk, may be more frequently prescribed in older age groups. A detailed description of individual groups and their adverse eﬀects is beyond the scope of this discussion. A summary of this information, however, is presented in Table 1. Given their eﬃcacy in lowering LDL, one of the statins is probably the best drug of choice to be added to a diet low in animal fat. Such drug therapy has been shown conclusively to inhibit the progression of coronary atherosclerosis, and to reduce morbidity and mortality from coronary artery disease and stroke.

Table 1

Lipid-Lowering Agents Change in lipid fraction (%)

Drug

LDL

TG

HDL

Eﬀect on lowering CHD risk

Adverse eﬀects

Bile acid sequestrant (cholestyramine, colestipol) Nicotinic acid

#15–30

0 or za

z3–5

Yes

#15–25

#20–50

z15–30

Yes

Bloating nausea constipation Flushing

HMG-CoA reductase inhibitorb (statins) Gemﬁbrozil

#20–40

#10–15 (greater with atorvastatin)

z5–10

Yes

Rare

0–15z

#20–50

z10–15

Yes

Rare

a

Toxicity None

Hepatotoxicity hyperuricemia hyperglycemia Myopathy hepatotoxicity

Hepatotoxicity myopathy perhaps gallstones

May increase in participants with high initial TG levels. Lovastatin, provastatin, simvastatin, ﬂuvastatin, and atorvastatin. Abbreviations: LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG, triglycerides; CHD, coronary heart disease; z, increased levels; #, decreased levels.

b

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159

In general, side eﬀects from statins have been very low and very well tolerated in most patients. Recent experience with cerivastatin, however, has underscored the need to be vigilant about side eﬀects even with these drugs [22]. Cerivastatin, after being approved in both Europe and the United States, was removed from the market because of a particular propensity to cause rhabdomyolysis in older patients. The likelihood of rhabdomyolysis with statins is, cerivastatin excepted, very low. When statins are used in combination with ﬁbrates, niacin, antifungal agents and other drugs that share a common hepatic catabolic pathway, however, the risk increases. Regular surveillance for both liver function abnormalities and muscle pain, as well as other evidence of potential myopathy, must be carried out in older patients, particularly those who are on multiple medications. Like statins, ﬁbric acid derivatives, including gemﬁbrozil and fenoﬁbrate, have a low incidence of adverse eﬀects and are well tolerated in older subjects. When ﬁbric acid derivatives are combined with statins there is an increased risk of rhabdomyolysis. When used as adjuncts to statin therapy, bile acid sequestrants usually do not cause a signiﬁcant problem for most older patients because the doses required are low enough to avoid constipation. Even so, the general slowing down of bowel function that occurs more frequently in older patients may be exacerbated by sequestrants. Similarly, adverse eﬀects associated with niacin, including cutaneous ﬂushing—although not necessarily more pronounced in the elderly—may nevertheless provide a signiﬁcant barrier to adherence particularly in patients who are using other drugs. From a practical point of view, neither bile acid sequestrants nor niacin are likely to enjoy widespread popularity in older subjects. For many of the reasons presented earlier, statins are prescribed with decreasing frequency in older patients. A recent study demonstrated that sustained statin use in those over 80 was about 19.8% compared to 21.1% in those 65 to 79 and 28% in those less than 65 [23]. Interestingly, in a group of older subjects with angiographically demonstrated signiﬁcant coronary heart disease, mortality among statin users was decreased 21% among those greater than 80 years of age, 12.7% among those from age 65 to 79, and 5.8% among those less than 65 years of age [24]. The absolute risk reduction was greater in those over 80 even though they were substantially less likely to receive a statin. Despite such data, adherence to statin therapy is quite low in older subjects who are prescribed such therapy. In one study, 79% of patients prescribed such therapy took greater than 80% of their drug in the ﬁrst 3 months, 56% in the second 3 months, and only 42% after 2 years [25]. Only 25% were meeting cholesterol-lowering targets after 5 years. Similar data, of course, have been reported with other chronic regimens in both older and younger subjects and indicate a real and persistent knowledge gap in our ability to maintain patients on chronic drug regimens. The reasons for this vary but include such things as poor patient understanding of what the medication is for, how it works, and why it is important to take it on a regular and persistent basis. In the elderly, other issues, including the cost of medication, may play an important role, particularly when there is no beneﬁt in terms of symptom relief to encourage regular use of the drug. Given the burden of atherosclerosis in older individuals that in western societies is almost universal, it might be argued that all older patients be given a statin, particularly in light of the fact that the HPS study has demonstrated that whatever one’s beginning cholesterol there is beneﬁt to lowering it. There are, as yet, insuﬃcient data to make such a recommendation for elderly subjects, but it is important that physicians be more alert to the potential beneﬁt of cholesterol lowering in the elderly and more willing to prescribe drugs, even for subjects who have no demonstrated clinical atherosclerosis but who have a risk factor constellation which, when combined with their age, puts them at high risk of a

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vascular event. Certainly, chronological age itself should be no contraindication to aggressive lipid-lowering therapy, including the use of statins and other lipid-lowering agents. Imaginative approaches to improving adherence to drug regimens are badly needed. Without question, however, an informed patient will be more likely to maintain such a regimen. In any consideration of treatment to alter levels of cholesterol and the subfractions in the elderly, the positive impact of such interventions on morbidity as well as mortality must be remembered. Even if it is not possible to signiﬁcantly increase the number of years to be lived, it is possible to increase the quality of life that is available to older subjects during whatever time remains to them. This is not an insigniﬁcant therapeutic beneﬁt and fully justiﬁes the eﬀort that may be required to bring it to fruition.

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16. Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RGJ, on behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623–1630. 17. The ALLHAT Oﬃcers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolmic, hypertensive patients randomized to pravastatin vs usual care; the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288:2998–3007. 18. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Eﬀects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. JAMA 2001; 285:1711–1718. 19. LaRosa JC. Pleiotropic eﬀects of statins and their clinical signiﬁcance. Am J Cardiol 2001; 88:291–293. 20. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285:2486-2497. 21. LaRosa JC. Diet and cardiovascular disease. Prev Cardiol 1998; 1:40–45. 22. FDA Talk Paper. US Food and Drug Administration Web site. Available at: http://www.fda. gov/bbs/topics/answers/2001/ans01095.html. Accessed October 26, 2001. 23. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002; 288:462–467. 24. Maycock CAA, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Pearson RR, Li Q, Anderson JL, for the Intermountain Heart Collaborative Study. Statin therapy is associated with reduced mortality across all age grous of individuals with signiﬁcant coronary disease, including very elderly patients. JACC 2002; 40(10):1777–1785. 25. Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weistein MC, Avorn J. Long-term persistence in use of statin therapy in elderly patients. JAMA 2002; 288:455–461.

7 Diabetes Mellitus and Cardiovascular Disease in the Elderly Gabriel Gregoratos and Gordon Leung University of California, San Francisco, California, U.S.A.

Diabetes mellitus aﬀects almost 17 million persons in the United States and more than 650,000 new cases are diagnosed annually. More than 100 million people are aﬀected worldwide; approximately 90% of these have the non-insulin-dependent type of the disease. Because of its serious long-term complications, diabetes mellitus has become a major public health problem [1,2]. The sequelae of diabetes mellitus are commonly divided into microvascular (mainly retinopathy, nephropathy, and neuropathy) and macrovascular (atherosclerotic disease of the coronary, cerebral, and peripheral arterial circulation). Multiple clinical studies over the years have documented the increased risk of diabetic patients to develop numerous cardiovascular disorders. The Framingham study of more than 5000 subjects showed diabetes mellitus to be a powerful risk factor for atherosclerotic coronary and peripheral vascular diseases with a relative risk averaging a twofold increase for men and threefold increase for women [3]. The Framingham study also showed that the risk of stroke is 2.5 times higher than average in diabetics [4]. These ﬁndings have been conﬁrmed by other epidemiological studies such as the Honolulu Heart Program, the Copenhagen Stroke Study, the Rancho Bernardo Study, and the MONICA Study [5–7]. More recently, a population-based study of elderly patients, concluded that diabetes mellitus is also an independent risk factor for heart failure and that the risk of heart failure increases with disease severity [8]. Epidemiological studies of diabetes mellitus have shown that gender, age, and ethnic background are important factors when considering the development of diabetic complications. In a population study from Sweden [9] of diabetes as a risk factor for acute myocardial infarction, the prevalence of diabetes was 5% in men and 4.4% in women. The relative risk for myocardial infarction in diabetic men was 2.9 (CI 2.6–3.4) and 5.0 (CI 3.9– 6.3) for women. Overall acute myocardial infarction mortality was four times higher for diabetic than nondiabetic men and seven times higher in diabetic women. These and data from other studies have led to the concept that diabetes mellitus causes a loss of the ‘‘female advantage’’ for women [10]. The clinical and economic burden of diabetes mellitus and its complications increases with advancing age. For example, in 2003, patients with a mean age of 80 F 8 years seen in an academic geriatic practice [11], the overall prevalence of diabetes was 17% and the prevalence of target organ damage and/or clinical cardiovascular disease was 85% 163

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in the 335 patient cohort with diabetes mellitus. In this elderly group of diabetic patients, 44% had coronary artery disease, 28% had sustained cerebrovascular accidents or transient ischemic attacks, 26% had peripheral vascular disease, 19% congestive heart failure, 32% nephropathy, 20% retinopathy, 75% had hypertension, and 90% had hypertension or hyperlipidemia. The prevalence of diabetes mellitus was highest amongst Hispanics (29%), lowest in whites (11%), and intermediate in African Americans. The economic costs of diabetes mellitus constitute a major burden on the United States and worldwide economies. In addition to being a signiﬁcant cause of cardiovascular disease, diabetes is the leading cause of renal failure in the United States and is responsible for over one-half of the nontraumatic lower limb amputations performed annually [12]. Direct and indirect cost of diabetes mellitus account for nearly 15% of total U.S. healthcare dollars and were estimated at 100 billion in 1992 [13]. These costs are due primarily to the macrovascular and microvascular complications of type 2 diabetes mellitus. In a retrospective cohort study from a large HMO, the annual cost of health care for a patient over the age of 65 was $3400.00 (in 1995 dollars). Excess expenditures (expressed as a multiple of the average annual cost listed above) for patients with diabetes mellitus ranged from 1.59 times in those with no diabetic complications to 4.1 times for those with myocardial infarction, 4.0 times for those with foot ulcers, and 4.3 times for those with endstage renal disease [14]. These data support the notion that early and aggressive preventive and therapeutic interventions in patients with diabetes mellitus and cardiovascular disease are desirable for economic as well as clinical reasons.

PATHOPHYSIOLOGY AND BIOCHEMICAL DEFECT OF DIABETES MELLITUS AND INSULIN RESISTANCE The current classiﬁcation of diabetes as either type I or type II is based on the pathophysiological diﬀerences between the two syndromes. In type I diabetes, hyperglycemia is due to the complete inability to produce insulin. In type II diabetes, hyperglycemia is the result of impaired insulin release and an increased resistance to insulin. The majority of the diabetic U.S. population has type II diabetes (over 90%). The pathogenesis of both forms of diabetes is complex with the development inﬂuenced both by genetic and environmental factors.

Type I Diabetes Mellitus Type I diabetes mellitus is mediated by the autoimmune destruction of pancreatic insulinsecreting beta-cells within the pancreatic islet of Langerhans. Islet-cell autoantibodies are detected in 80% of patients with newly diagnosed type I diabetes and measurement of serum islet-cell autoantibodies is a screening test to determine patients at risk for type I of this disorder [15]. The importance of genetics in the development of type I diabetes is supported by the observation that the incidence increases in relatives of type I diabetics. Whereas the lifetime risk for type I diabetes is 6% in the children of a type I diabetic, the risk decreases to 0.4% in families with no history of type I diabetes. An identical twin has a 30% lifetime risk of developing diabetes while a sibling or fraternal twin has a 5% risk [16]. Although

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four genes have been identiﬁed that increase the susceptibility to type I diabetes, none of these genes directly induces the disease. The role of environmental factors in the pathogenesis of type I diabetes is suggested by twins studies, which have demonstrated that in less than 50% of monozygotic twin pairs both develop diabetes. Type II Diabetes Mellitus Similar to type I diabetes mellitus, the pathogenesis of type II diabetes is also multifactorial with its development inﬂuenced both by environment (particularly by factors such as diet, advanced age, exercise level) and genetics (speciﬁcally the combined eﬀects of multiple gene alterations). The majority of type II diabetics are obese and over the age of 40. Unlike absolute absence of insulin in type I diabetes, type II diabetes mellitus is characterized by a combination of both relative deﬁciency of insulin and insulin resistance. Type II diabetes develops when the resistance to insulin activity is no longer compensated by increased insulin production from poorly functioning pancreatic beta-cells. Indeed, insulin resistance may be the best predictor of future type II diabetes [17]. Sedentary lifestyle and obesity dramatically increase the risk of type II diabetes by increasing insulin resistance. Insulin Resistance and Insulin Resistance Syndrome Insulin resistance is the physiological state in which a normal amount of insulin produces a subnormal physiological response. Lean, nondiabetic subjects are two times more sensitive to insulin than obese, nondiabetic subjects and obese type II diabetics are more insulinresistant than obese, nondiabetic subjects [18]. Plasma insulin levels increase as a result of a deﬁcient peripheral tissue response to insulin-mediated glucose metabolism. Insulin resistance occurs early in pre-type II diabetes and a majority, but not all, of insulin-resistant individuals will progress to clinical type II diabetes. Insulin resistance is most closely associated with acquired or lifestyle factors including obesity, aging, pregnancy, and physical inactivity [19] with currently identiﬁed gene mutations accounting for only a small minority of insulin resistance cases. Insulin resistance is one of the major path physiological abnormalities in type II diabetes and causes an atherogenic lipid proﬁle, endothelial dysfunction, increase in sympathetic nervous system activity, impaired ﬁbrinolysis, and a hypercoagulable state [20]. The Helsinki Policemen Study [21] demonstrated that insulin resistance alone was a predictor of coronary artery disease. Insulin resistance syndrome, also referred to as the metabolic syndrome, is a clinical syndrome that require three of the four following abnormalities [22]: (1) abdominal obesity (female waist circumference greater than 35 inches and male waist circumferences greater than 40); (2) dyslipidemia (triglycerides z150 mg/dL or HDL V40 mg/dL in men and V50 mg/dL in women); (3) hypertension (blood pressure z130/85 mmHg); and (4) hyperglycemia (fasting glucose z110 mg/dL). These parameters are often observed in the obese, prediabetic individual. The overall prevalence of the metabolic syndrome in the United States is 22%, with an age-dependent increase (6.7, 43.5, and 42.0% for age groups 20 to 29, 60 to 69, and >70 years, respectively) [23]. Patients with the metabolic syndrome are at signiﬁcantly increased risk of coronary artery disease as demonstrated by the Kuopio Ischemic Heart Disease Risk Factor Study [24]. In this Finnish, population-based, prospective cohort study, 1209 men without preexisting coronary disease or diabetes were tested for metabolic syndrome and followed

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for a mean of 11.4 years. Men with metabolic syndrome were 2.9 times (95% CI 1.2–7.2) to 4.2 (95% CI 1.6–10.8) more likely to die of ischemic heart disease after adjustment for conventional cardiac risk factors. CARDIOVASCULAR COMPLICATIONS OF DIABETES MELLITUS Pathophysiological Changes The complications of diabetes mellitus have traditionally been divided into two major categories: (1) microvascular complications including retinopathy, neuropathy, and nephropathy and (2) macrovascular complications including coronary artery disease, cerebrovascular disease, and peripheral vascular disease. The microvascular complications are unique to diabetes whereas the macrovascular ﬁndings are similar in patients with and without diabetes. Microvascular Pathophysiology Chronic hyperglycemia is a major initiator of microvascular complications. Two studies, the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), demonstrated that aggressive control of hyperglycemia reduces the onset or progression of nephropathy, retinopathy, and neuropathy associated with type I and type II diabetes [25,26]. Cardiac microvascular dysfunction is manifested by impaired autoregulation of coronary blood ﬂow and vascular tone in the absence of signiﬁcant epicardial coronary artery disease, with a resultant reduction of maximal coronary blood ﬂow and coronary ﬂow reserve [27,28]. Although no occlusive lesions in the diabetic coronary microcirculation have been demonstrated, other structural changes (medial hypertrophy, perivascular ﬁbrosis, and intimal hypertrophy) have been documented [29]. These histopathological changes in conjunction with impaired endothelial function at the microvascular level may explain the higher frequency of silent ischemia, exercise thallium defects, myocardial ﬁbrosis, and left ventricular dysfunction in diabetics in the absence of occlusive epicardial coronary disease [30]. Macrovascular Pathophysiology Diabetes mellitus accelerates atherosclerosis via chronic hyperglycemia, insulin resistance, and dyslipidemia. Both hyperglycemia and insulin resistance impair endothelium-dependent vasodilatation by decreasing nitric oxide formation [31]. Increased levels of endothelin-1 in diabetics stimulate vasoconstriction, induce vascular smooth muscle hypertrophy, and activate the renin-angiotensin system [32]. Diabetes promotes the accumulation of foam cells in the subendothelial space by increasing the production of leukocyte adhesion molecules and proinﬂammatory mediators [33]. Plaque instability and rupture is increased in diabetics as a result of decreased synthesis and increased breakdown of the collagen that plays a critical role in reinforcing the ﬁbrous cap of vulnerable plaques [34,35]. In addition to the proatherosclerotic eﬀects upon the arterial wall, diabetes also adversely aﬀects the hematological system. Diabetes promotes platelet activation by increasing platelet-surface expression of glycoprotein Ib, which mediates binding to the GpIIb/IIIa receptor and to the von Willebrand factor [36]. Inhibitors of platelet activity, including platelet-derived nitric oxide and endothelial-prostacyclin, are decreased in dia-

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betes. Diabetes also increases coagulation activity by stimulating production of procoagulants such as tissue factor and by reducing levels of anticoagulants such as protein C and antithrombin III [37,38]. Furthermore, decreased levels of plasminogen activator type I in diabetics results in impaired ﬁbrinolysis [39].

Clinical Consequences of Diabetes Mellitus Coronary Artery Disease The Framingham Study demonstrated that diabetes is a powerful predictor of coronary artery disease (CAD) with an average twofold increase in risk for men and threefold for women [40]. The elderly diabetic patient is at particularly high risk for coronary artery disease; 44% of octogenarians with diabetes were found to have CAD in the study by Ness et al. [11]. Diabetic women are also at increased risk for CAD, experiencing a CAD mortality rate similar to that of diabetic men, and a ﬁve- to sevenfold higher rate of CAD mortality compared with age-matched, nondiabetic women [41]. These data and data from other studies have led to the conclusion that diabetes has not only eliminated the usual female advantage for coronary disease mortality but also accounts for the higher coronary artery disease rates in premenopausal diabetic women [42]. This excess mortality from CAD in diabetic women compared to diabetic men also increases with advancing age. In the MONICA Study, the attack rate for acute myocardial infarction increased almost tenfold for diabetic women in the age bracket of 55 to 64 years compared to those in the age bracket of 45 to 54 years, whereas the increase was only twofold in the male subjects [9]. The aforementioned clinical ﬁndings of diabetes and coronary artery disease are supported by a recent population-based Mayo autopsy series [43] that characterized coronary atherosclerosis in 293 diabetic and 1736 nondiabetic autopsied subjects with a mean age of 73 to 75 and a male-to-female gender ratio of approximately 1:1. The study demonstrated that among diabetic decedents without clinical CAD, almost 75% had high-grade coronary atherosclerosis and more than half had multivessel disease. Nondiabetic women had less atherosclerosis than men, but this female advantage was lost with diabetes regardless of age. Finally, diabetic decedents without clinical CAD had a prevalence of high-grade atherosclerosis similar to that observed in nondiabetic decedents with clinical CAD. Although diabetes leads to increased incidence of coronary artery disease and myocardial infarction, controversy continues as to whether the distribution of coronary artery disease is diﬀerent in diabetics than in nondiabetic patients. Some investigators have found that diabetics referred for intervention (surgical or percutaneous) have diﬀusely diseased, frequently inoperable, vessels [44]. Others have reported a higher incidence of left main coronary artery disease (13% vs. 6% in nondiabetics), while other investigators have asserted more triple-vessel disease (43% vs. 25%) than nondiabetics [45]. However, other studies by Verska [46] and Sylvanne [47] have found no diﬀerence in the distribution of coronary artery disease in diabetic populations. Diabetes is associated with an increased prevalence of silent ischemia and unrecognized myocardial ischemia. In a study from Marseilles, France, the prevalence of silent ischemia was found to be approximately 30% in type II diabetic men with established coronary artery disease while the prevalence in nondiabetic patients was 1% to 4% [48]. Similarly, in a study by Naka, diabetics had a 2.2.times higher prevalence of silent myocardial ischemia compared to nondiabetic controls with established coronary artery di-

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sease [49]. Both the Framingham [50] and World Health Organization [51] epidemiological studies have reported the increased incidence of asymptomatic myocardial infarction in the elderly. Aronow and Epstein demonstrated silent myocardial ischemia by Holter monitoring in 34% of an elderly group of patients residing in a home for the aged [52]. Silent ischemia in diabetics is secondary not only to autonomic neuropathy but also to impaired pain perception and mental status alterations in elderly patients that make recognition of angina symptoms more diﬃcult [53]. Acute Coronary Syndromes Myocardial infarction rates are increased among diabetics of all ages [54]. For example, in a population-based study by Haﬀner [55], the 7-year incidence of ﬁrst myocardial infarction was 20% for diabetics but was only 3.5% for nondiabetics. Prior history of myocardial infarction increased the rate of recurrent MI and cardiovascular death in both groups (45% in diabetics and 18.8% in nondiabetics). Most importantly, in the absence of established CAD, diabetics experience CAD morbidity and mortality at a rate equal to that of nondiabetic individuals with established CAD (20% vs. 18.8% respectively). As a result, the National Cholesterol Education Program now classiﬁes diabetes as a CAD risk equivalent requiring aggressive intervention. Diabetes worsens short- and long-term outcomes and prognosis following acute myocardial infarction, especially in diabetic women. The Framingham Study determined that overall risk of cardiac mortality was 2 to 4 times higher in diabetics than in nondiabetics. One study described 1 month post-MI mortality rate of 14 to 26% in diabetic men and 21 to 30% in women, with a 10-year mortality rate of 6% in men and 8% in women [56]. Diabetic patients had a 1.36 relative risk of death compared with nondiabetic patients in the SHOCK study, a trial of revascularization post-MI complicated by cardiogenic shock [57]. In the GISSI-2 ﬁbrinolytic trial, the age-adjusted mortality relative risk for the diabetic subgroup was 1.4 for men and 1.9 for women [58]. Diabetes also appears to worsen the prognosis of unstable angina. In the six-nation OASIS registry of unstable angina and non-Q-wave MI, diabetes independently increased the risk of death by 57% [59]. Fava et al. evaluated a group of 166 type II diabetics with unstable angina and compared them to 162 nondiabetic subjects. They found that diabetic patients experienced a greater than threefold increase mortality at 3 months (8.6% vs. 2.5%) and this increased mortality was maintained at 1-year follow-up [60]. The pathophysiological explanation for the poorer prognosis among diabetic patients is not entirely clear. Diabetes is associated with complicated metabolic changes and alterations in coagulation parameters that may predispose to poorer outcome [61]. Diabetic patients tend to have fewer collateral vessels compared to nondiabetics and may have more diﬀuse coronary disease [62]. The poorer diabetic outcomes may also be partially explained by the observation that anterior infarction appears be more common than inferior infarction. In one study involving 54 diabetic patients who had sustained an infarct compared with 270 nondiabetic infarct patients, the incidence of anterior infarction was 43% in the diabetic group versus 13% in the control group [63]. Sixty-day mortality was 55% in diabetics versus 31% in the nondiabetic controls. Stroke The Framingham and other studies have demonstrated that the risk of stroke is increased 1.5 to 4 times for diabetic patients [64]. Four case-control studies and ﬁve prospective

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observational cohort studies have also established that insulin resistance alone is associated with a 60 to 160% increased risk for stroke in nondiabetic patients [65]. The risk of stroke is particularly increased in younger diabetic patients. In a study by Rohr et al. [66] involving 296 patients between the ages of 18 to 44, the diagnosis of diabetes increased the odds ratio for stroke from 3.3 for African American women up to 23.1 for Caucasian males. In stroke patients younger than 55 years, diabetes increases the risk of stroke over tenfold (odds ratio of 11.6, 95% CI = 1.2–115.2) [67]. Similar to myocardial infarction, diabetes is also associated with a poorer prognosis after stroke. Diabetes increases the rate of stroke-related dementia greater than threefold [68]. Two additional studies have determined that diabetes doubles the risk of stroke recurrence and increases stroke-related mortality [69,70]. Poorer glycemic control also elevates stroke risk. Male patients on diabetes medications were 3 times more like to incur a stroke in the Multiple Risk Factor Intervention Trial (MRFIT) of 347,978 men [71]. Several clinical trials suggest that reducing insulin resistance and improving glycemic control may prevent cerebrovascular atherosclerosis and stroke. In 1998, the U.K. Prospective Diabetes Study Group (UKPDS) concluded that metformin was eﬀective in preventing stroke based on a comparison of metformin therapy (n = 342) versus insulin or sulfonyurea therapy (n = 951). The metformin group not only achieved better glycemic control compared to the insulin/sulfonylurea group (hemoglobin A1c of 7.4% vs. 8.0%, respectively) but also achieved a lower stroke rate (12 stroke events in the metformin group [3.3 events/1000 patient-years] versus 60 stroke events in the sulfonyurea/insulin group [6.2 events/1000 patient-years]). Two other studies [72,73] have also demonstrated that thiazolidinediones, compared with sulfonylurea therapy, are more eﬀective in preventing carotid atherosclerosis in diabetic patients. Congestive Heart Failure and Left Ventricular Dysfunction The link that diabetes is an important risk factor for CHF was ﬁrst established in the Framingham Heart Study [74]. Among participants between the ages of 45 to 75 years, the frequency of CHF was increased ﬁvefold for diabetic women and 2.4 fold for diabetic men. Although the etiology for diabetic CHF is often multifactorial (concomittant hypertension, ischemic heart disease, or microvascular disease), the Framingham data established diabetes to be a risk factor independent of coexisting hypertension or coronary artery disease. Diabetes is observed in approximately 15 to 25% of heart failure patients in large clinical trials and up to 30% of heart failure inpatients hospitalized have diabetes as a comorbid condition [75,76]. In the large-scale ATLAS and SOVLD heart failure mortality trials [77,78] of patients with systolic dysfunction, diabetes was identiﬁed as an independent predictor of death. In the SOLVD study, diabetes was the third most important factor in predicting worsening heart failure, after age and ejection fraction. In a study of 9591 individuals with type II diabetes, independent risk factors for CHF included advanced age, diabetes duration, insulin use, ischemic heart disease, and elevated serum creatinine [79]. These ﬁndings are supported by a recent population-based study of elderly patients with a mean age of 78.6 years, which concluded that diabetes is an independent risk factor for CHF and the risk of CHF increases with diabetes severity [80]. Although ischemic heart disease contributes to CHF in a proportion of diabetic patients, some diabetic patients present with heart failure secondary to nonischemic diabetic cardiomyopathy. Diabetic cardiomyopathy patients usually present with heart failure secondary to systolic and/or diastolic dysfunction in the absence of signiﬁcant

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epicardial coronary artery disease [81]. The histopathological changes observed in diabetic cardiomyopathy are usually indistinguishable from those of other nonischemic cardiomyopathies. Several mechanisms may contribute to the development of diabetic cardiomyopathy. Autonomic neuropathy manifested by either depletion of myocardial catecholamine stores [82] or impaired ventricular response to exercise due to sympathetic nervous impairment [83] may play a role. A defect in GLUT4 receptor translocation to the cell surface in diabetic patients may interfere with myocardial energy metabolism [84]. Furthermore, the decrease in insulin levels with diabetes may also decrease myocyte uptake of glucose via the GLUT4 receptor, which is insulin-responsive [85]. There is a high prevalence of diastolic dysfunction within the diabetic population (27– 70%). In large population-based studies including the Strong Heart Study [86] and the Cardiovascular Health Study [87], echocardiograms of diabetic patients with no clinical history of heart failure demonstrated higher left ventricular mass, increased wall thickness, and greater arterial stiﬀness, predisposing diabetics to diastolic dysfunction. Diabetic patients also have reduced systolic function at rest, a lower ejection fraction with exercise [88], and a reduced exercise tolerance despite well-controlled type II diabetes and hypertension [89]. Functional impairment in vascular reserve in the peripheral, coronary, and cerebral circulation has also been demonstrated in diabetic patients. Reduced coronary ﬂow reserve and impaired reactivity have been observed in patients with diabetes and angiographically normal coronary arteries, suggesting the presence of early endothelial dysfunction in this group of patients [90,91]. This alteration in functional rather that structural coronary ﬂow may account for the beneﬁts of tight glycemic control and the use of endothelial functionenhancing ACE inhibitors in the diabetic heart failure population. The importance of glycemic control in heart failure is illustrated by a large population-based study of 48,858 type II diabetic patients with no known history of heart failure who were followed for a mean of 2.2 years [92]. After adjusting for multiple confounders including age, sex, hypertension, alcohol consumption, duration of diabetes, and use of beta-blockers or ACE inhibitors, each 1% increase in glycosylated hemoglobin was associated with an 8% increased risk of heart failure. Despite controlling for factors such as hypertension, age, and gender, heart failure itself has also been identiﬁed as a risk factor for the development of diabetes mellitus [93]. After a 3-year follow-up of an elderly heart failure patient population, Scherer et al. demonstrated that the incidence of new-onset diabetes was 29% in heart failure patients, compared with 18% in normal matched controls [94]. Autonomic Nervous System Dysfunction Diabetic autonomic neuropathy can aﬀect a variety of organ systems including gastrointestinal, neuroendocrine, genitourinary, and ocular systems. In a study of 120 asymptomatic diabetic patients with no known history of coronary artery disease and normal 12lead ECG, cardiovascular autonomic neuropathy (CAN) was present in 38.9% of the patients tested [95]. This study also determined that CAN may be an independent predictor of future major cardiac events with the proportion of major cardiac events signiﬁcantly higher in the CAN-positive patients than in the CAN-negative patients (8 out of 33 versus 3 out of 42; p = 0.04 with a RR = 4.16 and 95% CI 1.01–17.19). This ﬁnding may be explained by the observation that the parasympathetic system is aﬀected earlier than the sympathetic system in CAN, with a resultant relative increase in sympathetic tone accompanied by elevated blood pressure and increased vasoconstriction.

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Diabetic patients with diabetic autonomic nervous system dysfunction present frequently with orthostatic hypotension (fall in systolic blood pressure greater than 20 mmHg lasting 3 min or greater from supine to upright) and decreased exercise tolerance. Central and peripheral sympathetic denervation results in decreased splanchnic and peripheral vascular bed vasoconstriction with resultant orthostatic hypotension. Diabetic postural hypotension can be variable on a daily basis and may be exacerbated by insulin therapy and after meals [96]. Decreased exercise tolerance is due to impaired sympathetic output with a resultant decrease in cardiac output. In advanced autonomic nervous system dysfunction, cardiac denervation can result in a ﬁxed heart rate of 80 to 90 beats per minute [97], and sympathetic tone may be increased during the day and parasympathetic tone decreased at night, with a potential increased risk for nocturnal arrhythmias [98]. Cardiac autonomic function can be assessed indirectly by cardiovascular reﬂex testing or directly by scintigraphic imaging. Cardiovascular reﬂex testing includes assessment of both the sympathetic and parasympathetic system by assessing heart rate variability with deep breathing, blood pressure to handgrip, and fall in systolic blood pressure with position changes [99]. Scintigraphic imaging with meta-iodobenzylguanidine (MIBG) or 11-C-hydroxyephedrine (both radiolabeled norepinephrine analogs that undergo uptake in the cardiac sympathetic nerve terminals) is more sensitive than reﬂex testing but not widely available. Treatment of cardiovascular autonomic dysfunction includes lifestyle modiﬁcations, discontinuation of certain medications, and pharmacological therapy. Lifestyle modiﬁcations include a low-salt diet, avoiding alcohol, small meals, avoiding excessive heat, 30 degree head-up tilt while sleeping, gradual changes in position, lower extremity stockings, and isometric exercises while upright (handgrip or ‘‘crossing leg’’ exercises). Potentially aggravating medications include diuretics, antihypertensives, and antidepressants. Pharmacological therapy includes ﬂudrocortisone (mineralocorticoid), desmopressin (decreases vasopressin release), midodrine (alpha-receptor agonist), and pindolol (beta-blocker with intrinsic sympathomimetic activity), and octreotide (somatostatin analog). Elderly diabetic patients with orthostatic hypotension may be particularly diﬃcult to treat since many such patients have comorbid conditions that require the administration of antihypertensive drug and/or diuretics. Peripheral Vascular Disease Diabetic patients have a two- to four-fold increase in the incidence of peripheral vascular disease (PVD) [100]. Unlike microvascular disease, which is unique to diabetes, macrovascular disease manifesting as PVD is generally similar in both diabetics and nondiabetics and is the result of accelerated atherosclerosis. However, some clinical diﬀerences exist in diabetic peripheral vascular disease: (1) PVD is more likely to involve the infrapopliteal arteries of the lower extremities [101]; (2) claudication is more common in diabetics (3.5fold risk in men and 8.6-fold risk in women) [102,103]; and (3) amputation is much more frequent in all diabetics, but especially older diabetics. The 12.7 (95% CI, 10.9–14.9) relative risk of lower extremity amputation in diabetic versus nondiabetic patients increases to a high of 23.5 (95% CI, 19.3–29.1) in diabetic patients 65 to 74 years old [104]. Both the incidence and extent of the disease are directly associated with the duration and severity of the diabetes. In one study, for example, patients with normal glucose tolerance had a 7% prevalence of abnormal ankle-brachial indices, while patients on multiple diabetic medications had a 20.9% prevalence of abnormal indices [105].

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MANAGEMENT OF CARDIOVASCULAR DISEASES IN PATIENTS WITH DIABETES MELLITUS Acute Coronary Syndromes Few studies have addressed speciﬁcally the impact of modern medical therapies for acute coronary syndromes (ACS) in the diabetic population. Subgroup analyses, however, of several clinical trials suggest a generally consistent beneﬁcial eﬀect of modern therapies in the diabetic patient with these syndromes. The management of ACS is similar for elderly patients with and without diabetes with few exceptions, as will be noted subsequently. Three major issues will be considered here: (1) optimal reperfusion therapy for STelevation myocardial infarction (STEMI); (2) early invasive versus early conservative management of unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI); and (3) adjunctive pharmacotherapy and its applicability to the elderly diabetic patient with ACS. Reperfusion Therapy for STEMI Thrombolytic (TL) Therapy Thrombolytic therapy for STEMI has been shown to be equally or more beneﬁcial in the diabetic patient with an acute infarct than the nondiabetic. The Fibrinolytic Therapy Trialists (FTT) overview found a statistically greater mortality beneﬁt in the diabetic group: 37 lives saved per 1000 patients treated compared to 15 lives saved per 1000 treated patients in nondiabetics [106]. Similarly, an angiographic analysis that included 310 patients with diabetes in a GUSTO I substudy demonstrated comparable infarct-related artery patency at 90 min after TL therapy in patients with and without diabetes [107]. Concerns about possible increased ocular hemorrhagic complications because of underlying diabetic retinopathy have not been substantiated [108]. However, the beneﬁcial eﬀects of TL in the very elderly (>75 years of age) are uncertain and debatable. The FTT overview showed no statistically signiﬁcant survival beneﬁt in patients over the age of 75 years. Presumably, this was due to the increased incidence of hemorrhagic stroke. Two more recent population-based analyses suggest that short-term mortality from STEMI is not reduced and may even be increased in patients over 75 years who receive thrombolytic therapy [109,110]. Thus, the use of this form of reperfusion therapy in very elderly patients with and without diabetes remains controversial. For patients up to age 75, however, there is clear evidence from multiple randomized controlled trials that TL therapy aﬀords a signiﬁcant survival beneﬁt. Primary Percutaneous Coronary Intervention Acute success rates with (PPCI) are comparable in the presence or absence of diabetes, although the restenosis and long-term mortality rates are higher in diabetic patients [111,112]. Despite the well-known limitations of PPCI (lack of widespread availability and treatment delays), accumulating evidence suggests that this form of reperfusion therapy may well be superior to TL in improving clinical outcomes if performed expeditiously by experienced operators [113]. Data comparing TL with PPCI in elderly diabetic patients are limited. A recent observational study comparing early and late outcomes of PPCI and TL therapy of diabetic patients with STEMI concluded that PPCI was associated with reduced early and late adverse outcomes when compared to TL therapy [114]. However, mortality was similar in both groups. In this study over one-third of the patients were 65 years or older. From the limited data available, it is reasonable to conclude that PPCI may be preferable to TL in the elderly diabetic patient with STEMI, especially for patients over the age of 75.

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Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) Beginning with the TIMI III study of early invasive versus early conservative management of UA, subgroup analyses of several randomized controlled trials have demonstrated a consistent, modest beneﬁt of early invasive therapy in elderly patients (>65 years of age) and in diabetics. In the FRISC II trial [115] the reduction in the composite endpoint of death and nonfatal myocardial infarction among those assigned to the early invasive group resulted entirely from the beneﬁt realized by the over-65-year subgroup. In this trial, the overall results of the two strategies were similar for both diabetics and nondiabetics. The more recent TACTICS-TIMI 18 study compared outcomes of patients with ACS treated with the glycoprotein IIb/IIIa inhibitor tiroﬁban and assigned to either an early invasive strategy and revascularization if clinically indicated or to a more conservative strategy in which cardiac catheterization was undertaken only if the patient demonstrated spontaneous or provoked ischemia [116]. Although there was no clear survival beneﬁt, the results demonstrated a 3.1% absolute and 33% relative risk reduction of the combined endpoint of death, nonfatal MI, and rehospitalization for ACS at 6 months in patients assigned to an early invasive strategy. Subgroup analysis demonstrated that elderly patients over the age of 65 years had a 4.6% absolute reduction in the combined endpoint compared to a 2.9% reduction for patients under the age of 65. Similarly, diabetic patients realized a 7.6% absolute reduction compared to 2.2% for nondiabetic patients. Based on these and other trials, current thinking is that an early invasive strategy is the preferred method of managing ‘‘high-risk’’ patients with UA/NSTEMI. Since both advancing age and diabetes increase the risk of adverse outcomes, it is reasonable to conclude that an early invasive strategy is appropriate in the elderly diabetic patient with UA/NSTEMI. Adjunctive Therapies in Acute Coronary Syndromes In almost all respects, the adjunctive therapy of ACS is the same for patients with and without diabetes mellitus [117]. However, speciﬁc contraindications and risks must be recognized and will be mentioned below. Aspirin The beneﬁcial eﬀects of aspirin in ACS have been conclusively demonstrated in many studies. In the ISIS-2 study, aspirin was shown to be as eﬃcacious in older as in younger patients with myocardial infarction [118]. Consequently, it is generally accepted that aspirin in doses of 162 to 325 mg should be administered to all patients with ACS and should be continued indeﬁnitely if there are no major contraindications (e.g., bleeding peptic ulcer). Antithrombotic Therapy Intravenous unfractionated or low-molecular-weight heparin (LMWH) should be administered to all patients with ACS regardless of age and diabetic state unless there are major contraindications (e.g., intracranial bleed). Recent studies have shown that LMWH are superior to unfractionated heparin in patients with UA/NSTEMI and especially so in elderly patients [119,120]. Concerns regarding excess bleeding when patients who received LMWH undergo an invasive procedure have not been substantiated. Other Antiplatelet Therapy Platelet aggregability is enhanced in patients with diabetes mellitus. Several studies have shown that glycoprotein IIb/IIIa inhibitors, when added to aspirin, improve outcomes in high-risk patients with UA/NSTEMI, especially those undergoing PCI. A review of the results of four abciximab trials [121] reveals that this agent is safe and eﬀective in patients over the age of 70 years, although the net beneﬁt

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declines slightly with increasing age. Tiroﬁban and Eptiﬁbatide have also been shown to be eﬀective agents in this setting. Clopidogrel was shown in the CURE trial to improve long-term outcomes when administered for 3 to 9 months to patients with UA/NSTEMI who did not undergo PCI [122]. This improvement in outcomes was demonstrated across a number of subgroups, including patients over the age of 65 years and patients with diabetes mellitus. However, an excess of major bleeding complications was reported: 2.7% in the placebo group versus 3.7% in the clopidogrel group. Furthermore, limited data are available on the safety of adding heparin and a glycoprotein IIb/IIIa inhibitor in patients receiving aspirin and clopidogrel. Data on the eﬃcacy of long-term administration of clopidogrel are limited and, therefore, such decisions should be individualized. Beta-Adrenoreceptor Blockers Beta-blockers have been found to be eﬀective in improving outcomes when used for acute coronary syndromes in patients with diabetes. Several studies have consistently demonstrated an average twofold greater reduction in the relative risk of mortality as a result of beta-blocker therapy after myocardial infarction in patients with diabetes compared to those without diabetes. Despite these ﬁndings, diabetics with coronary artery disease are undertreated with beta-blocker drugs. Reviewing a large cohort of patients from the National Cooperative Cardiovascular Project, Chen et al. reported that even after adjusting for demographics and clinical factors, patients with diabetes were less likely to receive beta-blockers at discharge following acute myocardial infarction with an odds ratio for insulin-treated diabetics of 0.88 and 0.93 for non-insulin-treated diabetics [123]. In the same study, beta-blockers were found to be associated with lower 1-year mortality for insulin-treated diabetics (hazard ratio 0.87), for non-insulin-treated diabetics (hazard ratio 0.77), and for nondiabetics (hazard ratio 0.87). Furthermore, beta-blocker therapy was not signiﬁcantly associated with increased 6-month readmission rates for diabetic complications. The authors concluded that beta-blocker therapy following acute myocardial infarction was associated with a lower 1-year mortality rate for elderly diabetic patients to a similar extent as for nondiabetics without increased risk of diabetic complications. It is evident from the above and several other randomized controlled trials that beta-blockers are important agents and should be used in all elderly diabetic patients in the absence of major contraindications (severe bradycardia with heart rate <45–50 beats per minute, systolic blood pressure <100 mmHg, severe heart failure, PR interval >0.24 s or higher degrees of AV block and active bronchospastic lung disease). Angiotensin Converting Enzyme Inhibitors Early treatment with an angiotensin converting enzyme inhibitors (ACE-I) is recommended for patients with an anterior STEMI, left anterior STEMI, left ventricular systolic dysfunction with an ejection fraction of less than 0.4, or overt heart failure in the absence of contraindications such as hypotension, renal insuﬃciency, and hyperkalemia [124–126]. These agents are beneﬁcial in other forms of ACS as well, but the evidence for this is not as compelling. Despite the generally recognized beneﬁts of ACE-I in diabetic patients, these agents are underprescribed because of concerns regarding azotemia, hemodynamic instability (especially if diabetes-related autonomic neuropathy is present), and hyperkalemia. However, results from multiple studies do not support these concerns. A retrospective analysis of the GISSI 3 study suggests that most, if not all, of the mortality beneﬁt resulting from treatment with lisinopril versus placebo was found in the diabetic subgroup of patients [127]. In the CONSENSUS II study, hypotension in the intravenous enalapril-treated group neutral-

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ized any potential beneﬁt of early ACE inhibition. However, the diabetic cohort receiving enalapril exhibited a signiﬁcant improvement in outcomes at 6 months compared to the placebo group [128]. The Heart Outcomes Prevention Evaluation (HOPE) trial investigated the eﬀect of ramipril versus placebo in 9297 high-risk patients with evidence of vascular disease or diabetes plus one other cardiovascular risk factor and without left ventricular dysfunction or heart failure [129]. Patients with diabetes constituted 38 and 39% of the treatment and placebo groups, respectively. Ramipril was found to signiﬁcantly reduce the risk of myocardial infraction, stroke, or death from cardiovascular causes compared to placebo. The beneﬁcial eﬀect of treatment with ramipril on this composite outcome was consistently observed in patients both with and without diabetes mellitus. Thus, the HOPE trial conﬁrms results of prior studies regarding the beneﬁt that diabetic patients may obtain from treatment with ACE inhibitors. Chronic Ischemic Heart Disease The medical management of chronic ischemic heart disease and stable angina pectoris is the same for elderly patients with and without diabetes. All patients with stable angina should be treated with aspirin, beta-blockers, angiotensin converting enzyme inhibitors, and a statin. Additional drugs that may be required include long- and short-acting nitrates, calcium channel blockers, and clopidogrel. There is general agreement that the presence of diabetes does not require a change in the pharmacotherapy of stable angina, nor is there compelling evidence that the drugs mentioned have untoward eﬀects on diabetics. Standard contraindications to the use of these drugs should, of course, be observed. On the other hand, considerable uncertainty and controversy exist regarding what is the best form of revascularization therapy for the elderly diabetic patient with angina. This issue will be discussed below. Revascularization Therapy Almost 25% of the surgical and percutaneous coronary revascularization procedures performed annually in the United States are performed in patients with diabetes. Patients with diabetes have many comorbidities that contribute to worse short- and long-term outcomes after revascularization. These comorbidities include hypertension, dyslipidemia, systolic and diastolic left ventricular dysfunction, peripheral vascular disease, cerebrovascular disease, nephropathy, and a prothrombotic state. Acute success rates of percutaneous transluminal coronary angioplasty (PTCA) are basically the same for patents with and without diabetes. However, the incidence of restenosis and need for repeat revascularization is higher in diabetic patients and is of particular concern. Similarly, long-term mortality after PTCA is higher for patients with diabetes. Data from the NHLBI registry indicate that the 9-year mortality of diabetic patients after PTCA was almost double that for nondiabetics [130]. Such data have raised the possibility that coronary bypass surgery (CABG) may be advantageous in this group of patients. The Bypass Angioplasty Revascularization Investigation (BARI) trial compared the two types of revascularization therapy in patients with two- or three-vessel disease. The overall 5-year survival rate of 89.3% for the coronary artery bypass graft group and 86.3% in the angioplasty group is not a statistically signiﬁcant diﬀerence [131]. However, in the

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subgroup of BARI patients with treated diabetes mellitus (not a prespeciﬁed subgroup), a signiﬁcant diﬀerence was observed in favor of bypass surgery (76% for CABG vs. 56% for PTCA; p = 0.0011 [132]. Improved 5-year survival in CABG patients was due entirely to reduced cardiac mortality (5.8% vs. 20.6%; p = 0.0003). Improved outcome with bypass surgery in treated diabetics was further conﬁrmed in the reported 7-year results of the BARI trial [133]. It should be noted, however, that the beneﬁts of CABG were seen only in patients who received at least one arterial conduit. These results of the BARI trial could not be conﬁrmed in the Emory Angioplasty versus Surgery Trial (EAST) and the Duke registry [134,135]. However, a more recent analysis of the EAST data suggests that, after accounting for baseline diﬀerences between groups, there was a higher long-term mortality rate for diabetic patients treated with angioplasty when compared with diabetic patients treated with coronary bypass surgery [136]. Several possible mechanisms have been proposed for this higher mortality rate after PTCA in insulin-requiring patients with diabetes: impaired endothelial function, a prothrombotic state, increased intimal hyperplasia, and increased protein glycosylation and vascular matrix deposition. Alternatively, insulin-requiring diabetes may be a marker for more severe disease in those patients for whom surgery is a better option than angioplasty. The debate over surgery versus angioplasty for patients with treated diabetes may be moot as neither BARI nor the Duke registry included a signiﬁcant number of patients treated with the novel technologies of stenting and use of glycoprotein IIb/IIIa inhibitors. It is likely, that the advent of these treatment modalities will improve the outcomes of PCI in diabetics as they have done for non-diabetics. EPISTENT (Evaluation of Platelet IIb/ IIIa Inhibitors for Stenting Trial) was a randomized study of patients with at least one coronary vessel stenosis more than 60% with patients randomized into three treatment groups: stenting plus standard therapy and placebo, stenting plus standard therapy and abciximab, and angioplasty and standard therapy plus abciximab. Subgroup analysis centered on 491 patients with diabetes mellitus [137]. In this subgroup, an approximately equal number of patients were assigned to each of the three treatment arms and had similar baseline characteristics. Endpoints were 6-month death, myocardial infarction, and target vessel revascularization. In the diabetic patient cohort, a signiﬁcant reduction in the combined endpoint of death, myocardial infarction, and target vessel revascularization was noted m the group treated with the combination of stenting and abciximab. There was an absolute reduction of events and increased beneﬁt for all endpoints analyzed for the stent/abciximab group compared to the two other treatment groups. When the data were subjected to multivariate analysis to compensate for some of the imbalance of baseline clinical and angiographic ﬁndings, the beneﬁt of stent/abciximab in diabetics remained signiﬁcant with a p value of 0.008. These ﬁndings from EPISTENT and other ongoing trials suggest that the role of percutaneous coronary intervention in diabetics remains to be deﬁned and individualized decisions are necessary in selecting which type of revascularization therapy is optimal for a diabetic patient.

HYPERTENSION AND DIABETES MELLITUS Patients with diabetes have an increased prevalence of hypertension [138] and, conversely, several studies have shown that hypertensive patients have an increased incidence of impaired glucose tolerance and demonstrate increased insulin release following an oral glucose load. The results of these studies support the existence of the metabolic syndrome

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that includes insulin resistance and hyperinsulinemia, glucose intolerance, hypertension, elevated triglycerides and other metabolic abnormalities [139]. More than 7 million patients in the United States have both hypertension and diabetes, both independent risk factors for cardiovascular disease. The association between these risk factors and cardiovascular disease becomes stronger with advancing age. The high prevalence of these two diseases compounded by an aging population contributes to the high rate of cardiovascular disease in the United States. Epidemiological studies have demonstrated that hypertension increases the risk of atherosclerotic vascular disease in diabetics more than in nondiabetics. The Systolic Hypertension in the Elderly Program (SHEP) found an almost twofold increase in 5-year rate of major cardiovascular events, coronary events, and strokes among diabetic patients who received placebo versus nondiabetic patients in the placebo group [140]. The relative treatment beneﬁt of low-dose diuretic therapy was fairly similar in patients with diabetes compared to nondiabetic patients. However, the absolute beneﬁt was lower in patients with diabetes than in patients without this disorder. The SHEP trial results refuted the belief that diuretics, because of their action in raising blood glucose, must be avoided in treating patients with diabetes. Similar salutary eﬀects of thiazide treatment of hypertension in diabetic patients were seen in the ALLHAT trial in which over 35% of the patients had type II diabetes [141]. In general, we can conclude that the common drugs used to treat hypertension (beta-blockers, calcium-channel blockers, ACE inhibitors, and diuretics) are eﬀective in patients with diabetes [142]. Thiazide diuretics in high doses can indeed aggravate hyperglycemia, but at lower doses—which are equally eﬀective in treating hypertension—they do not signiﬁcantly increase glucose intolerance. Although beta-blockers may worsen insulin resistance and may mask sysptoms of hypoglycemia, they are generally well tolerated by patients with diabetes and are especially indicated if there is associated coronary artery disease present. In the large multicenter randomized trial UK Prospective Diabetes Study Group (UKPDS), one objective was to determine whether tight control of hypertension with either a beta-blocker or an angiotensin converting enzyme inhibitor had a speciﬁc advantage [143]. Patients were randomly assigned to captopril or atenolol for control of hypertension. This study concluded that both agents were equally eﬀective in reducing blood pressure as well as the risks of microvascular endpoints. Regarding macrovascular complications of diabetes, although the reduction in all-cause mortality and myocardial infarction did not achieve statistical signiﬁcance, there was a 44% reduction of stroke and a 56% reduction in heart failure in the tight blood pressure control group compared to the conventionally treated group. It is therefore necessary to conclude that aggressive therapy of hypertension in diabetic patients is the important issue and not which antihypertensive is optimal unless there are speciﬁc indications for one type of agent over another. ACE inhibitors and angiotensin receptor blockers have been shown to slow progression of diabetic nephropathy and may therefore be the preferred initial agents in the presence of microalbuminurea. Similarly, beta-blockers are the preferred agents in patients with angina or after myocardial infarction. Most elderly diabetic patients with hypertension will require more than one antihypertensive drug for optimal blood pressure control.

LIPID DISORDERS AND DIABETES MELLITUS Patients with diabetes mellitus have two lipid disorders that must be considered. The ﬁrst is an elevated LDL cholesterol level. This leads to atherogenesis and contributes to plaque

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rupture and acute coronary events. The second is atherogenic dyslipidemia, which is characterized by increased triglyceride levels, depressed high-density lipoprotein levels, and normal to mildly increased low-density liproprotein levels but increased levels of small dense (easily oxidizable) LDL particles. Both these disorders are independently associated with progressive atherosclerosis and increased prevalence of cardiovascular events [144,145]. The importance of controlling both of these diabetes-associated lipid disorders and the impact of such control on the macrovascular complications of this disease have been extensively studied. In 1992, the Helsinki Heart Study suggested a trend toward decreased coronary events in 135 diabetic patients treated with Gemﬁbrozil over a 5-year period, compared to those receiving placebo [146]. Because of concerns regarding the eﬃcacy and safety of ﬁbrate therapy, this form of treatment has not gained wide acceptance. However, the recent Diabetes Atherosclerosis Intervention Study (DAIS) has provided support for the use of ﬁbrates in the treatment of diabetic dyslipidemia [147]. DAIS was a randomized trial designed to assess the eﬀects of correcting lipoprotein abnormalities on coronary atherosclerosis in type 2 diabetes. Patients were assigned to micronized fenoﬁbrate or placebo and followed for at least 3 years. In addition to improved lipid proﬁles, the fenoﬁbrate-treated patients were shown to have signiﬁcantly less angiographic progression of their coronary artery disease than the placebo group. The study was not powered to assess clinical endpoints, but there were fewer events in the fenoﬁbrate group than the placebo group. Although the results of the ﬁbrate studies are inconclusive in terms of clinical outcomes, subset analysis of diabetic patients in three major secondary prevention trials comparing HMG CoA-reductase inhibitors (statins) with placebo demonstrate the importance of LDL cholesterol control in diabetics. The Scandinavian Simvastatin Survival Study (4S) showed that in the subgroup of 202 diabetic patients enrolled, a signiﬁcant reduction in major coronary artery disease over a 5-year follow-up period resulted from treatment with Simvastatin compared to placebo [148]. The Cholesterol And Reoccurring Events (CARE) trial enrolled 586 diabetic patients and also reported a signiﬁcant reduction in major coronary events when Pravastatin was compared with placebo [149]. The LIPID trial enrolled 811 patients with diabetes and reported a favorable trend in the diabetic subset treated with Pravastatin when compared to placebo with reference to a composite endpoint of coronary artery disease, death, and nonfatal myocardial infarction over an average follow-up of 6 years [150]. Two major primary prevention trials, West of Scotland Coronary Prevention Study (WOSCOPS) [151] and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCaps) [152], either included too few diabetic patients or speciﬁcally excluded certain subgroups of diabetics and thus do not provide us with reliable data. Despite the limited information that has emerged from the primary prevention trials, data from the secondary prevention trials suggest a deﬁnite role for lipid altering therapy in patients with type 2 diabetes mellitus. At least one trial (4S) showed that active statin treatment had a greater eﬀect on endpoint reduction in the subgroup with diabetes than in the nondiabetic group. Currently, data from studies designed prospectively to evaluate the impact of lipid-lowering therapy on clinical endpoints are sparse, but a number of trials are planned and are ongoing that will address this issue. These studies that are evaluating both statins and ﬁbrates will probably yield information that permits a more eﬀective targeting of speciﬁc lipid-altering therapies in patients with diabetes. Until more information is available, consistent with our understanding of the eﬀects of statin therapy in

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reducing coronary events, it seems appropriate to oﬀer the elderly diabetic patient treatment with a statin drug.

TREATMENT OF DIABETES MELLITUS AND GLYCEMIC CONTROL The current approach to the treatment of type 2 diabetes mellitus is a combination of lifestyle modiﬁcations and oral agents [153]. Although there is no reason why insulin should not be implemented early in the course of type 2 diabetes, the requirement of subcutaneous injection has relegated insulin therapy as a late intervention. Weight loss, increased physical activity, and restricted calorie diets are the main lifestyle changes. The two most common oral agents include sulfonylureas, which stimulate insulin secretion, and metformin, which decrease hepatic glucose production. Similar to sulfonylureas, glitinides also increase hepatic insulin secretion. Two additional oral hypoglycemics include alpha-glycosidase inhibitors, which inhibit gastrointestinal absorption of carbohydrates, and thiazolidinediones (TZDs). TZDs, including rosiglitazone and pioglitazone, enhance insulin sensitivity and decrease insulin resistance by binding to the peroxisome proliferator-activated receptor gamma; a nuclear receptor involved in adipose and vascular cell diﬀerentiation [154]. TZDs decrease inﬂammatory mediators [155], improve endothelialdependent vascular responses [156], decrease thrombotic potential by decreasing plasminogen activator inhibitor levels [157], improve the diabetic atherogenic proﬁle by increasing LDL particle size [158] reduce serum C-reactive protein levels [159], and reduce carotid intimal thickness [160]. However, it is unclear whether the improvement in insulin sensitivity by TZDs will translate into a long-term cardiovascular baneﬁt in metabolic syndrome and type 2 diabetes. Caution is advisable when treating heart failure patients with TZDs since these agents tend to cause ﬂuid retention. The Diabetes Control and Complication Trial (DCCT) demonstrated that tight glycemic control reduced the occurrence or progression of diabetic microvascular complications in type I diabetic patients [25]. However, the eﬀect of glycemic control on macrovascular complications is less clear. In the DCCT study, the trend toward less cardiovascular morbidity and mortality in type I diabetics was not signiﬁcant. Furthermore, the 18-month DCCT follow-up study (EDIC) of 1325 type I diabetic patients demonstrated that neither intensive therapy nor the glycosylated hemoglobin level aﬀected carotid intimal thickness [161]. The United Kingdom Prospective Diabetes Study (UKPDS) established that aggressive glycemic control reduces microvascular disease in type II diabetics, but the eﬀect of this intervention on macrovascular disease in type II diabetics was unclear, as the reduction of macrovascular complications failed to reach signiﬁcance [26]. The Veterans Aﬀairs Diabetes Feasibility Trial [162] was a study of 350 men with a mean age of 60 years and an average duration of type II diabetes of 7.8 years randomized to either standard or intensive management. This study demonstrated no diﬀerence in the total and cardiovascular mortality in the intensive versus standard treatment arms, despite a 2% diﬀerence in glycosylated hemoglobin levels during the 27-month follow-up period between the two groups. On the basis of the currently available data, tight glycemic control by itself appears to have little eﬀect on morbidity and mortality from cardiovascular disease in patients with diabetes mellitus. The multifactorial etiology of macrovascular disease suggests that optimal treatment of diabetic patients includes blood pressure management, correction of

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dyslipidemia, and modifying additional risk factors. The results of the recently reported Steno-2 study conﬁrm that a multifactorial approach that includes intensive treatment of hyperglycemia, hypertension, dyslipidemia, microalbuminurea, and behavior modiﬁcation in conjunction with aspirin is eﬀective in reducing the risk of cardiovascular events in patients with type 2 diabetes by about 50% [163]. Further large-scale, prospective, randomized trials are necessary to determine the role of aggressive glycemic control in the prevention of diabetic macrovascular disease.

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8 Epidemiology of Coronary Heart Disease in the Elderly Pantel S. Vokonas and William B. Kannel Boston University Medical Center, Boston, Massachussettes, U.S.A.

Coronary heart disease is the central component of a broad spectrum of disease conditions aﬀecting the heart and circulation, collectively termed atherosclerotic cardiovascular disease, that progress dramatically as age advances. Although coronary heart disease (CHD) in all its clinical manifestations contributes signiﬁcantly to disability and death throughout life, its toll is heaviest in the elderly [1–7]. Because there is a substantial paucity of epidemiological information regarding both the development and prevention of CHD in the elderly, a thorough evaluation of the role of risk factors for CHD in older persons and the potential beneﬁts of their amelioration would represent an important contribution to the clinical and preventive management of this disease in a large segment of the U.S. and world population. Considerations regarding the character of CHD and the role of risk factors for its development in older persons, which at the surface may appear straightforward, are in actuality quite complex because, of necessity, they involve interactions of the multiple and overlapping domains of aging, disease, and risk factors. This complexity is captured in the form of a Venn diagram proposed by Lakatta and his colleagues [8] (Fig. 1). In this representation, aging denotes the constellation of processes occurring over time in the adult organism resulting in characteristic alterations of structure and function of body tissues and organs including the heart and blood vessels. CHD represents ‘‘disease’’ in this context with underlying anatomical and pathophysiological features ultimately manifested as clinical symptoms and complications. Risk factors, in turn, index an array of atherogenic personal traits as well as lifestyle characteristics, including diet and exercise, which are associated with the development of CHD [9]. Separate perspectives for each interaction among these three domains will, therefore, constitute the framework for further discussion. First, we will examine the relation of CHD occurrence to advancing age and the character of CHD in older persons. Next, we will examine how established risk factors for CHD change with advancing age and their prevalence in the elderly. Finally, we will examine associations between speciﬁc risk factors and CHD in the elderly and comment on available information regarding the eﬃcacy of treating such factors. Each of these perspectives are systematically examined in 30-year, follow-up data from the Framingham Study, focusing on ﬁndings in subjects 65 to 94 years of age. Details 189

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Figure 1 Conceptualized model of interactions between aging, coronary heart disease (CHD) and risk factors for CHD in older persons. (Modiﬁed from Ref. 8.)

of the examination and laboratory procedures, response rates, and criteria for disease outcomes in the Framingham Study have previously been described [10].

CORONARY HEART DISEASE IN THE ELDERLY A fundamental observation of cardiovascular disease epidemiology is the distinct agerelated rise in the incidence of nearly all manifestations of heart and circulatory disease across the lifespan. In addition to CHD, such cardiovascular disease conditions include stroke, peripheral arterial disease, and congestive heart failure. The increase in incidence of CHD with advancing age is clearly the most striking (Fig. 2) and illustrates the most important element of the ﬁrst perspective (i.e., the relation between aging and CHD). Although calculated incidence rates in men and women at far-advanced age are based on relatively small numbers of CHD events, such rates clearly follow trends established earlier in life. Also, while incidence rates in men increase linearly with age, those in women tend to increase more steeply at advanced age approximating an expotential function. Similar trends of increasing incidence of disease events with age as noted in Figure 2 are observed in Framingham Study data for both men and women up to age 84 for nearly every major clinical manifestation of CHD, including angina pectoris, myocardial infarction, sudden death, and death due to CHD [10]. Another important observation regarding the relation of CHD and advancing age is the progressive attenuation of male predominance of disease. This is illustrated in Figure 3 which shows the marked decline in male-to-female ratio of incidence rates for CHD with the relation crossing the line of identity at far advanced age.

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Figure 2 Age trends in total CHD incidence for men and women. Framingham Study, 30-year follow-up.

The character of CHD according to speciﬁed clinical manifestations for older men and women in the Framingham cohort is presented in Table 1. Data indicate the proportion of total coronary events represented by a speciﬁc manifestation. Symptomatic categories are not mutually exclusive and percentages exceed 100% because a given subject may have more than one clinical manifestation at the time of their initial presentation within a biennial period. Myocardial infarction represents the most common initial manifestation for CHD in older men, whereas angina pectoris appears to be the most common presenting feature in older women. Angina pectoris in older women frequently occurs as an isolated clinical entity. Angina pectoris in older men, however, is more often associated with acute myocardial infarction, either preceding or occurring after the acute event. Coronary insuﬃciency is the traditional term for unstable angina pectoris referring to the clinical situation of either prolonged chest pain or a progressive increase in the frequency and/or intensity of ischemic chest pain. This manifestation occurs at similar frequencies in older men and women. Sudden death, as an initial manifestation of CHD, occurs somewhat more frequently in older men than women. Another characteristic of CHD in the elderly is the tendency for a larger proportion of myocardial infarction events to be clinically unrecognized (Table 2). The diagnosis of myocardial infarction in such instances is based on the occurrence of unequivocal electrocardiographic changes consistent with infarction between biennial examinations, where neither the subject nor his/her physician has suspected the diagnosis [11]. Symptoms associated with such events are usually attributed to musculoskeletal chest discomfort,

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Figure 3 Age-related change in male-to-female ratios for total CHD incidence. Framingham Study, 30-year follow-up.

upper gastrointestinal tract upset, gall bladder disease, or other conditions. Approximately one-half of such infarctions are completely silent. Unrecognized events represent a larger proportion of all infarctions in women and particularly older women.

CHANGES IN CHD RISK FACTORS WITH ADVANCING AGE Nearly all of the established CHD risk factors change with advancing age. These include changes in blood pressure, serum lipids, cigarette smoking, glucose metabolism, body weight, and other factors. Several age-related trends in risk factors and their prevalence in older persons are described below. This constitutes the second perspective of our discussion (i.e., the interaction between aging and risk factors). Table 1 Speciﬁed Clinical Manifestations of CHD: Men and Women Aged 65 to 94 Manifestation Myocardial infarction Angina pectoris Coronary insuﬃciency Sudden death

Men 135/244 73/244 16/244 37/244

(55%) (30%) (07%) (15%)

Source: Framingham Study, 30-year follow-up.

Women 108/269 123/269 21/269 31/269

(40%) (45%) (08%) (12%)

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Table 2 Proportion of Unrecognized Myocardial Infarctions by Age and Sex Age (years)

Men

Women

30–44 45–54 55–64 65–74 75–84 85–95%

29% 18% 25% 25% 42% 33%

— 41% 31% 35% 36% 46%

Average

28%

35%

Source: Framingham Study, 30-year follow-up.

The most well-characterized change in an established CHD risk factor with age is elevation of blood pressure. In longitudinal data from the Framingham Study, systolic blood pressure is observed to rise nearly linearly with advancing age in both men and women (Fig. 4). Diastolic blood pressure, in contrast, tends to rise throughout middle age in both sexes and actually declines at advanced age. Diastolic blood pressures in women, however, usually remain 5 to 10 mmHg lower than those in men throughout the lifespan [1].

Figure 4 Average age trends in systolic and diastolic blood pressure levels for men and women based on cross-sectional and longitudinal (cohort) data. Framingham Study, Biennial exams 3–10. (Modiﬁed from Ref. 1.)

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The consistent increase in systolic blood pressure is due to progressive vascular stiﬀening attributable, in turn, to alterations of the physicochemical properties of media of the arterial wall, including overall thickening and changes in the nature and content of collagen, elastin, and possibly other structural proteins that occur with advancing age [12]. This process is dissimilar to that of atherosclerosis, which underlies the preponderance of cardiovascular disease observed in older people. Although progressive elevation of systolic blood pressure with advancing age is consistently observed in nearly every Western industrialized population studied, it does not appear to represent a universal feature of the aging process. Data from a number of isolated primitive populations suggests that this relation is markedly blunted [13]. Possibilities accounting for diﬀerences in age-related change in blood pressure between populations likely include genetic factors as well as dietary inﬂuences, especially the higher intake of salt in industrialized nations [14]. Despite its ubiquity, however, progressive elevation of systolic blood pressure with advancing age should not be construed as an innocuous concommitant of the aging process, since it clearly confers increased risk for stroke, CHD, and other cardiovascular disease events in both elderly men and women [15]. Elevated diastolic blood pressure also occurs commonly in the elderly and remains an important risk factor for cardiovascular disease, particularly in older men. As a consequence of the progressive age-related increase, primarily in systolic blood pressure, approximately 40 to 50% of men and women in a typical Westernized population such as Framingham meet one or more of the established criteria for hypertension after the age of 65. For persons categorized as being hypertensive, isolated systolic hypertension (deﬁned as systolic blood pressure (BP) >160 mmHg with diastolic BP V95 mmHg) accounts for nearly two-thirds of the total prevalence of hypertension in both older men and women [16]. Combined hypertension characterized by abnormal elevations of both systolic and diastolic blood pressures accounts for less than one-third of the total prevalence. Isolated diastolic hypertension is considerably less prevalent in older men and women accounting for less than 15% of the prevalence. Blood lipids, including serum total cholesterol, also vary with age across the lifespan and trends appear to be diﬀerent in women as compared to men. Figure 5 shows longitudinal trends in average levels of serum cholesterol in the Framingham Study as a function of age. Note that levels in men tend to peak in early middle age and then slowly decline with advancing age. Levels in women peak later in middle age and remain relatively high until advanced age before a decline occurs. The practical implication of this trend is the relatively high prevalence of hypercholesterolemia likely to be encountered in comparable populations of older women. Corresponding age trends for speciﬁc lipoprotein–cholesterol subfractions in the Framingham Study are illustrated in Figure 6. Trends for low-density lipoprotein cholesterol (LDL), in general, are similar to those for serum total cholesterol. Mean levels of high-density lipoprotein cholesterol (HDL) are consistently higher in women than in men across the age span, but tend to decline slightly after menopause. Trends in men remain essentially unchanged throughout life. Mean values of very-low-density lipoproteins (VLDL) tend to be higher in men than women, but trends in both tend to rise throughout middle age and then remain relatively stable thereafter. Presumably, these trends reﬂect ﬂuctuations in body weight occurring at corresponding ages in the sexes. The prevalence of a number of cardiovascular risk factors in older subjects of the Framingham Study is presented in Table 3. Data are arrayed for each decade of age from 65 to 94 years and separately for men and women.

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Figure 5 Average age trends in serum cholesterol levels in cross-sectional and longitudinal (cohort) data. Framingham Study, Biennial exams 1–16.

Figure 6 Average age trends in lipoprotein cholesterol subfractions. Framingham Study. (Reproduced by permission.)

196 Table 3

Vokonas and Kannel Percentage Prevalence of Cardiovascular Risk Factors in the Elderly Deﬁnite hypertension

Hypercholesterolemia

Glucose intolerance

Age (years)

Men

Women

Men

Women

Men

Women

65–74 75–84 85–94

42.1 45.5 20.7

48.9 61.1 64.8

16.6 9.7 9.4

39.7 36.3 18.4

29.5 30.9 33.3

17.5 26.0 29.0

Obesity

Cigarette smoking

ECG–LVH

Age (years)

Men

Women

Men

Women

Men

Women

65–74 75–84 85–94

52.2 35.4 7.7

47.8 39.3 30.0

21.9 13.9 9.4

23.0 8.5 3.2

5.5 6.0 10.4

4.2 7.8 13.0

Deﬁnite hypertension: BP >160/95 mmHg; hypercholesterolemia: serum cholesterol >250 mg/dL; glucose intolerance: blood glucose >120 mg/dL, glycosuria, or diabetes mellitus; Obesity: relative weight >120%; cigarette smoking: any (Exam 15); ECG–LVH: evidence of left ventricular hypertrophy on electrocardiogram. Source: Framingham Study, Exam 16.

As would be expected from age trends observed earlier, hypercholesterolemia appears to be quite prevalent in older women. Glucose metabolism becomes progressively impaired with advancing age, resulting in increasing prevalence of glucose intolerance in both older men and women [17]. Body weight tends to decrease at far-advanced age. Weight loss, however, represents a reduction primarily in lean body mass (i.e., muscle and bone tissue) rather than adipose tissue. The result is an alteration of body composition in older persons with higher proportional adiposity per unit of weight [18]. Despite the tendency for lower body weights at advanced age, obesity appears to be well represented in both older men and women in this cohort. The prevalence of cigarette smoking appears to decrease with advancing age. This can be attributed not only to higher mortality rates in smokers but also to discontinuation of cigarettes because of health problems or concerns in older persons. The prevalence of ECG left ventricular hypertrophy (LVH) increases with advancing age in both older men and women. From the foregoing analysis, it is clear that the majority of established risk factors for CHD in middle-aged persons are prevalent in the elderly. What remains is the task of marshaling evidence to address the question of whether or not such risk factors continue to remain operative in the development of CHD in older persons. This constitutes the third and ﬁnal perspective of interactions alluded to earlier (i.e., associations between speciﬁc risk factors and CHD in older persons) which will be reviewed next.

ASSOCIATION BETWEEN SPECIFIC RISK FACTORS AND CHD IN THE ELDERLY Associations for a number of speciﬁc risk factors and CHD are summarized in Table 4. Putative risk factors are listed in the column on the left. Standardized, age-adjusted

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Associations Between Speciﬁc Risk Factors and Incidence of CHD Bivariate standardized regression coeﬃcients (age-adjusted) Ages 35–64

Risk factors Systolic pressure Diastolic pressure Serum cholesterol Cigarettes Blood glucose Vital capacity Relative weight

Ages 65–94

Men

Women

Men

Women

0.338c 0.321c 0.322c 0.259c 0.043 0.112a 0.190c

0.418c 0.363c 0.307c 0.095 0.206c 0.331c 0.264c

0.401c 0.296c 0.121 0.017 0.166c 0.127 0.177b

0.286c 0.082 0.213c 0.034 0.209c 0.253c 0.124a

Signiﬁcant at ap < 0.05; bp < 0.01; cp < 0.001. Source: Framingham Study, 30-year follow-up.

(bivariate) logistic regression coeﬃcients are categorized for younger and older subjects of the Framingham cohort and also arrayed separately for men and women. Regression coeﬃcients are derived using a logistic regression model to mathematically relate the level of a risk factor or its categorical value to the development of CHD events. The magnitude of the coeﬃcient and also the level of statistical signiﬁcance reﬂects the strength of the association between the speciﬁc risk factor and CHD for the age group and sex under consideration. A cursory inspection of the results indicates that the majority of signiﬁcant associations between risk factors and CHD apparent in younger men and women remain signiﬁcant in older age groups but not consistently in both sexes. Systolic blood pressure, for example, demonstrates strong risk associations for CHD in younger men and women and maintains strong associations in both older men and women. The risk association for diastolic blood pressure, in contrast, appears to lose signiﬁcance in older women. Serum total cholesterol demonstrates strong risk associations for CHD in younger men and women; however, the strength of this risk association clearly weakens in older men but remains signiﬁcant in older women. Cigarette smoking modeled using this methodology fails to show signiﬁcant risk associations in either older men or women. Blood glucose levels, as well as other parameters reﬂecting impaired glucose metabolism, including glucose intolerance and diabetes mellitus, show strong risk associations for CHD, in both older men and women. Vital capacity demonstrates strong negative risk associations, particularly in older women. Of interest, signiﬁcant risk associations between CHD and body weight expressed as Metropolitan Relative Weight are maintained in both older men and women. A number of these risk associations will be characterized in detail below. Similar data for associations between speciﬁc risk factors and CHD incidence can be derived using an alternative regression methodology, the Cox proportional hazards model [19]. Blood Pressure and Hypertension The relation between blood pressure and CHD, particularly in older persons, represents one of the most striking risk associations in data from the Framingham Study.

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Risk relations between CHD incidence and systolic blood pressure in men and women are shown in Figure 7. CHD incidence, expressed as age-adjusted annual rate of CHD events per 1000, appears on the ordinates of left and right panels, respectively. Systolic blood pressure appears on the abscissas of both panels. Two risk relations are illustrated in each panel, one for younger men and women, aged 35 to 64, another for older men and women, aged 65 to 94. While overall incidence rates for CHD in women are substantially lower than those at corresponding blood pressures in men, the same underlying risk associations are observed. Note that CHD risk for systolic blood pressure rises with increasing pressure in all age groups and that this rise is even more striking in older than in younger persons. These trends are interpreted as marked increases in relative risk indicating that progressively higher levels of blood pressure confer additional risk for CHD. Although these trends do not establish causality, they serve to emphasize an important role for blood pressure in the extended sequence of pathophysiological events that result in manifest CHD. Also note that risk relations in older men and women are conﬁgured well above those of younger persons in each sex indicating substantially higher incidence rates for CHD at similar blood pressures. This is interpreted as an increase in absolute risk for CHD in older men and women suggesting a substantially higher burden of disease at all levels of blood pressure in older as compared to younger persons, even at normal or low blood pressures. Risk relations between CHD incidence and diastolic blood pressure in men and women are shown in Figure 8. Again, risk appears to rise with increasing blood pressure in all age groups (i.e., increased relative risk) and incidence rates at the same level of blood pressure are higher in older than in younger persons (i.e., increased absolute risk). Although there is a minor deviation from the nearly linear trend for the relation between

Figure 7 Risk of CHD by level of systolic blood pressure according to speciﬁed age groups in men and women. Framingham Study, 30-year follow-up.

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Figure 8 Risk of CHD by level of diastolic blood pressure according to speciﬁed age groups in men and women. Framingham Study, 30-year follow-up.

diastolic blood pressure and CHD incidence in older men, the relation maintains strong statistical signiﬁcance. In contrast, the deviation in the relation corresponding to the fourth level of diastolic blood pressure (95–104 mmHg) in older women yields a statistically insigniﬁcant result using the logistic regression model, despite an apparent upper curvilinear trend. Although the discontinuities in these curves remain unexplained, these ﬁndings suggest a more consistent and reliable role for systolic as compared to diastolic blood pressure as a predictor for CHD in both elderly men and women. Risk gradients for CHD that, in general, are similar in direction and magnitude to those suggested earlier are observed when individuals are classiﬁed according to hypertensive status instead of absolute levels of blood pressure (Table 5). For all age and sex

Table 5

Risk of CHD by Hypertensive Status According to Age and Sex Average annual age-adjusted rate per 1000 Coronary heart disease 35–64a years

Hypertensive status Normal (<140/90 mmHg) Mild (140–160/90–95 mmHg) Deﬁnite (>160/95 mmHg)

65–94a years

Men

Women

Men

Women

8 15 21

3 7 10

14 28 41

11 16 22

a All trends signiﬁcant at p < 0.001. Source: Framingham Study, 30-year follow-up.

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groups considered, the overall risk of CHD is two to three times higher in subjects with deﬁnite hypertension compared with normotensives, while risk is intermediate for those with mild hypertension. Absolute risk is two to three times higher in older subjects, both in men and women, and risk is nearly always higher in men than women, regardless of age. Similar patterns of risk attributable to hypertension have been observed speciﬁcally for cerebrovascular events, congestive heart failure, and peripheral vascular disease [15]. When considered alone, isolated systolic hypertension also confers substantial risk for CHD and other cardiovascular disease outcomes. Previous data from randomized clinical trials have established a strong case for the eﬃcacy of treating combined elevations of systolic and diastolic blood pressure in older hypertensives [20,21], although considerable uncertainty remained regarding the treatment of isolated systolic hypertension. The ﬁndings of the Systolic Hypertension in the Elderly Program (SHEP) have served to dispel much of this uncertainty [22]. This study documented impressive reductions in total numbers of fatal and nonfatal strokes in the active treatment group as compared to the placebo group. Statistically signiﬁcant reductions in nonfatal myocardial infarctions plus coronary death, as well as combined CHD and total cardiovascular disease outcomes, were also noted in the group on active treatment. There appeared to be little or no evidence in this study that lowering of either systolic or diastolic blood pressure resulted in an increased risk of CHD events or mortality, particularly at the lower end of the distribution for blood pressure, the so-called J-shaped curve. Five other recent clinical trials of drug therapy for hypertension in the elderly that included patients with isolated systolic hypertension also showed beneﬁcial eﬀects [23–27]. In addition to substantial reductions in cerebrovascular events and congestive heart failure, the majority of intervention studies of drug therapy for hypertension in older persons to date have consistently demonstrated either beneﬁcial trends or signiﬁcant reductions in CHD events and mortality. Such ﬁndings appear to be considerably less prominent in clinical trials experiences derived from predominantly middle-aged hypertensives [20,21,28]. Details regarding clinical evaluation and treatment of the elderly hypertensive patient appear in Chapter XX. Blood Lipids The risk of CHD in older persons attributable to serum lipids represents an area of considerable uncertainty and controversy. Relations between CHD incidence and serum total cholesterol in the Framingham Study are shown in Figure 9. Separate trends are plotted in younger and older subjects for men and women, respectively. Note that absolute risk is substantially increased in older as compared to younger men. Note also that relative risk clearly rises over the entire distribution of serum total cholesterol in younger as well as older men. The break in continuity of the risk relation at the fourth level of the distribution in older men, however, yields results that narrowly miss statistical signiﬁcance both in bivariate (age-adjusted) and multivariate estimates using the logistic regression model, whereas the association remains strongly predictive in younger men. Although incidence rates for CHD at corresponding levels of cholesterol are lower in women than those in men, the same overall pattern pertains (i.e., an increase in both absolute and relative risk). In this instance, however, statistical signiﬁcance is maintained in both younger and older women. The ﬁnding that serum total cholesterol loses strength as a risk factor for CHD, particularly in older men of the Framingham cohort, has resulted in serious misinter-

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Figure 9 Risk of CHD by level of serum cholesterol according to speciﬁed age groups in men and women. Framingham Study, 30-year follow-up.

pretation by some authors who have used this information to argue that serum lipids do not represent important risk factors for CHD in the elderly and thus justify neither detection nor treatment [29,30]. This view is both extreme and unreasonable, since several other studies have clearly validated the role of serum total cholesterol as a predictor of CHD events in older men [31–37] and also older women [31,33,37]. Despite these ﬁndings, however, a recent meta-analysis encompassing data from 22 U.S. and international cohort studies concluded that serum cholesterol did indeed lose strength as a risk predictor for CHD mortality in older men and also in older women [38], a ﬁnding consistent with original observations made in data from the Framingham Study. Cholesterol emerges as a signiﬁcant predictor of CHD death when steps are taken to adjust for factors related to fraility or other comorbid conditions that serve to confound this risk association [39,40]. Focusing on serum cholesterol as the sole measure of risk for CHD attributable to serum lipids should now be considered obsolete based on our current understanding of lipoprotein subfractions and the availability of standardized laboratory methods to measure them in clinical practice. Substitution of either LDL or HDL cholesterol in the regression model fully restores statistical predictability for the risk relation between serum lipids and CHD [41]. HDL cholesterol, in particular, has emerged as an important lipid moiety that adds substantial precision to assessing coronary risk at limited additional cost [42]. Construction of a serum cholesterol/HDL ratio provides a highly accurate characterization of CHD risk in older men and women in the Framingham Study, which is illustrated in Figure 10. Indeed, data from Framingham as well as other studies conﬁrm the overall reliability of the cholesterol/HDL ratio in assessing CHD risk in younger and older persons and in men as well as women [33,41,43,44]. The rationale for this approach is

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Figure 10 Risk of CHD by total/HDL cholesterol ratios among men and women aged 50 to 90 years. Framingham Study, 26-year follow-up.

that the ratio reliably captures the eﬀect of a dynamic equilibrium of lipid transport into and out of body tissues, possibly including the intima of blood vessels. Several studies have suggested that serum triglycerides may be important predictors for CHD in either older men or older women, but not consistently in both sexes [33,41, 43,45]. Despite these observations, the present consensus holds that elevated levels of serum triglycerides represent a risk marker for obesity, glucose intolerance, and low HDL levels, all of which confer risk for CHD and, to the extent possible, deserve preventive attention. Data from intervention studies using dietary measures or drug therapy demonstrate the beneﬁt of lipid alteration in reducing risk of CHD events particularly in middle-aged men [46,47]. Systematic information from clinical trials regarding the eﬃcacy and safety of treating lipid abnormalities in the elderly, despite their prevalence in this population, is not yet available. A strong case for the widespread application of drug therapy to reduce risk of CHD in older persons as an element of primary prevention is not warranted at the present time. Of considerable interest, information from four large clinical trials makes a compelling case for reducing elevated or even average levels of LDL cholesterol with drugs in patients with established CHD: angina pectoris or following myocardial infarction [48– 52]. These eﬀects of drug therapy in the secondary prevention of CHD events (i.e., in persons with preexisting CHD) appear to be beneﬁcial in both middle-aged and older patients of both sexes. Nearly all such recent clinical trials have also demonstrated the beneﬁt of statin drug therapy in reducing the subsequent incidence of stroke events in treated patients [53]. Current management of hypercholesterolemia for an older person considered to be at risk should consist of a highly individualized approach beginning with appropriate dietary measures and weight control before initiating a trial of speciﬁc drug therapy, preferably at lower doses, to achieve a carefully monitored lipid-lowering eﬀect [54].

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Cigarette Smoking Cigarette smoking fails to demonstrate strong risk associations for total CHD events in either older men or older women using the logistic regression methodology indicated in Table 4. Signiﬁcant risk associations, however, are discerned between cigarette smoking and death due to CHD [10]. One explanation for this phenomenon is that smoking may be more closely related to lethal events than to outcomes composed of combinations of morbid and lethal events [55]. Another explanation is that the cross-sectional pooling approach used in the analysis may classify long-term smokers who have discontinued cigarettes for relatively brief periods as nonsmokers, in eﬀect diluting the strength of the association between the risk factor and the outcome [56]. Because of these diﬃculties, the most reliable approach to assessing risk associations between cigarette smoking and cardiovascular morbidity or mortality is to model these events prospectively for deﬁned categories of smoking behaviors (e.g., current smoker, former smoker, and never smoker) and for longer time intervals. Such approaches yield strong risk associations between cigarette smoking and a broad array of cardiovascular outcomes, including CHD, stroke, and peripheral arterial disease, even in older men and women. These observations have been documented using data from Framingham as well as other studies [33,57–59]. Reducing the risk of cardiovascular disease is not the only reason to encourage discontinuation of cigarettes in older persons. Cigarettes contribute to the development of chronic bronchitis and obstructive lung disease as well as lung cancer and other malignancies. These conditions also exact a heavy toll in terms of disability and death in the elderly. Thus, the clinician can make a compelling case that it is never too late to stop smoking and extend appropriate advice and encouragement to assist patients in their eﬀort to discontinue cigarettes.

Glucose Tolerance and Diabetes Mellitus Impaired glucose metabolism is not only highly prevalent in the elderly, but also confers substantial risk for CHD as well as other cardiovascular events in both older men and women. Various measures of glucose tolerance are employed and nearly all demonstrate signiﬁcant risk associations with CHD in the Framingham Study [10]. These measures include blood glucose levels, glycosuria, and the composite risk categories designated as glucose intolerance and diabetes mellitus. Although diabetes mellitus confers enhanced risk for both younger and older men, overall risk increases dramatically for both younger and older women [60] (Fig. 11). Similar patterns of risk are noted for coronary and cardiovascular mortality [10,60]. Diabetes also emerges as an important risk factor in the development of congestive heart failure, particularly in older women with insulin-dependent diabetes mellitus [61]. Presumably, the microvascular disease that is unique to diabetes, as well as other mechanisms, serves to produce progressive damage to heart muscle, ultimately resulting in compromised ventricular function and heart failure. There is little evidence that control of hyperglycemia, either by oral hypoglycemic agents or insulin, eﬀectively forestalls either the development or complications of cardiovascular disease [60,62], although encouraging trends in this regard were identiﬁed in the recently completed Diabetes Control and Complications Trial [63]. Available evidence would, therefore, suggest that there is more to be gained in reducing risk by correcting associated cardiovascular risk factors in persons with diabetes than by attention conﬁned to early detection and control of hyperglycemia.

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Figure 11 Age-adjusted incidence rates for CHD based on diabetic status classiﬁed according to age and sex. Solid bar = diabetic; open bar = nondiabetic; RR = risk ratio diabetic/nondiabetic. (From Ref. 55, with permission.)

Left Ventricular Hypertrophy Left ventricular hypertrophy as determined by the electrocardiogram (ECG–LVH) emerges as a strong risk factor for CHD in older men and women (Fig. 12). Marked increases in CHD incidence are noted for voltage criteria for LVH alone with additional risk conferred by deﬁnite LVH which, in addition to voltage criteria, includes repolarization (ST and T wave) abnormalities consistent with LVH. These electrocardiographic ﬁndings presumably reﬂect abnormalities of myocardial structure and function related to early compromise of the underlying coronary circulation that antedate the development of clinical manifestations of CHD [64–66]. In this context, left ventricular hypertrophy (LV mass) as determined by echocardiography has emerged as an extremely potent independent predictor of CHD as well as other cardiovascular disease events especially in older persons [67,68]. Body Weight Of considerable interest is the ﬁnding that increased body weight represents a signiﬁcant risk marker for CHD even at advanced age. The association between body weight and risk for CHD in older subjects of the Framingham Study is illustrated in Figure 13. Note that while CHD risk rises more strikingly

Epidemiology of CHD

Figure 12

205

Risk of CHD according to ECG-LVH status. Framingham Study, 30-year follow-up.

Figure 13 Risk of CHD according to body weight in men and women aged 65 to 94 years. Framingham Study, 30-year follow-up.

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with increasing body weight in older men, trends in older women clearly indicate enhanced risk at higher body weights. Progressive increases in body weight occurring earlier in life correlate closely with changes in the levels of several risk factors considered to be more directly related to pathogenesis of atherosclerosis [69]. These include increases in blood pressure, serum cholesterol, and triglycerides and blood glucose with a reduction in HDL cholesterol. These ﬁndings serve to emphasize the need to incorporate measures ultimately designed to either control or, if necessary, gradually reduce body weight as part of risk management even in older persons. When coupled with appropriate dietary measures, weight control would be particularly useful in the initial management of elderly patients with hypertension, dyslipidemia, and diabetes or combinations of these conditions. Vital Capacity Vital capacity is a simple and sensitive clinical technique for assessing compromise of pulmonary or cardiac function, or both, in individuals of all ages. In contrast to inconsistent risk associations with CHD found in younger subjects, vital capacity emerges as an important risk factor in the elderly, particularly with respect to risk for major coronary events [2,10]. Vital capacity normally declines with advancing age, an eﬀect that is strongly exacerbated by cigarette smoking and obesity [70]. Diminished vital capacity in older people is also correlated with loss of muscular strength as assessed by hand grip, presumably reﬂecting overall neuromuscular debility [71]. Low vital capacity remains a strong predictor of cardiovascular mortality, as well as mortality from all causes. Measurement of this parameter, therefore, should be considered as part of the standard risk assessment of all older patients. Heart Rate Recent data from the Framingham Study demonstrates that resting heart rate confers additional risk for CHD in men, both in younger as well as older men, although no similar risk association is observed in either younger or older women [2,10]. An explanation for this ﬁnding is not readily apparent. Heart rate in men may be a more sensitive indicator of underlying cardiac dysfunction than in women or the net impact of sympathetic nervous system inﬂuences in precipitating CHD events is greater in men. High heart rates may also reﬂect physical deconditioning. Physical Activity Accumulating evidence now suggests that lifetime vigorous physical activity may forestall CHD in the elderly [72–74]. Previously reported data from Framingham indicated that overall mortality, including coronary mortality, was inversely related to level of physical activity in middle-aged men [75]. A beneﬁt for exercise in older men was also suggested; however, the levels of exercise involved were quite modest. Although regular physical activity in the elderly is desirable and should be strongly encouraged, it would be unwise to place undue emphasis on this approach alone in attempting to reduce the risk for CHD. Prevalent CHD An important predictor of CHD events at all ages is the presence of antecedent CHD. It is therefore of interest that several of the risk factors associated with the initial development of

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CHD in the elderly not only continue to have strong correlations with prevalent disease but also maintain predictive associations for new CHD events in older persons with preexisting disease [33,35,76–78]. Serum lipids, cigarette smoking, and diabetes appear to be more prominent in this context than hypertension. Blood pressure may fall substantially following myocardial infarction, especially extensive anterior myocardial infarction which carries a poorer prognosis, thereby confounding the relation between hypertension and CHD morbidity and mortality [79]. Blood pressure, however, reemerges as a signiﬁcant predictor of recurrent CHD events in long-term survivors of myocardial infarction [80]. These ﬁndings serve to emphasize the critical role of controlling risk factors in older persons with established CHD. Eﬀective treatment of hypertension, discontinuation of cigarettes, and adequate control of hyperglycemia are important measures in the preventive clinical management of such individuals. The potential beneﬁt of lipid-lowering drugs in older persons with established CHD and hypercholesterolemia was alluded to earlier. Other Risk Factors Several hematological or hemostatic factors have been described as risk variables in the Framingham Study. Hematocrit appeared to contribute to CHD in younger men and women in this analysis, but not in older persons [10]. White blood cell count, which was strongly correlated with the number of cigarettes smoked per day, hematocrit, and vital capacity, was also associated with enhanced risk for CHD and other cardiovascular endpoints in older men, both in smokers and nonsmokers, but only in women who smoked [81]. These data were consistent with reports from other studies [82]. Plasma ﬁbrinogen showed strong risk associations for CHD and other cardiovascular disease outcomes in men, including older men [83], similar to ﬁndings from other studies [84]. Signiﬁcant risk associations, however, were not apparent in older women. An extensive array of psychosocial, occupational, dietary and other factors have been described as putative risk parameters for CHD in the Framingham Study [9,85]; however, only limited information is available regarding speciﬁc associations of these factors with CHD in older persons. Although family history of CHD is strongly related to early development of CHD (before age 60) in both men and women in the Framingham Study, predictive associations also remained signﬁcant for the late onset of CHD [86].

CHD RISK PROFILES IN THE ELDERLY Although associations between a speciﬁc risk factor and CHD can be considered in isolation as a single relation, in many instances combinations of several risk factors may constitute the observed risk proﬁle, especially in older persons. Risk of CHD, in such instances, can be reliably estimated by synthesizing a number of risk factors into a composite score, based on a multiple logistic function [87,88]. Risk factors are assessed by standard clinical procedures (smoking history, blood pressure, and electrocardiogram) and by routine laboratory studies (serum total cholesterol, HDL cholesterol, and blood glucose). This type of composite index permits detection of individuals at relatively high risk, either on the basis of marked elevation of a single factor or because of marginal abnormalities of several risk factors. This multivariate risk scenario is illustrated in Figure 14, which characterizes the risk of CHD at two predeﬁned levels of serum cholesterol and then considers changes in the

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Figure 14 Risk of CHD of two levels of serum cholesterol according to speciﬁed levels or categories of other risk factors for 70-yr-old women in the Framingham Study.

levels or values of other risk factors toward worsening risk, as indicated in the table below. Note that risk increases progressively with the additional impact of other risk factors for both categories of serum cholesterol, even in instances where a factor such as cigarette smoking has a relatively weak risk association with CHD when considered alone. The major risk factors, including age, when taken together, explain only a limited proportion of the variance of CHD incidence in younger as well as older persons [87,88]. It is likely that other major risk attributes exist among both the young and the elderly, but are yet to be identiﬁed. It must be emphasized, however, that the factors that have already been delineated do identify high-risk subgroups of the elderly population that should be targeted for preventive management.

PERSPECTIVES FOR PRIMARY PREVENTION OF CHD IN THE ELDERLY An important principle of prevention is the concept that measures limiting the eﬀect of known risk factors should be initiated as early in life as possible to minimize the subsequent development of disease in both the young and the elderly. It is unreasonable to conclude, however, that modiﬁcations of risk factors initiated at advanced age are likely to be ineﬀective in reducing the toll of related disease in older persons. A simple, but important, observation in this context is that the incidence of CHD in the elderly varies widely within distributions of continuous risk factors such as blood pressure or serum cholesterol. Incidence also appears to diﬀer markedly for values of categorical variables such as the presence or absence of left ventricular hypertrophy. In addition, data presented earlier indicate that the incidence of CHD, as well as other cardiovascular disease events, is not only substantially higher in populations of older persons but also continues to rise with advancing age across the lifespan. Because incidence is usually higher in older persons, the beneﬁcial eﬀect of a given intervention such as treatment of hypertension or hypercholesterolemia, as assessed by reduction in relative risk, may be similar to or lower than that observed in younger persons [2,20,89]. In many such instances, however, the same eﬀect measured as a diﬀerence in absolute risk, reﬂecting reduction in numerical toll

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of disease outcomes, actually remains higher in the elderly. A corollary of this eﬀect is that a smaller number of older as compared to younger people must be treated to yield the same beneﬁt in terms of numbers of disease events prevented. These considerations are more relevant today than ever before. Recently, a marked and progressive decline in mortality due to coronary and cardiovascular disease has occurred in the United States and several other industrialized nations [90]. Age-speciﬁc trends indicate decreasing mortality due to CHD and cardiovascular disease, both in the elderly and in younger adults of both sexes. Similar trends in cardiovascular mortality have been identiﬁed in the Framingham population [91]. At the same time, the prevalence of several coronary risk factors, such as untreated hypertension, elevated serum cholesterol levels, and cigarette smoking, has diminished in the population at large, including the elderly, while impressive improvements have occurred in the diagnosis and treatment of CHD. Although the available information supports the contention that both of these potentially beneﬁcial eﬀects have contributed to the observed decline in mortality from CHD, the present consensus gives greater weight to the success of widespread primary preventive strategies, resulting in lowered levels of major risk factors that contribute to disease rather than to improved diagnosis and treatment of established disease [92]. In this context, hypertension clearly emerges as the dominant, potentially remediable, risk factor for both CHD and cerebrovascular disease morbidity and mortality in the elderly. Hypertension is highly prevalent in the aged, easily detected, and can be corrected by the careful application of appropriate measures, including drug therapy. As mentioned earlier, direct evidence from clinical trials has already established the eﬃcacy of antihypertensive measures in reducing the frequency of both stroke and CHD events in elderly hypertensives. Available information also makes a compelling case for discontinuation of cigarettes at all ages, including the elderly. Information is needed, however, regarding the feasibility and eﬀectiveness of nonpharmacological approaches such as diet and weight reduction in treating older persons with hypertension and lipid abnormalities both as initial therapy and as adjuncts to speciﬁc drug therapy. Also, as a matter of critical importance, the eﬃcacy and safety of drug therapy for the treatment of lipid abnormalities in the elderly for the purpose of primary prevention should be established in large, well-designed clinical trials. Lack of such information severely limits our conﬁdence in extending what may be a potentially beneﬁcial preventive measure to greater numbers of older persons.

ACKNOWLEDGMENTS The authors wish to thank Claire Chisholm for her invaluable assistance in preparing this manuscript. This work was supported by the Cooperative Studies Program/ERIC of the Department of Veterans Aﬀairs and the Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), the Visiting Scientist Program of the Framingham Heart Study, and grant nos. NO1-HV-92922, NO1-HV52971, and 5T32-HL-0737413 of the National Institutes of Health.

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9 Pathophysiology of Coronary Artery Disease in the Elderly Roberto Corti University Hospital Zurich, Zurich, Switzerland

Antonio Ferna´ndez-Ortiz San Carlos University Hospital Madrid, Spain

Valentin Fuster Zena and Michael A. Wiener Cardiovascular Institute The Mount Sinai School of Medicine, New York, New York, U.S.A.

INTRODUCTION Atherosclerotic involvement of coronary artery arteries with subsequent coronary heart disease is the leading cause of death and disability in the elderly. Approximately half of all deaths of persons older than 65 years of age are the result of coronary artery disease and, of all coronary death, 80% occur in patients 65 years of age or older. Heart failure (which has enormous socioeconomic impact) is the terminal stage of all cardiac disease (Fig. 1) and coronary artery disease is the most frequent cause of heart failure. Despite crucial advances in our knowledge of the pathological mechanisms and the availability of eﬀective diagnostic and treatment modalities, coronary atherothrombosis remains the most frequent cause of ischemic heart disease. Plaque disruption with superimposed thrombosis is the main cause of unstable angina, myocardial infarction, and sudden death. New ﬁndings have recently introduced exciting concepts that could have major impact on the treatment of atherothrombotic disease [1–3]. We will discuss the mechanisms that lead to the development of atherothrombosis and those responsible for the acute coronary syndromes, as well as some of the concepts derived from in vivo observations using new imaging technologies (such as high-resolution magnetic resonance imaging). Although risk factor modiﬁcation and advances in therapeutic modalities have resulted in a welcome decline in cardiovascular mortality during the past two decades, recent statistics indicate that this decline is less notable in the elderly, the fastest growing segment of society. In fact, with the aging of the population, the overall prevalence, mortality, and cost of coronary artery disease will increase (Fig. 2). It has been projected that cardiovascular disease will climb from the second most common cause of death (29% of all deaths in 1990) to the ﬁrst, with more than 36% of all deaths by 2020. According to current estimates [4], 61,800,000 Americans have one or more types of cardiovascular 215

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Figure 1 Course of coronary heart disease beginning with endothelial dysfunction and ending in heart failure.

Figure 2 Prevalence of coronary heart disease by age and sex in the U.S. (1988-1994). (Reprinted from Ref. 4.)

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disease. Of these, 29,700,000 are male and 32,100,000 are female, 24,750,000 are estimated to be age 65 and older. Cardiovascular disease claimed 958,775 lives in the United States in 1999. This is 40.1% of all deaths or 1 of every 2.5 deaths. Cardiovascular disease was about 60% of ‘‘total mention mortality,’’ which means that of the more than 2,000,000 deaths from all causes, CVD was listed as a primary or contributing cause on about 1,391,000 death certiﬁcates. Since 1900, cardiovascular disease has been the No. 1 killer in the United States every year except 1918. Therefore, eﬀorts to increase our knowledge of the pathophysiology of the atherosclerotic involvement of coronary arteries aimed to reduce mortality, disability, and cost associated with coronary heart disease are an important public health priority. This chapter will provide a pathophysiological explanation for the broad spectrum of ischemic coronary syndromes based on the most recent cell and molecular biology studies of the arterial wall.

INITIATION OF ATHEROSCLEROTIC LESIONS Atherothrombosis is a systemic disease of the vessel wall that is characterized by the tendency to accumulate lipids, inﬂammatory cells, smooth muscle cells (SMC), and extracellular matrix within the subendothelial space, and to progress in an unpredictable way to diﬀerent stages. The molecular and biological mechanisms involved in the initiation and progression of atheroclerotic disease have been extensively studied during the past decades leading to the introduction of new concepts that form the basis for research eﬀorts in the ﬁeld of vascular biology [2,5]. The past two decades have elucidated the pivotal role of the endothelium in the process of atherogenesis. The endothelium is a monocellular layer that lines the luminal surface of the whole vascular tree. By means of its magnitude, with an estimated surface of more than 150 m2, and geographical location, it modulates vascular perfusion, permeability, and blood ﬂuidity. The endothelim is a dynamic autocrine/paracrine organ that regulates contractile, secretory, and mitogenic activities in the vessel wall and hemostatic processes within the vascular lumen. The endothelium responds to hemodynamic and blood-borne signal by synthesizing and/or releasing a variety of agents. The endothelial dysfunction, deﬁned as reduced synthesis and/or release of nitric oxide (NO), is now considered the earliest pathological signal of atherosclerosis. Interestingly, systemic risk factors and local risk factors (Table 1) may trigger endothelial dysfunction and lead to initiation of atherosclerotic lesions.

Table 1

Risk Factors for the Development of Atherosclerosis

Systemic risk factors

Local risk factors

Hypercholesterolemia Diabetes mellitus Arterial hypertension Cigarette smoke Systemic inﬂammatory disease Chronic infections (?) Low shear stress Arterial bifurcation and trifurcations Vascular bending points Vascular curvatures

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Systemic Atherogenic Risk Factors The initiation of atherosclerotic plaque has been correlated with the presence of a number of cardiovascular risk factors (such as hyperlipidemia, diabetes mellitus, hypertension, aging, and others), leading to endothelial dysfunction. Severe endothelial dysfunction in the absence of obstructive coronary artery disease has been shown to be associated with increased cardiac events supporting the concept that coronary endothelial dysfunction plays a pivotal role in the initiation and progression of coronary atherosclerosis [6]. Interestingly, atherosclerogenesis has been recognized as an inﬂammatory disease [7], characterized by accumulation of inﬂammatory cells within the vessel wall. Recently, endothelial dysfunction has been reported in patients with chronic inﬂammatory diseases, such as in rheumatoid arthritis, and endothelial function improves in these patients with anti-tumor necrosis factor–alpha [8]. More interestingly, treatment with potent anti-inﬂammatory drugs (selective COX-2 inhibitors) in patients with severe CAD and endothelial dysfunction leads to a signiﬁcant improvement of the endothelium-dependent vasodilation and reduces low-grade chronic inﬂammation and oxidative stress in coronary artery disease [9]. Thus potent anti-inﬂammatory drugs, such as selective COX-2 inhibitors, have the potential to beneﬁcially impact outcome in patients with cardiovascular disease. There is general agreement that hypercholesterolemia is an important causative factor in atherogenesis and that correcting it can strikingly reduce the risk of coronary heart disease. For instance, increased plasma levels of low-density lipoprotein (LDL) cholesterol induce endothelial dysfunction, the initial step in atherogenesis, whereas correction of this metabolic disorder by lipid apheresis or treatment with lipid-lowering drugs can normalize endothelial dysfunction [10–12]. In addition, recent observations have highlighted the role of high-density lipoproteins (HDL) and reverse cholesterol transport, as they are responsible for the removal of free cholesterol from the blood [13,14]. A low plasma level of HDL has been associated with increased cardiovascular risk, but only recently has this been recognized as a major risk factor requiring adequate treatment [15]. Several experimental studies have demonstrated the potential antiatherogenic properties of HDL which prevents plaque formation and even induces plaque regression [16]. More recently, it has been demonstrated that HDL administration restores normal endothelial function by increasing bioavailability of nitric oxide in hypercholesterolemic patients [17]. How cholesterol interacts with the cells of the arterial wall to initiate the atherogenic process has been only recently elucidated. Experimental studies have suggested a direct injurious eﬀect of elevated levels of LDL cholesterol, in particular its oxidative derivate, on the endothelium. Two distinct mechanisms that link oxidative stress with impairment in endothelium-dependent vasodilation have been described. First, lysolecithin, a product formed as a consequence of lipid peroxidation of LDL particles, may be involved in the development of abnormal arterial vasomotion [10,11]. Second, hypercholesterolemia may be a stimulus to augmented generation of superoxide radicals by the endothelium, which directly inactivates nitric oxide and also increases the subsequent oxidation of LDL particles by the formation of peroxynitrate. Chronic hyperglycemia may also impair the function of the endothelium, resulting in abnormal vasomotion. Extended exposure to hyperglycemia results in the glycation (i.e., the nonenzymatic conjugation of glucose) of extracellular matrix proteins, which leads to the formation of advanced glycosylation end products [18]. Accumulation of such end products in the vessel wall loads to increased vessel stiﬀness, lipoprotein binding, macro-

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phage recruitment, secretion of platelet-derived growth factor, and proliferation of vascular smooth muscle cells (SMC). Other forms of endothelial injury such those that can be induced by chemical irritants in tobacco smoke or circulating vasoactive amines may potentiate chronic endothelial injury favoring accumulation of lipids and monocytes into the intima. The endothelial dysfunction is characterized by increased permeability, reduced synthesis and release of nitric oxide, and overexpression of adhesion molecules (such as intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and selectins) and chemoattractants (such as monocyte chemoattractant protein-1, macrophage colony stimulating factor, IL-1/-6, and IFN-a/-g). Expression of endothelial adhesion molecules is induced by a variety of stimuli such as the classical cardiovascular risk factors (hyperilemia, diabetes, smoke, etc.), facilitating the recruitment and internalization of circulating monocytes and LDL cholesterol (Fig. 3) [5,19,20]. In fact, these molecules allow the internalization (homing) of inﬂammatory cells and bone marrow–derived vascular progenitor cells in the subendothelial space. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine, produced by the endothelial and smooth muscle cells (SMCs), which causes the directed migration of leukocytes. Macrophage colony stimulating factor (M-CSF) is an activator that can cause the expression of scavenger receptors on macrophages and a co-mitogen that leads to the proliferation of macrophages into the forming plaque. The lipid material accumulated within the subendothelial space becomes oxidized and triggers an inﬂammatory response that induces the release of diﬀerent chemotactic and proliferative growth factors. In response to these factors, SMC

Figure 3 Endothelial dysfunction and initiation of atherosclerotic plaques. Expression of endothelial adhesion molecules is induced by a variety of stimuli such as the classic cardiovascular risk factors (hyperilemia, diabetes, smoke, etc.). These molecules allow the internalization (homing) of inflammatory cells and bone marrow–derived vascular progenitor cells in the subendothelial space. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine, produced by the endothelial and smooth muscle cells (SMCs), which causes the directed migration of leukocytes. Macrophage colony stimulating factor (M-CSF) is an activator that can cause the expression of scavenger receptors on macrophages and a co-mitogen that led to the proliferation of macrophages into the forming plaque. (Reprinted from Ref. 143.)

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and macrophages will activate, migrate, and proliferate resulting in the thickening of the arterial wall. Local Atherogenic Risk Factors Despite exposure of diﬀerent areas of the endothelial surface to the same injurious stimuli concentration, spontaneous atherosclerotic lesions only develop in certain locations. Clearly, there must be local factors that modulate the impact of hypercholesterolemia and other risk factors on the vessel wall, determining the location and possibly the rate of atherosclerosis progression. Atherosclerotic plaques are located more frequently near bifurcations and in curvatures of the vessels. It is believed that disturbances in the pattern of local blood ﬂow are also responsible for development of atherosclerotic lesions. Recent studies have conﬁrmed the importance of hemodynamic shear stress in endothelial dysfunction, in atherogenesis, remodeling, and restenosis after angioplasty and thrombus formation. The endothelium, by virtue of its location interfacing between the blood and the vascular wall, responds rapidly and sensitively to biochemical and biomechanical stimuli in order to maintain constant rheological conditions. In numerous experiments, shear stress has been shown to actively inﬂuence vessel wall remodeling. Speciﬁcally, chronic increases in blood ﬂow, and consequently shear stress, lead to expansion of the luminal radius such that mean shear stress is returned to its baseline level. Conversely, decreased shear stress resulting from lower ﬂow or blood viscosity induces a decrease in internal vessel radius. Interestingly, two contradictory hypotheses were advanced more than 30 years ago to explain the typical distribution of atherosclerotic lesions at the vessel bifurcation. The ﬁrst implicated high shear stress via endothelial injury and denudation. The second proposed low shear stress as an atherogenic factor [5]. More conclusive evidence for the direct eﬀect of hemodynamic forces on endothelial structure and function derives from in vitro studies with cultured monolayers subjected to various rheological conditions [21]. Importantly, recognition of the modulator eﬀect of the changes of shear stress on cultured cell monolayers and on gene modulation led to further research under more complex ﬂow conditions. Several endothelial targets have been suggested to act as shear stress-responsive elements [21–23], which may be activated by changes in shear stress conditions leading to the various signaling cascades, and resulting in highly coordinated and orchestrated mechanotransduction messages with the ultimate goal of restoring physiological conditions. Despite the systemic nature of the major cardiovascular risk factors, atherosclerosis is a geometric focal disease preferentially aﬀecting the outer edges of vessel bifurcation [24] and is characterized by low and oscillatory shear stress as observed in the early 1970s [25]. Atherosclerotic lesions colocalize with regions of low shear stress throughout the arterial tree, from the carotid artery bifurcation [26,27] to the coronary [28], infrarenal, and femoral artery vasculatures [29]. The rate of atherosclerosis progression in patients with coronary artery disease was found, by serial quantitative coronary angiography, to correlate inversely with shear stress magnitude, even when corrected for other cardiovascular risk factors such as lipoproteins levels [30]. The interaction between rheology and the functional phenotype of endothelium plays a critical role in the atherosclerotic process. The early stage of atherosclerosis is characterized by an increased permeability of the vessel wall to blood-borne cells and proteins (macrophages, lymphocytes, LDL-lipoprotein, etc.). Caro et al. [31] ﬁrst proposed a shear stress–dependent transfer of lipids into the vessel wall. Interestingly,

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cultured endothelial cells exposed to physiological laminar shear stress elongate and align in the direction of blood ﬂow, while those exposed to low shear stress (or cultured in static condition) do not change their shape or orientation, presenting with polygonal shape (Fig. 4). All these alterations may explain changes in endothelial cell permeability for atherogenic lipoprotein particles [24,28,30].

PROGRESSION OF ATHEROSCLEROTIC LESIONS Atherogenesis is a dynamic process initiating at the level of the blood–endothelial surface, leading to inﬁltration of blood-derived products and cells into the subendothelial space, with progress actively involving the intimal–medial interface and the media itself in advanced disease. Based on the pathological and clinical characteristics of atherosclerotic plaques, the American Heart Association Committee on Vascular Lesions [32] has developed a standardized classiﬁcation of distinct plaques simpliﬁed by Fuster (Fig. 5) [33]. The homing of inﬂammatory cells into the subendothelial space, together with increased lipid accumulation and increased connective tissue synthesis, leads to atheroma formation. However, in some instances, a much faster process ensues and thrombosis associated with a ruptured plaque appears to be responsible (see plaque disruption). Ross [7] has recently stated that every step of the molecular and cellular responses leading to atherosclerosis is an inﬂammatory process. For instance, over the past decade, there has

Figure 4 Effect of shear stress on endothelial phenotype and activity. In physiological shear stress conditions (left panel) endothelial cells are elongated and align in the direction of blood flow and their function is mainly characterized by the production of vasodilators as well as substances with antithrombotic, anticoagulant, and antioxidant properties. In low-flow conditions (such as turbulent flow, right panel) cultured endothelial cells show a random pattern and produce substances favoring cell apoptosis and proliferation inflammation, vasoconstriction, thrombosis and atherogenesis. (Reprinted from Ref. 144.)

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Figure 5 Schematic summary of the different stages that characterize the progression of atherosclerotic plaques. (Reprinted from Ref. 145.)

been increasing evidence that this inﬂammatory response may, in part, be elicited by the oxidation of phospholipids contained in LDL, which are responsible for the endothelial expression of adhesion molecules and the induction of endothelial and SMC production of chemoattractants and chemokines [34]. More importantly, Sata et al. [35] recently reported that bone marrow cells, including hematopoietic stem cells, give rise to most of the SMCs that contribute to arterial remodeling observed in the experimental model of postangioplasty restenosis, graft vasculopathy, and atherosclerotic plaque growth. This new ﬁnding provides new and intriguing insights into the pathogenesis and are the basis for the development of new therapeutic strategies for vascular disease, by targeting mobilization, homing, diﬀerentiation, and proliferation of bone marrow–derived vascular progenitor cells [35]. Endothelial dysfunction alters the normal homeostatic properties of the endothelium, thereby initiating inﬂammatory cell activation. Continued inﬂammation results in increased numbers of macrophages and lymphocytes migrating from the blood into the lesion. Activation of these cells leads to release of hydrolytic enzymes, cytokines, chemokines, and growth factors causing overall growth of the plaque and ultimately leading to cellular necrosis in advanced lesions. While the artery initially compensates by dilating (remodeling), at some point it can no longer do so and the lesion protrudes into the lumen compromising the blood ﬂow. Endothelial dysfunction is considered the precursor that initiates the atherosclerotic process and is characterized by the increased expression of adhesion molecules (e.g., selectins, VCAMs, and ICAMs) that participate in ‘‘homing’’ and inﬁltrating monocytes

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[7,11]. The process of leukocyte binding and extravasation is critically dependent on both selection and immunoglobulin adhesion molecules on endothelial cells interacting with integrin receptors on leukocytes. Immunohistochemical analysis of human atherosclerotic coronary lesions shows expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, macrophages, and smooth muscle cells within the plaque (Table 2). The extracellular portion of these molecules can be enzymatically cleaved and detected in serum and is referred to as soluble intercellular adhesion molecules (sICAM). Increased concentration of sICAM-1 was detected in patients with acute coronary syndromes (ACS) [36]. Increased concentrations of sP-selectin were detected after a chest pain episode in patients with unstable angina but not in those with stable angina or control subjects [37]. Concentration of sICAM-1, sVCAM-1, and sP-selectins remain increased throught the ﬁrst 72 h after presentation in unstable angina and non-Q-wave myocardial infarction, whereas the concentration of sE-selectin falls during this time [38]. Evidence indicates prognostic value of adhesion molecules. In fact, adverse outcome has been associated with increased concentration of sVCAM-1 in ACS. These observations conﬁrm the critical pathogenic role of inﬂammation in acute coronary syndrome. The recruitment of monocytes seems to be induced by intimal LDL accumulation and its oxidative modiﬁcations [39]. The monocytes migrate into the subendothelium, where they transform into macrophages (Fig. 3). This diﬀerentiation process includes the up-regulation of various receptors such as CD36 and the scavenger receptor A (SR-A), which are responsible for the internalization of oxidized LDL. The expression of scavenger receptors is regulated by peroxisome proliferator-activated receptor-g, a nuclear transcription factor that controls a variety of cellular functions whose ligands include oxidized fatty acids, and cytokines such as tumor necrosis factor-a and interferon-g. Native LDL is not taken up by macrophages rapidly enough to generate foam cells, and so it was proposed that LDL undergoes ‘‘modiﬁcation’’ in the vessel wall [40]. It has been shown that trapped LDL does undergo ‘‘modiﬁcation,’’ including oxidation, lipolysis, proteolysis, and aggregation, and that such modiﬁcations contribute to inﬂammation and foam-cell formation. Indeed, oxidized LDL is recognized by the scavenger receptor of the macrophages that enable the intracellular accumulation of lipids. Oxidized LDL was demonstrated in vivo to induce endothelial dysfunction and ultimately to alter the barrier function of the endothelium [41,42]. LDL undergoes oxidative modiﬁcation as a result of interaction with reactive oxygen species, including products of 12/15-lipoxygenase [20]. Lipoxygenases insert molecular oxygen into polyenoic fatty acid, which are likely to be transferred across the cell membrane to ‘‘seed’’ the extracellular LDL. High-density

Table 2

Adhesion Molecules Expressed in Atherosclerotic Lesions

Family

Molecule (CD nomenclature)

Selectins

E-selectin (ELAM-1, CD62E) P-selectin (CD62P, PAGEM) L-selectin (CD62L) ICAM-1 (CD54) ICAM-2 ICAM-3 (CD50) VCAM-1 (CD106) PECAM-1 (CD31)

Immunoglobulins

Expressed by Endothelial Endothelial Leukocytes Endothelial Endothelial Leukocytes Endothelial Endothelial

cells cells cells, leukocytes cells, platelets cells, smooth muscle cells cells, platelets, leukocytes

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lipoprotein (HDL) is considered strongly protective against atherosclerosis. Several mechanisms may explain the protective eﬀect of HDL. HDL plays a pivotal role in the removal of excess cholesterol from the peripheral tissue through the reverse cholesterol transport mechanism. HDL may also protect by inhibiting lipoprotein oxidation and improving endothelial dysfuction. Recently, low HDL cholesterol was recognized as an independent risk factor, suggesting the possible need for therapy in patients with low HDL plasma levels [43]. Exogenous administration of recombinant HDL was found to restore endothelial function in patients with hypercholesterolemia and to induce regression of atherosclerotic plaque in cholesterol-fed rabbits [16,17]. Once they are lipid-enriched, macrophages transform into foam cells leading to the formation of fatty streaks (Fig. 6). These activated macrophages release mitogens and chemoattractants that perpetuate the process by recruiting additional macrophages as well as vascular smooth muscle cells from the media into the injured intima (Fig. 3). This process may eventually compromise the vascular lumen. The classic hypothesis of atherosclerosis initiation has been challenged by a recent observation demonstrating in the murine model that the majority of smooth muscle cells present in the subendothelial space of atherosclerotic lesions, as well as in graft vasculopathy and restenosis following arterial injury, derive from undiﬀerentiated bone marrow cells and do not express replication of smooth muscle cells present in the media [35]. This important information could explain why antiproliferative agents did not completely succeed in the eﬀort to control atherosclerotic disease and could led to the development of new therapeutic approaches.

Figure 6 Gross pathology of early atherosclerotic lesions in the abdominal aorta: the fatty streaks.

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The recruited smooth muscle cells and macrophages signiﬁcantly contribute to plaque growth, not only by increasing their number, but also by synthesizing extracellular matrix components. The ratio between smooth muscle cells and macrophages plays an important role in plaque vulnerability because of their lytic activity. Activated macrophages within atheroma are able to elaborate a number of matrix metalloproteinases (MMPs) and elastolytic enzymes, including certain nonmetalloenzymes such as cathepsins S and K (Table 3) [44]. MMPs are an ever-expanding family of endopeptidases with common functional domains and mechanisms of action discovered because of their ability to degrade extracellular matrix components [45]. These enzymes facilitate plaque disruption and thrombus formation by digesting the extracellular matrix [5]. Enzymes of the MMPs family can attack interstitial collagen ﬁbrils, molecules ordinarily exceedingly resistant to proteolytic degradation [46]. Recent work has localized the potent elastases, cathepsins S and K, in macrophages and smooth muscle cells located in complicated human atherosclerotic lesions [47]. Thus, members of several proteinase families may participate in the degradation of structurally important components of the extracellular matrix. All protease families have endogenous inhibitors both tissue inhibitors of the metalloproteinase families (TIMPs) and the endogenous inhibitor of cathepsin S, cystein, have been localized in human atheroma [45]. The balanced production and degradation of extracellular matrix components may determine the changes in vascular wall shape seen in the process of vascular remodeling, plaque growth, and plaque disruption. The rate of progression of atherosclerotic lesions is variable and poorly understood. Atherogenesis and lesion progression may be expected to be linear. However, coronary angiographic studies have demonstrated that progression in humans is neither linear nor predictable. An analysis of various studies unexpectedly revealed that over 75% of acute fatal myocardial infarcts occur in areas supplied by mildly stenosed (<50%) coronary arteries identiﬁed by prior angiogram (Fig. 7) [48]. Nevertheless, on the basis of pathological ﬁndings, plaque development can be divided into slow or rapid progression.

Table 3

Matrix Degrading Proteases

Name Collagenases MMP-1 MMP-8 MMP-13 MMP-18 Gelatinases MMP-2 MMP-9 Stromelysin MMP-3 MMP-7 MMP-10 MMP-11 MMP-12 Cathepsins

Substrate Collagen Collagen Collagen Collagen

I, II, III, VII; gelatins; aggrecan I, II, III; aggrecan; proteoglycan I, II, III I

Gelatins; collagen I, IV, VII, XI; laminin; aggrecan; ﬁbronectin Gelatins; collagen IV, V, XIV; aggrecan; vitronectin; elastin Aggrecan; gelatins; ﬁbronectin; laminin; collagen III, IV, V, X Aggrecan; ﬁbronectin; laminin; gelatins; collagen IV; elastin Aggrecan; ﬁbronectin; laminin; collagen IV ? Elastin Elastin

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Figure 7 Severity of the coronary stenosis detected by angiography prior to the acute myocardial infarction. Most of the lesions were found to be only mildly or moderately stenotic. (Adapted from Ref. 48.)

Slow Plaque Progression As previously discussed, endothelial dysfunction underlies slow progression by facilitating the internalization of circulating lipids and monocytes, ultimately leading to foam-cell formation and release of mitogenic and growth factors (Fig. 3). The continuing inﬁltration of monocytes/macrophages into plaques is partly dependent on factors such as endothelial adhesion molecules (i.e., VCAM-1), monocyte chemotactic protein-1 (MCP-1), monocyte colony-stimulating factor (M-CSF), and interleukin-2 for lymphocytes. Macrophages may eventually undergo apoptotic death in what appears to be a defensive strategy to protect the vessel wall from an excess accumulation of lipoproteins. Although it is still uncertain whether apoptotic death triggers the release of MMPs, this phenomenon likely leads to the shedding of membrane microparticles, causing exposure of phosphatidylserine on the cell surface and conferring a potent procoagulant activity. The shed particles account for almost all of the TF activity present in plaque extract and may be a major contributor in the initiation of the coagulation cascade and thrombosis after plaque disruption [49]. Such phenomena initiate the phase of rapid plaque growth. Rapid Plaque Growth Rapid plaque growth is thrombus-mediated. Evidence suggests that plaque rupture, subsequent thrombosis, and ﬁbrous thrombus organization are also important in the progression of atherosclerosis (Fig. 8) in both asymptomatic patients and those with stable angina. Plaque disruption with subsequent change in plaque geometry and thrombosis results in a complicated lesion. Such a rapid change in atherosclerotic plaque geometry may result in acute occlusion or subocclusion with clinical manifestations of unstable angina or other ACS. More frequently, however, the rapid changes seem to result in a mural thrombus without evident clinical symptoms. This type of thrombus may be a main contributor to the progression of atherosclerosis. A number of local and systemic circulating factors may inﬂuence the degree and duration of thrombus deposition at the time

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Figure 8 Plaque disruption leads to both fibrin and platelet deposition. The growing thrombus may lead to peripheral embolization or stabilize and undergo reorganization leading to plaque growth. (Reprinted from Ref. 143.)

of disruption of the coronary plaque (Table 4) [50]. The thrombus may then either be partially lysed or become replaced in the process of vascular repair response (Fig. 8).

The Role of the Media and Adventitia The role of media and adventitia has been recently highlighted by the discovery of their active involvement in the process of arterial remodeling. Media expansion following internal elastic lamina (IEL) disruption has been associated with outward plaque growth, plaque hemorrhage, plaque instability, and even the development of arterial aneurysm. Silence and colleagues [51] showed, using apolipoprotein E (Apo-E) knock-out mice with or without combined MMP-3 deﬁciency, that in mice lacking both genes atherosclerotic plaques were larger and contained more ﬁbrillar collagen, whereas in Apo-E mice without MMP-3 deﬁciency signiﬁcantly higher incidences of aortic aneurysms associated with IEL disruption were detected. This study conﬁrmed the possible etiological role of atheroma in experimental aneurysm formation and highlighted the involvement of inﬂammatory cells as a source of proteinases, eliciting this complex pathophysiological process within the arterial wall. A further intriguing new concept in the pathogenesis of atherosclerosis derives by experimental observations of adventitial inﬂammation and increased plaque invasion of vasa vasorum [52–54]. Moreno and colleagues [55] recently associated the stage of atherosclerotic plaques with the composition of the media and adventitia and found that disrupted plaques not only correlated with IEL disruption, but also had higher levels of media inﬂammation, ﬁbrosis, and atrophy as well as higher presence of adventitia inﬂammation and vasa vasorum.

228 Table 4

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Local Rheological Conditions Blood ﬂow, shear stress, etc. Nature of the Exposed Substrate Degree of injury (mild vs. severe arterial injury) Composition of atherosclerotic plaque Residual mural thrombus Systemic Thrombogenic Factors Hypercholesterolemia Catecholamines (smoking, cocaine, stress, etc.) Smoking Diabetes Homocysteine Lipoprotein (a) Infections (Chlamydia pneumoniae, Helicobacter pylori, CMV) Hypercoagulable state (z ﬁbrinogen, z vWF, z TF, z Factor VII, z FI.2) Defective ﬁbrinolytic state (z PAI-1, # tPA, #uPA, etc.) Abbreviations: CMV: cytomegalovirus; TF: tissue factor; vWF: von Willebrand factor; F1.2: prothrombin fragment F1+ 2; PAI-1: plasminogen activator inhibitor 1; tPA: tissue plasminogen activator; uPA: urokinase.

The Role of Vasa Vasorum Increased density of vasa vasorum in atherosclerotic coronary artery has been reported in the past in pathology studies. Increased number of vasa vasorum were found in the adventitia and in the plaque itself [56–58]. Proteolytic enzymes such as MMP are crucial for the invasion of the vasa vasorum in the vessel wall, a process mediated through inﬂammatory mechanisms. More recently, using a novel ex vivo imaging technique (high-resolution micro-CT), it was possible to visualize the vasa vasorum structure in a volumetric (3-dimensional) fashion and to assess the eﬀects of several interventions (such as lipid lowering and endothelin inhibition in a hypercholesterolemic pig model of atherosclerosis) on coronary vasa vasorum neovascularization [52,59,60]. Hypercholesterolemia was associated with an increase in the spatial density of coronary vasa vasorum surrounding atherosclerotic lesions in pigs [52,59]. Notably, this neovascularization process occurred very early in the atherosclerotic process and before epicardial endothelial dysfunction [60]. Coronary vasa vasorum neovascularization was prevented by treatment with simvastatin [61] or selective endothelin-A receptor antagonists [62].

PLAQUE DISRUPTION Serial angiographic studies have indicated that mild or moderately stenotic plaques (<50%) are most frequently the cause of acute ischematic events (Fig. 7) [63–66]. Postmortem analysis of patients who died of acute ischematic events concluded that the culprit atherosclerotic lesions shared some common characteristics. [48,67–69]. These high risk ‘‘vulnerable lesions’’ (more prone to disruption) are histologically characterized by the presence of an eccentric plaque, containing a soft lipid-rich core that is separated from the

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arterial lumen by a thin cap of ﬁbrous tissue (Fig. 9). The ﬁbrous cap is generally highly inﬁltrated by macrophages and T-cells [70]. The presence of activated macrophages and Tcells around the disrupted areas of the vulnerable plaques led to the hypothesis of an important inﬂammatory component on plaque disruption [5]. Angiographically, fairly small coronary lesions maybe associated with acute progression to severe stenosis or total occlusion and may eventually account for as many as two-thirds of the patients who develop unstable angina or other ACS (Fig. 7) [48]. The degree of plaque disruption (ulceration, ﬁssure, or erosion) or substrate exposure is a key factor for determining thrombogenicity at the local arterial site. In fact, throbogenicity of a disrupted human atherosclerotic plaque can be predicted by its content on TF activity. In an experimental setting in which disrupted human aortic plaques were exposed to ﬂowing blood at high shear rates, the lipid core was found to be the most thrombogenic of the various plaque components. The lipid core also showed the most intense TF staining

Figure 9 Morphological characteristics of stable plaque (A), vulnerable plaque (B), eroded plaque (C) and disrupted plaque (D). Stable plaques are characterized by high content in collagen and smooth muscle cells, thick fibrous cap, and lower content in lipid and inflammatory cells, in this case, a severely stenotic coronary lesion. Vulnerable plaques, which account for 60 to 70% of acute coronary thrombosis leading to MI and sudden death, are typically only mildly tenotic, have a large lipid core, and thin fibrous cap that is highly infiltrated from inflammatory cells (in particular, at the shoulder). In about 30% of the sudden cardiac death, an erosion of the plaque surface is responsible for the thrombotic complication. Plaque disruption is the most frequent cause of coronary thrombosis and mostly happens in vulnerable plaques. (Courtesy of Dr. Renu Virmani, MD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C.)

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compared with other components [33,71]. Residual mural thrombus also appears to be highly thrombogenic [72]. The unpredictable and episodic progression is most probably caused by disruption of lipid-rich high-risk ‘‘vulnerable’’ (AHA type IV and type V) lesions with a subsequent change in plaque geometry and thrombosis results in complicated lesions. Such a rapid change in the geometry of athrosclerotic plaques may result in acute occlusion or rapid plaque growth and consequently to subocclusion and leads to acute or intermittent silent plaque growth or acute symptomatic, occlusive coronary syndromes (Fig. 10) with clinical manifestations of unstable angina or other acute coronary syndromes. More frequently, however, the rapid changes seem to result in mural thrombus without evident clinical symptoms, which, by self-organization, may be a main contributor to the progression of atherosclerosis. Plaque disruption seems to depend on both passive and active phenomena. Passive Process: Physical and Structural Variables Related to physical forces, passive plaque disruption occurs most frequently where the ﬁbrous cap is weakest, that is, where it is thinnest and most heavily inﬁltrated by foam cells. For eccentric plaques, this is often the shoulder or between the plaque and the adjacent vessel wall [73]. Speciﬁcally, pathoanatomical examination of intact and disrupted plaques and in vitro mechanical testing of isolated ﬁbrous caps from aorta indicated that their vulnerability depends on several factors [48,69,74]. (1) circumferential wall stress or cap ‘‘fatigue’’; (2) location, size, and consistency of the atheromatous core; and (3) blood-

Figure 10 Gross anatomy and cross-section pathology of acute coronary thrombosis that caused the patient’s death. White arrow indicates lipid-rich plaque, black arrow indicates thrombus.

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ﬂow characteristics particularly the impact of ﬂow on the proximal aspect of the plaque (i.e., conﬁguration and angulation of the plaque) [33]. Active Process: MMPs and TF The process of plaque disruption is, however, not purely mechanical. Inﬂammation, for instance, plays a pivotal role in plaque disruption. Atherectomy specimens from patients with ACS reveal areas very rich in macrophages [75], and these cells are capable of degrading extracellular matrix by secretion of proteolytic enzymes (Table 3), such as MMPs (collagenases, gelatinases, stromelysins, and others). These enzymes may weaken the ﬁbrous cap and predispose it to rupture [5]. Indeed, the MMPs and their co-secreted tissue inhibitors of metalloproteinases (TIMP), TIMP-1 and TIMP-2, are critical for vascular remodeling. Certain MMPs may be particularly active in destabilizing plaques [76]. More intriguing is the recent observation showing that in a patient who died from ACS the internal elastic lamina is often disrupted and the adjacent media is frequently atrophic and occasionally destroyed (Fig. 11) [55]. In addition, recent studies have highlighted the important role of the media and adventitia in atherogenesis, in particular in the process of remodeling. Likewise, the ﬁbrous cap may be eroded from below, resulting in thinning and further weakening, both important predictors of plaque vulner-

Figure 11 High-power histological detail of a disrupted class VI human atherosclerotic plaque showing the interface area with rupture of the internal elastic lamina (arrow). Disrupted atherosclerotic plaques, which are characterized by eccentric expansion, have larger plaque areas and higher incidence of disruption of the internal elastic lamina, suggesting an active role of the internal elastic lamina in the pathophysiology of vascular remodeling in complex atherosclerotic lesions. (Courtesy of Dr. Pedro R. Moreno, MD, Veterans Administration Medical Center, Lexington, KY.)

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ability [46]. Recent evidence seems to suggest that metalloproteinase inhibition may be a novel strategy to induce regression of cardiovascular diseases by interfering with interactions of smooth muscle cells and extracellular matrix survival, facilitating apoptosis and matrix resumption [77]. The plaque’s smooth muscle cell population also inﬂuences the level of extracellular matrix. Sites of fatal thrombosis where plaques fail mechanically and rupture typically have few smooth muscle cells [73,78]. Apoptotic death of these cells, a critical source of extracellular matrix in the artery wall, can occur in atherosclerotic lesions [79]. Inﬂammatory stimuli such as cytokines can trigger the complex mechanisms of apoptosis [19,80].

THROMBUS FORMATION Insights into the disease have advanced beyond the notion of progressive occlusion of the coronary artery into the recognition that plaque disruption and superimposed thrombus formation are the leading cause of acute coronary syndromes and cardiovascular death [81]. Acute thrombus formation on a disrupted atherosclerotic plaque seems fundamental in the onset of acute ischemic events as shown in pathological studies of patients who died suddenly after a coronary event. Plaque composition rather than luminal stenosis has consequently been recognized as the major determinant of this disease. The fact that plaque disruption was important clinically was demonstrated by tracing thrombi causing myocardial infarction (reconstructed from serial sections of coronary arteries) to cracks or ﬁssures within a plaque. Further work has subsequently conﬁrmed that plaque rupture underlies the majority of thrombi responsible for acute coronary syndromes [74,82]. A meta-analysis of pathological studies indicated than in patients dying from a cardiovascular cause, approximately 70% showed that the disrupted lesions were in areas supplied by mildly stenosed (<50%) coronary arteries [48]. Histologically these rupture-prone (also called vulnerable) lesions consist of a large core of extracellular lipid, a high density of macrophages containing lipid, reduced numbers of SMCs, a thin cap, and a toothpastelike consistency at room temperature, but softer at body temperature. It is therefore not surprisingly that these soft plaques are less stable and have a higher propensity to rupture than the ﬁbrotic plaques. Plaque disruption occurs frequently at the weakest point, usually where the ﬁbrous cap is thinnest and most heavily inﬁltrated with foam cells. The activated macrophages abundant in atheroma can produce and secrete very potent proteolytic enzymes capable of degrading collagen such as matrix metalloproteinases, which may further destabilize the plaque. Thus, plaque disruption appears to be, at least in part, a late complication of an insidious process of chronic inﬂammation. Upon disruption (Fig. 5), the atheromatous gruel, abundant in macrophages and TF, is the most thrombogenic component of an atherosclerotic plaque [33,71]. TF is a cell surface low-molecular-weight glycoprotein that is expressed by endothelial cells, monocytes, and smooth muscle cells in response to a variety of stimuli including oxidized-LDL. TF is a major regulator of coagulation, hemostasis, and thrombosis [2]. TF, the most potent trigger of the coagulation cascade, forms a high-aﬃnity complex with coagulation factors VII/VIIa leading to activation of factors IX and X, and therefore triggering both the intrinsic and extrinsic blood coagulation cascade [83–85]. Activation of the clotting cascade by TF results in the generation of thrombin, platelet activation, and ﬁbrin deposition. The importance of TF in thrombosis has been signiﬁcantly enhanced by the recent report on a blood-borne pool of TF [86]. Because of the key position of tissue factor

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as the major initiator of the coagulation pathway and thrombosis, speciﬁc inhibitors of the tissue factor pathway with theoretical advantage over therapies that target more ‘‘downstream’’ components of coagulation cascade has been recently proposed, and they are being actively investigated at the clinical level [87]. Recently apoptotic phenomena have been linked to atherothrombosis and to the production of TF [49]. Early during development of the ﬁbrous cap, SMCs are present in signiﬁcantly numbers, but as the lesion progresses, there is a steady decline in numbers. SMCs could vanish as a result of programmed cell death or apoptosis [88], signiﬁcantly reducing ﬁbrous cap stiﬀness. More recently, apoptosis of plaque macrophages has been shown to colocalize with TF expression, suggesting a potential pathogenic mechanism leading to increased plaque thrombogenicity [89]. Apoptotic death of macrophages within lesions leads to shed membrane microparticles causing exposure of phosphatidylserine on the cell surface and conferring a potent procoagulant activity. The shed particles account for almost all the TF activity present in plaque extract and may be a major contributor in initiation of the coagulation cascade following plaque disruption [49]. Thrombosis on Nondisrupted Plaques In one-third of the acute coronary syndromes, particularly in acute sudden coronary death, there is no disruption of a lipid-rich high-risk (vulnerable) plaque, but only a superﬁcial erosion of a markedly stenotic and ﬁbrotic plaque [74]. Thrombosis due to disruption is usually seen in plaques with lower degrees of initial stenosis, which may not be visible by coronary angiography. Thrombosis due to endothelial erosion is usually seen at sites of preexisting high-grade stenosis and has been reported to be more common in women and at a younger age and in men with some prothrombotic risk factors (smoking, diabetes, hypercholesterolemia) [90]. Thus, thrombus formation in these cases, where plaque disruption is absent, may depend on a hyperthrombogenic state triggered by systemic factors. Indeed, systemic factors, including elevated LDL, cigarette smoking, hyperglycemia, hemostasis, and others are associated with increased blood thrombogenicity. Diabetes mellitus, for instance, is associated with platelet hyperaggregability, increased PAI-I, ﬁbrinogen and von Willebrand’s factor, and decreased antithrombin III activity [91]. In addition, improvement in glycemic control is associated with a reduction in blood thrombogenicity [92]. Signiﬁcant evidence exists to link hyperlipidemia with a hypercoagulable and prothrombotic state [93,94]. This association has been substantiated by the normalization of this hypercoagulability with treatment of the hypercholesterolemic state [94]. Recently, the cardiovascular risk factors have been associated with increased blood TF activity in humans [95]. These ﬁndings suggest that high levels of circulating TF may be the mechanism of action responsible for the increased thrombotic complications associated with the presence of these cardiovascular risk factors. These observations strongly emphasize the usefulness of the management of the patients based on their global risk assessment [96]. Tissue Factor: A Strong Link Between Inflammation and Thrombosis The close association between inﬂammation and thrombosis emanates from several clinical scenarios like endotoxemia, cancer, and pancreatitis, where disseminated intravascular coagulation (DIC) is a key clinical feature. The interplay between inﬂammation and thrombosis in atherosclerosis occurs through diﬀerent pathways involving (many but most importantly) tissue factor, apoptosis, and leukocyte-platelet interaction [3]. The CD-15/P-

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selectin receptor mediates the transfer of TF from leukocytes to platelets leading to thrombus propagation [97]. Tissue factor is a small glycoprotein (45 kDa) that initiates the extrinsic coagulation cascade, leading to activation of the prothrombinase complex and thrombin generation. It is present in the adventitia of normal vessels, but has higher expression in atherosclerotic vessels. TF in the atheromatous core is responsible for the high thrombogenicity of disrupted lipid-rich plaque [71,98]. Thus macrophages appear to play a pivotal role in inducing instability (inﬂammatory-plaque rupture) and thrombosis. Therefore, plaque rupture will facilitate the interaction between the vascular TF and the blood components. The putative role of TF has been recently enhanced by the report of a blood-borne pool of activable TF [99]. This circulating TF could have an important role in perpetuating the thrombotic process. Furthermore, common triggers of the vascular thrombotic and inﬂammatory pathways exist. For instance, smoking, increased TF immunoreactivity, macrophage inﬁltration, and VCAM in aortic plaques [100]. Common signaling pathways for both inﬂammation and thrombosis in the vessel wall exist as well. The CD40–CD40 ligand signaling system, for example, induces in vitro human monocytes expression of MMP and TF, responsible respectively for the inﬂammatory disruption and thrombotic complication of the vulnerable plaque. Another example are PPARs, which are part of transcription factor complexes regulating expression of genes implicated in atherogenesis and plaque instability. PPAR-aagonists decrease cytokineinduced endothelial VCAM-1 up-regulation and TF expression [101]. Finally, common inhibitors of both pathways exist. For example, TFPI-2, an inhibitor of TF, exerts anti-inﬂammatory eﬀects by decreasing MMP activity [102]. Likewise, the pleiotropic eﬀects of statins extend beyond their anti-inﬂammatory eﬀects (plaque stabilization by inhibiting MMP expression, decreasing proinﬂammatory adhesion molecules and neovascularization, decreasing serum CRP levels) to include antithrombotic properties (decreasing PAI-1 expression in vascular wall cells, decreasing TF expression) [94,103]. Apoptosis: A Further Link Between Inflammation and Thrombosis? Apoptosis, or programmed cell death, is a dynamic phenomenon occurring in atherosclerotic plaques, especially in regions with high inﬂammatory burden involving all cell types, predominantly macrophages [49]. Coronary atherectomy specimens from patients with unstable angina showed more cellular apoptosis than those from stable angina [79,104]. Studying human carotid endarterectomy specimens, Hutter et al. also found higher TF expression in apoptotic macrophages and postulated its central role to the vulnerable plaque thrombogenicity [89]. Hutter’s ﬁndings were corroborated by Mallat; they found a close colocalization between TF and apoptotic cells with PS-containing apoptotic microparticles. These membrane-shed apoptotic microparticles were detected in extracts from atherosclerotic plaques, were mainly of monocytic and lymphocytic origin, and accounted for most of plaque TF activity [105]. Elevated levels of circulating TF-containing microparticles were found in patients with acute coronary syndromes compared to those with stable angina, and may contribute to blood thrombogenicity in acute coronary syndromes [49]. Triggers of apoptosis are for the most part the same proinﬂammatory risk factors for atherosclerosis, and most apoptotic microparticles are believed to arise from inﬂammatory cells. Moreover, unlike what is commonly believed, apoptotic cells can perpetuate further inﬂammation in the plaque through Fas-mediated activation of proinﬂammatory genes,

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by immunogenic properties, and by occasional secondary necrosis of the apoptotic cells [49]. Thus apoptosis may be an important link between inﬂammation (triggering and perpetuated by inﬂammatory cell apoptosis) and thrombosis (TF-shed microparticles). The Vicious Cycle Between Inflammation and Thrombosis While inﬂammation of the vessel wall and blood induces a prothrombotic state, thrombosis further perpetuates inﬂammation, creating a vicious cycle in atherosclerosis. Vascular SMC, when stimulated by thrombus-released PDGF and thrombin, produces IL-6 that induces systemic inﬂammation and increases blood thrombogenicity by increased PAI-1 and ﬁbrinogen blood levels. Likewise, platelet-generated thrombin stimulates macrophage production of IL-1 that induces ICAM-1 expression [106]. Therefore, inﬂammation can facilitate and perpetuate the onset of thrombotic events.

SYSTEMIC INFLAMMATORY MARKERS The search for systemic indicators to serve as predictors of clinical events led to the emergence of several markers, among which are hs-CRP (high-sensitivity C-reactive protein) and neopterin. hs-CRP is an inﬂammatory marker with independent and incremental clinical predictive value when added to the more ‘‘classic’’ cardiovascular risk factors. Several studies have indicated the value of hs-CRP levels as a strong predictor of cardiovascular events and peripheral arterial disease in healthy men and women and in other populations including smokers, elderly, and postmenopausal women [107–109]. hsCRP oﬀers further advantages also: its variability is similar to that of total cholesterol, it is stable over long periods of time, and has no circadian variation (like IL-6). Some of its drawbacks, however, include its elevation in chronic inﬂammatory conditions, its nonspeciﬁcity, the fact that testing should be avoided within 2 to 3 weeks from an acute illness, and the unproven utility of testing across diﬀerent ethnic groups. Moreover, despite consistency of data in primary prevention, testing in postinfarction patients should be interpreted cautiously [110]. hs-CRP may also help tailor therapy, as stronger beneﬁts from aspirin and statin therapies were seen with higher hs-CRP levels [107,111]. It also helps target therapy among individuals without overt hyperlipidemia but high hs-CRP levels [107]. Although no data exist to suggest that reduction of hs-CRP will reduce CV events, a report from the CARE study showing a 40% LDL-independent decrease in mean hs-CRP after pravastatin therapy [111] generated ample interest, given the emerging data that CRP might be actively implicated in atherogenesis. Recent data showed that CRP and complement proteins (which they activate) are produced by macrophages and SMC in atherosclerotic plaques [112]. CRP ampliﬁes inﬂammation and may directly perpetuate atherosclerosis by stimulating monocyte release of cytokines up-regulating adhesion molecules in endothelial cells [113], chemotactically recruiting monocytes to the atherosclerotic intima [114], and mediating macrophage scavenging of CRP-opsonized native LDL (in vitro) [115].

CLINICAL CONSEQUENCES OF CORONARY PLAQUE EVOLUTION Atherosclerotic lesions in the coronary tree may cause stable syndromes of ischemia by means of direct luminal narrowing (stable lesions) or unstable ischemic syndromes by

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inducing acute intraluminal thrombus formation (unstable lesions). Clinical consequences of coronary lesions depend on many factors such as the degree and acuteness of blood ﬂow obstruction, the duration of decreased perfusion, and the relative myocardial oxygen demand at the time of blood ﬂow obstruction. In patients with chronic coronary artery disease, angina commonly results from increases in myocardial oxygen demand that outstrips the ability of stenosed coronary arteries to increased oxygen delivery. In contrast, acute coronary syndromes are usually characterized by an abrupt reduction in coronary blood ﬂow due to atherosclerotic plaque rupture whereby thrombogenic material is exposed to blood ﬂow and thrombosis develops. Overall, the term ‘‘nonsigniﬁcant,’’ when applied to atherosclerotic lesions with less than 50% luminal stenosis at coronary angiography, may often be misleading and should be revised. It is not quite evident that a ﬁssure may develop in an atherosclerotic plaque that occupies less than 50% of the diameter of the coronary artery, and such plaques may become nidus for thrombosis. Overall, angiography may underestimate the extent and severity of atherosclerotic involvement of coronary arteries and it does not necessarily indicate the site at which coronary occlusion will occur. However, angiography is helpful as a determinant of the severity of coronary disease, and the number of diseased vessels are known markers of cardiac morbidity and mortality [116,117]. The more severe the coronary disease at angiography, the higher the likelihood of the presence of small plaques prone to disruption. The Coronary Artery Surgery Study (CASS) used angiography to evaluate nearly 3000 nonbypassed coronary segments in approximately 300 patients, with follow-up over a period of 42 to 66 months [118]. It showed that although an individual severe stenosis becomes occluded more frequently than a less severe stenosis, less obstructive plaques (<80% stenotic at baseline) give rise to more occlusions than severely obstructive plaques because of their greater number [118]. In the CASS registry, the subsequent coronary occlusion rate was 2% for diameter stenosis of 5% to 49% and 24% for stenosis of 81% to 95%; because nonobstructive lesions are common and obstructive lesions are rare, the ratio of occlusion at sites with <50% stenosis was 7.4 to 1 (2591 vs. 347) [119]. Ambrose et al. and Little et al. ﬁrst demonstrated that, in approximately half the cases of MI studied, the lesions leading to occlusion were less than 50% stenotie [65,66]. Consequently, most myocardial infarctions evolve from mild-to-moderate stenosis. Therefore, the risk of an acute event such as unstable angina or acute myocardial infarction to a patient with coronary artery disease ultimately depends on how many vulnerable plaques are present. Interestingly, although one single lesion is clinically active at the time of ACS, the syndrome seems nevertheless associated with overall coronary instability. In fact, in a three-vessel intravascular ultrasound study in patients with ACS, at least one plaque rupture was found somewhere other than on the culprit lesion in most of the patients (79%) [120]. These lesions were in a diﬀerent artery than the culprit artery in 70.8% and were in both of the other arteries in 12.5% of these patients. Complete intravascular ultrasound. (IVUS) examination of all three coronary axes in patients who had experienced a ﬁrst ACS revealed that multiple atherosclerotic plaque ruptures were detected by IVUS; these multiple ruptures were present simultaneously with the culprit lesion; they were frequent and located (in three-quarters of cases) on the three principal coronary trunks; and the multiple plaque ruptures in locations other than on the culprit lesion were less severe, nonstenosing, and less calciﬁed [120]. Similarly, an angioscopic study demonstrated the frequent presence of ‘‘vulnerable, yellow’’ coronary plaques distant from the culprit lesion in patients with ACS [121], and

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thermal heterogeneity within human atherosclerotic coronary arteries has been documented with the use of special thermography catheters [122]. Areas with higher temperatures are thought to be associated with plaque instability. In subsequent studies, temperature heterogeneity has been found to be larger in patients presenting with ACS [123]. These clinical ﬁndings support our present understanding of the pathophysiology of coronary artery disease. Rather than a simple mechanical problem, the development of coronary lesions is a complex biological process. The transition to an unstable atheroma is characterized by the accumulation of a large necrotic core, containing extracellular lipids, macrophages, and often microcalciﬁcations. These unstable, vulnerable sites are frequently not highly stenotic before rupture because the accumulating plaque is accommodated by positive remodeling, alleviating the reduction of luminal size [124,125]. Both positive remodeling [126] and eventual plaque rupture [48] are related to an inﬂammatory response, supporting the role of systemic inﬂammation in patients with a high propensity for acute coronary events. The diagnosis of vulnerable lesions before rupture would have tremendous potential for event prevention. Several approaches are presently being explored: invasive and noninvasive imaging modalities could allow the assessment of individual plaques and overall plaque burden. The tagging of markers speciﬁc to activated, vulnerable plaques could further enhance imaging techniques. Other diagnostic approaches could assess the biochemical activity by either measuring the local temperature heterogeneity or biochemical markers, as exempliﬁed by C-reactive protein. These present approaches have tremendously advanced our understanding of plaque vulnerability and rupture, but several questions remain unsolved: 1. 2. 3.

Will it be more important to identify individual vulnerable lesions or the number of vulnerable lesions at any one time? Is a plaque that has recently ruptured as dangerous as a plaque before rupture? when does a ruptured plaque lose its potential to form a superimposed thrombus?

An optimal diagnostic test would be noninvasive, safe, and easily repeatble. It would not only identify vulnerable and ruptured lesions but also diﬀerentiate plaques that are more likely to cause ACS. Such a test does not yet exist.

VISUALIZATION OF ATHEROSCLEROTIC PLAQUES IN VIVO In vivo, high-resolution, multicontrast, magnetic resonance imaging (MRI) is the most promising method of noninvasively imaging vulnerable plaques and determining diﬀerent plaque components in all arteries, including the coronary arteries [127]. By using various imaging modalities, MRI allows the discrimination of lipid core, ﬁbrosis, calciﬁcation, and thrombus deposits [128]. MRI ﬁndings have been extensively validated against pathology in ex vivo studies of carotid, aortic, and coronary artery specimens obtained at autopsy [129]. In vivo, MRI of carotid arteries of patients referred for endarterectomy has shown a high correlation with pathology and with previous ex vivo results [130]. A recent study in patients with plaques in the thoracic aorta showed that, compared with transesophageal echocardiography, plaque composition and size are more accurately characterized and measured using in vivo MRI [127].

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MRI to Study the Progression of Cardiovascular Disease Carotid and aortic atherosclerotic assessment by MRI may lend itself to use as a screening tool for prediction of future cardiovascular events and for the evaluation of therapeutic intervention beneﬁts. MRI techniques have been adapted for the study of plaque progression, regression, and stabilization in transgenic and nontransgenic animal models [131,132]. Preliminary studies in a porcine model have shown that the major diﬃculties in using MRI to study coronary walls are the combination of cardiac and respiratory motion artifacts, the nonlinear course of the coronary arteries, and their relatively small size and location [133]. For the ﬁrst time, a recent study demonstrated that in vivo MRI can provide highresolution images of the coronary artery wall in normal and diseased human arteries [134]. A black-blood MRI method was used, with velocity-selective inversion preparatory pulses to eliminate the signal from ﬂowing blood, to assess the vessel lumen and wall morphology of eight normal subjects and ﬁve patients with coronary artery disease (Fig. 12) [134]. This technique has shown that an artery with a normal angiogram can, in fact, have extensive plaque formation (Fig. 13). It has also illustrated that plaques, particularly in carotid arteries, are much more diﬀuse than was previously thought. This has changed the concept of what a ‘‘vulnerable’’ plaque is: the fat in a plaque is not focal, it is the clot that is focal, and it is the clot that is responsible for plaque rupture. It is, therefore, very diﬃcult to characterize a plaque as ‘‘vulnerable’’ before it has ruptured. MRI to Detect the Effect of Statin Therapy MRI has recently been utilized to study the eﬀect of lipid-lowering statin therapy in asymptomatic, untreated hypercholesterolemic patients with carotid and aortic athero-

Figure 12 Black-blood coronary plaque MRI. Significant atherosclerosis despite normal or ecstatic coronary arteries have been recently documented in vivo using noninvasive black-blood MR imaging. MR cross-sectional images of coronary arteries demonstrate a plaque presumably with fat deposition (arrow, A) and a concentric fibrotic lesion (B) in the left anterior descending artery as well as an ecstatic, but atherosclerotic, right coronary artery (C). RV indicates right ventricle, LV indicates left ventricle. (Modified from Ref. 134.)

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Figure 13 AHA Type Va (fibroatheroma) aortic plaque. Aortic in vivo MR image from a patient with a 4.5-mm-thick plaque in descending thoracic aorta (A) and corresponding TEE image (B). MR image shows an example of a plaque with a dark area in the center (arrow) identified on the T2W image as a lipid-rich core (A). Lipid-rich core is separated from lumen by a fibrous cap.

sclerosis [135]. Serial black-blood MRI of the aorta and carotid arteries of 18 patients was performed at baseline, and 6 and 12 months after lipid-lowering therapy with simvastatin. A total of 35 aortic and 25 carotid artery plaques were detected. The eﬀect of simvastatin on the atherosclerotic plaques was measured in terms of changes in lumen area, vessel wall thickness, and vessel wall area (a surrogate marker of atherosclerotic burden). At 6 weeks, simvastatin had signiﬁcantly reduced total cholesterol and low-density lipoprotein cholesterol levels, and these reductions were maintained thereafter. At 6 months, treatment with simvastatin resulted in no changes in lumen area, vessel wall thickness, or vessel wall area, but at 12 months, there was signiﬁcant reduction in vessel wall thickness and vessel wall area, without any changes in lumen area (Figs. 14 and 15) [135]. This indicates that eﬀective lipid-lowering therapy is associated with a signiﬁcant regression of atherosclerotic lesions, and suggests that statins induce vascular remodeling, reducing atherosclerotic burden without changing the lumen [136]. It appears that statins induce the growth of connective tissue, particularly in the adventitia, which replaces the fat that they remove. During this study, two blinded independent readers took measurements from ﬁve aortic and four carotid artery plaques in order to determine the sensitivity and speciﬁcity of the technique. A 2.6% error was associated with measurements of the aortic plaques, and a 3.5% error with the carotid artery plaques. This technique can, therefore, be conﬁdently used to detect a change in a plaque of approximately 5% in the aorta or carotid arteries [135]. Since the early 1990s, MR coronary angiography has been emerging as a noninvasive tool for coronary artery imaging. However, serious diﬃculties resulting from the small size of the coronary artery, cardiac and respiratory motion, the highly tortuous course of the vessels, and the limited spatial resolution of the actual available MR systems restrict its clinical application. The sensitivity and speciﬁcity at present are not high enough for reliable clinical application. We recently reported the possibility of characterizing the plaque composition in coronary artery disease using high-resolution MR black-blood technique

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Figure 14 Carotid atherosclerotic plaque evaluated by MR. Effect of statin therapy. Statin treatment induced significant decrease of the plaque size (as indicated by the reduction in vessel wall area) without affecting the lumen. Despite significant reduction of lipid plasma levels within 4 to 6 weeks, a minimum of 12 months was needed to observe changes in the vessel wall. (Modified from Refs. 135, 147.)

in the atherosclerotic porcine model and in human [133,134]. The coronary MR plaque imaging was performed during breath-hold in order to minimize respiratory motion. To alleviate the need for breath holding, a real-time navigator for respiratory gating and realtime slice-position correction has recently been proposed [136]. The study of the atherosclerotic plaques is, however, mainly performed using cross-sectional imaging of the vessel. This spatial representation allows accurate comparison of the same segment at diﬀerent time points (using anatomical references), but is time consuming and therefore not yet applicable to screening the entire coronary tree. The ongoing technical improvement in

Figure 15 Aortic atherosclerotic plaque evaluated by MR. Effect of statin therapy. Aortic plaques, similarly to the carotid arteries, showed a significant reduction in size at 12 months. More importantly, the changes in signal intensity within the plaque may indicate changes in plaque composition. The significant reduction in lesion size without affecting the lumen seems to be mediated by reduction in the plaques, lipid content and thus indicative of structural changes favoring their stabilization. (Modified from Refs. 135, 147.)

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both hardware and software will provide faster image acquisition and improvement in image resolution, both needed for the clinical application of this technique.

The Use of Molecular Enhancer with MRI Tissue factor is secreted by macrophages in plaques at high risk of rupture [137–139]. When rupture occurs, this is released into the bloodstream and results in blood clot formation. Taking advantage of the molecular processes involved in atherothrombosis and of the rapidly evolving technology, new molecular imaging modalities have been developed and are presently under investigation by several research groups. It has recently been shown that it is possible to target molecules with antibodies coupled to a contrast molecule, which can be detected with MRI. Novel ﬁbrin-speciﬁc MR contrast agents, obtained from phage display screening, coupled to several gadolinium chelates have been used for the detection of blood clots in vivo [140]. Emerging molecular imaging technologies, such as these ﬁbrintarget agents, may provide early direct diagnosis of impending stroke or infarction in patients presenting with heralding symptoms and support early therapeutic intervention. Targets of great interest for molecular imaging technology that may potentially increase our knowledge in the atherothrombotic process are the platelet membrane glycoprotein IIb/IIIa (the central molecule in platelet adhesion and aggregation) and tissue factor. They play a pivotal role in the initiation of the thrombus formation, in particular in the platelet activation and adhesion, and in the triggering of the coagulation cascade. All these molecular enhancers can potentially boost the ability of noninvasive MR imaging to detect high-risk vulnerable plaque and enhance patients’ risk stratiﬁcation.

MRI and Arterial Thrombus Aging Patients with unstable angina who suﬀer an event frequently suﬀer a second event within the following 6 weeks, because thrombus that caused the original event has not yet been organized into connective tissue and is still active, allowing the propagation of the thrombus and formation of a secondary clot. Since MRI is able to discriminate and characterize the plaque components on the basis of biophysical and biochemical parameter, we used MRI to visualize and characterize arterial thrombi in vivo [141]. Recently, in a porcine model of obstructive carotid thrombosis, we showed that MRI is a reliable tool to noninvasively detect thrombotic material in the arterial circulation and that the characteristic visual appearance of the thrombus signal intensity allows accurately deﬁnition of thrombus age [142]. Therefore, MRI not only provides a method of noninavasively visualizing plaque and discriminating its components, but also a means of accurately assessing the eﬀects of treatments, such as lipid-lowering therapy, and of timing the activity of clots and determining when they become inactive.

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10 Diagnosis of Coronary Artery Disease in the Elderly Wilbert S. Aronow Westchester Medical Center/New York Medical College, Valhalla, and Mount Sinai School of Medicine, New York, New York, U.S.A.

Jerome L. Fleg National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

Coronary atherosclerosis is very common in the elderly population, with autopsy studies demonstrating a prevalence of at least 70% in persons over age 70 [1,2]. These autopsy ﬁndings may be coincidental, with the disease clinically silent throughout the person’s life; however, 20 to 30% of persons over age 65 show clinical manifestations of coronary heart disease (CHD). In some elderly persons, CHD will manifest itself much earlier in life, but in others, the disease is entirely silent until the person’s seventh or eighth decade. Clinical CHD was present in 502 of 1160 men (43%) of mean age 80 years, and in 1019 of 2464 women (41%), of mean age 81 years [3]. Unfortunately, even though CHD is so prevalent in elderly persons, the disease is often undiagnosed or misdiagnosed in this age group. Failure to correctly diagnose the disease in the elderly may be due to a diﬀerence in clinical manifestations in this age group compared to that of younger patients. Such diﬀerences may reﬂect a diﬀerence in the disease process between older and younger patients, or it may be related to the superimposition of normal aging changes with the presence of concomitant diseases that may mask the usual clinical manifestations.

MYOCARDIAL ISCHEMIA Exertional angina pectoris caused by myocardial ischemia is commonly the ﬁrst manifestation of CHD in young and middle-aged persons. It is usually easily recognized due to its typical features; however, in the olderly, this may not be the case. Due to limited physical activity, many elderly persons with CHD will not experience exertional angina pectoris. Even when angina pectoris does occur, the patient and physician may often attribute it to cause other than CHD. For example, myocardial ischemia, appearing as shoulder or back pain, may be misdiagnosed as degenerative joint disease or, if the pain is located in the 251

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epigastric area, it may be ascribed to peptic ulcer disease. Nocturnal or postprandial epigastric discomfort that is burning in quality is often attributed to hiatus hernia or esophageal reﬂux instead of CHD. Furthermore, the presence of comorbid conditions, so frequent in the elderly patient, adds to the confusion and may lead to misdiagnosis of the patient’s symptoms, which are actually due to myocardial ischemia. Instead of typical angina pectoris, myocardial ischemia in elderly patients is commonly manifested as dyspnea, which is referred to as an ‘‘angina equivalent.’’ Usually the dyspnea is exertional and is thought to be related to a transient rise in left ventricular (LV) end-diastolic pressure caused by ischemia superimposed on reduced ventricular compliance. Reduction in LV compliance may reﬂect normal aging changes or, more likely, is caused by the presence of coexisting hypertension and LV hypertrophy, disorders commonly present in elderly patients. Not infrequently, the dyspnea will occur in combination with angina pectoris, although the angina may be mild and of little concern to the patient. In other elderly individuals, myocardial ischemia is manifested clinically as frank heart failure, with some patients presenting with acute pulmonary edema. Chest pain may not be present, although the myocardial ischemia is severe enough to produce a combination of diastolic and systolic LV dysfunction. Siegel and associates [4] reported on a group of elderly patients, mean age 69 years, with CHD in whom the disease manifested as acute pulmonary edema. The majority of patients were without angina pectoris, and many were without a prior history of CHD. Ninety percent, however, had a past history of hypertension, and their electrocardiogram showed LV hypertrophy. Angiographically, the majority of patients had three-vessel CHD, although LV systolic function was only moderately depressed, with a mean LV ejection fraction of 43%. Over 60% of these patients underwent coronary bypass surgery or percutaneous transluminal angioplasty, and the long-term prognosis was excellent. Similar ﬁndings have been reported in other studies of acute pulmonary edema caused by CHD [5–9]. Graham and Vetrovec [9] compared patients with CHD hospitalized with acute pulmonary edema to patients hospitalized with angina pectoris without heart failure. The patients with acute pulmonary edema were older and, as in Siegel’s study [4], most of the patients had preexisting hypertension. Three-vessel CHD was common in both groups, although angina pectoris was infrequent in patients with pulmonary edema. LV ejection fraction was more depressed in patients with pulmonary edema (42%) than in the angina pectoris group (59%). In another study, Kunis and associates [7] reported ﬁndings of a small group of elderly patients with CHD who had recurrent pulmonary edema that could not be prevented with medical therapy. Angiographic studies demonstrated three-vessel coronary disease with preserved LV systolic function. Only after undergoing coronary bypass surgery was the recurrent pulmonary edema prevented in these very elderly patients. Another subset of elderly patients with CHD who present with acute pulmonary edema will demonstrate mitral valvular regurgitation that may be secondary to papillary muscle ischemia. In a study of 40 patients with acute pulmonary edema who had CHD, Stone and associates [10] found that 67% of the patients demonstrated moderate-to-severe mitral regurgitation on Doppler echocardiographic examination. The mean age of the patients was 76 years. In the majority of patients (74%), a murmur of mitral regurgitation was not detected despite examination by multiple observers. The authors concluded that mitral valve regurgitation is not uncommon in elderly patients with CHD who present with acute LV failure and may contribute to the genesis of pulmonary edema. Tresch and associates [11] studied the initial manifestations of CHD in a group of elderly patients who underwent coronary angiography. The mean age of the group was 71 years, with some of the patients over the age of 80 before the onset of symptoms. The initial

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manifestation in the majority of patients was unstable ischemic chest pain; 34% of the patients presented with an acute myocardial infarction. In 8% of these elderly patients, the initial manifestation was acute heart failure unassociated with an acute myocardial infarction. On cardiac catheterization, multivessel disease was common, although LV systolic function was often normal. Only 9% of the patient had a LV ejection fraction of less than 35%. In contrast, patients younger than 65 years more commonly sustained an acute myocardial infarction as the initial manifestation of CHD, were less likely to present with heart failure, and had less multivessel CHD. Postprandial angina pectoris tends to occur among elderly and hypertensive patients with severe CHD and a markedly reduced ischemic threshold [12]. Cardiac arrhythmias, particularly complex ventricular arrhythmias, may be a manifestation of myocardial ischemia in elderly patients with CHD. In Tresch’s study [11], 9 of 66 elderly patients (14%) had arrhythmias as the initial manifestation of CHD. Sudden death may be the initial manifestation of CHD in older adults; in Framingham volunteers 65 to 94 years old, CHD was manifest as sudden death in 15% of men and 12% of women [13]. Silent or asymptomatic myocardial ischemia is a common problem in elderly patients with CHD. Approximately 15% of the elderly patients in Tresch’s study [11] were asymptomatic, with myocardial ischemia detected by exercise stress testing during a preoperative evaluation. In a study of 185 patients with CHD, mean age 83 years, silent myocardial ischemia (SI) was detected by 24-h ambulatory electrocardiography (AECG) in 62 patients (34%) [14]. SI was detected by 24-h AECG in 51 of 117 patients (44%) with CHD or hypertension and an abnormal LV ejection fraction [15]. Hedblad et al. [16] also detected SI by 24-h AECG in 19 of 39 patients (49%) with CHD. The reason for the frequent absence of chest pain in elderly patients with CAD is unclear. Various speculations have included (1) mental deterioration with inability to verbalize a sensation of pain; (2) better myocardial collateral circulation related to gradual progressive coronary artery narrowing; and (3) a decreased sensitivity to pain because of aging changes. Ambepitiya and associates [17] recently investigated the issue of age-associated changes in pain perception by comparing the time delay between the onset of 1 mm of electrocardiographic ST-segment depression and the onset of angina pectoris during exercise stress testing. The mean delay was 49 s in patients aged 70 to 82 years compared to 30 s in patients aged 42 to 59 years. The reason for this delay in perception of myocardial ischemia in the elderly is unexplained. The authors postulated that the impairment is most likely multifactorial in origin, involving peripheral mechanisms such as changes in the myocardial autonomic nerve endings with blunting of the perception of ischemic pain, as well as changes in central mechanisms. Another theory has suggested that the increase in silent myocardial ischemia and infarction in elderly patients with CHD is related to increased levels of, or receptor sensitivity to, endogenous opioids [18]. This explanation does not appear likely because studies have demonstrated a similar increase in response of beta-endorphin levels to exercise in both elderly and younger patients [19], and animal studies show a decrease in opioid receptor responsivity with advancing age [20].

MYOCARDIAL INFARCTION As with myocardial ischemia, some patients with myocardial infarction may be completely asymptomatic or the symptoms may be so vague that they are unrecognized by the patient or physician as an acute myocardial infarction. The Framingham Heart Study [21] found

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that, in the general population, approximately 25% of myocardial infarctions diagnosed by pathological Q-waves on electrocardiography were clinically unrecognized and, of these, 48% were truly silent. The incidence increased with age, with 42% of infarctions clinically silent in males aged 75 to 84 years. In women, the proportion of unrecognized myocardial infarctions was greater than in men, but the incidence was unaﬀected by increasing age. Other studies [22–29] have also reported a high prevalence of silent or unrecognized myocardial infarction in elderly patients, with rates from 21 to 68% (Table 1). These studies also demonstrated that the incidence of new coronary events, including recurrent myocardial infarction, ventricular ﬁbrillation, and sudden death, in patients with unrecognized myocardial infarction is similar to [21,26–28,30] or higher [29] than in patients with recognized myocardial infarction. Symptoms when present in elderly patients with an acute myocardial infarction may be extremely vague and, as with myocardial ischemia, the diagnosis may be easily missed. Numerous studies have demonstrated the atypical features and wide variability of symptoms in elderly patients with acute myocardial infarction (Table 2) [22–24,31–35]. Rodstein [22] found in 52 elderly patients with acute myocardial infarction that 31% had no symptoms, 29% had chest pain, and 38% had dyspnea, neurological symptoms, or gastrointestinal symptoms (Tables 1 and 2). Pathy [31] demonstrated in 387 elderly patients with acute myocardial infarction that 19% had chest pain, 56% had dyspnea, neurological, or gastrointestinal symptoms, 8% had sudden death, and 17% had other symptoms (Table 2). In 110 elderly patients with acute myocardial infarction, Aronow [24] showed that 21% had no symptoms, 22% had chest pain, 35% had dyspnea, 18% had neurological symptoms, and 4% had gastrointestinal symptoms (Tables 1 and 2). Other studies have also shown a high prevalence of dyspnea and neurological symptoms in elderly patients with acute myocardial infarction [32–34]. In these studies, dyspnea was present in 22% of 87 patients [32], in 42% of 777 patients [33], and in 57% of 96 patients [34]. Neurological symptoms were present in 16% [32], 30% [33], and 34% [34], respectively. In 777 elderly patients with acute myocardial infarction, Bayer and associates [33] reported that, with increasing age, the prevalence of chest pain decreased whereas the prevalence of dyspnea increased.

Table 1 Prevalence of Silent or Unrecognized Q-Wave Myocardial Infarction in Elderly Patients Study (Ref.) Rodstein (n=52) [22] Aronow et al. (n=115) [23] Aronow (n=110) [24] Vokonas et al. (n=199 men) [21] Vokonas et al. (n=162 women) [21] Muller et al. (n=46 men) [25] Muller et al. (n=67 women) [25] Nadelmann et al. (n=115) [26] Sigurdsson et al. (n=237) [27] Sheifer et al. (n=901) [28] Abbreviations: MI=myocardial infarction.

Unrecognized MI

Age (years)

(No.)

(%)

61–92 mean, 82 mean, 82 65–94 65–94 65–95 65–95 75–85 58–62 mean, 72

16 78 23 66 58 14 34 50 83 201

31 68 21 33 36 30 51 43 35 22

Diagnosis of CAD

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Table 2 Prevalence of Dyspnea, Chest Pain, Neurological Symptoms, and Gastrointestinal Symptoms Associated with Acute Myocardial Infarction in Elderly Patients Study (Ref.) Rodstein (n=52) [22] Pathy (n=387) [31] Tinker (n=87) [32] Bayer et al. (n=777) [33] Aronow (n=110) [24] Wroblewski (n=96) [34]

Age (years) 61–92 z65 mean, 74 65–100 mean, 82 mean, 84

Dyspnea 10 77 19 329 38 57

(19%) (20%) (22%) (42%) (35%) (59%)

Chest pain 15 75 51 515 24 19

(29%) (19%) (59%) (66%) (22%) (20%)

Neurological symptoms 7 126 14 232 20 33

(13%) (33%) (16%) (30%) (18%) (34%)

GI symptoms 3 10 0 145 5 24

(6%) (3%) (0%) (19%) (4%) (25%)

Abbreviations: GI=gastrointestinal.

In the Multicenter Chest Pain Study, the clinical presentation of acute myocardial infarction was compared in 1615 patients older than 65 years to 5109 younger patients [36]. Because of the decreased prevalence in elderly patients of some typical features of acute myocardial infarction present in younger patients, such as pressure-like chest pain, the initial symptoms and signs had a lower predictive value for diagnosing acute myocardial infarction in the older group [36]. Other features that are diﬀerent between elderly and younger patients with acute myocardial infarction, and which may modify therapy, need to be emphasized. An important diﬀerence is that elderly patients delay longer in seeking medical assistance after the onset of chest pain [37–39]. In a study of out-of-hospital chest pain, Tresch and associates [37] reported that elderly patients 80 years or older delayed greater than 6.5 h in calling paramedics, compared to a 3.9 h delay in patients younger than 70 years. Interestingly, this prolonged delay occurred even though more than 50% of the elderly patients had a past history of either a myocardial infarction or coronary bypass surgery. Such delay may be one of the reasons why elderly patients with acute myocardial infarction are less likely to receive thrombolytic therapy or primary coronary angioplasty compared to younger patients. Sheifer et al. [39] showed in the Cooperative Cardiovascular Project that among 102,339 patients older than 65 years with conﬁrmed acute myocardial infarction, 29.4% arrived at the hospital z 6 h after symptom onset. Another important age diﬀerence found in Tresch’s study [37], which has been reported in other studies [40], was the greater incidence of non-Q-wave myocardial infarctions in the elderly; 40% of elderly patients with acute myocardial infarction demonstrated non-Q-wave infarction compared to only 20% of the younger patients with infarction. In younger patients, non-Q-wave myocardial infarctions are usually associated with a more benign acute hospital course than Q-wave myocardial infarctions, although this does not pertain to elderly patients. Chung and associates [41] reported a 10% hospital mortality and a 36% 1-year mortality in a group of elderly patients sustaining acute non-Q-wave myocardial infarction. In contrast, the acute hospital and 1-year mortality in younger patients was 3% and 16%, respectively. Moreover, 23% of the elderly patients with non-Q-wave myocardial infarction developed atrial ﬁbrillation, and 53% had congestive heart failure (CHF). Regardless of the type of myocardial infarction, elderly patients with acute myocardial infarction usually demonstrate more left ventricular dysfunction than younger patients upon hospital admission and have a more complicated hospital course. Complications are common in elderly patients [42], including heart failure, ventricular rupture, shock, and

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death; and, not infrequently, the elderly patient’s initial complaints will reﬂect these complications instead of chest pain. Fedullo and Swinburne [43] compared complications from acute myocardial infarction in 104 patients aged z 70 years versus 157 patients V 70 years. Mortality was 22% in the older group versus 5% in the younger group. Cardiogenic shock occurred in 7% of the older group versus 1% of the younger group. Pulmonary edema occurred in 18% of the older group versus 4% of the younger group. CHF occurred in 29% of the older group versus 14% of the younger group. A rhythm disturbance requiring pacemaker implantation occurred in 5% of the older group versus 2% of the younger group [43]. The increased mortality and complication rates in older patients with acute myocardial infarction suggest that an aggressive diagnostic and therapeutic approach may be beneﬁcial in these patients [42]. More aggressive therapy, including use of aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, statins, thrombolytic therapy, and coronary revascularization by percutaneous transluminal coronary angioplasty or by coronary bypass surgery should be considered (see Chap. 12).

DIAGNOSTIC TECHNIQUES Resting Electrocardiogram In addition to diagnosing recent or previous myocardial infarction, the resting electrocardiogram (ECG) may show ischemic ST-segment depression, arrhythmias, conduction defects, and LV hypertrophy that are related to subsequent coronary events. At 37-month mean follow-up, elderly patients with ischemic ST-segment depression 1 mm or greater on the resting ECG were 3.1 times more likely to develop new coronary events (myocardial infarction, primary ventricular ﬁbrillation, or sudden cardiac death) than were those with no signiﬁcant ST-segment depression [44]. Elderly patients with ischemic ST-segment depression 0.5 to 0.9 mm on the resting ECG were 1.9 times more likely to develop new coronary events during 37-month follow-up than were those with no signiﬁcant ST-segment depression [44]. At 45-month mean follow-up, pacemaker rhythm, atrial ﬁbrillation, premature ventricular complexes, left bundle branch block, intraventricular conduction defect, and type II second-degree atrioventricular block were all associated with a higher incidence of new coronary events in elderly patients [45]. Numerous studies have documented that older adults with ECG LV hypertrophy have an increased incidence of new cardiovascular events [46–48]. Men and women 65 to 94 years of age participating in the Framingham Heart Study who had ECG LV hypertrophy had an increased incidence of new coronary events, atherothrombotic brain infarction, CHF, and peripheral arterial disease compared to persons without ECG LV hypertrophy [46]. Aronow and associates [47,48] also found that elderly patients with hypertension or CHD and ECG LV hypertrophy had an increased incidence of new coronary events, atherothrombotic brain infarction, and CHF. Ambulatory Electrocardiography Numerous studies have demonstrated that complex ventricular arrhythmias in older adults without underlying cardiovascular disease are not associated with an increased incidence of new coronary events (Table 3) [49–54]. In contrast, complex ventricular arrhythmias in elderly persons with underlying cardiovascular disease are associated with a increased

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257

Table 3 Association of Complex Ventricular Arrhythmias and Ventricular Tachycardia with New Coronary Events in Elderly Patients Study (Ref.) Fleg et al. (n=98) [49] Kirkland et al. (n=30) [50] Aronow et al. (n=843) [51] Aronow et al. (n=104) [51] Aronow et al. (n=391) [52]

Mean age (years) 69 79 82 82 82

Aronow et al. (n=76) [52] Aronow et al. (n=468) [53]

82

Aronow et al. (n=86) [53] Aronow et al. (n=395 men) [54] Aronow et al. (n=385 men) [54] Aronow et al. (n=135 men) [54] Aronow et al. (n=771 women) [54] Aronow et al. (n=806 women) [54] Aronow et al. (n=297 women) [54]

82

82

80

Cardiac status

Follow-up (months)

Incidence of new coronary events

No heart disease No heart disease Heart disease No heart disease Heart disease

120

No association

29

No association

39

Increased 1.7 times by complex VA No association

No heart disease Heart disease

24

No heart disease CAD

39 24

27

27

With normal LVEF, increased 2.5 times by complex VA and 3.2 times by VT; increased 7.6 times by complex VA plus abnormal LVEF and increased 6.8 times by VT plus abnormal LVEF No association With no LVH, SCD or VF increased 2.4 times by complex VA and 1.8 times by VT; SCD or VF increased 7.3 times by complex VA plus LVH and increased 7.1 times by VT plus LVH No association

45

Increased 2.4 times by complex VA and 1.7 times by VT

80

HT, VD, or CMP

45

Increased 1.9 times by complex VA and 1.9 times by VT

80

No heart disease

45

No association

81

CAD

47

Increased 2.5 times by complex VA and 1.7 times by VT

81

HT, VD, or CMP

47

Increased 2.2 times by complex VA and 2.0 times by VT

81

No heart disease

47

No association

Abbreviations: VA=ventricular arrhythmias; VT=ventricular tachycardia; LVEF=left ventricular ejection fraction; LVH=left ventricular hypertrophy; SCD=sudden coronary death; VF=primary ventricular ﬁbrillation; CAD=coronary artery disease; HT=hypertension; VD=valvular heart disease; CMP=cardiomyopathy.

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incidence of new coronary events, including sudden cardiac death (Table 3) [51–54]. The incidence of new coronary events is especially increased in elderly patients with complex ventricular arrhythmias and abnormal LV ejection fraction [52] or LV hypertrophy [53]. Complex ventricular arrhythmias detected by 24-h AECG in elderly nursing home patients with heart disease predicted a 2.5 times greater incidence of new coronary events at 2-year follow-up in persons with normal LV ejection fraction and 7.6 times greater incidence in those with abnormal LV ejection fraction (Table 3) [53]. In elderly persons with heart disease, nonsustained ventricular tachycardia detected by 24-h AECG was associated with a 3.2 times increased incidence of new coronary events at 2-year follow-up in persons with normal LV ejection fraction and 6.8-fold higher incidence in those with abnormal LV ejection fraction (Table 3) [52]. Those with heart disease, normal LV mass, and complex ventricular arrhythmias detected by 24-h AECG experienced a 2.4-fold greater incidence of primary ventricular ﬁbrillation or sudden cardiac death at 27-month follow-up than those without such arrhythmias. This risk was 7.3 times higher in persons with both complex ventricular arrhythmias and echocardiographic LV hypertrophy (Table 3) [53]. AECG performed for 24 h is also useful in detecting myocardial ischemia in elderly persons with suspected CHD who cannot perform treadmill or bicycle exercise stress testing because of advanced age, in termittent claudication, musculoskeletal disorders, CHF, or pulmonary disease. Ischemic ST-segment changes demonstrated on 24-h AECG correlate with transient abnormalities in myocardial perfusion and LV systolic dysfunction. The changes may be associated with symptoms, or symptoms may be completely absent, which is referred to as silent myocardial ischemia. Silent myocardial ischemia is predictive of future coronary events, including cardiovascular mortality in older persons with CHD [14–16,55– 59] and in those with no clinical heart disease [16,49,60] (Table 4). The incidence of new coronary events is especially increased in elderly individuals with silent myocardial ischemia plus complex ventricular arrhythmias [55], abnormal LV ejection fraction [15], or echocardiographic LV hypertrophy [61]. In a population of institutionalized elderly with CHD or hypertension, at 40-month follow-up, silent myocardial ischemia predicted a doubled incidence of new coronary events in persons with normal LV ejection fraction and a 3.2-fold increase in those with abnormal LV ejection fraction (Table 4) [15]. The combination of complex ventricular arrhythmias plus silent myocardial ischemia was associated with a 4-fold higher incidence of new coronary events (Table 4) [15]; echocardiographic LV hypertrophy plus silent myocardial ischemia predicted a 3.4-fold greater incidence of new coronary events at 31-month follow-up [61]. Silent myocardial ischemia was associated with approximately a doubled incidence of new coronary events over nearly 4 years of follow-up in both elderly men and women with CHD, hypertension, valvular heart disease, or cardiomyopathy. Among those without clinical heart disease, silent myocardial ischemia predicted an incidence of new coronary events 6.3-fold higher in men and 4.4-fold higher in women (Table 4) [60]. Hedblad and associates [16] showed at 43-month follow-up that silent myocardial ischemia predicted a 16-fold higher incidence of new coronary events in men with CHD and a 4.4-fold higher event rate in men without CHD (Table 4) [16]. Fleg and associates [49] showed at 10-year follow-up in elderly persons without heart disease that silent myocardial ischemia was associated with a 3.8-fold increased incidence of new coronary events (Table 4) [49]; two of the three persons who died suddenly had evidence of silent myocardial ischemia plus ventricular tachycardia detected by 24-h AECG. Silent myocardial ischemia detected by 24-h AECG has been used in the assessment of patients undergoing nocardiac surgery. Such use of 24-h AECG may be especially beneﬁcial

Diagnosis of CAD Table 4

259

Association of Silent Ischemia with New Coronary Events in Elderly Patients Mean age (years)

Cardiac status

Follow-up (months)

69

No heart disease

120

Increased 3.8 times by SI

82

Heart disease

26

Increased 2.3 times by SI

82

No heart disease

26

82

CAD or HT

40

Aronow et al. (n=404) [55]

82

CAD or HT

37

Hedblad et al. (n=39 men) [16] Hedblad et al. (n=385 men) [16] Aronow et al. (n=395 men) [60] Aronow et al. (n=385 men) [60] Aronow et al. (n=135 men) [60] Aronow et al. (n=771 women) [60] Aronow et al. (n=806 women) [60] Aronow et al. (n=297 women) [60]

68

CAD

43

Nonsigniﬁcantly increased 5.0 times by SI Increased 2.0 times by SI; increased 2.4 times by SI with normal LVEF; increased 3.2 times by SI with abnormal LVEF Increased 2.0 times by SI; increased 4.0 times by SI plus complex VA; increased 2.5 times by SI plus VT Increased 16.0 times by SI

68

No CAD

43

Increased 4.4 times by SI

80

CAD

45

Increased 2.1 times by SI

80

HT, VD, or CMP

45

Increased 1.8 times by SI

80

No heart disease

45

Increased 6.3 times by SI

81

CAD

47

Increased 2.1 times by SI

81

HT, VD, or CMP

47

Increased 1.7 times by SI

81

No heart disease

47

Increased 4.4 times by SI

Study (Ref.) Fleg et al. (n=98) [49] Aronow et al. (n=534) [14] Aronow et al. (n=92) [14] Aronow et al. (n=393) [15]

Incidence of new coronary events

Abbreviations: SI=silent ischemia; CAD=coronary artery disease; HT=hypertension; LVEF=left ventricular ejection fraction; VA=ventricular arrhythmias; VT=ventricular tachycardia; VD=valvular heart disease; CMP=cardiomyopathy.

in elderly persons, who frequently are at high surgical risk and may not be able to undergo preoperative exercise stress testing because of concomitant illness. No study, however, has shown silent myocardial ischemia detected by 24-h AECG to be more accurate than pharmacological stress testing in stratifying preoperative elderly patients into high-and low-risk groups. Raby and associates [62] studied 176 patients who underwent 24-h AECG before noncardiac surgery. Eighteen percent of the patients had signs of myocardial ischemia on

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their preoperative 24-h AECG, with the ischemia silent in the majority of patients. Preoperative myocardial ischemia was highly predictive of postoperative cardiac events. The sensitivity of preoperative myocardial ischemiafor postoperative cardiac events in this study was 92%, the speciﬁcity 88%, the positive predictive value 38%, and the negative predictive value 99% [62]. Multivariate analysis showed preoperative myocardial ischemia to be the most signiﬁcant variable correlating with postoperative cardiac events. The authors concluded that the absence of preoperative myocardial ischemia on a 24-h AECG indicates a very low risk for postoperative cardiac events. Thirty-eight percent of the patients in this study were older than 69 years, and preoperative myocardial ischemia was more prevalent in these elderly patients compared with the younger patients. In a follow-up study, Raby and associates [63] assessed the signiﬁcance of intraoperative and postoperative silent myocardial ischemia in addition to preoperative ischemia detected on a 24-h AECG in relationship to postoperative cardiac events in patients undergoing peripheral vascular surgery. The mean age of the patients in this study was 67 years, and 37% were 70 years or older. As in their previous study, the investigators found preoperative silent myocardial ischemia to be the most important predictor of postoperative cardiac events. Preoperative myocardial ischemia also strongly correlated with intraoperative and postoperative ischemia, and perioperative myocardial ischemia commonly preceded clinical cardiac events. Signal-Averaged Electrocardiography Signal-averaged electrocardiography (SAECG) was performed in 121 elderly postinfarction patients with asymptomatic complex ventricular arrhythmias detected by 24-h AECG and a LV ejection fraction z 40% [64]. At 29-month follow-up, the sensitivity, speciﬁcity, positive predictive value, and negative predictive value for predicting sudden cardiac death as 52%, 68%, 32% and 83%, respectively, for a positive SAECG; 63%, 70%, 38%, and 87% respectively, for nonsustained ventricular tachycardia; and 26% 89%, 41%, and 81%, respectively, for a positive SAECG plus nonsustained ventricular tachycardia [64]. Echocardiography Echocardiography is useful in detecting regional LV wall motion abnormalities, acute myocardial ischemia, and complications secondary to acute myocardial infarction, LV aneurysm, cardiac thrombi, left main coronary artery disease, LV hypertrophy, and associated valvular heart disease. Echocardiography is useful in evaluating LV function and cardiac chamber size in elderly persons with CHD. Echocardiographic LV ejection fraction is also important in predicting new coronary events in elderly persons with CHD [15,52,65]. New coronary events developed at 2-year follow-up in 30 of 45 elderly nursing home patients with CHD and abnormal LV ejection fraction (<50%) and in 24 of 90 such patients with CHD and normal LV ejection fraction (relative risk=2.5) [52]. In older adults with CHD and heart failure, cardiovascular mortality is higher among individuals with abnormal than those with normal LV ejection fraction [65,66]. Multivariate analysis showed that LV ejection fraction was the most important prognostic variable for mortality in elderly persons with CHF associated with CHD; those with abnormal LV ejection fraction had approximately twice the mortality of persons with normal LV ejection fraction [65,66]. Numerous studies have demonstrated that elderly patients with echocardiographic LV hypertrophy have an increased incidence of new cardiovascular events [47,48,53,61,67,68]. At 4-year follow-up, elderly men and women in the Framingham Study with echocardio-

Diagnosis of CAD

261

graphic LV hypertrophy had a relative risk for new coronary events of 1.67 for men and of 1.60 for women per 50 g/m increase in LV mass/height (Table 5) [67]. Echocardiographic LV hypertrophy was 15.3 times more sensitive than ECG LV hypertrophy in predicting new coronary events in elderly men and 4.3 times more sensitive than ECG LV hypertrophy in predicting new coronary events in elderly women [67]. Over 27-months of follow-up, institutionalized elderly adults with echocardiographic LV hypertrophy developed a 2.7-fold higher incidence of new coronary events, 3.7-fold higher rate of new atherothrombotic brain infarction (ABI), and 3.3-fold greater rate of primary ventricular ﬁbrillation or cardiac death (Table 5) [53]. At 37-month follow-up of elderly persons with CHD or hypertension, echocardiographic LV hypertrophy predicted a doubled incidence of new coronary events and a 2.8-fold greater rate of new ABI (Table 5) [47]. Echocardiographic LV hypertrophy was approximately four times more sensitive than ECG LV hypertrophy in predicting new coronary events or new ABI in this population [47]. Multiple logistic regression analysis showed that echocardiographic LV hypertrophy was a strong independent risk factor in such a population for new coronary events (odds ratio of 3.2), new ABI (odds ratio of 4.2), and new CHF (odds ratio of 2.6) [48]; increased risk was similar in African-Americans and whites (Table 5). Exercise and Pharmacological Stress Testing Although age per se signiﬁcantly inﬂuences the cardiovascular response to aerobic exercise, treadmill or cycle ergometer exercise testing remains a useful diagnostic and prog-

Table 5 Association of Echocardiographic Left Ventricular Hypertrophy with New Cardiovascular Events in Elderly Persons Study (Ref.)

Mean age (years)

Follow-up (years)

Framingham Study (n=406 men) [67]

65–94

4

Framingham Study (n=735 women) [67]

65–94

4

Cardiovascular disease (n=557) [68] Hypertension or CHD (n=360) [47] Heart disease (n=468) [53]

82

2.3

82

3.1

82

2.3

78

3.1

82

3.6

African-Americans with hypertension (n=84) [48] Whites with hypertension (n=326) [48]

Incidence of new cardiovascular events Coronary events increased 1.67 times per 50 g/m increase in LV mass/height Coronary events increased 1.60 times per 50 g/m increase in LV mass/height LVH increased coronary events 2.7 times and ABI 3.7 times LVH increased coronary events 2.0 times and ABI 2.8 times LVH increased primary ventricular ﬁbrillation or sudden cardiac death 3.3 times LV increased coronary events 3.3 times, ABI 2.8 times, and CHF 3.7 times LV increased coronary events 2.7 times, ABI 3.3 times, and CHF 3.5 times

Abbreviations: LVH=left ventricular hypertrophy; CHD=coronary heart disease; ABI=atherothrombotic brain infarction; CHF=CHF.

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nostic tool for evaluating older patients with suspected or documented CHD. Exercise ECG is also a useful prognostic indicator of subsequent coronary events in patients with documented CAD, with or without previous myocardial infarction. Exercise testing in elderly patients should evaluate symptoms that develop during exercise (especially angina pectoris or dyspnea, which may be an anginal equivalent), the maximal workload achieved, the heart rate and blood pressure response, the presence, magnitude, and onset time of ischemic ST-segment depression or elevation, and the presence of exercise-induced arrhythmias. These variables must be interpreted in light of normative age-associated changes including a decline of maximal aerobic capacity averaging 8 to 10% per decade [69,70], a reduced maximal heart rate of approximately 1 beat/min/year, and an exaggerated rise in systolic blood pressure [71,72]. Maximal LV systolic emptying is impaired in older adults, resulting in a higher end-systolic volume and lower ejection fraction compared to younger individuals [71–73]; stroke volume is preserved, however, by a greater reliance on the FrankStarling mechanism to augment LV end-diastolic volume [72,73]. Exercise-induced supraventricular [74] and ventricular arrhythmias [75] both increase exponentially with age in clinically healthy volunteers and do not increase the risk for future CHD events in such a population. Given the cardiovascular and noncardiovascular limitations to exercise in older adults, exercise testing protocols should employ low starting work rates and smaller work increments than in younger patients. Thus, protocols such as the Naughton or Balke, in which the speed is held constant and only the elevation is increased, are ideal for the elderly. Individuals with gait disturbances can often be tested on a cycle ergometer although their aerobic capacity and peak heart rate are usually lower than those achieved with treadmill exercise. Diagnostic sensitivity of the exercise ECG for CHD appears to increase with age at the expense of a modest reduction in speciﬁcity. Hlatky et al. [76] found the exercise ECG to have a sensitivity of 84% and a speciﬁcity of 70% for the diagnosis of CHD in patients 60 years of age or older. In contrast, sensitivity was only 56% in patients <40 years of age, although speciﬁcity was 84%. In patients aged 65 years and older, Newman and Phillips [77] found a sensitivity of 85%, a speciﬁcity of 56% and a positive predictive value of 86% for the exercise ECG in diagnosing CHD. The increased sensitivity and high positive predictive value of the exercise ECG with increasing age found in these two treadmill exercise studies was probably due to the increased prevalence and severity of CHD in elderly persons [78]. Reduced speciﬁcity is largely explained by a higher prevalence of ST-T-wave abnormalities on the preexercise ECG. Prognostic Utility of the Exercise ECG Numerous studies in patients with known or suspected CAD have shown that the standard treadmill exercise test provides valuable prognostic information. In a sample of 2632 patients z65 years of age undergoing clinically indicated exercise testing, a lower peak treadmill workload was a strong independent predictor of cardiac death over the subsequent 2.9-year mean follow-up period [79]. Of note, neither ischemic ST changes nor angina were predictive. In a similar population, however, Glover et al. demonstrated that an ischemic ST-segment response to exercise predicted an eight-fold cardiovascular mortality (17% vs. 2%) over a 2-year follow-up [80]. The Duke treadmill score, which incorporates exercise duration, magnitude of ischemic ST-segment depression, and presence of exercise-induced angina, has demonstrated prognostic utility in younger populations [81,82], but appears to be less useful in patients z75 years of age [82].

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263

Exercise testing after myocardial infarction (MI) has prognostic value in older patients, as it does in younger ones. Identiﬁcation of jeopardized myocardium in such post-MI patients may be useful because recurrent MI and sudden cardiac death are the most common causes of 1-year mortality post-hospital discharge [83]. In 188 patients z70 years old who underwent exercise testing a mean of 14 days post-MI, Ciaroni et al. [84] found that a rise in SBP of <30 mmHg, a maximal cycle workrate <60 Watts, and exercise duration <5 min predicted cardiovascular death whereas ST-segment depression and ventricular arrhythmias predicted reinfarction and need for coronary revascularization. Similar to the general postinfarction population, older patients excluded from exercise testing after MI have the highest cardiovascular risk. For example, Deckers et al. [85] found a mortality of 4% for patients z65 years old who were able to perform a cycle exercise test post-MI versus a mortality of 37% for those excluded. Although the diagnostic and prognostic utility of exercise testing is the general population is modest, such testing may have greater value in asymptomatic older persons with multiple CHD risks factors [86]. Older subjects embarking on a vigorous training program or those entrusted with the safety of others, such as school bus drivers, are appropriate candidates for testing. Exercise Cardiac Imaging Exercise stress testing incorporating thallium perfusion scintigraphy, radionuclide ventriculography, or echocardiography provides additional value in the diagnosis and prognosis of CHD compared to the exercise ECG alone. Iskandrian et al. [87] showed that exercise thallium-201 imaging can be used for risk stratiﬁcation of elderly patients with CHD. The risk for cardiac death or nonfatal myocardial infarction at 25-month follow-up in 449 patients 60 years of age or older was less than 1% in patients with normal images, 5% in patients with single-vessel thallium-201 abnormality, and 13% in patients with multivessel thallium-201 abnormality. In 120 patients z70 years old with known or suspected CHD who underwent exercise thallium-201 scintigraphy, Hilton et al. [88] showed that the combination of low peak exercise capacity and any thallium-201 perfusion defect was the most powerful predictor of new cardiac events (relative risk, 5.3 at 1 year). Individuals with >2 mm of ischemic ST-segment depression and a thallium defect who failed to complete Stage 1 of a Bruce protocol suﬀered a 47% event rate. Fleg et al. [89] performed maximal treadmill exercise ECGs and thallium scintigraphy in 407 asymptomatic volunteers 40 to 96 years of age from the Baltimore Longitudinal Study on Aging. At 4.6 years of follow-up, new cardiac events developed in 7% of patients who had negative results on both tests, in 8% of patients with a single positive result, and in 48% of patients with both results positive. Persons with both a positive exercise ECG and a thallium perfusion defect averaged 69 years of age and had 3.6 times the relative risk for new coronary events as those with negative results, independent of standard coronary risk factors [89]. Echocardiography during, or more commonly, immediately after treadmill or cycle exercise has also proven useful in the detection and prognostication of CAD. Overall sensitivity of exercise-induced wall motion abnormalities for CAD using this technique is 74 to 97% with speciﬁcity of 64 to 88%, similar to values of exercise thallium scintigraphy [90,91]. As with other diagnostic modalities, the sensitivity of exercise echocardiography increases with the extent of CAD, which should result in a high sensitivity in the elderly. Although a lower technical success of echocardiographic imaging in older versus younger

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patients is probably responsible for a lesser utilization of exercise echocardiography in the elderly, recent advances in echocardiographic equipment have largely overcome this deﬁciency. In 2632 patients z65 years old referred for clinically indicated exercise echocardiography, the exercise-induced changes in LV end-systolic volume and the exercise LV ejection fraction or wall motion score were predictors of cardiac events and cardiac death, independent of clinical status, resting echocardiography, and exercise duration [79] (Fig. 1). Pharmacological Stress Testing The largest advance in stress testing over the past decade has been the widespread application of pharmacological stress testing to populations unable to perform diagnostically adequate exercise tests. The elderly are clearly the greatest beneﬁciaries of pharmacological stress testing due to their high prevalence of exercise-limiting conditions such as obstructive lung disease, peripheral arterial insuﬃciency, arthritis, and neuromuscular disorders. The agents most commonly used for this purpose are the vasodilators, dipyridamole and adenosine, and the synthetic catecholamine, dobutamine, in conjunction with either radionuclide or echocardiographic imaging. Dipyridamole is a phosphodiesterase inhibitor that blocks degradation of adenosine, thereby increasing plasma adenosine, which is a potent arteriolar dilator. Both dipyridamole and adenosine dilate normal coronary arteries more than stenotic vessels, creating a coronary steal that causes a myocardial perfusion defect or wall motion abnormality. With either drug, serious side eﬀects, including bronchospasm, hypotension, and arrhythmias, occur in 2 to 3% of patients but do not appear to be age-related [92–94]. In 101 subjects older than 70 years, the sensitivity and speciﬁcity of dipyridamole thallium imaging for CAD were 86% and 75%, respectively, compared with corresponding values of 83% and 70% in younger patients [93]. Prognostic utility of dipyridamole in combination with echocardiography was shown in 190 patients z65 years old (mean 68 F 3), evaluated at a mean of 10 days after uncomplicated MI. Patients with a positive test experienced a three-fold risk of future cardiac events and 4.4-fold risk of death compared to those with negative, i.e., normal results [95]. An abnormal dipyridamole thallium scan was the best predictor of subsequent events in 348 patients z70 years old with known or suspected CAD conferring a relative risk of 7.2 on multivariate analysis [96]. Dipyridamole stress imaging has also been used to identify

Figure 1 Exercise echocardiographic wall motion score as a predictor of survival free of cardiac events in 2632 patients z65 years old referred for exercise testing. A higher wall motion score index (WMSI) denotes worse LV function. (From Ref. 79).

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patients at high CV risk prior to vascular surgery. Hendel et al. [97] observed that a reversible thallium perfusion defect conferred a 9-fold risk of perioperative MI or cardiac death in 360 such patients whose mean age was 65 years. Adenosine echocardiography has also demonstrated both diagnostic and prognostic utility in older patients with known or suspected CAD [94]. In 120 such patients z70 years old, sensitivity for CAD was 66% with speciﬁcity of 90% and diagnostic accuracy of 73% [94]. Sensitivity increased from 42% in patients with single-vessel CAD to 73% in those with multivessel disease. An abnormal adenosine echocardiogram predicted a three-fold risk of future cardiac events, independent of clinical CHD risk factors. The only serious eﬀect was transient atrioventricular (AV) block, which occurred in 6% of patients, but was asymptomatic and self-limited in all. In another study, the risk of such transient AV block after adenosine infusion was 18% in patients z75 years versus 8% in younger patients [98]. Combining adenosine infusion with symptom-limited treadmill exercise reduced the incidence of premature infusion termination from 15 to 5%. Dobutamine is a synthetic catecholamine that is frequently used as a pharmacological stressor in older patients, in combination with echocardiography or thallium imaging. Dobutamine produces dose-related increases in heart rate and inoptopy that augment coronary artery blood ﬂow, thereby inducing ischemia by a mechanism similar to exercise in patients with CAD. Atropine is frequently combined with dobutamine to help insure an adequate chronotropic response. The classic ischemic response induced by dobutamine is characterized by improved wall motion at low doses but worsening wall motion at high doses. Dobutamine is particularly useful in older patients with obstructive lung disease, in whom both dipyridamole and adenosine are contraindicated. In 120 patients z70 years with known or suspected CAD, dobutamine echocardiography had a sensitivity of 87%, speciﬁcity of 84%, and accuracy of 86%, all higher than corresponding ﬁgures for adenosine in the same patients (Table 6) [94]. Patients with a positive dobutamine stress test had a 7.3fold risk for a future cardiac event compared to those with a normal test. Dobutamine thallium scintigraphy demonstrated sensitivity of 86% and speciﬁcity of 90% in 144 patients aged 65 F 10 years [99], numbers very similar to the echocardiographic data with this drug. Dobutamine has also been used to predict perioperative coronary events in older patients undergoing vascular surgery [100]. Although dobutamine is generally well tolerated in all age groups, higher rates of asymptomatic hypotension and both supraventricular and ven-

Table 6 Comparison of Dobutamine and Adenosine Echocardiography in Detection of CAD in Patients z70 Years Old

Sensitivity Overall 1-Vessel CAD 2-Vessel CAD 3-Vessel CAD Speciﬁcity Accuracy

Dobutamine

Adenosine

p Value

87% 74% 88% 91% 84% 86%

66% 42% 76% 71% 90% 73%

<0.001 NS NS 0.02 NS 0.01

Abbreviations: CAD = coronary artery disease. Source: Adapted from Ref. 94 with permission.

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tricular arrhythmias, but a lower rate of chest pain, were reported in patients older versus younger than 70 years [101,102].

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11 Angina in the Elderly Wilbert S. Aronow Westchester Medical Center/New York Medical College, Valhalla, Mount Sinai School of Medicine, New York, New York, U.S.A.

William H. Frishman Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A.

Coronary artery disease (CAD) is the number one cause of death in elderly patients and also the major cause of hospitalization and rehospitalizations in this age group. Clinically, CAD manifests as acute ischemic syndromes, and it is important that the practicing physician have an understanding of the pathophysiology of these syndromes, as well as conﬁdence in management of these syndromes in elderly patients. This chapter will discuss the evaluation and management of elderly patients who demonstrate two of these ischemic syndromes—stable and unstable angina. Recent advances in cellular and molecular biology have provided a better understanding of coronary atherosclerosis, the underlying disease process causing myocardial ischemia. Due to these advances and the development of new therapies, we are now not only able to relieve the patient’s symptoms, but are able to modify the underlying pathophysiology. Evaluation and treatment of myocardial ischemia in elderly patients pose unique challenges to the physician. Although the pathophysiology of myocardial ischemia and the treatment options are similar in elderly and younger patients, there are signiﬁcant diﬀerences in presentation and response to treatment between the age groups. Elderly CAD patients with myocardial ischemia often present with ‘‘atypical’’ symptoms, and have more comorbid illnesses, greater number of vessels involved, and worse left ventricular (LV) function [1–6]. Pharmacokinetics of medications is altered in elderly patients, and there is often a greater sensitivity to medication and greater potential for side eﬀects and drug–drug interactions. Since elderly patients often present with more advanced CAD and their prognosis is often worse, there is greater potential for gain from aggressive interventions, such as angioplasty (PTCA) and bypass surgery (CABG), although the risks are greater compared to younger patients. Finally, elderly patients and their families may place diﬀerent values on risk, quality of life, and the importance of prognosis, all of which must be considered by the practicing physician. 273

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EVALUATION AND MANAGEMENT The most common symptom of myocardial ischemia in elderly patients as well as in younger patients is exertional chest pain (angina); however, in many older patients, instead of chest pain, exertional dyspnea may be the initial manifestationof ischemia. Other common symptoms experienced by elderly patients with myocardial ischemia are dizziness, mental confusion, or easy fatiguability. In some elderly patients with myocardial ischemia, the presentation will be the sudden onset of heart failure (‘‘ﬂash’’ pulmonary edema) [7–9] or arrhythmias, including sudden death [10]. Silent ischemia is particularly common in elderly patients with CAD, occurring in up to one-third of elderly patients, as documented by ambulatory ECG monitoring [11,12]. The initial evaluation of the elderly patient with possible myocardial ischemia should begin with a thorough history and complete physical examination, and determination of coronary risk factors and comorbid illnesses. The assessment should determine if the patient is stable or unstable and the risk stratiﬁcation of the patient. In addition to advanced age, morbidity and mortality in elderly patients with acute ischemia are directly related to LV function, extent of CAD, and presence of comorbidity. During the evaluation, the physician caring for elderly patients with myocardial ischemia will need to consider the eﬀects of the disease on the whole person (including physical, psychosocial, and economic aspects) and the impact of the disease on the patient’s family. Angina is a clinical syndrome reﬂecting inadequate oxygen supply for myocardial metabolic demands with resultant ischemia. Depending upon the underlying pathophysiology, the patient will present with stable or unstable angina. The goals of therapy in elderly patients with angina (ischemic syndromes) are to (1) relieve the acute symptoms and stabilize the acute pathophysiological process; (2) minimize the frequency and severity of recurrent anginal attacks; and (3) prevent progression, plus cause regression of the underlying pathophysiological process. Therapeutic measures are directed at modifying the underlying pathophysiology with therapeutic agents and reducing myocardial ischemia by (1) reducing myocardial oxygen demand and (2) increasing coronary blood ﬂow. The main underlying pathological process in patients with angina is coronary atherosclerosis with plaque formation and narrowing of the vessel luminal diameter, plus intermittent rupture of the atherosclerotic plaque. Because thrombus formation is an important factor in the progression of atherosclerotic lesions and in the conversion of clinical to acute events after plaque rupture, antiplatelet and anticoagulant therapy is important in the management of elderly CAD patients. In additon, stabilization and regression of the atherosclerotic lesions are possible by vigorous control of the patient’s serum lipids, particularly with hydroxymethylglutaryl coenzyme A (HMG CoA)-reductase inhibitors (statins), and treatment of other risk factors, such as hypertension, smoking, and diabetes mellitus. The main determinants of myocardial oxygen demand are heart rate, myocardial contractility, and intramyocardial tension, which is a function of systemic pressure and ventricular volume. Reduction of the myocardial oxygen demand includes correction of potentially reversible factors, such as heart failure, hyperthyroidism, valvular heart disorders (particularly aortic stenosis), obesity, emotional stress, hypertension, and arrhythmias, such as atrial ﬁbrillation. Drug therapy to reduce myocardial oxygen demand is directed at reducing myocardial contractility, slowing heart rate, and limiting myocardial tension by reducing systemic pressure (afterload) and preload. Coronary blood ﬂow is dependent upon the duration of diastole, coronary arterial resistance, aortic diastolic pressure, and availability of coronary collateral vessels. Improve-

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ment in coronary blood ﬂow can be accomplished by drugs that increase the duration of diastole, decrease coronary artery resistance by vasodilatation or by reduction of intramyocardial tension, and stimulate development of and ﬂow through collateral vessels.

SPECIFIC DRUG THERAPIES The principles of drug therapy for treating angina in elderly patients are the same as those for younger patients [13]. The physician treating elderly patients, however, must be aware that the pharmacokinetics of drugs may be diﬀerent in this age group. Gastrointestinal disorders may potentially interfere with drug absorption, although drug bioavailability is usually unaﬀected by the aging process [14]. The decrease in lean body mass and increase in adipose tissue associated with aging aﬀects the volume of drug distribution. Hepatic blood ﬂow and hepatic oxidation (phase I reactions) decrease with aging, whereas hepatic conjugation is unchanged. Not only is renal dysfunction common in elderly patients but aging is associated with a decline in glomerular ﬁltration rate of 30% between the ﬁfth and ninth decades in normal patients [14]. The elderly often demonstrate increased sensitivity to drugs at any given dosage and may tolerate side eﬀects less well. The presence of cormorbid conditions increases the potential for adverse drug reactions. The axiom to remember when prescribing drugs in elderly patients is to start low and titrate up slowly. Given the pharmacological considerations of drug therapy in elderly patients, the speciﬁc antianginal drugs can be very eﬀective in controlling symptoms and modifying the underlying pathophysiological process in elderly patients with angina. The classes of drugs commonly used include (1) nitrates; (2) beta-blockers; (3) calcium channel blockers; and (4) antiplatelet and/or anticoagulant agents. Nitrates Nitrates are safe, eﬀective, and usually the ﬁrst choice for treatment of angina. Denitration of the organic nitrate with the subsequent liberation of nitric oxide (NO) is necessary for the drug to have therapeutic eﬀects. Nitric oxide stimulates guanylyl cyclase, which leads to the conversion of guanosine triphosphate to cyclic guanosine monophosphate, which causes relaxation of vascular smooth muscle with vasodilatation [15,16]. The exact mechanism by whichthe organic nitrates undergo denitration and thus liberate NO remains controversial [17,18]. The active metabolite, NO, is also known as the endothelium-derived relaxing factor (EDRF) [19] which, in addition to relaxing vascular smooth muscle, reduces platelet adhesion and aggregation [20]. In vessels with atherosclerosis, it has been shown that the endothelium is dysfunctional with attenuation of EDRF activity [21]. Such attenuation of EDRF has been found in patients with hypercholesterolemia without overt coronary atherosclerosis [22]. Due to this attenuated activity of EDRF, vascular vasoconstriction is predominant in patients with CAD. Therefore, nitrates as exogenous donors of NO would appear to be the ideal drug to use in elderly patients with angina (myocardial ischemia). The mechanisms by which nitrates relieve and prevent myocardial ischemia include both (1) a reduction in myocardial oxygen demand and (2) an increase in myocardial oxygen supply due to the drug’s potent vasodilator properties (Table 1). Dilatation of capacitance veins reduces ventricular volume and preload, thus lowering myocardial oxygen requirement and improving subendocardial blood ﬂow. Dilatation of systemic conductive arteries decreases afterload, another determinant of oxygen consumption. Nitrates

276 Table 1

Aronow and Frishman Cardiovascular Effects of Nitrates and Mechanisms To Relieve Angina (Ischemia)

Decreased myocardial O2 demand Venodilatation !# preload !# wall tension Arteriolar dilatation !# afterload !# wall tension Increase myocardial blood ﬂow (O2) Coronary dilatation !z coronary ﬂow !z regional myocardial perfusion (subendocardial) Increase collateral ﬂow !z myocardial perfusion (subendocardial) Decrease coronary resistance !z coronary ﬂow

dilate epicardial coronary arteries with an increase in coronary ﬂow and an improvement in subendocardial perfusion. Nitrates also dilate collateral vessels, which can improve blood ﬂow to the areas of ischemia [23]. In the doses used clinically, nitrates do not aﬀect coronary resistance vessels [24]. Thus, the risk of myocardial ischemia due to coronary steal is minimal, which has been shown to occur with drugs such as dipyridamole and short-acting calcium channel blockers that cause arteriolar dilatation [25]. Nitrate Preparations Short-Acting Nitrates. Nitroglycerin is the drug most frequently used for relief of the acute anginal attack. It is given either as a sublingual tablet or as a sublingual spray and is absorbed rapidly with hemodynamic eﬀects occurring within 2 min after drug administration. The advantage of the spray is that sublingual tablets deteriorate when exposed to light and will need to be renewed every 4 to 6 months to ensure complete bioavailability. The other advantage of nitroglycerin spray is that it may be easier to administer in elderly patients who have diﬃculty with the ﬁne motor skills necessary to administer sublingual tablets. Intravenous nitrates are also available to abort acute anginal attacks that are not relieved with sublingual tablets or spray, and to prevent recurrent anginal attacks. Table 2 lists the diﬀerent nitrate preparations and dosages [26]. Long-Acting Nitrates. Nitrates have been proven not only eﬀective in relieving acute anginal pain, but also beneﬁcial in preventing recurrent anginal attacks. Long-acting nitrates also improve exercise time until the onset of angina and reduce exercise-induced ischemic ST-segment depression [27,28]. The oral preparation is usually the nitrate of choice in the prevention of angina. Standard-formulation isosorbide dinitrate is rapidly absorbed and is typically administered 3 times a day with a 14-h nitrate-free interval. Sustained-release isosorbide dinitrate has a slower rate of absorption and results in a therapeutic plasma concentraton for 12 h. The usual dosage schedule is twice daily in doses of 20 to 80 mg. An isosorbide mononitrate is also available for the prevention of angina. The major advantage of the mononitrate preparation is that it is completely bioavailable because it does not undergo ﬁrst-pass hepatic metabolism. To avoid drug tolerance, it is recommended that the 20- to 40-mg tablets be given twice daily with 7 h between doses. A sustained-release formulation of isosorbide moninitrate is also available that provides therapeutic plasma drug concentrations for up to 12 h each day and low concentrations during the latter part of the 24-h period. The drug dose range is 30 to 240 mg given once daily. Transdermal nitroglycerin is a topical nitroglycerin preparation that is eﬀective in preventing angina, and may be particularly beneﬁcial in elderly patients who are taking numerous pills and have diﬃculty in remembering drug schedules. Moreover, transdermal nitrate preparations will be more eﬀective than oral preparations in elderly patients who

Angina Table 2

277 Different Nitrate Preparations and Dosages

Medication Short-acting Sublingual nitroglycerin Aerosol nitroglycerin Sublingual and chewable isosorbide dinitrate Intravenous Long-acting Oral isosorbide dinitrate Oral isosorbide dinitrate (SR) Oral erythrityl tetranitrate Oral isosorbide mononitrate Transdermal nitroglycerin

Usual dose (mg) 0.3–0.6 0.4 2.5–10 5 Ag/min to 30–80 Ag/min

Onset of action (min) 2–5 2.–5 3–15 1

Duration of action 10–30 min 10–30 min 1–2 h Sustained during infusion

5–40 40

15–30 30–60

3–6 h 6–10 h

10 5–60 5–15

30 30 30–60

Variable 6–8 h 8–14 h

Abbreviations: SR=sustained release. Source: Adapted from Ref. 26.

have problems with gastrointestinal malabsorption. Transdermal nitroglycerin is available as an ointment or patch preparation. Both preparations are eﬀective, although the patch obviates some of the inherent messiness of the ointment. As with the oral preparation, a 12to 14-h nitrate-free interval is necessary to avoid tolerance when using nitroglycerin ointment or patches. Adverse Effects Elderly patients in general tolerate nitrates without signiﬁcant adverse eﬀects, although the two major side eﬀects, hypotension and headaches, can be extremely bothersome in certain patients. Hypotension may occur within minutes after sublingual administration of a nitrate or 1 to 2 h after oral ingestion and is caused by the reduction in preload and afterload caused by the vasodilator eﬀect of the drug. Symptoms may range from lightheadedness to syncope and are commonly positional, precipitated by standing. The hypotension related to nitrates more commonly occurs following the initial use of the drug, when hypovolemia is present, or with concomitant vasodilator therapy use, such as calcium channel blockers or other antihypertensive drugs. The hypotension episode may also be potentiated by alcohol. The episodes can be alleviated by reduction of the dose of nitrate, correction of hypovolemia, and avoidance of immediately standing after sublingual use of the drug. In certain elderly patients, the hypotension will be associated with bradycardia, similar to a typical vasovagal reaction. The hypotension associated with nitrate use will usually be alleviated by the patients lying down; in certain patients with a severe hypotensive reaction, elevation of the legs plus administration of ﬂuid will be necessary. The headache associated with nitrates can be a signiﬁcant problem in certain elderly patients. It may be a mild, transient frontal headache, although in other patients the headache will be diﬀuse and throbbing, with persistent head and neck pain associated with nausea or vomiting. Such severe headaches are more common with the use of intravenous or transdermal nitrates. Nitrates may also aggravate vascular headaches and even initiate

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episodes of ‘‘cluster headaches.’’ As in the management of hypotension related to nitrates, the best approach to alleviate or prevent headaches is to use the lowest doses of nitrates possible and titrate slowly upward if necessary. The use of an analgesic such as aspirin or acetaminophen in conjunction with the nitrate administration may prevent the associated headache. Commonly, due to vascular adaptation, within 7 to 10 days after initiation of nitrate use, the headache will diminish and subside. However, while waitng for adaptation to occur, elderly patients will require much reassurance to continue using the drug; and in certain elderly patients, a diﬀerent antianginal drug will have to be substituted for the nitrate because the patient will not be able to tolerate the recurrent headaches. Nitrate tolerance, deﬁned as the loss of hemodynamic and antianginal eﬀects during sustained therapy [29], is another consideration when treating elderly CAD patients. Tolerance has been shown to occur, regardless of the nitrate preparation, if the patient is continuously exposed to nitrates throughout a 24-h period. The clinical impact of nitrate tolerance, however, is unknown, and the mechanism of nitrate tolerance remains unclear [29,30]. Various possible hypotheses include (1) increased intravascular blood volume; (2) depletion of sulfhydryl groups, which are needed for conversion of nitrates to NO; (3) activation of vasoconstriction hormones; and (4) increase in free-radical production by endothelium during nitrate therapy [31–33]. To prevent tolerance, it is recommended that a 12- to 14-h nitrate-free interval be established when using long-acting nitrate preparations. During the nitrate-free interval, the use of another antianginal drug will be necessary. In elderly patients with unstable angina who are receiving continuous intravenous nitrates, tolerance is not a consideration; if tolerance develops in this setting, the dose of the nitrate should be increased. Studies have demonstrated that abrupt withdrawal of nitrate exposure may produce nonatherosclerotic ischemic cardiac events, including MI [34,35]. Such events are presumably due to coronary artery spasm. Therefore, caution should be exercised when high-dose nitrate therapy is discontinued in elderly patients; if possible, the nitrate dose should be slowly tapered downward before discontinuation. Beta-Blockers Beta-adrenergic blocking agents are eﬀective in preventing angina and are considered by many authorities to be the drug of choice to prevent ischemic events. Beta-blockers also improve exercise time until the onset of angina and reduce exercise-induced ischemic STsegment depression [36]. Beta-blockers prevent angina mainly by reduction in myocardial oxygen demand related to slowing the heart rate, depressing myocardial contractility, and reducing blood pressure (Table 3). These eﬀects are particularly impressive in the setting of

Table 3 Cardiovascular Effects of Beta-Blockers and Mechanisms To Relieve Angina (Ischemia) Decrease myocardial O2 demand Decrease contractility !# blood pressure and # CO Decrease heart rate !# blood pressure and # CO Increase myocardial blood ﬂow (O2) Decrease heart rate !z diastolic perfusion time Abbreviations: CO = cardiac output.

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increased emotional and physical stress, such as during exercise and high anxiety states. In addition to the reduction of myocardial oxygen demand, beta-blockers will increase myocardial oxygen supply by slowing the heart rate and extending the period of diastole. Beta-adrenergic blocking agents can be classiﬁed according to (1) cardioselectivity; (2) intrinsic sympathomimetic activity; and (3) lipophilic activity (Table 4). Consideration of these speciﬁc properties is important when using the drug in elderly CAD patients. Cardioselectivity is determined by the extent the agent is capable of blocking h1-receptors and not h2-receptors [37]. Certain agents, such as metoprolol and atenolol, are relatively more cardioselective than propranolol, which makes these drugs less prone to inducing bronchospasm or peripheral arterial vasoconstriction, as compared to the nonselective agents. At higher doses, however, cardioselective beta-blockers react like nonselective agents with full potential for bronchospasm and peripheral arterial constriction. Some beta-blockers, such as pindolol and acebutolol, in addition to blocking betaadrenergic receptors, possess partial agonist properties and, therefore, are capable of producing intrinsic sympathetic stimulation (ISA) [38]. The degree to which sympathomimetic activity is clinically apparent depends upon the underlying sympathetic activity of the patient receiving the drugs. Beta-blockers with ISA may prevent slowing of the heart rate, depression of atrioventricular conduction, and a decrease in myocardial contractility in the setting of a low sympathetic state, such as when the patient is resting. When the

Table 4

Pharmacology of Beta-Blockers and Dosage

General drug (brand) Propranolol (Inderal) Propranolol LA (Inderal LA) Atenolol (Tenormin) Metoprolol (Lopressor) Metroprolol ER (Toprol XL) Timolol (Blocadren) Acebutolol (Sectral) Pindolol (Visken) Labetalol (Normadyne) Nadolol (Corgard) Esmolol (Brevebloc injection)

Cardioselectivity (relative B1 sensitivity)

Intrinsic sympathetic activity

0

0

high

0

0

high

+

0

low

+

0

moderate

+

0

moderate

0

0

low

+

+

low

0

+

moderate

0

0

low

0

0

low

+

0

low

Abbreviations: ER = extended release; LA = long-acting.

Lipophilic properties

Usual maintenance dose 10–40 mg, q.i.d. 40–240 mg, q.d. 25–100 mg, q.d. 25–100 mg, b.i.d. 50–200 mg, q.d. 10–20 mg, b.i.d. 200–600 mg, b.i.d. 5–2- mg, t.i.d. 100–600 mg, b.i.d. 40–80 mg, q.d. 0.10–0.15 Ag/kg/min

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sympathetic state is high, however, the eﬀect of beta-blockers with ISA is similar to that of the usual beta-blockers, with a slowing of heart rate and a decrease of blood pressure and ventricular contractility. It should be emphasized that beta-blockers with ISA do not prevent sudden death in post-MI patients, which has been demonstrated with the use of the usual beta-blockers; therefore, these agents are not recommended in elderly patients who have had a MI [39]. The various beta-blockers diﬀer with regard to their lipophilic properties. Some betablockers, such as propranolol and metoprolol, are highly lipophilic, which facilitates transfer of the drug across the blood–brain barrier and, therefore, the lipophilic agents are more likely to produce central nervous system side eﬀects, including mood changes, depression, and sleeping disturbances [40]. In contrast, the hydrophilic beta-blockers, such as atenolol and nadolol, are less likely to produce central nervous system side eﬀects. In general, beta-blockers are well tolerated in elderly patients, and some studies have not shown any diﬀerence in prevalence of drug side eﬀects between older and younger patients [41]. However, signiﬁcant drug side eﬀects may occur in elderly patients and may be life-threatening. Bradycardia, secondary to the drug eﬀects upon the sinus node and atrioventricular conduction may occur, and, due to attenuation of bronchodilatation, asthmatic attacks may be precipitated by the drugs. Therefore, beta-blockers are contraindicated in patients with signiﬁcant bradycardia, unless a pacemaker is inserted, and in persons with a history of bronchospasm. The drugs should also be avoided, or used with caution, in persons with hypotension, hypoglycemic reactions, severe peripheral vascular disease with gangrene, mental depression, and severe heart failure secondary to severe LV systolic dysfunction. The possibility of a withdrawal rebound phenomenon with activation of acute ischemic events should be considered when discontinuing beta-blockers in elderly patients. Accordingly, if possible, the dose of beta-blockers should slowly be tapered downward before discontinuation and another antianginal drug should be started; in addition, the patient should be advised to avoid strenuous activities during the tapering period. Beta-blockers do have eﬀects on serum lipids, which need to be considered when managing elderly CAD patients. Some studies have shown beta-blockers to increase triglycerides and to decrease HDL cholesterol, although no signiﬁcant change was noted in total cholesterol or LDL cholesterol [42]. Other studies have not demonstrated a signiﬁcant eﬀect of long-term propranolol use in serum lipids in elderly persons [43]. Calcium Channel Blockers Calcium channel blockers are usually not considered as ﬁrst-line drugs in elderly patients with acute coronary artery syndromes. Unlike beta-blockers, their eﬀects are less predictable and they have not been shown to reduce mortality, sudden death, or reinfarction in post-MI patients. The studies that have shown increase in morbidity and mortality with the use of these drugs in treating hypertension or CAD are also disturbing [44,45]. In turn, calcium blockers have cardiovascular eﬀects that can be beneﬁcial in preventing and controlling angina. In general, the calcium blockers exert their eﬀect by inhibiting inﬂux of calcium ions through calcium channels of cardiac and vascular smooth muscle cells. Due to this inhibition of calcium inﬂux, myocardial contractility is decreased, dilatation of peripheral and coronary vasculature occurs, and sinus node and atrioventricular conduction function are suppressed. Therefore, myocardial oxygen demand is reduced by the decrease in preload and afterload and the decrease in myocardial contractility. Slowing of heart rate, which occurs with the use of nondihydropyridine calcium blockers, such as

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Table 5 Cardiovascular Effects of Calcium Blockers and Mechanisms to Relieve Angina Decreased myocardial O2 demand Arteriolar vasodilatation !# afterload !# wall tension Decrease contractility Decrease heart rate Increase myocardial blood ﬂow (O2) Decrease heart rate !zdiastolic perfusion time Coronary vasodilatation !zﬂow

verapamil and diltiazem, is also eﬀective in decreasing myocardial oxygen demand. In addition to reducing myocardial oxygen demand, calcium blockers can improve myocardial oxygen supply by relaxing the tone of coronary arteries and by promoting the development of coronary collaterals (Table 5). This property of relaxing coronary vasculature tone is particularly beneﬁcial when Prinzmetal angina (vasospasm) is present. Calcium channel blockers are usually divided into the dihydropyridine and nondihydropyridine groups (Table 6). Nifedipine was the ﬁrst dihydropyridine available for the treatment of angina, but newer generations of dihydropyridine agents are now available, including nicardipine, nisoldipine, nimodipine, felodipine, amlodipine, and isradipine. Nifedipine is a potent coronary and peripheral artery vasodilator with negative inotropic properties. Signiﬁcant afterload reduction occurs due to the vasodilation. At therapeutic doses, nifedipine has only a minor eﬀect on the sinus and atrioventricular nodes; thus due to the decrease in afterload, sympathetic reﬂex increases in heart rate commonly occur when the drug is administered. The increased heart rate may ameliorate the negative inotropic eﬀect, and clinically hemodynamic indices of contractility generally are unaﬀected. Due to intense vasodilation of the peripheral coronary circulation, however,

Table 6

Calcium Channel Blocker Preparations and Dosage

Generic drug (brand) Nifedipine (Procardia) (Adalat) Nifedipine GITS (Procardia XL) Nicardipine (Cardene) Amlodipine (Norvasc) Felodipine (Plendil) Diltiazem (Cardizem) Diltiazem CD (Cardizem CD) Verapamil (Isoptin) (Calan) (Verelan) Verapamil SR (Isoptin SR) (Calan SR)

Potential for SA node and AV node depression

Potential for depression of myocardial contractility

Usual adult oral dosage (mg)

0 0 0 0 0 ++ ++ ++ ++

0 to + 0 to + 0 to + 0 0 + + ++ ++

10–30, t.i.d. 30–90, q.d. 20–30, t.i.d. 2.5–10, q.d. 2.5–20, q.d. 30–90, t.i.d. 120–300, q.d. 40–120, t.i.d. 120–240, q.d.

Abbreviations: CD = extended release; GITS = gastrointestinal therapeutic system; SR = sustained release. Source: Adapted from Ref. 26.

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the possibility of a coronary steal phenomenon has to be considered when using the drug [46]. Such a phenomenon is more common when using a short-acting drug preparation and in patients with severe three-vessel CAD. Therefore, a beta-blocker should be added if nifedipine is used to treat elderly patients with acute ischemic syndromes. A sustainedrelease preparation of nifedipine is now available, which results in less sympathetic activity and is considered to be a safer agent than the shorter-acting preparations. Nevertheless, the addition of a beta-blocker with nifedipine, regardless of the type of preparation, is considered the best approach when managing elderly patients with acute ischemic syndromes. The second-generation dihydropyridines, amlodipine and felodipine, have greater vascular selectivity and less negative inotropy and have no clinical eﬀect on the sinus or atrioventricular nodes. Therefore, coronary artery steal does not appear to be a major concern with these drugs, and the drugs can be used in elderly patients with LV systolic dysfunction. Verapamil and diltiazem, two nondihydropyridine agents, are both potent inhibitors of sinus node activity and atrioventricular node conduction, in addition to being peripheral vasodilators (Table 6). Both drugs have signiﬁcant negative inotropic eﬀects. Due to these eﬀects, the drugs are eﬀective antianginal agents; however, caution is necessary when using the drugs in elderly patients with bradycardia and depressed LV systolic function. These drugs are contraindicated in patients with LV systolic dysfunction with or without clinical heart failure, in patients with disorders of the sinus node, and in patients with heart block. The Multicenter Diltiazem Post Infarction study reported an increased mortality in postinfarction patients with heart failure or abnormal LV ejection fraction who were randomized to diltiazem therapy [47]. Therefore, if a calcium channel blocker is necessary to control angina in elderly postinfarction patients with depressed LV systolic function, the second-generation dihydropyridines, amlodipine or felodipine, should be used instead of diltiazem or verapamil. Extreme caution is required when using diltiazem or verapamil in combination with a beta-blocker, particularly in elderly patients who demonstrate sinus node or atrioventricular conduction dysfunction, or in elderly patients who have depressed LV systolic function. Some authorities recommend ECG monitoring when initiating these drugs, particularly verapamil, in combination with beta-blockers. It should be emphasized that the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines state that there are no Class I indications for using calcium channel blockers during or after MI [48]. However, if angina pectoris persists despite the use of beta-blockers and nitrates, long-acting calcium channel blockers such as dilatiazem or verapamil should be used in elderly patients with CAD and normal LV systolic function and amlodipine or felodipine in patients with CAD and abnormal LV systolic function as antianginal agents. Aspirin Recent knowledge of the importance of thrombus formation in acute coronary syndromes and the results of studies that demonstrate a decreased incidence of MI in patients taking daily aspirin compared to patients receiving placebo [49] indicate that a daily aspirin should be prescribed for all elderly patients with angina. The speciﬁc dosage of oral aspirin is unclear, since the dosage in studies has varied; the usual dosage is considered to be 160 to 325 mg/day.

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In an observational prospective study of 1410 patients, mean age 81 years, with prior MI and hypercholesterolemia, 59% of patients were treated with aspirin [50] at 36-month follow-up; use of aspirin was associated with a 52% reduction in new coronary events [50]. Ticlopidine and Clopidogrel Not all patients can tolerate aspirin, and recently an aspirin-resistance phenomenon has been described in patients where there is little-to-no antiplatelet eﬀect from the drug. Ticlopidine and clopidogrel are useful alternatives to aspirin when the drug is not tolerated, although ticlopidine and clopidogrel have their own associated toxicities [51]. Angiotensin Converting Enzyme Inhibitors Based on the results of various clinical trials, there is now strong evidence that angiotensin converting enzyme (ACE) inhibitors can reduce the frequency of new cardiovascular events in both normotensive and hypertensive patients with known vascular disease and in patients with diabetes mellitus. If tolerated, ACE inhibitors should be part of a medical regimen to treat chronic ischemic heart disease [52].

AN APPROACH TO MANAGEMENT: SPECIFIC PRACTICE CONSIDERATIONS Unstable Angina Unstable angina is a transitory syndrome that results from disruption of a coronary atherosclerotic plaque with the subsequent cascade of pathological processes, including thrombosis formation that critically decreases coronary blood ﬂow resulting in new onset or exacerbation of angina (ischemia) [53]. Transient episodes of vessel occlusion or near occlusion by thrombus at the site of plaque injury may occur and lead to angina at rest. The thrombus may be labile and result in temporary obstruction to ﬂow. Release of vasoconstriction substances by platelets and vasoconstriction secondary to endothelial vasodilator dysfunction contribute to further reduction in blood ﬂow [54], and in some patients myocardial necrosis (non-Q-wave infarction) is documented. Table 7 lists the various clinical presentations that are classiﬁed as unstable angina. In contrast to elderly patients with stable angina who do not require hospitalization, elderly patients with unstable angina are usually hospitalized and, depending upon their

Table 7

Unstable Angina Presentations

Rest angina within 1 week of presentation New-onset angina of Canadian Cardiovascular Society Classiﬁcation (CCSC) class III or IV within 2 months of presentation Angina increasing in CCSC class to at least CCSC III or IV Variant angina Non-Q-wave myocardial infarction Postmyocardial infarction angina (>24 h)

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risk stratiﬁcation, may require monitoring in an intensive care unit. Severe classiﬁcation schemes of risk stratiﬁcation have been developed. Table 8 lists a classiﬁcation that subdivides patients into high-, intermediate-, and low-risk groups [55]. As noted by this classiﬁcation, clinical characteristics are readily identiﬁable on the initial patient evaluation that stratiﬁes the patient into low-, intermediate-, or high-risk subgroups for hospital complications. For example, acute resting ECG abnormalities markedly worsen the prognosis. Other characteristics that identify the high-risk patient include prolonged ongoing rest pain longer than 20 min and signs of LV dysfunction (S3, rales, new murmur or mitral regurgitation). Within each subgroup of unstable angina, it is important to recognize certain elderly patients who have speciﬁc characteristics that will inﬂuence therapy. Recurrent angina after PTCA is a common clinical event related to partial artery restenosis and occurs in as many as 40% of patients within the ﬁrst 3 to 6 months postPTCA, regardless of the patient’s age. The prognosis is favorable, and the elderly patient can usually be stabilized medically prior to a scheduled repeat angiogram and a possible repeat PTCA. Angina after intracoronary stent placement occurs less frequently than after isolated angioplasty and is often the result of subacute closure due to thrombus formation. These patients are at higher risk for MI and are usually managed as higher risk patients [56]. Patient with angina following CABG are another subgroup of elderly patients who require speciﬁc considerations. Since the risk of reoperation is higher than that of the initial surgery, surgeons are often reluctant to reoperate in elderly patients, especially on those elderly patients who have had internal mammary grafting. Medical therapy is usually the ﬁrst approach to this subgroup of elderly patients with unstable angina. Other clinical subgroups of elderly patients with unstable angina who require special considerations are the patient with a non-Q-wave infarct, variant angina, and cocaine intoxication. Table 9 lists the ACC/AHA stratiﬁcation of patients with unstable angina into highrisk, intermediate-risk, and low-risk groups for short-term risk of death or nonfatal MI [57]. Following risk stratiﬁcation of the elderly patient with unstable angina, therapy should be initiated. The initial goals of therapy should be to alleviate symptoms by decreasing myocardial oxygen demand and increasing myocardial blood ﬂow and to stabilize the atherosclerotic plaque. Furthermore, a plan to promote regression of the atherosclerotic lesion should be initiated during the patient’s hospitalization.

Table 8 Risk Stratification Scheme of Unstable Angina Based on Presenting Clinical Characteristics Risk Classa IA IB II III IV a

Clinical Characteristics Acceleration of previous exertional angina without ECG changes Acceleration of previous exertional angina with ECG changes New onset of exertional angina New onset of rest angina Coronary insuﬃciency syndrome; protracted chest pain >20 min with persistent ECG changes

IA = lowest risk for in-hospital complications; IV = highest risk for in-hospital complications. Source: Adapted from Ref. 55.

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Table 9 Risk Stratification of Patients With Unstable Angina for Short-Term Risk of Death or Nonfatal Myocardial Infarction High Risk (at least 1 of following factors) Accelerating tempo of ischemic symptoms in prior 48 h Prolonged ongoing (>20 min) rest pain

Pulmonary edema; new or worsening MR murmur; S3 or new/ worsening rales; hypotension, tachycardia, bradycardia; age >75 years Angina at rest with transient ST-segment changes >0.05 mV; bundle branch block, new or presumed new; sustained ventricular tachycardia Markedly elevated troponin T or I (>0.1 ng/ml)

Intermediate Risk (No high-risk feature but 1 of following features)

Low Risk (No high or intermediate risk feature)

Prior MI or CABG; peripheral or cerebrovascular disease; prior aspirin use Prolonged (>20 min) rest angina, now resolved, with moderate or high likelihood of CAD; rest angina (<20 min or relieved with rest or sublingual NTG) Age >70 years

—

New-onset CCS Class III or IV angina in past 2 weeks with moderate or high likelihood of CAD

—

T-wave inversions >0.2 mV; pathological Q waves

Normal or unchanged ECG during episode of chest discomfort

Slightly elevated troponin T or I (>0.01 but <0.1 ng/mL)

Normal

Abbreviations: MI = myocardial infarction; CABG = coronary artery bypass graft surgery; CAD = coronary artery disease; CCS = Canadian Cardiovascular Society; NTG = nitroglycerin; MR = mitral regurgitation. Source: Adapted from Ref. 57.

Therapy, including drug therapy, should be started in the emergency department; it should not be delayed until hospital admission. Reversible factors causing angina should be identiﬁed and corrected. Electrocardiographic monitoring is important since arrhythmias can occur and ST-T changes are a marker of increased risk of complications. The aggressiveness of the drug dosage will depend upon the severity of symptoms and will need modiﬁcation through the elderly patient’s hospitalization. Oxygen should be given to patients with cyanosis, respiratory distress, heart failure, or high-risk factors. Oxygen therapy should be guided by arterial saturation; its use when the baseline saturation is more than 94% is questionable. Morphine sulfate should be administered intravenously when

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symptoms are not immediately relieved with nitroglycerin or when acute pulmonary congestion and/or severe agitation is present. Aspirin should be given to all patients with unstable angina unless contraindicated and continued indeﬁnitely. Clopidogrel should be administered to patients who are unable to tolerate aspirin because of hypersensitivity or major gastrointestinal intolerance. Data from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial favors the use of aspirin plus the use of clopidogrel for 9 months in patients with unstable angina [58]. The ACC/AHA guidelines for unstable angina revised at the ACC Meeting on March 15, 2002 support the use of aspirin plus clopidogrel in high-risk and intermediate-risk patients with unstable angina, with clopidogrel withheld for 5 to 7 days if CABG is planned. Parenteral anticoagulation with intravenous infractionated heparin or preferably with subcutaneous low-molecular-weight heparin [59–62] should be added to antiplatelet therapy in patients with high-risk or intermediate-risk unstable angina. The revised ACC/ AHA guidelines for unstable angina also recommend adding a platelet glycoprotein IIb/ IIIa inhibitor in addition to aspirin, clopidogrel, and low-molecular-weight heparin in patients with continuing ischemia or with other high-risk features, and to patients in whom PTCA is planned. Eptiﬁbatide and tiroﬁban are approved for this use [57]. Abciximab can also be used for 12 to 24 h in patients with unstable angina in whom PTCA is planned within the next 24 h [57]. As with the use of aspirin, nitrates should be instituted quickly in the emergency department. Patients whose symptoms are not fully relieved with three sublingual nitroglycerin tablets should receive continuous intravenous nitroglycerin. The initial dose is 5 to 10 mg/min, and the dose should be titrated every 3 to 5 min to relieve symptoms or hypertension. If angina is relieved, then an oral or transdermal preparation can be started after 24 h of intravenous therapy. Beta-blockers (in addition to aspirin, heparin, and nitrates) should also be started in the emergency room unless there are contraindications. Intravenous loading (e.g., metoprolol 5 mg for 5 min, repeated every 15 min for a total of 15 mg) followed by oral therapy is recommended. A continuous beta-blocker intravenous infusion may be used (esmolol, starting maintenance dose of 0.1 g/kg/min intravenously with titration upward in increments of 0.5 g/kg / min every 10 to 15 min as tolerated by blood pressure until the desired response has been obtained, limiting symptoms develop, or a dose of 0.20 mg/min is reached). An oral angiotensin converting enzyme inhibitor should also be administered unless there are contraindications. Interventional Therapy The majority of elderly patients with stable and unstable angina can be stabilized with medical management. Patients who continue to have unstable angina 30 min after initiation of therapy or who have recurrent unstable angina during the hospitalization are at increased risk for MI or cardiac death. In addition, patients who demonstrate major ischemic complications, such as pulmonary edema, ventricular arrhythmias, or cardiogenic shock associated with unstable angina also have a poor prognosis. In these patients, emergency cardiac catheterization should be performed with the consideration of interventional therapy (CABG or PTCA). Insertion of an intra-aortic balloon pump may be necessary in some of these elderly patients. For the majority of elderly patients whose angina is stabilized, two alternate strategies for deﬁnitive treatment of angina need to be considered: ‘‘early invasive’’ and ‘‘early conservative’’ [63]. The ‘‘early invasive strategy’’ approach is to perform cardiac catheterization in all patients after 48 h of presentation unless interventional therapy is contra-

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indicated due to extensive comorbidities. In contrast, the ‘‘early conservative’’ strategy is to perform cardiac catherization only in patients who have one or more of the following high-risk indicators: prior revascularization, associated congestive heart failure or depressed LV ejection fraction (<50%) by noninvasive study, malignant ventricular arrhythmia, persistent or recurrent pain/ischemia, and/or a functional study (stress test) indicating high risk. On the basis of data from the TACTICS—Thrombolysis in Myocardial Infarction 18 study, an early invasive strategy is superior to a conservative strategy in high-risk unstable angina patients [64]. The revised ACC/AHA guidelines recommend an early invasive strategy for all high-risk patients with unstable angina. A stress test can be performed 48 to 72 h after the patient has stabilized. The choice of the type of stress testing (exercise, exercise with imaging, or pharmacological) will depend upon the resting ECG ﬁndings and the patient’s ability to exercise. Myocardial revascularization is indicated in patients who at catheterization are found to have signiﬁcant left main CAD (z50%) or signiﬁcant (z70%) three-vessel disease with depressed left ventricular function (LV ejection fraction <50%); patients with twovessel disease with proximal severe subtotal stenosis (z95%) of the left anterior descending coronary artery and depressed LV ejection fraction; and patients with signiﬁcant CAD if they fail to stabilize with medical treatment, have recurrent angina/ischemia at rest or with low-level activities, and/or if ischemia is accompanied by congestive heart failure symptoms, an S3 gallop, new or worsening mitral regurgitation, or deﬁnite ECG changes [63]. The ACC/AHA guidelines recommend CABG for patients with unstable angina with signiﬁcant left main CAD, three-vessel CAD, and for two-vessel CAD with signiﬁcant proximal left anterior descending CAD and either abnormal LV function (ejection fraction <50%) or demonstrable ischemia on noninvasive testing [57]. PTCA or CABG is recommended for patients with one-vessel or two-vessel CAD without signiﬁcant proximal left anterior descending CAD, but with a large area of viable myocardium and high-risk criteria on noninvasive testing. PTCA is recommended for patients with multivessel CAD with a suitable coronary anatomy with normal LV function and without diabetes mellitus [57]. For some patients without these high-risk features, revascularization may still be an option, depending on recurrent symptoms, test results, and patient preferences. The healthcare team should educate the patient and his or her family or advocate about the expected risks and beneﬁts of revascularization and determine individual patient preferences and fears that may aﬀect the selection of therapy. Interventional therapy with PTCA, atherectomy, and/or some combination of PTCA and coronary artery stenting has increased in usage in patients with CAD, diminishing the frequency of CABG. Studies comparing PTCA and CABG have been performed, and generally the results of PTCA and CABG are similar in reference to mortality. However, an increased incidence of recurrent angina and need for revascularization procedure occurs with PTCA [65–67]. Further studies are necessary to determine if coronary stenting in conjunction with PTCA will decrease the incidence of recurrent angina and the need for revascularization. Stable Angina Elderly patients with stable angina who are at ‘‘low risk’’ (preserved LV function and no left main CAD) can be treated as eﬀectively with medical therapy as with interventional therapy. In patients with stable angina, the atherosclerotic lesions are predominantly

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advanced ﬁbrolipoid plaques or ﬁbrotic lesions [68]. Usually no plaque ulceration or thrombosis is present, and the main cause of angina is the reduction of luminal diameter of the coronary vessel due to chronic atherosclerosis. Therefore, therapy is directed at decreasing myocardial oxygen demand and increasing coronary blood ﬂow. In addition, prevention of plaque instability and initiation of therapy to cause regression of the atherosclerotic lesion are necessary. Studies have not demonstrated any signiﬁcant beneﬁt of a speciﬁc class of antianginal drugs compared to other classes in treatment of stable angina. Therefore, the choice of a single antianginal drug will depend upon the clinical situation, contraindications, and the physician’s preference. Surely a beta-blocker should be the ﬁrst choice in elderly patients who have a history of MI or demonstrate electrocardiographic evidence of silent infarction or silent myocardial ischemia [69]. Combination drug therapy, in which a beta-blocker and a vasodilator are used, is highly advantageous in treating elderly patients with angina. Studies have shown that combination therapy with a nitrate and beta-blocker decreases the number of anginal attacks and increases the duration of time of treadmill stress testing as compared to either nitrates or beta-blockers alone [70]. The combination of a beta-blocker and a calcium channel blocker has also been shown to be more eﬀective in reducing angina and extending exercise time than monotherapy [70]. Such a combination can be very beneﬁcial when attempting to control both hypertension and angina in elderly patients. In turn, caution is necessary when using beta-blockers in combination with diltiazem or verapamil due to the potential risk of provoking serious bradycardia or precipitating heart failure. This is particularly a concern when verapamil and a beta-blocker are used in combination, and when underlying sinus or atrioventricular nodal disease or LV systolic dysfunction is present. In elderly patients whose angina is refractory to double drug therapy, triple drug therapy may be necessary. Such therapy would include a beta-blocker, a long-acting nitrate, and a calcium channel blocker. Such therapy may be beneﬁcial in preventing anginal attacks. Howver, elderly patients takig these multiple dugs will need to be monitored closely for side eﬀects, and the drugs should be started at low doses. Patients aged 75 years or older with angina despite standard drug therapy beneﬁt more from coronary revascularization than from optimal medical therapy in terms of symptom relief and quality of life [71,72]. A preventive program in elderly patients with angina is mandatory, including abstinence from smoking, treatment of hypertension, use of aspirin and ACE inhibitors, an exercise program, and control of lipids and weight. Treatment of associated heart failure and anemia can also prevent or relieve symptoms of angina. The recent studies that have demonstrated the eﬃcacy of statin therapy in lowering serum lipids and in preventing future coronary events in elderly patients with CAD [73–77] compel physicians to screen elderly anginal patients for elevated serum lipids and to be aggressive in their treatment of lipid abnormalities. In the Heart Protection Study, 20, 536 adults up to age 80 years with CAD, other occlusive arterial disease, or diabetes mellitus were randomized to simvastatin 40 mg daily or double-blind placebo and followed for a mean of 5 years [77]. All-cause mortality, coronary events, stroke, and coronary and noncoronary revascularization were signiﬁcantly reduced by simvastatin, regardless of age and initial serum lipids [77]. In addition, elderly patients will require counseling in reference to lifestyle, with avoidance of activities that ‘‘trigger’’ ischemic attacks [78]. The physician will need to be aware of the potential for the development of mental depression in elderly CAD patients. The symptoms of depression may be subtle in elderly patients and will progress unless the

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disease is treated. Depression has also been shown to be a risk factor for future coronary events in patients with CAD [79]. The role of exercise should be emphasized when managing elderly patients with angina. Exercise programs that progressively increase physical endurance and reduce the heart rate and cardiac work at any given level of activity lead to improvement in cardiac performance and prolong exercise time before onset of angina [80]. In addition, some studies have shown stress-induced myocardial ischemia (as assessed by thallium 201 scintigraphy) to be signiﬁcantly decreased after a 1-year program of supervised exercise and low cholesterol diet in patients with stable angina [81]. Caution is necessary, however, when initiating an exercise program in elderly CAD patients. Elderly patients should be screened for high-risk characteristics, including results of a stress test, before starting an exercise program since exercise can provoke serious arrhythmias in high-risk patients, especially in poorly conditioned patients. Other exercise programs can be advised according to the patient’s needs and preference, such as swimming or stationary cycling. New Approaches to Management of Angina Over the years, the management of patients with angina has changed, and new approaches have developed. Some of these changes are due to increased knowledge of the underlying pathophysiology of myocardial ischemia with the development of new drugs. Other changes are related to the development of innovative mechanical devices and techniques that theoretically should relieve angina. Innovative new drugs being considered for FDA approval include ranolazine, an orally active drug that improves myocardial metabolism by inhibiting the uptake of free fatty acids [82]. Nicorandil is also under investigation as a coronary vasodilator with a unique dual mechanism of action that involves a nitrate-like eﬀect and a potassium ion channel opening action [82]. Two recent mechanical techniques for the treatment of angina include transmyocardial laser revascularization (TMLR) and enhanced external counter pulsation (EECP). Both of these approaches have been used in patients with severe angina who are not candidates for PTCA or CABG, usually due to diﬀuse CAD or extreme comorbidities. Such approaches would appear to be suitable for many elderly CAD patients who may have inoperable CAD and multiple comorbidities plus angina that is diﬃcult to control with medical therapy. TMLR employs a high-energy laster beam to create channels in the myocardium from the epicardial to the endocardial surface [83]. The channels allow oxygenated LV blood to perfuse ischemic myocardial zones [84]. The human myocardium contains an extensive network of sinusoids, and TMLR theoretically delivers oxygenated blood to these sinusoids with improved myocardial oxygen delivery to the ischemic region. Data on the eﬃcacy of TMLR in improving anginal symptoms and exercise capacity are controversial [85–87]. EECP is a noninvasive outpatient treatment designed to increase coronary ﬂow in the treatment of angina [88]. This treatment involves wrapping the calves, thighs, and buttocks with pneumatic cuﬀs. Synchronized pulsatory pressure is applied sequentially from calves to thighs during diastole, returning arterial blood to the heart to increase diastolic pressure in the coronary vessels. Pressure is relieved during systole, reducing afterload and cardiac work, thus decreasing myocardial oxygen demand. The typical course of treatment is 35 1-h sessions over a period of 7 weeks. EECP has been shown to improve

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ischemia in patients who have thallium reperfusion evidence of ischemia. In one study of patients who received EECP, 75% of subjects had resolution of ischemia, demonstrated by improved thallium scintigraphy with normal thallium stress tests, except for areas scarred by previous MIs [89]. In addition, the subjects showed exercise improvement. A controlled study of 139 patients showed a reduction in anginal episodes, an increase in the time to 1-mm ischemic ST-segment depression, and a trend toward reduced nitroglycerin use in the EECP group but a similar increase in exercise duration in both groups [90]. Based on the results of these preliminary studies, these new techniques may have a role in the management of certain elderly patients with angina. Further studies are necessary, however, before these new approaches can be recommended as therapy for the management of elderly patients with severe angina refractory to conventional medical therapy.

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65. 66.

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68. 69.

70. 71.

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12 Therapy of Acute Myocardial Infarction Michael W. Rich Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri, U.S.A.

In 2000, there were 781,000 hospital admissions in the United States with a ﬁrst-listed diagnosis of acute myocardial infarction (MI) [1]. Of these, 499,000 (63.9%) occurred in patients 65 years of age or older, and approximately one-third occurred in patients over the age of 75 [1,2]. Moreover, 85% of all deaths attributable to acute MI occurred in patients over age 65, and 60% occurred in patients over age 75 [2,3]. It is thus clear that acute MI is exceedingly common in older adults, and the case-fatality rate in this population is particularly high. In this chapter, the treatment of elderly patients with acute MI, including the management of selected complications, will be reviewed.

GENERAL PRINCIPLES Numerous studies have demonstrated that elderly patients with acute MI are at increased risk for a variety of complications, including atrial ﬁbrillation, congestive heart failure, myocardial rupture, cardiogenic shock, and death [4–9]. The risk of each of these complications is two- to four-fold higher in patients over age 65 than in younger patients. Older age thus deﬁnes a high-risk subgroup of MI patients who could potentially derive substantial beneﬁt from aggressive therapeutic interventions. On the other hand, elderly patients are at increased risk for serious adverse consequences arising from aggressive treatments such as thrombolytic therapy or early catheterization and angioplasty. In addition, the risk–beneﬁt ratio may be modulated by the presence of comorbid conditions (e.g., diabetes, renal insuﬃciency, dementia), as well as social considerations and patient preferences. It is thus evident that the potential beneﬁts and risks of each intervention must be carefully considered on an individualized basis. While elderly MI patients clearly represent a high-risk subgroup, it is important to recognize that they also comprise an extremely heterogeneous subgroup, and this heterogeneity has important therapeutic implications. For example, an 80-year-old patient presenting with a large anterior MI complicated by heart failure and hypotension has an expected mortality of over 50%. As a result, the potential beneﬁt to be derived from maximally aggressive therapy (e.g., immediate catheterization and angioplasty) is large, thereby 297

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justifying a moderate increase in procedural risk. In contrast, an 80-year-old individual presenting with a small inferior MI of more than 12 h duration who is hemodynamically stable and free of chest pain has a relatively favorable prognosis, and the risks associated with thrombolysis and direct angioplasty may not be justiﬁed. Thus, in considering the interventions described below, the clinician should keep in mind that the ‘‘sickest’’ patients often have the most to gain from aggressive treatment, while those with a more favorable prognosis often respond satisfactorily to conservative management.

GENERAL MEASURES As in younger patients, the early management of older patients with acute MI should include measures designed to relieve the patient’s discomfort and treat any hemodynamic disturbances, such as heart failure or hypotension (Table 1). Morphine sulfate in doses of 2 to 4 mg intravenously is the recommended agent for treating chest pain in patients with acute MI [10]. Empiric administration of supplemental oxygen is appropriate, but it is unlikely to improve tissue oxygen delivery if the baseline arterial saturation exceeds 92%. Nitroglycerin is safe in the majority of patients with acute MI, and it is eﬀective in reducing myocardial oxygen demand when administered sublingually, transdermally, or intravenously. Nitrates can occasionally result in a precipitous fall in blood pressure, especially when given sublingually to patients with inferior MI associated with right ventricular involvement [11]. Intravenous beta-blockers are also highly eﬀective in relieving chest pain, and both metoprolol and atenolol have been approved for use in patients with acute MI [12,13]. As discussed below, contraindications to beta-blockers include marked bradycardia, hypotension, moderate or severe heart failure, advanced atrioventricular block, and signiﬁcant bronchospastic lung disease. Heart failure (HF) and hypotension are common complications of acute MI in the elderly, and each is discussed in more detail later in this chapter. They are mentioned brieﬂy here because they are often present when the patient arrives in the emergency room and empiric therapy may be necessary. In most cases, HF occurring in the early stages of acute MI can be eﬀectively treated with a combination of diuretics, nitrates, and supplemental oxygen. In patients who do not respond to these measures, further investigation into the etiology of HF is appropriate. Urgent echocardiography is the most useful noninvasive test in this setting, since it allows assessment of left and right ventricular function, valvular structures, and the pericardium. Sympathomimetic agents such as dobutamine and dopamine are best avoided in the early hours of acute MI because they increase myocardial oxygen demand and may worsen ischemia, but patients with severe heart failure, particularly when accompanied by hypotension, may require inotropic therapy. In the absence of supraventricular tachyarrhythmias, digitalis has little value in the management of HF associated with acute MI. Hypotension, particularly when accompanied by HF or impaired tissue perfusion, is a grave prognostic sign warranting prompt intervention. Hypotension without HF should be treated with intravenous ﬂuids at a rate of 75 to 250 cc/h until an adequate blood pressure has been restored or until signs of HF develop. In patients with inferior MI, hypotension associated with bradycardia may be due to heightened vagal tone, and may respond to subcutaneous or intravenous atropine, 0.5 to 1.0 mg. Further investigation is required if the blood pressure fails to respond to ﬂuid resuscitation, and both noncardiac

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Table 1 General Measures for the Early Management of Elderly Patients with Acute Myocardial Infarction Symptom or sign Chest pain

Agent Oxygen

2–5 L/min

Morphine

Dobutamine

2–4 mg IV, q 5–10 min 0.4 mg sublingually 2% ointment, 1/2–2VV transdermally 10–200 Ag/min i.v. 2.5–5 mg i.v., up to 15 mg 2.5–5 mg i.v., up to 10 mg As needed to maintain arterial saturation z 92% 20–80 mg i.v. 0.5–2 mg i.v. 2% ointment, 1/2–2VV transdermally 10–200 Ag/min i.v. As needed to maintain adequate perfusion 2.5–10 Ag/kg/min

Dopamine Norepinephrine

2–40 Ag/kg/min 0.5–30 Ag/min

Nitroglycerin

Metoprolol Atenolol Congestive heart failure

Oxygen

Furosemide Bumetanide Nitroglycerin

Hypotension

Dose

IV ﬂuids

Comment Probably not helpful if O2 saturation z92% Watch for respiratory depression Watch for hypotension, especially in inferior MI

Watch for bradycardia, hypotension, heart, block, bronchospasm, worsening HF

Watch for hypotension Watch for hypotension Avoid hypotension

Watch for worsening heart failure Watch for worsening hypotension; may aggravate ischemia May worsen ischemia May worsen ischemia

Abbreviations: HF = heart failure; IV = intravenously; MI = myocardial infarction.

(e.g., sepsis, pulmonary embolism, medications) and cardiac causes of hypotension should be considered. In patients with persistent unexplained hypotension, the use of an inotropic or vasopressor agent may be necessary, but the precautions discussed above should be borne in mind.

FIBRINOLYTIC THERAPY In the mid-to-late 1980s, a series of large randomized clinical trials demonstrated that intravenous administration of a ﬁbrinolytic agent within 6 to 12 h of symptom onset in patients with acute MI associated with ST-segment elevation or left bundle branch block led to a signiﬁcant reduction in short-term and long-term mortality [14–18]. These studies ushered in the reperfusion era and revolutionized the approach to treatment of patients

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with acute coronary syndromes. However, despite the fact that more than 15 years have elapsed since publication of the ﬁrst large trial of ﬁbrinolytic therapy [14], the value of this treatment in patients over age 75 remains controversial. In 1994, the Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group published a meta-analysis of all major trials, including a subgroup analysis by age (Fig. 1) [19]. Although the greatest absolute beneﬁt was seen in patients 65 to 74 years of age (26 fewer deaths per 1000 treated patients), the beneﬁt was more modest in patients over age 75 years (10 fewer deaths per 1000 treated patients) and failed to achieve statistical signiﬁcance. Reanalysis of the FTT data, limited to patients presenting within 12 h of symptom onset with ST-segment elevation or left bundle branch block, showed that among patients 75 years of age or older, mortality was reduced from 29.4% to 26.0% (34 fewer deaths per 1000 treated patients, p = 0.03) [20]. Moreover, the absolute beneﬁt was similar to that seen in other age groups, and greater than in patients younger than age 55. In contrast to the FTT analysis, three recent observational studies have suggested that the use of thrombolytic therapy in patients over 75 years of age may be associated with adverse outcomes [21–23]. In one study, Thiemann et al. examined outcomes in 7864 Medicare patients with acute MI who were suitable candidates for thrombolytic therapy [21]. Among patients 65 to 75 years of age, administration of a thrombolytic agent was associated with reduced mortality, consistent with the randomized trials. However, among patients aged 76 to 86, mortality was 38% higher in those who received a thrombolytic drug. In another study, also based on the Medicare database, Berger et al. found that 30day mortality tended to be higher among patients over 75 years of age receiving thrombolytic therapy, although 1-year mortality was lower (perhaps reﬂecting selection bias) [22]. Finally, Soumerai et al. examined outcomes of thrombolytic therapy at 37 Minnesota hospitals and found that ﬁbrinolytic treatment was associated with a 40% higher mortality rate among patients 80 years of age or older [23]. One plausible explanation for the apparent discrepancy between the clinical trials and community-based analyses is that criteria for thrombolysis were strictly regulated in

Figure 1 Efficacy of thrombolytic therapy by age. Source: Ref. 19.

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clinical trials, thus ensuring an optimal beneﬁt–risk ratio. Nonadherence to these criteria in clinical practice may have led to overutilization of ﬁbrinolytic agents in patients who were less-than-ideal candidates for such therapy, resulting in diminished beneﬁt and increased complications. In summary, data from multiple randomized clinical trials demonstrate that thrombolytic therapy is beneﬁcial in appropriately selected elderly patients, including those over 75 years of age. However, observational studies indicate that caution is advised in the very elderly, and suggest that strict adherence to established criteria for use of thrombolytic drugs is essential in patients over age 75 in order to maximize beneﬁt and minimize risk. One factor that limits utilization of ﬁbrinolytic therapy in elderly patients is concern about increased risk of bleeding, particularly intracranial hemorrhage. In the FTT overview of nine large thrombolytic trials, strokes occurred in 1.2% of patients receiving a thrombolytic agent, compared to 0.8% in control group patients (absolute diﬀerence 0.4%; p < .0001) [19]. Moreover, the excess in strokes attributable to thrombolysis increased with age. Thus, in patients over 75 years of age, the stroke rate was 2.0% in patients receiving thrombolytic therapy, as compared to 1.2% in controls. Other serious bleeding complications, deﬁned as either life-threatening or requiring transfusion, were relatively uncommon, occurring in 1.1% of patients over 75 years of age receiving thrombolytic treatment, as compared to 0.5% of control group patients. Notably, the excess in major bleeding complications attributable to thrombolysis was similar in older and younger patients. Thus, the absolute excess risk for both strokes and major bleeding is less than 1%. Nonetheless, caution is advised when using thrombolytic agents in elderly patients at increased risk for stroke (e.g., those with prior cerebrovascular disease, severe uncontrolled hypertension, or a markedly increased arterial pulse pressure), as well as in patients at increased risk for serious bleeding [24–26]. Several large trials have compared the eﬀects of diﬀerent ﬁbrinolytic agents on clinical outcomes [27–30]. In the GUSTO-I trial (Global Utilization of Streptokinase and tPA for Occluded Arteries), which randomized over 40,000 acute MI patients to one of four thrombolytic regimens, alteplase was associated with lower 30-day mortality than streptokinase in patients up to the age of 85 [30]. However, the absolute beneﬁt was small in patients over 75 years of age, and alteplase was associated with a signiﬁcantly higher risk of intracranial hermorrhage (ICH) compared to streptokinase in this age group (2.1% vs. 1.2%; p < 0.05) [31]. More recent studies with the newer ﬁbrinolytic agents reteplase and tenecteplase failed to demonstrate a survival advantage of these agents compared to alteplase [32,33], and in the GUSTO-III trial, reteplase was associated with a higher rate of ICH than alteplase (2.5% vs. 1.7%) among patients over 75 years of age [32]. Thus, currently available data indicate that the more ﬁbrin-speciﬁc ﬁbrinolytic agents (i.e., alteplase, reteplase, tenecteplase) are associated with increased risk of ICH compared to streptokinase in patients over age 75, and the merits of these agents with respect to other clinical outcomes, including mortality, have not been convincingly established in the very elderly. Streptokinase is administered in a dose of 1.5 million units intravenously over 1 h, and no dosage adjustment is required for elderly patients. Alteplase should be administered as an initial bolus of 15 mg, followed by 0.75 mg/kg over 30 min (not to exceed 50 mg), and 0.5 mg/kg over the next 60 min (not to exceed 35 mg) [30]. Reteplase is administered in two bolus doses of 10 MU at an interval of 30 min [32]. Tenecteplase is given as a single 30- to 50-mg bolus based on weight [33]. Aspirin 160 to 325 mg should be given to all patients receiving thrombolytic therapy. Patients treated with alteplase, reteplase, or tenecteplase should also receive intravenous heparin to maintain the activated

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partial thromboplastin time (aPTT) in the range of 50 to 70 s for the ﬁrst 24 to 48 h [34,35]. For patients treated with streptokinase, data from the GUSTO study indicate that intravenous heparin increases bleeding complications but does not improve survival relative to high-dose subcutaneous heparin (12,500 U every 12 h) [30].

CORONARY ANGIOPLASTY Percutaneous transluminal coronary angioplasty (PTCA) has several potential applications in the acute MI setting: as a primary reperfusion strategy; as an adjunct to thrombolysis; as a ‘‘rescue’’ procedure for failed thrombolysis; and in the management of recurrent ischemia [36,37]. In several studies, PTCA has been shown to be more eﬀective than thrombolytic therapy in recanalizing the infarct-related coronary artery, with reperfusion rates of over 90% in some series [37]. In addition, an overview of seven randomized trials comparing PTCA with thrombolysis found that PTCA was associated with lower mortality, better left ventricular function, and fewer intracranial bleeds [36]. Moreover, high-risk subgroups, including the elderly and patients with large infarcts, appear to derive the most beneﬁt from primary PTCA [38]. Consequently, it has been suggested that PTCA may be the preferred treatment for elderly patients who are suitable candidates for reperfusion [39]. Unfortunately, most of the studies comparing PTCA and thrombolytic therapy have been relatively small and have included very few elderly patients. Thus, there are limited data on the use of primary PTCA in the elderly, particularly in patients over 75 years of age. The largest study to date comparing angioplasty and thrombolysis for acute MI was the GUSTO-IIB trial (Global Use of Strategies to Open Occluded Coronary Arteries) [40]. In this study, which involved 1138 patients, the composite outcome of death, nonfatal reinfarction, and disabling stroke at 30 days follow-up was reduced 33% with PTCA compared to alteplase ( p = .033), but mortality did not diﬀer between groups. Among 300 patients over 70 years of age, mortality tended to be lower with PTCA, but again the diﬀerence was not signiﬁcant. With respect to the composite endpoint, patients 70 to 79 years of age appeared to beneﬁt from PTCA, but there was no apparent beneﬁt in a small subgroup of patients over the age of 80 [41]. Similarly, several large observational studies have provided mixed results on the relative merits of primary PTCA compared to ﬁbrinolytic therapy in the very elderly [42–45]. An important limitation of all of these studies is that they were conducted prior to the widespread use of glycoprotein IIb/IIIa inhibitors and intracoronary stents. However, while both of these innovations have been associated with improved outcomes in patients up to 75 years of age, their value in treating very elderly patients with acute MI remains to be established. In summary, current data suggest that PTCA can be performed safely in elderly patients with acute MI, and that it is associated with fewer hemorrhagic strokes than thrombolysis. While present data are insuﬃcient to allow deﬁnitive conclusions on the relative merits of primary PTCA compared to thrombolysis in the elderly, PTCA is an eﬀective alternative in appropriately selected patients, and should be strongly considered when thrombolytic therapy is contraindicated [10,46]. Very high-risk elderly patients, such as those with large anterior MIs or severe hemodynamic disturbances, may also beneﬁt from this approach. However, data from the SHOCK trial suggest that MI patients over 75 years of age with cardiogenic shock do not beneﬁt from an aggressive strategy that includes early percutaneous revascularization [47].

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The routine use of PTCA following thrombolysis has been evaluated in several trials, none of which have demonstrated improved outcomes relative to conservative management [48–53]. Patients who experience recurrent ischemic pain or marked ST-segment changes on a predischarge stress test are at high risk for recurrent ischemic events following hospital discharge. Coronary angiography and revascularization with either PTCA or coronary bypass surgery is appropriate in these patients [54], and age per se is not a contraindication to these procedures [36,37]. Patients with persistent ischemic pain following administration of a thrombolytic agent, particularly when accompanied by hemodynamic instability (e.g., hypotension or marked HF), are also at high risk for adverse outcomes, and ‘‘rescue’’ PTCA may improve prognosis in this subgroup [36,37,55]. Thus, although cardiac catheterization and revascularization are not recommended as routine procedures for all patients with acute MI, they should be strongly considered in patients with persistent chest pain, marked hemodynamic instability, or recurrent ischemia in the early post-MI period [10,46].

ANTITHROMBOTIC AGENTS Aspirin Aspirin is of proven beneﬁt in patients with either unstable angina [56,57] or acute MI [16], and it should be considered standard therapy in all patients presenting with acute ischemic heart disease in the absence of major contraindications. Evidence supporting the use of aspirin for acute MI derives from the second International Study of Infarct Survival (ISIS2), in which 17,187 patients with suspected MI were randomized to receive either aspirin 162.5 mg or placebo, and either streptokinase 1.5 million units or placebo [16]. Overall, patients receiving aspirin experienced a 23% reduction in the risk of vascular death within 35 days of hospitalization, and this eﬀect was independent of whether or not the patient received streptokinase. Among 3411 patients over 70 years of age, aspirin was associated with a 21% reduction in vascular deaths (17.6% vs. 22.3%; p<.01) [16]. With respect to aspirin dosage, available evidence suggests that the minimum eﬀective dose in patients with acute MI is 160 mg, and that doses in excess of 325 mg provide no additional beneﬁt [58]. Importantly, the initial dose of aspirin should be administered as soon as possible after presentation, and the nonenteric-coated form should be used to ensure rapid absorption. When possible, the ﬁrst dose should be chewed rather than swallowed. Following MI, aspirin should be continued indeﬁnitely at a dose of 75 to 325 mg daily or every other day [59,60].

Heparin Subcutaneous heparin in a dose of 7500 U every 12 h reduces the risk of venous thromboembolic complications in patients hospitalized with acute MI [10,61]. Since older patients are at increased risk for deep vein thrombosis and pulmonary embolism, prophylaxis against these events is particularly appropriate in this age group. At present, the value of routine intravenous heparin for all patients with acute MI remains unproven [62], but several subgroups do appear to beneﬁt [10,63]. Patients with large anterior MIs, acute or chronic atrial ﬁbrillation, or severe left ventricular dysfunction with congestive heart failure are at increased risk for mural thrombus formation and

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embolization. Intravenous heparin at doses adjusted to maintain the aPTT at 1.5 to 2 times the control value appears to reduce arterial thromboembolism in patients with large anterior MIs [61,63,64], and routine heparinization is appropriate [10]. Patients with atrial ﬁbrillation should be anticoagulated with heparin or warfarin, but the value of systemic anticoagulation in patients with severe left ventricular dysfunction is unproven, and its use in this situation should be individualized [10]. Patients who experience recurrent ischemia during the ﬁrst few days after MI are at increased risk for infarct extension, and i.v. heparin is recommended [10,61]. Low-Molecular-Weight Heparin Compared to unfractionated intravenous heparin, low-molecular-weight heparins (LMWHs) oﬀer several advantages: once or twice daily subcutaneous dosing, no need to monitor aPTTs, and fewer side eﬀects (especially thrombocytopenia). Moreover, in a randomized trial involving 3171 patients with unstable angina or non-ST-elevation MI, the LMWH enoxaparin was associated with a 15% reduction in the composite endpoint of death or recurrent ischemia at 30 days compared to conventional heparin therapy [65]. Subsequent studies with enoxaparin and dalteparin have conﬁrmed these results [66,67]. In all of these studies, the beneﬁts of LMWH were at least as great in older as in younger patients. Based on these trials, current ACC/AHA guidelines for management of patients with acute MI recommend LMWH in preference to unfractionated heparin [68]. Glycoprotein IIb/IIIa Inhibitors The glycoprotein (GP) IIb/IIIa inhibitors are potent antiplatelet agents that block the ﬁnal common pathway leading to platelet aggregation. Three GP IIb/IIIa inhibitors—abciximab, epitﬁbatide, and tiroﬁban—have been shown to improve outcomes in patients with acute coronary heart disease [69–73]. However, although the beneﬁts of GP IIb/IIIa inhibitors in patients up to the age of 75 are similar to those in younger patients, the value of these agents in older patients is less clear. For example, in a trial involving over 10,000 patients, eptiﬁbatide reduced the risk of death or nonfatal MI in patients up to the age of 79, but there was an increase in event rates among patients over 80 years of age receiving eptiﬁbatide [73]. In another study involving a smaller number of patients (n=1915), tiroﬁban was associated with improved outcomes in patients younger or older than age 65, but outcomes for patients over 75 years have not been reported [72]. Based on currently available evidence, the addition of a GP IIb/IIIa inhibitor to aspirin and heparin is recommended for all patients with acute MI for whom cardiac catheterization and percutaneous coronary intervention is planned [68]. Treatment with either eptiﬁbatide or tiroﬁban is also recommended for high-risk patients (age>75, persistent symptoms, hemodynamic instability, signiﬁcant ST-segment changes, or elevated cardiac biomarker proteins) not expected to undergo early catheterization [68]. However, it should be recognized that the risk of bleeding complications increases with age, and this may attenuate the net clinical beneﬁt of GP IIb/IIIa inhibitors in the very elderly. Thienopyridines Ticlopidine and clopidogrel are thienopyridine derivatives that inhibit platelet aggregation through multiple mechanisms; both are more eﬀective antiplatelet agents than aspirin.

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Although both drugs reduce restenosis rates following coronary stent implantation, clopidogrel is preferred due to superior eﬃcacy and safety [74]. In addition, the combination of clopidogrel and aspirin has been shown to reduce the risk of cardiovascular death, MI, or stroke by about 20% compared to aspirin alone during the 12-month period following hospitalization for unstable angina or non-ST-elevation MI, with similar absolute beneﬁts in patients younger or older than age 65 [75]. Despite these beneﬁts, the role of clopidogrel in the long-term management of patients with acute coronary syndromes remains undeﬁned due to the high cost of the drug. Warfarin Long-term anticoagulation with warfarin has been shown to reduce the risk of reinfarction and cardiac death in post-MI patients, including the elderly [76–78], and recent studies have shown that warfarin, with or without aspirin, is superior to aspirin alone [79,80]. However, the addition of warfarin to aspirin increases the risk of bleeding, and this risk is greatest in elderly patients. Current indications for warfarin in the post-MI setting include chronic atrial ﬁbrillation, the presence of a mechanical prosthetic heart valve, or active thromboembolic disease. Anticoagulation for a minimum of 3 months is also recommended for patients with a left ventricular mural thrombus following acute MI [10]. Warfarin should also be considered in other patients deemed to be at high risk for recurrent coronary events (e.g., persons who develop acute MI while already receiving aspirin). Bleeding Complications An important consideration when using antithrombotic therapy in older patients is the increased bleeding risk accompanying the administration of multiple antithrombotic agents (e.g., aspirin, heparin, clopidogrel, and a glycoprotein IIb/IIIa inhibitor). Although there is no precise way to quantify this risk and to accurately assess the risk–beneﬁt ratio of using multiple antithrombotic drugs in an individual patient, it is worth noting that in a recent study to evaluate the eﬀects of LMWH and abciximab (a glycoprotein IIb/IIIa inhibitor) in patients receiving tenecteplase for acute MI, abciximab was associated with a marked increase in bleeding complications among patients over 75 years of age, resulting in overall worse outcomes in this age group [81]. Thus, the beneﬁts of aggressive antithrombotic therapy in reducing recurrent ischemic events must be carefully balanced against the risk of serious bleeding complications, particularly in the very elderly. B-BLOCKADE Most of the major trials evaluating h-blockers for the treatment of acute MI were conducted prior to the reperfusion era. However, since most elderly patients with acute MI do not undergo primary angioplasty or thrombolysis [82,83], the results of these earlier trials remain applicable. Table 2 summarizes data from three large randomized trials of early intravenous hblockade in patients with suspected MI [12,13,84]. In the ISIS-1 study, administration of intravenous atenolol followed by oral therapy was associated with a 15% reduction in vascular deaths within the ﬁrst 7 days [12]. Among 5222 patients 65 years of age or older, there was a 23% mortality reduction ( p = .001) [12]. Similarly, in two trials using

306 Table 2

Rich Mortality in Three Large Trials of Intravenous h-Blockade Mortality (%)

Atenolol ISIS-1 [12] <65 yrs z65 yrs Metoprolol Goteborg [84] <65 yrs 65–74 yrs MIAMI [13] <60 yrs 61–74 yrs Pooled totals Younger Older

No.

Active

Control

Diﬀerence

% Change

16,027 10,805 5,222

2.5 6.8

2.6 8.8

0.1 2.0

4.0 22.7

NS 0.001

4.5 8.1

5.7 14.8

1.2 6.6

21.1 45.0

NS 0.03

1.9 6.8

1.8 8.2

+0.1 1.5

+3.1 17.8

NS NS

2.5 6.9

2.6 8.9

0.1 2.1

5.0 23.2

NS 0.0005

1,395 917 478 5,778 2,965 2,813 23,200 14,687 8,513

p value

Abbreviations: ISIS-1 = First International Study of Infarct Survival; MIAMI = Metoprolol in Acute Myocardial Infarction; NS = not signiﬁcant. Source: Ref. 176.

intravenous metoprolol, older patients beneﬁted more than younger patients [13,84]. In pooling the results of these three trials, mortality was reduced by 23% in older patients ( p = .005), but by only 5% in younger patients ( p = NS). These data clearly indicate that older patients, who are at higher risk for adverse outcomes, derive proportionately greater beneﬁt from early h-blocker therapy than younger patients. As a result, intravenous hblockers should not be withheld on the basis of age. The value of intravenous h-blockade in combination with thrombolytic therapy was assessed in the second Thrombolysis in Myocardial Infarction trial (TIMI-II) [85,86]. In this study, 1434 patients with acute MI were treated with alteplase and then randomized to receive intravenous metoprolol or placebo. Although there was no diﬀerence in hospital or 6-week mortality, patients receiving metoprolol experienced signiﬁcantly fewer nonfatal ischemic events during follow-up. These ﬁndings provide support for the use of early intravenous h-blockade as an adjunct to thrombolysis in patients with acute MI. The long-term use of h-blockers for secondary prevention following acute MI has been extensively investigated, and Table 3 summarizes data from three of the largest and most frequently cited trials [84,87–91]. As with early h-blockade, reductions in mortality and reinfarction during long-term therapy were at least as great in the elderly as in younger patients. In addition, the survival beneﬁts of h-blockers following MI appear to extend to patients over 75 years of age [92], and h-blockers are highly cost-eﬀective in all age groups [93]. Thus, h-blockers should be administered to all patients following acute MI in the absence of contraindications. At the present time, only atenolol and metoprolol have been approved for intravenous (i.v.) use in the acute MI setting. The recommended dose for intravenous atenolol

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Table 3 Mortality in Three Large Trials of Long-Term h-Blockade Mortality (%)

Propranolol BHAT [87,88] 30–59 yrs 60–69 yrs Timolol Norwegian [89–91] <65 yrs 65–75 yrs Metoprolol Goteborg [84] <65 yrs 65–74 yrs Pooled totals Younger Older

No.

Active

Control

Diﬀerence

% Change

3,837 2,588 1,249

6.0 9.7

7.4 14.7

1.4 5.0

18.7 33.7

NS 0.01

1,884 1,149 735

5.0 8.0

9.7 15.3

4.7 7.3

48.3 47.8

0.003 0.003

4.5 8.1

5.7 14.8

1.2 6.6

21.1 45.0

NS 0.03

5.5 8.9

7.6 14.9

2.2 6.0

28.3 40.1

0.004 0.0001

1,395 917 478 7,116 4,654 2,462

p value

Abbreviations: BHAT= Beta Blocker Heart Attack Trial; NS= not signiﬁcant.

is two 5-mg boluses at an interval of 10 mins. Oral atenolol 50 mg every 12 h should be initiated 10 min after the second i.v. dose. For metoprolol, the recommended i.v. dose is 15 mg (three 5-mg doses at 2-min intervals). Oral metoprolol 25 to 50 mg every 6 h should be started 15 min after the last i.v. dose, progressing to 100 mg twice daily in 24 to 48 h. In very elderly patients, it may be advisable to reduce the dosages of both agents. Contraindications to the use of intravenous h-blockers include marked sinus bradycardia (heart rate <45/min), systolic blood pressure <100 mmHg, marked ﬁrst degree AV block (PR interval z0.24 s) or higher levels of block, moderate or severe HF, active wheezing, or a history of signiﬁcant bronchospastic pulmonary disease. Mild HF and chronic lung disease without bronchospasm are not contraindications to h-blocker therapy. Propranolol, metoprolol, and timolol have all been approved for long-term use following MI. Recommended daily dosages for these agents are as follows: propranolol 180 to 240 mg, metoprolol 200 mg, and timolol 20 mg. Elderly patients may require lower doses to avoid adverse eﬀects, and recent data indicate that lower dosages may be as effective as higher doses for reducing mortality in older patients [94]. Contraindications to oral h-blockers are similar to those listed for the IV drugs.

NITRATES Nitrates are widely used in the treatment of acute MI [95], but two large studies (GISSI-3 and ISIS-4) failed to conﬁrm a beneﬁcial eﬀect when nitrates were initiated within 24 h of MI onset [96,97]. However, among 5234 patients 70 years of age or older enrolled in GISSI-3, the combined endpoint of death or severe left ventricular dysfunction at 6

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months follow-up was signiﬁcantly reduced by nitroglycerin (odds ratio 0.88; p = .04) [98]. This ﬁnding, coupled with the fact that both GISSI-3 and ISIS-4 demonstrated that nitrates can be administered safely to the majority of older patients, suggests that the continued use of nitrates for treating ischemic pain and peri-infarctional heart failure is appropriate. Routine use of nitrates in elderly patients without pain or pulmonary congestion is of unproven value.

CALCIUM ANTAGONISTS Calcium channel blockers have been widely studied in both the acute MI and post-MI settings [99,100]. At present, there is no evidence that treatment with calcium antagonists is beneﬁcial in patients with acute MI, and the use of short-acting calcium antagonists may be harmful [99]. One relatively small study showed that diltiazem 60 to 90 mg q.i.d. initiated 24 to 72 h after admission for non-ST-elevation MI reduced the rate of reinfarction during short-term follow-up, but there was no eﬀect on mortality [101]. In another study, long-term diltiazem administration following MI did not aﬀect overall mortality, but a modest beneﬁt was seen in the subgroup of patients with preserved left ventricular function and no heart failure [102]. Similar results have been reported with long-term verapamil use in post-MI patients [103], although a more recent study failed to conﬁrm these ﬁndings [104]. Thus, calcium antagonists are not recommended for routine use in acute MI patients, but short-term administration of diltiazem may be of value in patients with non-ST-elevation infarction, and the long-term use of either diltiazem or verapamil may be appropriate in patients with preserved ventricular function who are not candidates for h-blockade [10].

ANGIOTENSIN CONVERTING ENZYME INHIBITORS Early administration of an ACE inhibitor to acute MI patients has been evaluated in several large trials. The ﬁrst of these, CONSENSUS-2 (Cooperative New Scandinavian Enalapril Survival Study), was discontinued after 6000 patients were enrolled due to a higher frequency of adverse outcomes in patients receiving intravenous enalapril [105]. Moreover, patients over 70 years of age experienced an increased incidence of serious hypotension. In contrast, the GISSI-3 and ISIS-4 trials reported small but statistically signiﬁcant reductions in mortality in patients receiving oral captopril or lisinopril within 24 h of MI onset [96,97]. In addition, patients 70 years or older treated with lisinopril in GISSI-3 experienced a 14% reduction in the combined endpoint of death or severe left ventricular dysfunction at 6 months follow-up ( p = .01) [98]. More recently, the Survival of Myocardial Infarction Long-term Evaluation (SMILE) investigators randomized 1556 patients with anterior MI who were not candidates for thrombolytic therapy to either the ACE inhibitor zofenopril or to placebo within the ﬁrst 24 h after symptom onset [106]. The incidence of death or severe heart failure at 6 weeks follow-up was reduced 34% by zofenopril, and this beneﬁt was maintained for 1 year. Moreover, the absolute beneﬁt was threefold greater in individuals over 65 years of age compared to younger patients [106]. The applicability of the above ﬁndings to the general MI population is unclear, since the small beneﬁt seen in the largest trials (absolute mortality reduction less than 1%) [96,97] may reﬂect a larger beneﬁt in some patients (e.g., those with anterior MI or signiﬁcant left ventricular dysfunction), but no beneﬁt or even harm in other subgroups.

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At the present time, early administration of an ACE inhibitor is recommended in hemodynamically stable patients with large anterior MIs, as well as in patients with heart failure or a left ventricular ejection fraction of less than 40% [10]. In other cases, early ACE inhibitor therapy is optional [10]. The value of ACE inhibitors in post-MI patients with signiﬁcant left ventricular dysfunction (ejection fraction < 40%) or clinical heart failure has been well established by the Salvage and Ventricular Enlargement (SAVE) [107] and Acute Infarction Ramipril Eﬃcacy (AIRE) trials [108,109]. In SAVE, captopril reduced mortality and the occurrence of other cardiac events during an average follow-up of 42 months in asymptomatic or minimally symptomatic patients with left ventricular dysfunction after MI (ejection fraction V 40%) [107]. In AIRE, ramipril produced similar eﬀects in post-MI patients with clinical heart failure [108,109]. Therapy was initiated 3 to 16 days after MI in SAVE (mean 11 days), and 2 to 10 days after MI in AIRE (mean 5 days). The maximum dose of captopril in SAVE was 50 mg t.i.d., while the target dose of ramipril in AIRE was 5 mg b.i.d. Importantly, in both SAVE and AIRE, the beneﬁcial eﬀects of therapy were most pronounced in elderly patients [107,108]. In 783 patients over 65 years of age enrolled in SAVE, mortality was reduced 23% with captopril (27.9% vs. 36.1%; p = .017); by comparison, patients under age 65 experienced a statistically insigniﬁcant 9% mortality reduction (16.6% vs. 18.3%) [107]. Similarly, ramipril signiﬁcantly decreased mortality in patients over age 65 enrolled in AIRE, but not in younger patients [108]. More recently, the Heart Outcomes Prevention Evaluation (HOPE) study showed that the ACE inhibitor ramipril in a dose of 10 mg once daily reduced mortality and major vascular events in a broad range of patients 55 years of age or older with established vascular disease (including chronic coronary artery disease) or diabetes [110]. In summary, ACE inhibitors are indicated for all patients, including the elderly, who have heart failure or signiﬁcant left ventricular dysfunction following MI (i.e., ejection fraction < 40%). Therapy should be initiated within the ﬁrst several days in hemodynamically stable patients, but may be deferred in other cases. In addition, based on data from the HOPE study, long-term treatment with an ACE inhibitor should be strongly considered in all older patients with known vascular disease or diabetes.

ANGIOTENSIN RECEPTOR BLOCKERS Angiotensin receptor blockers (ARBs) bind to the angiotensin1 (AT1) receptor on the cell membrane, thereby inhibiting the eﬀects of angiotensin II. Although ARBs tend to be better tolerated than ACE inhibitors, primarily due to a lower incidence of cough, recent data indicate that ARBs are somewhat less eﬀective than ACE inhibitors in improving clinical outcomes following acute MI [111]. Therefore, ACE inhibitors remain the preferred agents in this population. However, ARBs provide a reasonable alternative for patients who require an ACE inhibitor but who are intolerant to these agents due to cough.

MAGNESIUM Although several relatively small studies suggested that selected patients with acute MI, including the elderly, might beneﬁt from routine administration of magnesium [112,113], two large randomized trials failed to conﬁrm a beneﬁcial eﬀect [97,114]. Therefore, the rou-

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tine use of intravenous magnesium in elderly patients with acute MI is not recommended [10].

ANTIARRYTHMIC AGENTS The administration of prophylactic lidocaine to patients with acute MI was once common practice. However, a meta-analysis suggested that lidocaine does not improve survival and may increase the incidence of asystolic cardiac arrest [115]. Moreover, elderly patients hospitalized with acute MI appear to be at lower risk for primary ventricular ﬁbrillation than younger patients [116], and toxicity from lidocaine is more common in the elderly. Thus, although lidocaine remains an eﬀective agent for treating life-threatening ventricular arrhythmias, its routine use in elderly patients with acute MI is not recommended [10]. Intravenous amiodarone is more eﬀective than lidocaine in the treatment of lifethreatening ventricular arrhythmias in the setting of acute ischemic heart disease, and two trials have addressed the role of prophylactic oral amiodarone in the treatment of highrisk post-MI patients [117,118]. In these studies, which involved a total of 2688 patients, amiodarone reduced the incidence of arrhythmic death by 35 to 38%, but there was no diﬀerence in total mortality. In one study, the absolute reduction in arrhythmic deaths was greatest in patients over 70 years of age [118]. A recent meta-analysis, based on data from 13 amiodarone trials, found that amiodarone was associated with a 13% reduction in total mortality ( p = .03) and a 29% reduction in arrhythmic deaths ( p = .0003) [119]. In patients over 65 years of age, amiodarone reduced arrhythmic deaths by 32%, but total mortality was reduced by only 8% (not signiﬁcant) [119]. Thus, the use of amiodarone in elderly patients following MI requires further investigation. In contrast, implantable cardioverter deﬁbrillators (ICDs) have been shown to reduce mortality in post-MI patients with reduced left ventricular systolic function (ejection fraction < 30%) [120,121]. Based on these data ICD implantation should be considered in appropriately selected elderly patients who are at high risk for sudden cardiac death.

STATINS Statins have been shown to reduce long-term mortality and morbidity in patients up to 85 years of age with vascular disease [122,123]. In addition, early administration of high-dose statin therapy within the ﬁrst 96 h of acute MI has been shown to reduce the risk of recurrent ischemic events during the 4-month period following hospital discharge, with similar eﬀects in older and younger patients [124].

MANAGEMENT OF COMPLICATIONS Elderly patients are at increased risk for several major complications of acute MI, including HF, hypotension, supraventricular arrhythmias, conduction disturbances, myocardial rupture, and cardiogenic shock. In general, the management of these complications is similar in older and younger patients. In the following sections, the treatment of each of these complications is brieﬂy reviewed, with special attention to the elderly.

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311

Heart Failure Several factors predispose the elderly patient with acute MI to the development of HF, including an increased incidence of prior MI, higher prevalence of multivessel disease, impaired diastolic relaxation, reduced contractile reserve, and an increased prevalence of comorbid illnesses, both cardiac (e.g., aortic stenosis) and noncardiac (e.g., renal insuﬃciency) [125]. As a result, HF occurs in approximately 50% of older patients with acute MI [7], and HF is often the presenting manifestation of MI in the elderly [126]. The initial treatment of HF includes supplemental oxygen, diuretics, and nitrates. In more severe cases, morphine should also be given. Once therapy has been initiated, it is essential to determine the etiology of HF, which is frequently multifactorial in elderly patients. Commonly occurring factors that may contribute to HF in the elderly include persistent or recurrent ischemia, extensive myocardial damage, aortic or mitral valve disease (especially aortic stenosis or mitral regurgitation), arrhythmias (especially atrial ﬁbrillation), uncontrolled hypertension, diastolic dysfunction due to left ventricular hypertrophy, inappropriate bradycardia, mechanical complications (e.g., papillary muscle rupture or ventricular septal perforation), severe renal insuﬃciency, and medications (e.g., h-blockers, calcium antagonists, and antiarrhythmic agents). In most cases, an echocardiogram with Doppler studies, in conjunction with a careful review of the patient’s medications and laboratory data, will be suﬃcient for determining the pathogenesis of HF [10]. Occassionally, supplemental studies, such as pulmonary artery catheterization or left ventricular angiography, may be necessary [10]. Once the etiology has been established, an eﬀort should be made to correct treatable disorders and to reduce the dose or discontinue oﬀending medications. If HF persists despite aggressive diuresis, placement of a pulmonary artery catheter should be considered as an aid to diagnosis and therapy. When indicated, treatment with an inotropic agent and/or an intravenous vasodilator should be instituted. Dobutamine is the most frequently used intravenous inotrope for treating severe left ventricular dysfunction, but dobutamine may be less eﬀective in the elderly due to an age-related decline in h-adrenergic responsiveness [127,128]. Phosphodiesterase inhibitors such as amrinone and milrinone have theoretical advantages over sympathomimetic agents in coronary patients because they augment cardiac output without increasing myocardial oxygen demand [129]. Nonetheless, in elderly patients with severe HF without recent MI, dobutamine appears to be at least as eﬀective as amrinone [130]. Recently, nesiritide (recombinant B-type natriuretic peptide) has been introduced as an alternative or adjunct to inotropic therapy [131,132]. Nesiritide reduces left ventricular ﬁlling pressure and enhances natriuresis; the net hemodynamic eﬀects are similar to those of dobutamine but without an increase in heart rate, arrhythmias, or myocardial oxygen demand. Although experience with nesiritide is limited in the elderly, there is no evidence for reduced eﬃcacy or increased toxicity in older patients. Nitroglycerin and nitroprusside are the most commonly used intravenous vasodilators. Both have very short half-lives, which permit rapid drug titration. Hypotension can occur with either agent, but is more common with nitroprusside. Nitroprusside can also result in thiocyanate toxicity during prolonged administration, particularly in elderly patients with impaired renal function. As a result, thiocyanate levels should be monitored closely. Clinical manifestations of thiocyanate toxicity include nausea, vomiting, mental status changes, and metabolic acidosis. Intravenous enalaprilat is an alternative to nitrovasodilators, and may be useful in patients who are likely to require long-term ACE inhibition. However, enalaprilat may also induce hypotension and renal dysfunction, and it oﬀers no clear advantage over conventional agents in the acute MI setting [133].

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Patients who fail to respond to the above measures have refractory HF, and the prognosis is grave unless a correctable problem, such as a ventricular aneurysm, can be identiﬁed. Additional interventions that may help stabilize patients with refractory HF include endotracheal intubation with assisted ventilation and placement of an intra-aortic balloon pump. Such therapies are usually appropriate only in patients with potentially reversible pathology.

Hypotension Hypotension in the setting of acute MI usually reﬂects a low cardiac output state arising from extensive myocardial damage, intravascular volume depletion, right ventricular infarction, valvular dysfunction (especially mitral regurgitation) pericardial eﬀusion, or arrhythmias (both tachycardias and bradycardias). Other factors that may contribute to hypotension in elderly patients include preexisting cardiac conditions, such as aortic stenosis or cardiomyopathy, ventricular septal perforation, aortic dissection, sepsis, bleeding (e.g., from thrombolytic therapy or catherization), and medications. The cause of hypotension is frequently multifactorial, and it is incumbent upon the physician to consider all potential etiologies and to perform appropriate diagnostic investigations as indicated. If the history, physical examination, and laboratory data fail to provide an explanation, echocardiography should be performed promptly [10]. If hypotension persists or if the etiology remains unexplained, pulmonary artery catheterization is indicated [10]. In the absence of HF, intravascular volume expansion is the appropriate initial treatment for hypotension. Subsequent therapy will depend on the response to ﬂuid administration and the underlying etiology. Patients who fail to respond to i.v. ﬂuids or who have coexistent HF may require pulmonary artery catheterization [10]. Based on the hemodynamic ﬁndings and the severity of hypotension, treatment with sympathomimetic agents such as dobutamine, dopamine, or norepinephrine may be necessary to maintain organ perfusion. Other supportive measures include assisted ventilation and intra-aortic balloon counterpulsation [10]. It is important to emphasize that all of these interventions are palliative, and unless the underlying etiology of hypotension can be corrected, the prognosis is grave.

Arrhythmias and Conduction Disturbances Elderly patients with acute MI are at increased risk for supraventricular arrhythmias, particularly atrial ﬁbrillation, and for conduction disturbances, including bundle branch block and high degree atrioventricular block. The incidence of ventricular tachycardia is similar in older and younger patients, but primary ventricular ﬁbrillation occurs less frequently in the elderly [116], possibly reﬂecting reduced h-adrenergic responsiveness in this age group. New-onset atrial ﬁbrillation following acute MI usually results from atrial distension due to an increase in ventricular diastolic pressure. Contributing factors may include mitral or tricuspid regurgitation, atrial infarction, pericarditis, electrolyte abnormalities (particularly hypokalemia), and medications (e.g., inotropic agents, theophylline). Because elderly patients frequently have preexisting diastolic dysfunction and an increased reliance on atrial contraction to augment ventricular ﬁlling (the ‘‘atrial kick’’) [125], atrial ﬁbrillation often precipitates heart failure or a low cardiac output state.

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Treatment of atrial ﬁbrillation includes correcting any reversible abnormalities (e.g., hypokalemia), controlling the ventricular rate, and restoring sinus rhythm. In patients who are hemodynamically stable, rate control with beta-blockers or rate-lowering calcium channel blockers (i.e., diltiazem or verapamil) is appropriate. In most cases, heparinization to maintain the activated partial thromboplastin time (aPTT) in the range of 50 to 70 s is also indicated. Although eﬀective rate control often results in spontaneous conversion to sinus rhythm, if atrial ﬁbrillation persists longer than 24 h, pharmacological or electrical cardioversion should be considered. Antiarrhythmic agents commonly used in the cardioversion of recent-onset atrial ﬁbrillation include ibutilide, sotalol, and amiodarone. All of these agents are negatively inotropic, and they should be used with caution in the presence of signiﬁcant left ventricular dysfunction. In patients who exhibit hypotension, severe heart failure, or organ hypoperfusion attributable to atrial ﬁbrillation, immediate direct current (DC) cardioversion is the treatment of choice [10]. Patients should be sedated before cardioversion is attempted, and an initial energy level of 100 to 200 Joules is appropriate [10]. Patients with persistent or chronic atrial ﬁbrillation should receive longterm antithrombotic therapy [134]. Warfarin remains the preferred agent in this setting, but aspirin is an acceptable alternative in patients with major contraindications to warfarin [134]. The treatment of peri-infarctional ventricular tachyarrhythmias is similar in older and younger patients and will not be reviewed here. In general, initial therapy should follow the Advanced Cardiac Life Support (ACLS) guidelines [135], and subsequent therapy should be individualized, based on symptoms, severity of arrhythmia, and other factors, such as left ventricular function. Similarly, the treatment of bradyarrhythmias and conduction disturbances does not diﬀer in younger and older patients. In general, temporary pacing (transthoracic or transvenous) should be considered in patients with symptomatic or hemodynamically compromising bradyarrhythmias unresponsive to atropine, in patients with new bundle branch block, and in patients with second- or third-degree infranodal block complicating anterior MI. The ACLS guidelines should be followed in treating life-threatening bradyarrhythmias such as asystole [135]. Right Ventricular Infarction Right ventricular infarction occurs in up to 50% of patients with inferior MI, with somewhat higher frequency in older than in younger patients [136]. The pathophysiology, clinical features, and treatment of right ventricular infarction have previously been reviewed and will not be discussed in detail here [11]. However, it is worth noting that the presence of right ventricular infarction, as evidenced by ST-segment elevation in the right precordial electrocardiographic leads, is associated with a marked increase in hospital mortality in both younger and older patients [136,137]. Myocardial Rupture Myocardial rupture is an infrequent complication of acute MI, occurring in less than 5% of patients [138–140]. However, when rupture does occur, the course is frequently catastrophic, with death ensuing in over 50% to almost 100% of cases, depending on location. There are three principal types of rupture: ventricular free wall rupture, papillary muscle rupture (PMR), and ventricular septal perforation (acute VSD). Papillary muscle rupture almost always occurs following an inferoposterior or posterolateral MI, whereas

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septal rupture occurs somewhat more frequently following an anterior infarct. Free wall rupture can complicate an infarct of any location. Although precise ﬁgures are unavailable, all forms of rupture appear to occur more frequently in patients over 65 years of age [139,140]. Other risk factors for myocardial rupture include female gender and persistent peri-infarctional hypertension [138]. Thrombolytic therapy may also increase the risk of myocardial rupture within the ﬁrst 24 to 48 h after treatment, particularly in older patients undergoing delayed thrombolysis (i.e., more than 6 h after symptom onset) [138,140,141]. Impending myocardial rupture is occasionally heralded by persistent vague chest discomfort or unexplained hypotension, but sudden hemodynamic deterioration, new or worsening heart failure, or asystolic cardiac arrest may be the ﬁrst indication that rupture has occurred [142]. The presence of a new systolic murmur, particularly in association with hemodynamic deterioration, strongly suggests the possibility of papillary muscle dysfunction or ventricular septal perforation, and prompt investigation is warranted. Urgent bedside Doppler echocardiography should be performed, since this will enable accurate diagnosis in the majority of cases [143,144]. Pulmonary artery catherization can provide deﬁnitive conﬁrmation of a septal perforation by demonstrating an oxygen saturation stepup of greater than 10% at the level of the shunt (usually the right ventricle). Similarly, the presence of an abnormally elevated V-wave in the pulmonary capillary wedge pressure waveform suggests acute mitral regurgitation. Cardiac catherization is usually necessary to deﬁne coronary anatomy in elderly patients with cardiac rupture, and left ventriculography can provide diagnostic information on the severity of mitral regurgitation and on the presence and location of an acute VSD. Once a diagnosis of acute VSD or PMR has been conﬁrmed, supportive measures should be rapidly instituted, and urgent surgical consultation should be obtained. Diuretics, an intravenous inotropic agent, and afterload reduction with intravenous nitroprusside (blood pressure permitting) are appropriate therapy in most cases. Intra-aortic balloon counterpulsation is often eﬀective in stabilizing the patient and should be strongly considered in all surgical candidates [10]. Mechanical ventilation is indicated in patients with severe heart failure or persistent hemodynamic instability. Surgery is recommended in almost all cases of acute VSD or PMR, since medical therapy is associated with mortality rates in excess of 75% [138,145]. Perioperative mortality rates range from 10% to 70%, with preoperative left ventricular function and the presence of cardiogenic shock being the most important factors inﬂuencing survival [145–147]. The long-term prognosis following successful surgical repair of acute VSD or PMR is favorable [145–147]. Rupture of the left ventricular free wall usually progresses rapidly to pericardial tamponade, asystole, and death. Occasionally, however, the rupture will be locally contained as a result of pericardial adhesions or other factors, resulting in the formation of a pseudoaneurysm. Diﬀerentiation of a pseudoaneurysm from a true left ventricular aneurysm may be diﬃcult, but echocardiography, magnetic resonance imaging, and left ventriculography are all useful in making this distinction. The hemodynamic eﬀects of a pseudoaneurysm are variable, depending on its size and location, but there is a tendency for pseudoaneurysms to undergo further rupture, resulting in pericardial tamponade [148,149]. Although conservative management may be associated with a favorable outcome in some cases [150], prompt surgical attention is usually recommended once a pseudoaneurysm has been identiﬁed [149,151].

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Cardiogenic Shock Cardiogenic shock is deﬁned as the combination of markedly reduced cardiac output (cardiac index < 1.8 L/min/M2), increased left ventricular diastolic pressure or pulmonary wedge pressure (z 22 mmHg), hypotension (systolic blood pressure < 80 mmHg), and tissue hypoperfusion (e.g., prerenal azotemia, impaired sensorium) [152]. This syndrome occurs twice as frequently in elderly patients with acute MI as in younger subjects, and it accounts for most of the excess mortality associated with acute MI in the elderly [153]. Moreover, despite major advances in the treatment of acute MI over the last 30 years, the case fatality rate from cardiogenic shock remains high [153–155]. The causes of cardiogenic shock complicating acute MI are similar to the causes of HF and hypotension. Since few patients survive cardiogenic shock in the absence of a treatable underlying disorder, immediate evaluation for a potentially correctable problem is critical. Emergent Doppler echocardiography should be performed to assess overall left ventricular function and to rule out valvular lesions, pericardial disease, and septal perforation [10]. Pulmonary artery catheterization is indicated both to facilitate diagnosis and as an aid to therapy [10]. Cardiac catheterization may be necessary in some cases if the diagnosis remains in doubt, or as a prelude to angioplasty or corrective surgery. Although emergent catheterization and coronary revascularization have been shown to improve outcomes in patients up to age 75 with cardiogenic shock complicating acute MI, patients over age 75 may not beneﬁt from these interventions [47]. In patients with a potentially reversible cause of shock, maximally aggressive therapy is indicated to stabilize the patient. In most cases, this will include assisted ventilation, an intra-aortic balloon pump [156], and intravenous vasoactive therapy. However, when shock is due to irreversible myocardial damage or other untreatable disorder, invasive interventions are unlikely to inﬂuence survival and should generally be avoided.

NON-ST-ELEVATION MYOCARDIAL INFARCTION Non-ST-elevation MI increases in frequency with advancing age and accounts for over 50% of all MIs in patients over the age of 70 [7,157]. While Q-wave MIs are almost always caused by total thrombotic occlusion of the infarct-related vessel [158], the pathogenesis of non-ST-elevation MI is more variable. In the elderly, non-ST-elevation MI may be precipitated by a sustained imbalance between myocardial oxygen supply and demand resulting from severe hypertension, marked hypoxemia due to heart failure or pulmonary embolus, atrial ﬁbrillation with rapid ventricular response, or acute hypotension due to sepsis or other causes. Diﬀuse, multivessel coronary disease is often present, but total occlusion of the infarct artery is the exception rather than the rule [159,160]. The short-term prognosis following non-ST-elevation MI tends to be better than that following ST-elevation MI, since non-ST-elevation MIs are usually smaller and associated with greater preservation of ventricular function [161]. However, patients with non-ST-elevation MI are at increased risk for recurrent ischemia and reinfarction, and long-term survival is similar to that of patients with ST-elevation MI [161,162]. In one series, over 60% of all deaths within the ﬁrst year after hospitalization for acute MI occurred in patients over the age of 70 presenting with non-ST-elevation infarctions [163]. Because the clinical course following non-ST-elevation MI is distinct from that following ST-elevation MI, numerous studies have focused speciﬁcally on the management

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of this disorder. In general, the pharmacotherapy of non-ST-elevation MI should include aspirin, low-molecular-weight heparin or unfractionated heparin, and a beta-blocker [68,164]. Nitrates should be administered for persistent or recurrent chest pain or if heart failure is present. A glycoprotein IIb/IIIa inhibitor should also be initiated in most cases, especially in patients likely to undergo early percutaneous coronary revascularization [68,72,73]. In the absence of ST-elevation or left bundle branch block, ﬁbrinolytic therapy has not been shown to be eﬃcacious and should be avoided [19]. Several studies have compared early cardiac catheterization and revascularization with conventional medical therapy in patients with unstable angina or non-ST-elevation MI. Although the results of these trials have been somewhat inconsistent, the most recent studies suggest that early revascularization is beneﬁcial in high-risk patients, including the elderly [165–167]. These ﬁndings are reﬂected in the recently revised guidelines for management of non-ST-elevation acute coronary syndromes, which suggest that an invasive approach to therapy is warranted in appropriately selected patients [68].

RISK STRATIFICATION In the past 20 years, the concept of risk stratiﬁcation has been developed as a means for selecting subgroups of post-MI patients who are most likely to beneﬁt from further diagnostic and therapeutic measures, and, conversely, to identify those with a favorable prognosis who are unlikely to beneﬁt from high-cost interventions [168]. Factors associated with an increased risk for adverse outcomes include older age, anterior MI location, ischemia occurring either spontaneously or during a post-MI stress test, reduced left ventricular systolic function (especially an ejection fraction less than 40%), frequent premature ventricular contractions or higher grades of ventricular ectopy, reduced heart rate variability [169], increased ﬁbrinogen [170], and elevated C-reactive protein [170,171]. Although none of the major risk stratiﬁcation studies have speciﬁcally targeted older patients, key factors identiﬁed in younger individuals, particularly ventricular function and residual myocardial ischemia, almost certainly retain their prognostic signiﬁcance in the elderly. In older patients who are suitable candidates for invasive treatment, further risk stratiﬁcation seems appropriate, and should include an echocardiogram or radionuclide ventriculogram to assess left ventricular function, and an exercise or pharmacological stress test (e.g., adenosine-thallium or dobutamine-echocardiogram) to determine the extent of residual ischemia [172–174]. Based on the results of these investigations, additional intervention may be appropriate, but further study is needed to deﬁne the optimal approach to managing high-risk elderly patients [175].

ETHICAL ISSUES In general, the foregoing discussion has been predicted on the notion that a given patient is an ‘‘appropriate’’ or ‘‘suitable’’ candidate for each intervention under consideration. These terms, while vague, imply that not all patients should receive every intervention, and that multiple factors must be taken into consideration during the decision-making process. Among these are the wishes of the patient, as expressed either directly or through a prior communication such as a living will; the anticipated impact of the intervention on

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quality of life and long-term prognosis; the potential for the intervention itself to add to the patient’s suﬀering; and the concerns of the patient’s family and friends. The physician’s role in guiding these decisions is critically important, and a high level of compassion, honesty, and respect for the patient’s autonomy is required. Thus, the physician must provide a balanced view of the available therapeutic options, including a realistic appraisal of the likelihood of various outcomes and adverse events. The physician should avoid creating an overly grim picture, but at the same time must avoid fostering unrealistic hopes. Finally, when the patient’s condition is such that death seems inevitable, the physician must be able to provide appropriate counsel to forego or withdraw interventions that are unlikely to be helpful, and which will only serve to prolong the dying process. In addition, the physician must provide comfort and emotional support for the patient and family. In this regard, the importance of the nursing staﬀ, members of the clergy, and other health professionals in helping the patient and family deal with emotional issues and other concerns cannot be overemphasized.

SUMMARY Acute myocardial infarction occurs at increasing frequency with advancing age, and older patients with acute MI are at increased risk for major complications, including heart failure, arrhythmias and conduction disturbances, myocardial rupture, cardiogenic shock, and death. Older patients thus comprise a large high-risk subgroup of the MI population who may derive substantial beneﬁts from appropriately selected therapeutic interventions. At the same time, many interventions are associated with increased risk in the elderly, so

Table 4 Efficacy of Selected Treatments for Acute Myocardial Infarction in Elderly Patients Eﬀective Acute Phase Aspirin Fibrinolysisa LMWHa Glycoprotein IIb/IIIa inhibitorsa Primary angioplastya Chronic Phase Aspirin h-blockers ACE inhibitors Statins

a

Probably eﬀective Intravenous h-blockade ACE inhibitorsa

Uncertain eﬃcacy Nitrates

Calcium antagonists Antiarrhythmic agents Magnesium

Heparina Statins

Clopidogrel Warfarina Angioplastya Coronary bypass surgerya ICDs

Ineﬀective

Amiodarone Calcium antagonists

Other antiarrhythmics Nifedipine

Selected subgroups; see text. Abbreviations: ACE = angiotensin converting enzyme; ICDs = implantable cardioverter-deﬁbrillators; LMWH: low-molecular-weight heparin.

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that individualization of treatment is essential. Optimal therapy is thus based on a careful risk–beneﬁt assessment of the available treatment options in conjunction with appropriate consideration of patient preferences and other relevant factors. Although many therapeutic trials in acute MI patients have either excluded elderly patients or enrolled too few older subjects to permit deﬁnitive conclusions, suﬃcient data are available to make speciﬁc recommendations in several areas. As shown in Table 4, aspirin, low-molecular-weight heparin, glycoprotein IIb/IIIa inhibitors, ﬁbrinolytic agents, and primary angioplasty are of proven value during the acute phase of MI in selected elderly patients. Intravenous h-blockers and oral ACE inhibitors and statins are also likely to be of beneﬁt. Following MI, aspirin, h-blockers, ACE inhibitors, and statins are of proven beneﬁt and should be considered standard therapy in most patients. Selected patients may also beneﬁt from clopidogrel, warfarin, percutaneous or surgical revascularization, or implantation of an ICD. Conversely, routine use of calcium channel blockers and antiarrhythmic agents is not recommended. As the age of the population continues to increase, the number of older patients at risk for acute MI will rise commensurately. Although progressively more sophisticated interventions may result in sizable reductions in post-MI morbidity and mortality, it is apparent, given the high risk of adverse outcomes in the elderly population, that the best treatment is prevention. Thus, the greatest potential for the future, as well as the greatest challenge, will be to develop more eﬀective strategies for preventing atherosclerosis and for conquering the epidemic of coronary heart disease in our aging population.

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13 Management of the Older Patient After Myocardial Infarction Wilbert S. Aronow Westchester Medical Center/New York Medical College, Valhalla, and Mount Sinai School of Medicine, New York, New York, U.S.A.

INTRODUCTION Coronary artery disease (CAD) is the leading cause of death in older persons. Although persons older than 65 years comprise 12% of the population [1], approximately 60% of hospital admissions for acute myocardial infarction (MI) occur in persons older than 65 years of age, and persons older than 75 years of age account for nearly half of these admissions of patients with MI older than 65 years [2]. Not only is the in-hospital mortality higher in older patients with MI than in younger patients with MI, but the post-discharge mortality rate is higher in older persons, with the 1-year cardiac mortality rate 12% for patients aged 65 to 75 years and 17.6% for patients older than 75 years [3]. Approximately two-thirds of these 1-year deaths were sudden or related to a new MI [3]. This chapter discusses the management of the older patient after MI.

CONTROL OF CORONARY RISK FACTORS Cigarette Smoking The Chicago Stroke Study demonstrated that current cigarette smokers 65 to 74 years of age had a 52% higher mortality from CAD than nonsmokers, ex-smokers, and pipe and cigar smokers [4]. Ex-smokers who had stopped smoking for 1 to 5 years had a similar mortality from CAD as did nonsmokers [4]. The Systolic Hypertension in the Elderly Program pilot project showed that smoking was a predictor of ﬁrst cardiovascular event and MI/sudden death [5]. At 30-year follow-up of persons 65 years of age and older in the Framingham Study, cigarette smoking was not associated with the incidence of CAD in older men and women but was associated with mortality from CAD in older men and women [6]. At 12-year follow-up of men aged 65 to 74 years in the Honolulu Heart Program, cigarette smoking was an independent risk factor for nonfatal MI and fatal CAD [7]. The absolute excess risk associated with cigarette smoking was 1.9 times higher in older men than in middle-aged men. At 5-year follow-up of 7178 persons 65 years of age or older in three communities, current cigarette smokers had a higher incidence of cardiovascular 329

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mortality than nonsmokers (relative risk = 2.0 for men and 1.6 for women) [8]. The incidence of cardiovascular death in former smokers was similar to those who had never smoked [8]. At 6-year follow-up of older men and women in the Coronary Artery Surgery Study registry, the relative risk of MI or death was 1.5 for persons aged 65 to 69 years and 2.9 for persons 70 years of age or older who continued smoking compared with quitters during the year before study enrollment [9]. At 40-month follow-up of 664 older men, mean age 80 years, and at 48-month followup of 1488 older women, mean age 82 years, current cigarette smoking increased the relative risk of new coronary events (nonfatal or fatal MI or sudden cardiac death) 2.2 times in older men and 2.0 times in older women (Table 1) [10]. We have also observed that cigarette smoking aggravates angina pectoris and precipitates silent myocardial ischemia in older persons with CAD. On the basis of the available data, older men and women who smoke cigarettes should be strongly encouraged to stop smoking because it will reduce cardiovascular mortality and all-cause mortality after MI.

Hypertension Increased peripheral vascular resistance is the cause of systolic and diastolic hypertension in older persons. Systolic hypertension in older persons is diagnosed if the systolic blood pressure is 140 mmHg or higher on three occasions [11]. Diastolic hypertension in older persons is diagnosed if the diastolic blood pressure is 90 mmHg or higher on three occa-

Table 1 Risk Factors for New Coronary Events in 664 Older Men and in 1488 Older Women Relative risk of new coronary events Risk Factor

Men

Women

Age Prior coronary artery disease Cigarette smoking Hypertension Diabetes mellitus Obesity Serum total cholesterol Serum HDL cholesterol Serum triglycerides

1.04 1.7 2.2 2.0 1.9 NS 1.12a 1.70b NS

1.03 1.9 2.0 1.6 1.8 NS 1.12a 1.95c 1.002

Abbreviations: NS = not signiﬁcant by multivariate analysis; HDL = high-density lipoprotein. Source: Adapted from Ref. 10. a 1.12 times higher probability of developing new coronary events for an increment of 10 mg/dL of serum total cholesterol. b 1.70 times higher probability of developing new coronary events for a decrement of 10 mg/dL of serum HDL cholesterol. c 1.95 times higher probability of developing new coronary events for a decrement of 10 mg/dL of serum HDL cholesterol.

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sions [11]. Isolated systolic hypertension in older persons is diagnosed if the systolic blood pressure is 140 mmHg or higher on three occasions, and the diastolic blood pressure is normal [11]. Isolated systolic hypertension occurred in 51% of 499 older persons with hypertension [11]. Isolated systolic hypertension and diastolic hypertension are both associated with increased cardiovascular morbidity and mortality in older persons [12]. Increased systolic blood pressure is a greater risk factor for cardiovascular morbidity and mortality than is increased diastolic blood pressure [12]. The higher the systolic or diastolic blood pressure, the greater the morbidity and mortality from CAD in older men and women. At 30-year follow-up of persons aged 65 years and older in the Framingham Study, systolic hypertension correlated with the incidence of CAD in older men and women [6]. Diastolic hypertension correlated with CAD in older men but not in older women [6]. At 40month follow-up of older men and 48-month follow-up of older women, systolic or diastolic hypertension increased the relative risk of new coronary events 2.0 times in men and 1.6 times in women (Table 1) [10]. Older persons with hypertension should be treated initially with salt restriction, weight reduction, if necessary, cessation of drugs that increase blood pressure, avoidance of alcohol and tobacco, increase in physical activity, reduction of dietary saturated fat and cholesterol, and maintenance of adequate dietary potassium, calcium, and magnesium intake. Antihypertensive drugs have been demonstrated to decrease new coronary events in older men and women with hypertension (Table 2) [13–17]. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends as initial drug therapy diuretics or beta-blockers because these drugs have been shown to reduce cardiovascular morbidity and mortality in controlled clinical trials [18]. Persons with prior MI should be treated with beta-blockers and angiotensin-converting enzyme (ACE) inhibitors and not treated with calcium channel blockers or alpha blockers [19–26]. In an observational prospective study of 1212 older men and women,

Table 2 Decrease in New Coronary Events in Older Persons with Hypertension Treated with Antihypertensive Drugs Versus Placebo Study European Working Party on High Blood Pressure in the Elderly [13] (age 60–97 years) Swedish Trial in Old Patients With Hypertension [14] (age 70–84 years)

Follow-up

Result

4.7 years

Drug therapy caused a 60% reduction in fatal MIs and a 47% reduction in cardiac deaths Drug therapy caused a 25% decrease in fatal MIs and a 67% decrease in sudden deaths Drug therapy caused a 19% reduction in coronary events Drug therapy caused a 27% decrease in nonfatal MIs plus coronary deaths Drug therapy caused a 26% reduction in fatal and nonfatal cardiac events

25 months

Medical Research Council [15] (age 65–74 years) Systolic Hypertension in the Elderly Program [16] (mean age 72 years)

5.8 years

Systolic Hypertension in Europe [17] (mean age 70 years)

2.0 years

Abbreviations: MIs = myocardial infarctions.

4.5 years

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mean age 80 years, with prior MI and hypertension treated with beta-blockers, ACE inhibitors, diuretics, calcium channel blockers, or alpha-blockers, at 40-month follow-up, the incidence of new coronary events in persons treated with one antihypertensive drug was lowest in persons treated with beta-blockers or ACE inhibitors [26]. In older persons treated with two antihypertensive drugs, the incidence of new coronary events was lowest in persons treated with beta-blockers plus ACE inhibitors [26]. The beneﬁt of beta-blockers in reducing coronary events in older persons with prior MI is especially increased in persons with diabetes mellitus [22], symptomatic peripheral arterial disease [23], abnormal left ventricular ejection fraction (LVEF) [21,27], complex ventricular arrhythmias with abnormal LVEF [28] or normal LVEF [29], and with congestive heart failure (CHF) with abnormal LVEF [30] or normal LVEF [31]. Beta-blockers should also be used to treat older persons with hypertension who have angina pectoris [32], myocardial ischemia [33], supraventricular tachyarrhythmias such as atrial ﬁbrillation with a rapid ventricular rate [34], hyperthyroidism [35], preoperative hypertension, migraine, or essential tremor. In addition to beta-blockers, older persons with hypertension and CHF should be treated with diuretics and ACE inhibitors [36,37]. ACE inhibitors should also be administered to persons with diabetes mellitus, renal insuﬃciency, or proteinuria [18]. The blood pressure should be lowered to 130/80 mmHg or lower in persons with diabetes mellitus or renal insuﬃciency [18].

Dyslipidemia Serum Total Cholesterol In the Framingham Study, serum total cholesterol was an independent risk factor for CAD in older men and women [38]. Among patients aged 65 years or older with prior MI in the Framingham Study, serum total cholesterol was most strongly related to death from CAD and to all-cause mortality [39]. Many other studies have documented that a high serum total cholesterol is a risk factor for new coronary events in older men and women [5,10,40–42]. During 9-year follow-up of 350 men and women, mean age 79 years, in the Bronx Aging Study, a consistently increased serum low-density lipoprotein (LDL) cholesterol was associated with the development of MI in older women [43]. In the Established Populations for Epidemiologic Studies of the Elderly study, serum total cholesterol was a risk factor for mortality from CAD in older women but not in older men [44]. At 40month follow-up of older men and 48-month follow-up of older women, an increment of 10 mg/dL of serum total cholesterol increased the relative risk of new coronary events 1.12 times in men and 1.12 times in women (Table 1) [10]. Serum High-Density Lipoprotein Cholesterol A low serum high-density lipoprotein (HDL) cholesterol is a risk factor for new coronary events in older men and women [5,10,38,43–46]. In the Framingham Study [38], in the Established Populations for Epidemiologic Studies of the Elderly Study [44], and in our study [10], a low serum HDL cholesterol was a more powerful predictor of new coronary events than was serum total cholesterol. During 9-year follow-up of 350 men and women in the Bronx Aging Study, a consistently low serum HDL cholesterol level was independently associated with the develop-

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ment of MI, cardiovascular disease, or death in men [43]. At 40-month follow-up of 664 older men and 48-month follow-up of 1488 older women, multivariate analysis showed that there was a 1.70 times higher probability of developing new coronary events in men and a 1.95 times higher probability of developing new coronary events in women for a decrement of 10 mg/dL of serum HDL cholesterol (Table 1) [10]. Serum Triglycerides Hypertriglyceridemia has been reported to be a risk factor for new coronary events in older women but not in older men [10,38]. At 40-month follow-up of older men and at 48month follow-up of older women, multivariate analysis demonstrated that serum triglycerides were not a risk factor for new coronary events in older men and was a very weak risk factor for new coronary events in older women (Table 1) [10]. Drug Therapy of Hypercholesterolemia At 5.4-year median follow-up of 4444 men and women (1021 aged 65 to 70 years) with CAD and hypercholesterolemia in the Scandinavian Simvastatin Survival Study, compared with placebo, simvastatin 20 to 40 mg daily signiﬁcantly decreased total mortality by 34% in patients aged 65 to 70 years, CAD mortality by 43%, major coronary events by 34%, nonfatal MI by 33%, any acute CAD-related endpoint by 33%, any atherosclerosis-related endpoint by 34%, and coronary revascularization procedures by 41% (Table 3) [47]. The absolute risk reduction for both all-cause mortality and CAD mortality was approximately twice as great in persons 65 to 70 years of age at study entry as in those youinger than 65 years [47]. At 5-year follow-up of 4159 men and women (1283 aged 65 to 75 years) with MI and serum total cholesterol levels below 240 mg/dL but serum LDL cholesterol levels z115 mg/ dL in the Cholesterol and Recurrent Events trial, compared with placebo, pravastatin 40 mg daily signiﬁcantly reduced in patients aged 65 to 75 years CAD death by 45%, CAD death or nonfatal MI by 39%, major coronary events by 32%, coronary revascularization by 32%, and insigniﬁcantly reduced unstable angina pectoris by 8% and CHF by 23% (Table 3) [48]. For every 1000 patients 65 years and older treated for 5 years with pravastatin, 225 cardiovascular hospitalizations would be prevented compared with 121 cardiovascular hospitalizations in 1000 patients younger than 65 years [48]. At 6.1-year mean follow-up of 9014 men and women (3514 of whom were aged 65 to 75 years) with MI (64%) or unstable angina pectoris (36%) and serum total cholesterol levels of 155 to 271 mg/dL in the Long-Term Intervention With Pravastatin in Ischaemic Disease Study, compared with placebo, pravastatin 40 mg daily signiﬁcantly reduced all-cause mortality by 22%, death from CAD by 24%, fatal and nonfatal MI by 29%, death from cardiovascular disease by 25%, need for coronary artery bypass surgery by 22%, need for coronary angioplasty by 19%, hospitalization for unstable angina pectoris by 12%, and stroke by 19% (Table 3) [49]. The absolute beneﬁts of treatment with pravastatin were greater in groups of persons at higher absolute risk for a major coronary event such as older persons, those with higher serum LDL cholesterol levels, those with lower serum HDL cholesterol levels, and those with a history of diabetes mellitus or smoking [49]. At 5-year follow-up of 20,536 British men and women (10,697 of whom were aged 65 to 80 years) with either CAD, occlusive arterial disease of noncoronary arteries, diabetes mellitus, or treated hypertension and no serum lipid requirement in the Heart Protection Study, compared with placebo, simvastatin 40 mg daily signiﬁcantly reduced all-cause

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Table 3 Effects of Lowering Increased Serum Total Cholesterol and Low-Density Lipoprotein Cholesterol Levels by Simvastatin and Pravastatin Versus Placebo in Older Patients with Coronary Artery Disease Study

Follow-up

Results

Scandinavian Simvastatin Survival Study [47] (4444 men and women, 1021 aged 65–70 years, with CAD and hypercholesterolemia)

5.4 years

Cholesterol and Recurrent Events trial [48] (4159 men and women, 1283 aged 65–75 years, with MI and serum total cholesterol<240 mg/dL but serum LDL cholesterol z115 mg/dL)

5.0 years

Long-Term Intervention With Pravastatin in Ischaemic Disease Study [49] (9014 men and women, 3514 aged 65–75 years, with MI or unstable angina and mean serum total cholesterol 218 mg/dL)

6.1 years

Heart Protection Study [50] (20536 men and women, 10697 aged 65–85 years, with CAD, occlusive arterial disease of noncoronary arteries, diabetes, or treated hypertension and no serum lipid requirement)

5.0 years

In patients 65 years and older, compared with placebo, simvastatin decreased all-cause mortality by 34%, CAD mortality by 43%, major coronary events by 34%, nonfatal MI by 33%, any acute CAD-related event by 33%, any atherosclerosis-related endpoint by 34%, and coronary revascularization procedures by 41% Compared with placebo, pravastatin decreased CAD death by 45%, CAD death or nonfatal MI by 39%, major coronary events by 32%, coronary revascularization by 32%, stroke by 40%, and insigniﬁcantly decreased unstable angina by 8% and congestive heart failure by 23% Compared with placebo, pravastatin reduced all-cause mortality by 22%, death from CAD by 24%, fatal and nonfatal MI by 29%, death from cardiovascular disease by 25%, need for coronary artery surgery by 22%, need for coronary angioplasty by 19%, hospitalization for unstable angina by 12%, and stroke by 19% Compared with placebo, simvastatin reduced all-cause mortality by 13%, any vascular mortality by 17%, major coronary events by 27%, any stroke by 25%, any revascularization procedure by 24%, and any major vascular event by 24%

Abbreviations: CAD = coronary artery disease; MI = myocardial infarction; LDL = low-density lipoprotein.

mortality by 13%, any vascular mortality by 17%, major coronary events by 27%, any stroke by 25%, any revascularization procedure by 24%, and any major vascular event by 24% (Table 3) [50]. In the 1263 persons aged 75 to 80 years at study entry and 80 to 85 years at follow-up, any major vascular event was signiﬁcantly reduced 28% by simvastatin. Lowering serum LDL cholesterol from<116 mg/dL to<77 mg/dL by simvastatin caused a 25% signiﬁcant reduction in vascular events [50]. On the basis of the available data, the American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines [19] and the Third Report of the Expert

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Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [51] recommend reducing the serum LDL cholesterol to<100 mg/dL in persons with CAD. However, data from the Heart Protection Study favor treating all postinfarction patients with statins, regardless of the initial serum lipid values [50]. Diabetes Mellitus Diabetes mellitus is a risk factor for new coronary events in older men and in older women [10,52]. At 40-month follow-up of older men and 48-month follow-up of older women, diabetes mellitus was found by multivariate analysis to increase the relative risk of new coronary events 1.9 tims in men and 1.8 times in women (Table 1) [10]. Diabetic patients are more often obese and have higher serum LDL cholesterol and triglycerides levels and lower serum HDL cholesterol levels than do nondiabetics. Diabetics also have a higher prevalence of hypertension and left ventricular hypertrophy than do nondiabetics. These risk factors contribute to the higher incidence of new coronary events in diabetics than in nondiabetics. Older persons after MI who have diabetes mellitus should be treated with dietary therapy, weight reduction, if necessary, and appropriate drugs, if needed, to control hyperglycemia. Other coronary risk factors such as smoking, systolic or diastolic hypertension, dyslipidemia, obesity, and physical inactivity should be controlled. The blood pressure should be lowered to 130/80 mmHg or lower in diabetics by an ACE inhibitor [18] or by an angiotensin II receptor blocker [53] if the ACE inhibitor cannot be tolerated. The serum LDL cholesterol level should be reduced to <100 mg/dL [51]. Because there are data showing an increased incidence of coronary events and of mortality in diabetics with CAD treated with sulfonylureas [54–56], these drugs should be avoided, if possible, in postinfarction patients with diabetes mellitus. Obesity In the Framingham Study, obesity was an independent risk factor for new coronary events in older men and in older women [52]. Disproportionate distribution of fat to the abdomen assessed by the waist-to-hip circumference ratio was also found to be a risk factor for cardiovascular disease, mortality from CAD, and total mortality in older men and women [57,58]. At 40-month follow-up of older men and 48-month follow-up of older women, obesity was a risk factor for new coronary events in men and in women by univariate analysis but not by multivariate analysis (Table 1) [10]. Obese patients who have had a MI must undergo weight reduction. Weight reduction is also a ﬁrst approach to controlling hyperglycemia, mild hypertension, and dyslipidemia before placing persons on long-term drug therapy. Regular aerobic exercise should be added to diet in treating obesity. Physical Inactivity Physical inactivity is associated with obesity, dyslipidemia, hyperglycemia, and hypertension. At 12-year follow-up in the Honolulu Heart Program, physically active men aged 65 years or older had a relative risk of 0.43 for CAD compared with inactive men [59]. Exercise training programs are not only beneﬁcial in preventing CAD [60] but also have

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been shown to improve endurance and functional capacity in older persons after MI [61,62]. Moderate exercise programs suitable for older persons after MI include walking, climbing stairs, bicycling, or swimming.

ASPIRIN Aspirin decreases the aggregation of platelets exposed to thrombogenic stimuli by inhibiting the cyclooxygenase enzyme reaction within the platelet and thereby blocking synthesis of thromboxane A2, a powerful stimulus to platelet aggregation and vasoconstriction [63]. Randomized trials involving 20,006 patients showed that aspirin and other antiplatelet drugs administered to patients after MI decreased the incidence of recurrent MI, stroke, or vascular death by 36 events per 1000 patients treated for 2 years [64]. The beneﬁt of aspirin in decreasing MI, stroke, or vascular death in patients after MI was irrespective of age, sex, blood pressure, and diabetes mellitus [64]. Data from the Multicenter Study of Myocardial Ischemia in 936 patients enrolled 1 to 6 months after an acute MI (70% of patients) or unstable angina pectoris (30% of patients) showed at 23-month follow-up that the cardiac mortality rate was 1.6% for aspirin users and 5.4% for nonusers of aspirin [65]. Cardiac mortality was reduced 90% in aspirin users who underwent thrombolytic therapy compared with nonusers of aspirin who underwent thrombolytic therapy [65]. The Coumadin Aspirin Reinfarction Study (CARS) randomized 8803 low-risk patients after MI to aspirin 160 mg daily, aspirin 80 mg plus warfarin 1 mg daily, or to aspirin 80 mg plus warfarin 3 mg daily [66]. At follow-up, the combined incidence of cardiovascular death, recurrent MI, and stroke was similar in the three treatment groups [66]. The incidence of mortality was similar in the three treatment groups. However, the incidence of nonfatal stroke was reduced by aspirin 160 mg daily [66]. Data from the Combination Hemotherapy and Mortality and Prevention Study showed in 5059 postinfarction patients that warfarin administered in a dose to achieve an INR of 1.8 combined with low-dose aspirin did not provide a clinical beneﬁt beyond that achieved with aspirin alone [67]. Of 5490 survivors of acute MI aged z65 years with no contraindications to aspirin, 4149 patients (76%) received aspirin at the time of hospital discharge [68]. At the 6-month follow-up evaluation, aspirin users had a signiﬁcant 23% reduction in mortality [68]. In an observational prospective study of 1410 patients, mean age 81 years, with prior MI and a serum LDL cholesterol of 125 mg/dL or higher, 832 patients (59%) were treated with aspirin [69]. At 3-year follow-up, use of aspirin caused a 52% signiﬁcant independent reduction in new coronary events (95% CI, 0.41–0.55) [69]. Use of statins caused a 54% signiﬁcant independent reduction in the incidence of new coronary events (95% CI, 0.40– 0.53) [69]. On the basis of the available data, all patients should receive aspirin in a dose of 160 to 325 mg daily on day 1 of an acute MI and continue this dose of aspirin for an indeﬁnite period unless there is a speciﬁc contraindication to its use [70]. Clopidogrel is also an excellent antiplatelet drug which is eﬀective in reducing MI, ischemic stroke, and vascular death in postinfarction patients [71]. The ACC/AHA guidelines recommend the use of clopidogrel in postinfarction patients who cannot tolerate aspirin for an indeﬁnite period unless there is a speciﬁc contraindication to its use [70].

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ANTICOAGULANTS The routine use of warfarin after MI is controversial [72]. However, three well-controlled studies have shown a reduction in mortality and/or morbidity in patients receiving longterm oral anticoagulation therapy after MI [73–75]. The Sixty Plus Reinfarction Study Group reported at 2-year follow-up after MI of patients, mean age 68 years, that compared with placebo, acenocoumarin or phenprocoumon caused a 26% nonsigniﬁcant decrease in mortality, a 55% signiﬁcant reduction in recurrent MI, and a 40% nonsigniﬁcant decrease in stroke [73]. The Warfarin Reinfarction Study Group showed at 37-month follow-up after MI of patients 75 years of age or younger that compared with placebo, warfarin caused signiﬁcant reductions in mortality (24%), recurrent MI (34%), and stroke (55%) [74]. The Anticoagulation in the Secondary Prevention of Events in Coronary Thrombosis Research Group reported at 37-month follow-up after MI of patients, mean age 61 years, that compared with placebo, nicoumalone or phenprocoumon caused a 10% nonsigniﬁcant decrease in mortality, a 53% signiﬁcant reduction in recurrent MI, and a 42% signiﬁcant decrease in stroke [75]. The ACC/AHA guidelines recommend as Class I indications for long-term oral anticoagulant therapy after MI (1) secondary prevention of MI in post-MI patients unable to tolerate daily aspirin or clopidogrel; (2) in post-MI patients with persistent atrial ﬁbrillation; and (3) post-MI patients with left ventricular thrombus [70]. Long-term warfarin should be administered in a dose to achieve an INR between 2.0 and 3.0 [70].

BETA-BLOCKERS Beta-blockers are very eﬀective antianginal and anti-ischemic agents and should be administered to all patients with angina pectoris or silent myocardial ischemia due to CAD unless there are speciﬁc contraindications to their use. Teo et al. [76] analyzed 55 randomized controlled trials comprising 53268 patients that investigated the use of beta-blockers after MI. Beta-blockers signiﬁcantly decreased mortality by 19% in these studies [76]. A randomized, double-blind, placebo-controlled study of propranolol in high-risk survivors of acute MI at 12 Norwegian hospitals showed a 52% reduction in sudden cardiac death in persons treated with propranolol for 1 year [77]. Table 4 shows that metoprolol [78], timolol [79,80], and propranolol [81] caused a greater decrease in mortality after MI in older persons than in younger persons. The reduction in mortality after MI in patients treated with beta-blockers was due both to a reduction in sudden cardiac death and recurrent MI [79–81]. A retrospective cohort study also showed that MI patients aged 60 to 89 years treated with metoprolol had an ageadjusted mortality decrease of 76% [82]. In the Beta-Blocker Heart Attack Trial, propranolol caused a 27% decrease in mortality in patients with a history of CHF and a 25% decrease in mortality in patients without CHF [83]. In this study, propranolol caused a 47% reduction in sudden cardiac death in patients with a history of CHF and a 13% reduction in sudden cardiac death in patients without CHF [83]. In the Beta-Blocker Pooling Project, results from nine studies involving 3519 patients with CHF at the time of acute MI demonstrated that beta-blockers caused a 25% decrease in mortality [84]. In the Multicenter Diltiazem Post-Infarction Trial, the 2.5-year risk of total mortality in patients with a left ventricular ejection fraction (LVEF)<30% was 24%

338 Table 4

Aronow Effect of Beta-Blockers on Mortality After Myocardial Infarction

Study

Follow-up

Goteborg Trial [78]

90 days

Norwegian Multicenter Study [79]

17 months (up to 33 months)

Norwegian Multicenter Study [80]

61 months (up to 72 months)

Beta-Blocker Heart Attack Trial [81]

25 months (up to 36 months)

Results Compared with placebo, metoprolol caused a 21% nonsigniﬁcant decrease in mortality in patients <65 years and a 45% signiﬁcant decrease in mortality in patients 65–74 years Compared with placebo, timolol caused a 31% signiﬁcant reduction in mortality in persons<65 years and a 43% signiﬁcant reduction in mortality in persons 65–74 years Compared with placebo, timolol caused a 13% nonsigniﬁcant decrease in mortality in persons <65 years and a 19% signiﬁcant decrease in mortality in persons 65–74 years Compared with placebo, propranolol caused a 19% nonsigniﬁcant reduction in mortality in persons <60 years and a 33% signiﬁcant reduction in mortality in persons 60–69 years

for patients receiving beta-blockers (relative risk = 0.53) versus 45% for patients not receiving beta-blockers [85]. Beta-blockers have also been found to reduce mortality in patients with CAD and CHF associated with a LVEF V35% [86] or z40% [31]. An observational prospective study was performed in 477 patients, mean age 79 years, with prior MI and a LVEF<40% (mean LVEF 31%) [21]. At 34-month follow-up, patients treated with beta-blockers without ACE inhibitors had a 25% signiﬁcant reduction in new coronary events and a 41% signiﬁcant reduction in CHF [21]. At 41-month follow-up, patients treated with both beta-blockers and ACE inhibitors had a signiﬁcant 37% reduction in new coronary events and a signiﬁcant 60% reduction in CHF [21]. A retrospective analysis of the use of beta-blockers after MI in a New Jersey Medicare population from 1987 to 1992 showed that only 21% of older persons after MI without contraindications to beta-blockers were treated with beta-blockers [87]. Older patients who were treated with beta-blockers after MI had a 43% decrease in 2-year mortality and a 22% decrease in 2-year cardiac hospital readmissions than older patients who were not treated with beta-blockers [87]. Use of a calcium channel blocker instead of a beta-blocker after MI doubled the risk of mortality [87]. Beta-blockers have also been demonstrated to reduce mortality in older patients with complex ventricular arrhythmias after MI and a LVEF z40% [29] or V40% [28]. The decrease in mortality in older patients with heart disease and complex ventricular arrhythmias caused by propranolol is due more to an anti-ischemic eﬀect than to an antiarrhythmic

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eﬀect [33]. In these patients, propranolol also markedly decreased the circadian variation of ventricular arrhythmias [88], abolished the circadian variation of myocardial ischemia [89], and abolished the circadian variation of sudden cardiac death or fatal MI [90]. A meta-analysis of trials also showed that the use of beta-blockers after non-Q-wave MI is likely to reduce mortality and recurrent MI by 25% [91]. Therefore, older patients with Q-wave MI or non-Q-wave MI without contraindications to beta-blockers should be treated with beta-blockers for at least 6 years after MI. Beta-blockers with intrinsic sympathomimetic activity should not be used. The American College of Cardiology/American Heart Association guidelines recommend that patients without a clear contraindication to beta-blocker therapy should receive beta-blockers within a few days of MI (if not initiated acutely) and continue them indeﬁnitely [70].

NITRATES Long-acting nitrates are eﬀective antianginal and anti-ischemic drugs [92]. These drugs should be administered along with beta-blockers to patients after MI who have angina pectoris. The dose of oral isosorbide dinitrate prescribed should be gradually increased to a dose of 30 to 40 mg administered three times daily if tolerated. Isosorbide-5-mononitrate in a dose of 60 mg may also be administered once daily. To avoid nitrate tolerance, there should be a nitrate-free interval of 12 h each day [93]. Beta-blockers should be used to prevent angina pectoris and rebound myocardial ischemia during the nitrate-free interval.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS ACE inhibitors improve symptoms, quality of life, and exercise tolerance in patients with CHF and an abnormal LVEF [94] or a normal LVEF [95]. An overview of 32 randomized trials comprising 7105 patients with CHF showed that ACE inhibitors reduced mortality by 23% and mortality or hospitalization for CHF by 35% [96]. Patients who develop CHF after MI should be treated with ACE inhibitors unless there are speciﬁc contraindications to their use. Table 5 shows that ACE inhibitors reduce mortality in patients after MI [20,97–100]. In the Survival and Ventricular Enlargement Trial, asymptomatic patients with a LVEF V40% treated with captopril 3 to 16 days after MI had at 42-month follow-up compared with placebo, a 19% reduction in mortality, a 21% decrease in death from cardiovascular causes, a 37% reduction in development of severe CHF, a 22% decrease in development of CHF requiring hospitalization, and a 25% reduction in recurrent MI [97]. Captopril decreased mortality independent of age, sex, blood pressure, LVEF, and use of thrombolytic therapy, aspirin, or beta-blockers [97]. In the Heart Outcomes Prevention Evaluation Study, 9217 patients aged z55 years (55% aged z65 years) with MI (53%), cardiovascular disease (88%), or diabetes mellitus (38%), but no CHF or abnormal LVEF, were randomized to ramipril 10 mg daily or placebo [20]. At 4.5-year follow-up, compared with placebo, ramipril signiﬁcantly reduced the incidence of MI, stroke, and cardiovascular death by 22% (95% CI, 0.70–0.86) [20]. On the basis of the available data, ACE inhibitors should be administered to all patients after MI unless there are speciﬁc contraindications to their use [70].

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Table 5 Effect of Angiotensin-Converting Enzyme Inhibitors on Mortality in Patients After Myocardial Infarction Study

Follow-up

Results

Survival and Ventricular Enlargement Trial [70]

42 months (up to 60 months)

Acute Infarction Ramipril Eﬃcacy Study [71]

15 months

Survival of Myocardial Infarction Long-Term Evaluation Trial [72]

1 year

Trandolapril Cardiac Evaluation Study [73]

24 to 50 months

Heart Outcomes Prevention Evaluation Study [20]

4.5 years (up to 6 years)

In patients with MI and LVEF V40%, compared with placebo, captopril reduced mortality 8% in patients aged V55 years, 13% in patients aged 56–64 years, and 25% in patients aged z65 years In patients with MI and clinical evidence of CHF, compared with placebo, ramipril decreased mortality 2% in patients aged <65 years and 36% in patients aged z65 years In patients with anterior MI, compared with placebo, zofenopril reduced mortality or severe CHF 32% in patients aged<65 years and 39% in patients aged z65 years In patients, mean age 68 years, with LVEF V35%, compared with placebo, trandolapril reduced mortality 33% in patients with anterior MI and 14% in patients without anterior MI In patients aged z55 years with MI (53%), cardiovascular disease (88%), or diabetes (38%) but no CHF or abnormal LVEF, ramipril reduced MI, stroke, and cardiovascular death 22%

Abbreviations: MI = myocardial infarction; LVEF = left ventricular ejection fraction; CHF = congestive heart failure.

CALCIUM CHANNEL BLOCKERS Teo et al. [76] analyzed randomized controlled trials comprising 20,342 patients that investigated the use of calcium channel blockers after MI. Mortality was insigniﬁcantly higher (relative risk = 1.04) in patients treated with calcium channel blockers [76]. A metaanalysis of randomized, clinical trials of the use of calcium channel blockers in patients with MI, unstable angina pectoris, and stable angina pectoris showed that the relative risk

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for mortality in the trials using dihydropyridines such as nifedipine that increase heart rate was 1.16 [101]. The calcium channel blockers diltiazem and verapamil which reduce heart rate had no eﬀect on survival [101]. Furberg et al. [102] performed a meta-analysis of the eﬀect of nifedipine on mortality in 16 randomized secondary prevention clinical trials in patients with CAD. In this study, the relative risk for mortality was 1.06 for patients treated with nifedipine 30 mg to 50 mg daily, 1.18 for patients treated with nifedipine 60 mg daily, and 2.83 for patients treated with nifedipine 80 mg daily [102]. The Multicenter Diltiazem Postinfarction Trial demonstrated at 25-month follow-up in patients after MI that, compared with placebo, diltiazem caused no signiﬁcant eﬀect on mortality or recurrent MI [103]. However, in patients with pulmonary congestion at baseline or a LVEF<40%, diltiazem caused a signiﬁcant increase in new cardiac events (hazard ratios = 1.41 and 1.31, respectively) [103]. In this study, diltiazem also increased the incidence of late-onset CHF in patients with a LVEF<40% [104]. Use of a calcium channel blocker instead of a beta-blocker after MI in a New Jersey Medicare population also doubled the risk of mortality [87]. Since no calcium channel blocker has been shown to improve survival after MI except for the subgroup of patients with normal LVEF treated with verapamil in the Danish Verapamil Infarction Trial II [105], calcium channel blockers should not be used in the treatment of patients after MI. However, if patients after MI have persistent angina pectoris despite treatment with beta-blockers and nitrates, a nondihydropyridine calcium channel blocker such as verapamil or diltiazem should be added to the therapeutic regimen if the LVEF is normal. If the LVEF is abnormal, amlodipine or felodipine should be added to the therapeutic regimen. The ACC/AHA guidelines state that there are no Class I idications for the use of calcium channel blockers after MI [19].

ANTIARRHYTHMIC THERAPY Class I Drugs A meta-analysis of 59 randomized controlled trials comprising 23,229 patients that investigated the use of quinidine, procainamide, disopyramide, imipramine, moricizine, lidocaine, tocainide, phenytoin, mexiletine, aprindine, encainide, and ﬂecainide after MI demonstrated that mortality was signiﬁcantly higher in patients receiving class I antiarrhythmic drugs than in patients receiving no antiarrhythmic drugs (odds ratio = 1.14) [76]. None of the 59 studies showed a decrease in mortality by class I antiarrhythmic drugs [76]. In the Cardiac Arrhythmia Suppression Trials I and II, older age also increased the likelihood of adverse eﬀects including death in patients after MI receiving encainide, ﬂecainide, or moricizine [106]. Compared with no antiarrhythmic drug, quinidine or procainamide did not decrease mortality in older patients with CAD, normal or abnormal LVEF, and presence versus absence of ventricular tachycardia [107]. On the basis of the available data, patients after MI should not receive class I antiarrhythmic drugs. d, l-Sotalol and d-Sotalol Studies comparing the eﬀect of d, l-sotalol with placebo on mortality in patients with complex ventricular arrhythmias have not been performed. Compared with placebo, d, l-sotalol did not reduce mortality in post-MI patients followed for 1 year [108]. In the

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Survival with Oral d-Sotalol (SWORD) trial, 3121 survivors of MI with a LVEF V40% were randomized to d-sotalol or placebo [109]. Mortality was signiﬁcantly higher at 148day follow-up in patients treated with d-sotalol (5.0%) than in patients treated with placebo (3.1%) [109]. On the basis of the available data, d,l-sotalol and d-sotalol should not be used to treat patients after MI. Amiodarone In the European Myocardial Infarction Amiodarone Trial, 1486 survivors of MI with a LVEF V40% were randomized to amiodarone (-743 patients) or to placebo (743 patients) [110]. At 2-year follow-up, 103 patients treated with amiodarone and 102 patients treated with placebo had died [110]. In the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial, 1202 survivors of MI with nonsustained ventricular tachycardia or complex ventricular arrhythmias were randomized to amiodarone or to placebo [111]. Amiodarone was very eﬀective in suppressing ventricular tachycardia and complex ventricular arrhythmias. However, the mortality rate at 1.8-year follow-up was not signiﬁcantly diﬀerent in the patients treated with amiodarone or placebo [111]. In addition, early permanent discontinuation of drug for reasons other than outcome events occurred in 36% of patients taking amiodarone [111]. In the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation Study, the incidence of pulmonary toxicity was 10% at 2 years in patients receiving amiodarone in a mean dose of 158 mg daily [112]. The incidence of adverse eﬀects for amiodarone also approaches 90% after 5 years of therapy [113]. On the basis of the available data, amiodarone should not be used in the treatment of patients after MI. Beta-Blockers However, beta-blockers have been demonstrated to reduce mortality in patients with nonsustained ventricular tachycardia or complex ventricular arrhythmias after MI in patients with normal or abnormal LVEF [28,29,114,115]. On the basis of the available data, betablockers should be used in the treatment of older patients after MI, especially if nonsustained ventricular tachycardia or complex ventricular arrhythmias are present, unless there are speciﬁc contraindications to their use. Automatic Implantable Cardioverter Defibrillator In the Antiarrhythmics Versus Implantable Deﬁbrillators (AVID) trial, 1016 patients, mean age 65 years, with a history of ventricular ﬁbrillation or serious sustained ventricular tachycardia were randomized to an automatic implantable cardioverter deﬁbrillator (AICD) or to drug therapy with amiodarone or d, l-sotalol [116]. Patients treated with an AICD had a 39% reduction in mortality at 1 year, a 27% decrase in mortality at 2 years, and a 31% reduction in mortality at 3 years [116]. If patients after MI have life-threatening ventricular tachycardia or ventricular ﬁbrillation, an AICD should be inserted. The eﬃcacy of the AICD implanted for ventricular ﬁbrillation or recurrent sustained ventricular tachycardia on survival is similar in older and younger patients [117]. The Multicenter Automatic Deﬁbrillator Implantation Trial (MADIT) randomized 196 patients with prior MI, a LVEF V35%, a documented episode of asymptomatic nonsustained ventricular tachycardia, and inducible ventricular tachycardia or ventricular

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ﬁbrillation not suppressed by intravenous procainamide or an equivalent drug at electrophysiological study to conventional medical therapy or implantation of an AICD [118]. At 27-month follow-up, patients treated with an AICD had a 54% reduction in mortality [118]. These data favor the prophylactic implantation of an AICD in post-MI patients at very high risk for sudden cardiac death. MADIT II randomized 1232 patients, mean age 64 years, with a prior MI and a LVEF of V30% to an AICD or to conventional medical therapy [119]. At 20-month follow-up compared with conventional medical therapy, the AICD signiﬁcantly reduced all-cause mortality from 19.8% to 14.2% (hazard ratio = 0.69; 95% CI, 0.51–0.93) [119]. The eﬀect of AICD therapy in improving survival was similar in patients stratiﬁed according to age, sex, LVEF, New York Heart Association class, and QRS interval [119]. These data favor considering the prophylactic implantation of an AICD in postinfarction patients with a LVEF of V30%.

HORMONE REPLACEMENT THERAPY The Heart Estrogen/Progestin Replacement Study (HERS) investigated in 2763 women with documented CAD the eﬀect of hormonal therapy versus double-blind placebo on coronary events [120]. At 4.1-year follow-up, there were no signiﬁcant diﬀerences between hormonal therapy and placebo in the primary outcome (nonfatal MI or CAD death) or in any of the secondary cardiovascular outcomes. However, there was a 52% signiﬁcantly higher incidence of nonfatal MI or death from CAD in the ﬁrst year in patients treated with hormonal therapy (relative hazard = 1.52; 95% CI, 1.01–2.29) than in patients treated with placebo [120]. Women on hormonal therapy had a signiﬁcantly higher incidence of venous thromboembolic events (relative hazard = 2.89, 95% CI, 1.50–5.58) and a signiﬁcantly higher incidence of gallbladder disease requiring surgery (relative hazard = 1.38, 95% CI, 1.00–1.92) than women on placebo. The Estrogen Replacement and Atherosclerosis trial randomized 309 postmenopausal women, mean age 66 years, with coronary angiographic evidence of signiﬁcant CAD to estrogen plus progestin, estrogen alone, or double-blind placebo [121]. At 3.2-year followup, quantitative coronary angiography showed no between-group diﬀerences in progression of coronary atherosclerosis [121]. At 6.8-year follow-up in the HERS trial, hormonal therapy did not reduce the risk of cardiovascular events in women with CAD [122]. The investigators concluded that hormonal therapy should not be used to reduce the risk of coronary events in women with CAD [122]. At 6.8-year follow-up in the HERS trial, all-cause mortality was insigniﬁcantly increased 10% by hormonal therapy (relative hazard = 1.10; 95% CI, 0.92–1.31) [123]. The overall incidence of venous thromboembolism at 6.8-year follow-up was signiﬁcantly increased 208% by hormonal therapy (relative hazard = 2.08; 95% CI, 1.28–3.40) [123]. At 6.8-year follow-up, the overall incidence of biliary tract surgery was signiﬁcantly increased 48% (relative hazard = 1.48; 95% CI, 1.12–1.95), the overall incidence for any cancer was insigniﬁcantly increased 19% (relative hazard = 1.19; 95% CI, 0.95–1.50), and the overall incidence for any fracture was insigniﬁcantly increased 4% (relative hazard = 1.04; 95% CI, 0.92–1.31) [123]. The estrogen plus progestin component of the Women’s Health Initiative (WHI) study included 16,608 healthy postmenopausal women aged 50 to 79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo [124]. At 5.2-year follow-up,

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this component of the WHI study was prematurely discontinued because the excess risk of events included in the global index was 19 per 10,000 person-years [124]. Absolute excess risks per 10,000 person-years included seven more coronary events, eight more strokes, eight more episodes of pulmonary embolism, and eight more invasive breast cancers, while absolute risk reductions per 10,000 person-years were six fewer colorectal cancers and ﬁve fewer hip fractures [124]. On the basis of the available data, hormonal therapy should not be used in postmenopausal women with CAD [19].

REVASCULARIZATION Medical therapy alone is the preferred treatment in older patients after MI. The two indications for revascularization in older patients after MI are prolongation of life and relief of unacceptable symptoms despite optimal medical management. In a prospective study of 305 patients aged z75 years with chest pain refractory to at least two antianginal drugs, 150 patients were randomized to optimal medical therapy and 155 patients to invasive therapy [125,126]. In the invasive group, 74% had coronary revascularization (54% coronary angioplasty and 20% coronary artery bypass graft surgery). During the 6-month followup, one-third of the medically treated group needed coronary revascularization for uncontrollable symptoms. At 6-month follow-up, death, nonfatal MI, or hospital admission for an acute coronary syndrome was signiﬁcantly higher in the medically treated group (49%) than in the invasive group (19%) [125,126]. Revascularization by percutaneous transluminal coronary angioplasty (Chap. 15) or by coronary artery bypass graft surgery (Chap. 14) is extensively discussed elsewhere. If coronary revascularization is performed, aggressive medical therapy must be continued.

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Aronow H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303–310. Aronow WS, Kronzon I. Eﬀect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993; 71:602–604. Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273:1450–1456. Pfeﬀer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, on behalf of the SAVE Investigators. Eﬀect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992; 327:669–677. The Acute Infarction Ramipril Eﬃcacy (AIRE) Study Investigators. Eﬀect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342:821–828. Ambrosioni E, Borghi C, Magnani B, for the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The eﬀect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995; 332:80–85. Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lynborg K, Videbaek J, Cole DS, Auclert L, Pauly NC, Aliot E, Persson S, Camm AJ, for the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333:1670–1676. Yusuf S, Held P, Furberg C. Update of eﬀects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991; 67:1295–1297. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92:1321–1326. The Multicenter Diltiazem Postinfarction Trial Research Group. The eﬀect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988; 319:385–392. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S, the Adverse Experience Committee, and the Multicenter Diltiazem Postinfarction research Group. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation 1991; 83:52–60. Danish Study Group on Verapamil in Myocardial Infarction. Trial II-DAVIT II. Eﬀect of verapamil on mortality and major events after acute myocardial infarction. Am J Cardiol 1990; 66:779–785. Akiyama T, Pawitan Y, Campbell WB, Papa L, Barker AH, Rubbert P, Friedman L, Keller M, Josephson RA, the CAST Investigators. Eﬀects of advancing age on the eﬃcacy and side eﬀects of antiarrhythmic drugs in post-myocardial infarction patients with ventricular arrhythmias. J Am Geriatr Soc 1992; 40:666–672. Aronow WS, Mercando AD, Epstein S, Kronzon I. Eﬀect of quinidine or procainamide versus no antiarrhythmic drug on sudden cardiac death, total cardiac death, and total death in elderly patients with heart disease and complex ventricular arrhythmias. Am J Cardiol 1990; 66:423–428. Julian DJ, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol for one year after myocardial infarction. Lancet 1982; 1:1142–1147. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CA,

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111.

112. 113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

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Schwartz PJ, Veltri EP, for the SWORD Investigators. Eﬀect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996; 348:7–12. Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, Simon P, for the European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of eﬀect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997; 349:667–674. Cairns JA, Connolly SJ, Roberts R, Gent M, for the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet 1997; 349:675–682. Green HL, for the CASCADE Investigators. The CASCADE study. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest in Seattle. Am J Cardiol 1993; 72:70F–74F. Herre J, Sauve M, Malone P, Griﬃn JC, Helmy I, Langberg JJ. Long-term results of amiodarone therapy in patients with recurrent sustained ventricular tachycardia or ventricular ﬁbrillation. J Am Coll Cardiol 1989; 13:442–449. Friedman LM, Byington RP, Capone RJ, Furberg CD, Goldstein S, Lichstein E. Writing Group for the Beta-Blocker Heart Attack Trial Research Group. Eﬀect of propranolol in patients with myocardial infarction and ventricular arrhythmia. J Am Coll Cardiol 1986; 7: 1–8. Norris RM, Barnaby PF, Brown MA, Geary GG, Clarke ED, Logan RL. Prevention of ventricular ﬁbrillation during acute myocardial infarction by intravenous propranolol. Lancet 1984; 2:883–886. The Antiarrhythmics Versus Implantable Deﬁbrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable deﬁbrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997; 337:1576–1583. Tresch DD, Troup PJ, Thakur RK, Veseth-Rogers J, Tucker V, Wetherbee JN, Hoﬀman RG, Chapman PD. Comparison of eﬃcacy of automatic implantable cardioverter deﬁbrillator in patients older and younger than 65 years of age. Am J Med 1991; 90:717–724. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M, for the Multicenter Automatic Deﬁbrillator Implantation Trial Investigators. Improved survival with an implanted deﬁbrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996; 335:1933– 1940. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML, for the Multicenter Automatic Deﬁbrillator Implantation Trial II Investigators. Prophylactic implantation of a deﬁbrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877–883. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoﬀ E, for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605–613. Herrington DM, Reboussin DM, Brosnihan B, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Eﬀects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000; 343: 522–529. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoﬀ E, Wenger N, for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA 2002; 288:49–57. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Knopp R, Lowery M, Satterﬁeld S, Schrott H, Vittinghoﬀ E, Hunninghake D, for the HERS Research Group.

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Noncardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA 2002; 288:58–66. 124. Writing Group for the Women’s Health Initiative Investigators. Risks and beneﬁts of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333. 125. The TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial. Lancet 2001; 358: 951–957. 126. Aronow WS. Commentary. Approach to symptomatic coronary disease in the elderly: TIME to change? Lancet 2001; 358:945–946.

14 Surgical Management of Coronary Artery Disease in the Elderly Edward A. Stemmer University of California at Irvine, Irvine, California, U.S.A. Veterans Affairs Medical Center, Long Beach, California, U.S.A.

Wilbert S. Aronow Westchester Medical Center/New York Medical College, Valhalla, and Mount Sinai School of Medicine, New York, New York, U.S.A.

Since 1990, the U.S. population over the age of 65 years has been growing rapidly in both absolute and relative numbers. Currently, 33.5 million individuals are over 65 years of age. By 2010, when the ﬁrst of the baby boomers (those born between 1946 and 1964) reach 65, there will be 40 million people aged 65 years or older. By 2030, when the last of the baby boomers reach 65, the number of individuals aged 65 years or older is projected to reach 70 million. Moreover, the elderly are living longer. In 1900, at age 65, 13% of men and 16% of women could expect to live to age 85 years. By 1992, these percentages were 30% and 50%, respectively. As the baby boomers age, the percentage of the population aged 85 years or older will grow from the current level of 1.4% to 2.4% in 2030 and to 4.6% in the year 2050. Octogenarians are, in fact, the fastest growing segment of the population in the United States (Table 1) [1,2]. While arthritis is the most common chronic disease borne by the elderly, heart disease is the most common cause of major disability in the elderly as well as the most common reason for hospitalization and death. Clinically evident heart disease aﬀects 30% of those aged 65 years or older [1,3]. Approximately 12% of the elderly population suﬀer from major limitations of activity because of heart disease [4]. Forty percent of deaths in the over-65 population are due to heart disease [5]. Clinically recognized ischemic heart disease (and its complications) are responsible for 70% of the deaths due to heart disease [6,7]. In 1993, seven to 8% of men and women aged 65 years or older were hospitalized for ‘‘diseases of the heart,’’ with an average hospital stay of 6 to 7 days [1,8]. Congestive heart failure was the most common reason for hospitalization [9], but from 6 to 9% of the elderly discharged with a diagnosis of ‘‘diseases of the heart’’ had undergone coronary arterial bypass (CABG) at an estimated cost of 6 to 7 billion dollars per year [8,10–15]. As modern medical treatment is being employed for increasing numbers of progressively older patients, dire predictions about the solvency of Social Security and Medi353

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Table 1 Demographics of Current and Projected Resident Population of the United States: 1900–2050

Year 1900 1995 2010 2030 2040 2050

Resident population (in 1000s) 75 263 297 346 369 393

995 434 716 899 980 931

Number of persons (in 1000s) z65 3 33 40 70 80 77

116 648 104 175 109 014

z85 3 5 8 13 18

125 598 671 455 552 223

Percentage of resident population

Life expectancy (years)

z65

z85

at birth

at age 65

4.1 12.8 13.2 20.0 20.3 20.0

0.2 1.4 1.9 2.4 3.7 4.6

49.2 76.3 77.9 78.8 79.3 79.8

11.9 17.7 18.6 20.0 20.7 21.6

care abound. By 2030, the number of individuals over the age of 65, will more than double [2]. It has been suggested that by 2050 outﬂow of funds from Social Security and Medicare will exceed inﬂow by 75% [16]. Rationing (in one form or another) of health-care coverage for the elderly is being discussed openly. Health-care planners question whether the rapidly increasing expenditure of funds, particularly for highly technical procedures, is justiﬁed in a population that is nearing the end of life or, at least, the end of active life [17]. It is against this background that the merits of performing CABG in the elderly must be discussed. Before deciding whether or not the beneﬁts that the elderly reap from sophisticated surgical procedures are worth the risks and the costs, however, it is important to appreciate the characteristics of the population commonly referred to as elderly. How sick, impaired, and disabled are the elderly? How prevalent is coronary artery disease (CAD) in the elderly? Does the nature and presentation of CAD in the elderly diﬀer from that in a younger population? Can current medical and surgical treatments of ischemic heart disease prevent disabilities, restore function, prolong life, and increase the quality of life in the elderly with CAD?

CHARACTERISTICS OF THE OVER-65 POPULATION Most discussions about the elderly center on prevalence of disease, degrees of physical or mental impairment, need for hospitalization or institutionalization, and end-of-life expenses. Indeed, 80% of the elderly population do suﬀer from one or more chronic conditions. Overall, however, the elderly population is surprisingly healthy. Only 20% of those in the 65- to 74-year-old group have major or severe limitations of activities due to their chronic diseases (Table 2) [18]. Only 5% reside in institutions (many temporarily) [19]. In 1994, 77% of those older than 65 years of age were living in their own households. Of these, 55% were living with their spouses; 30% lived alone but independently; 12% lived with other relatives; only 2% resided with nonrelatives [20]. Half of those aged 85 or older still live alone or with their spouses [21]. In the community, about 5% of the elderly have some clinically detectable impairment of cognitive function but only 2% of the elderly have major limitations of activity because of mental or nervous disease [22]. Seventy percent of the elderly rate their health as good, very good, or excellent [23]. Whatever the nature, degree, and permanence of their disabilities might be, it is apparent that the chronic diseases that cause severe disability and death in the elderly can be treated very

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Table 2 Percentage of Noninstitutionalized Population Whose Activities Are Limited by One or More Chronic Conditions Degree of Limitation Age group (Years)

None

Minor

Major

Severe

65 or older 65 to 74 75 or older

61.2 65.6 54.7

15.6 13.6 18.6

12.5 10.4 15.7

10.6 10.4 11.1

successfully by currently available methods (Tables 3, 4). It is also apparent that heart disease stands out as the most common chronic disease that results in major limitations of activity and death in the elderly [4,18,24].

PREVALENCE OF CAD IN THE ELDERLY While there is general agreement that prevalence of CAD increases markedly with increasing age, the true prevalence of CAD in the elderly is diﬃcult to determine. About 28% of those over 65 die from ischemic heart disease [6,7]. Epidemiological studies, relying on history and resting electrocardiographs, have found symptomatic coronary disease in 20 to 22% of the general population over 70 [25,26]. When rest and stress criteria are combined, at least half of those over 70 were found to have CAD [27]. Autopsy studies indicate the prevalence of signiﬁcant CAD (stenosis z60% of at least one coronary artery) to be as high as 60 to 70% in the elderly [28].

EVOLUTION OF THE TREATMENT OF CORONARY ARTERY DISEASE Evolution of the treatment of CAD took place over a period of 200 years. During the eighteenth century, angina pectoris was recognized as a common and lethal illness that

Table 3 Percentage of Population Age 65 or Older with Major Limitations of Activities Because of Specific Conditions Major limitations (%) Disease/condition Heart Arthritis Visual impairment Emphysema Hypertension Cerebrovascular disease Mental/nervous Diabetes mellitus Other circulatory

Men

Women

12 8 4 4 3 3 2 3 3

10 13 5 XX 5 3 2 3 3

356 Table 4

Stemmer and Aronow Selected Causes of Death in 65-Year-Old or Older Population (1992) Men

Women

Cause

Number

Percent of total

Number

Percent of total

All causes Heart disease Cancer Stroke Obstructive pulmonary disease Pneumonia/inﬂuenza Diabetes mellitus Accidents

735,298 271,214 191,204 46,722 42,961 30,374 14,865 13,335

100.0 36.9 26.0 6.4 5.8 4.1 2.0 1.8

839,916 324,100 170,856 78,670 35,221 37,115 22,463 13,298

100.0 38.5 20.3 9.4 4.2 4.4 2.7 1.6

frequently attacked without warning and was associated with sudden death. Its relationship to arterial disease was recognized. During the nineteenth century, the basic instruments necessary for detecting coronary artery disease were developed as were the basic medications for treating its symptoms. Myocardial infarction was recognized as a pathological entity. The early and midportion of the twentieth century saw the development of sophisticated diagnostic techniques that made modern treatment of coronary artery disease and its complications a reality during the last half of the twentieth century. Recognition of Angina Pectoris Twenty-four-hundred years ago, Hippocrates noted that frequent attacks of pain in the heart in an old person often predicted sudden death. Treatises describing the pulse and its abnormalities date far back in history as do descriptions of the anatomy of the heart. Nevertheless, appreciation and understanding of the role of the coronary arteries in the production of cardiac disease did not begin to develop until the late eighteenth century when Heberden introduced the term angina pectoris (Greek for strangling or choking and breastbone or breast) during a lecture before the Royal College of Physicians of London in July, 1768. He described symptoms he had observed in ‘‘at least twenty men almost all above 50 years old, most with a short neck, and inclining to be fat.’’ Heberden commented that angina pectoris was ‘‘not extremely rare,’’ that it was associated with walking, particularly after eating, and that the uneasiness vanished the moment the patient stood still. He noted the symptoms worsened with time and could occur while lying down. He reported that although the natural tendency of the illness was to kill the patient suddenly, the disorder could last ‘‘near twenty years.’’ Because the patient’s pulse was not usually disturbed by the pain, Heberden concluded that ‘‘the heart is not disturbed by it.’’ He ascribed the illness to ‘‘a strong spasm sometimes accompanied by an ulcer,’’ but commented that he had never had it in his power to ‘‘see anyone opened who had died of it.’’ Heberden published his report in 1772 [29–31]. In 1775, Edward Jenner helped his close friend, John Hunter, perform an autopsy on one of Heberden’s patients who had died suddenly following an anginal attack associated with a sense of impending death. Ossiﬁed coronary vessels were found but the arteries were not examined carefully. In 1785, Jenner made the connection between angina pectoris and coronary artery disease but did not publish his conclusions until 1799 (in a letter to Parry

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who included it his text, Syncope Anginosa). John Hunter, who had developed angina pectoris in 1773, ﬁnally died of the disease in 1793 at age 65. His death occurred suddenly during a dispute with the board of St. George’s hospital. Jenner’s delay in reporting his conclusions about the basis of angina pectoris until after Hunter’s death has been attributed to his desire not to alarm his life-long friend [32–34]. Defining the Pathophysiology of CAD Although the frightening and disabling nature of angina pectoris was clearly recognized as a major clinical problem during the nineteenth century, little that was new was added to the basic understanding of coronary artery disease during that time. In his 1809 textbook on diseases of the heart, Burns attributed angina pectoris to myocardial ischemia. In 1819, Laennec introduced the stethoscope. In 1840, Williams suggested that obstruction of a coronary artery was the cause of the pallid, yellowish appearance of a segment of myocardium discovered at autopsy. The term myocardial infarction was not then in use (as late as 1884, what is now known as a myocardial infarction was referred to as ‘‘ﬁbrinoid degeneration’’). In 1867, Brunton introduced amyl nitrite for the treatment of angina pectoris. Nitroglycerin, the mainstay of the treatment of angina pectoris even today, was introduced by Murrell in 1879. Riva-Rocci developed the ﬁrst practical sphygmomanometer in 1891. The year following the serendipitous discovery of x-rays by Roentgen, in 1895, roentgen studies of the heart were being performed by Williams. That same year, Pierre Marie writing his thesis on complications of cardiac disease used the term myocardial infarction. Dock, in 1896, was the ﬁrst physician in the United States to make a diagnosis of coronary thrombosis during life [32,35,36]. Widespread appreciation of the relationship between coronary artery disease, angina pectoris, and myocardial infarction did not occur until the second quarter of the twentieth century. Sir Cliﬀord Allbutt, in 1900, attributed angina pectoris to disease of the aorta, an understandable conclusion in view of the likelihood of coronary ostial occlusion secondary to the syphilitic aortitis that was so common at the time [36]. A major contribution to establishing the pathophysiology of coronary arterial disease was made by Einthoven in 1903, when he developed a practical method for performing electrocardiography. Sir William Osler commented in 1910 that he did not see a case of coronary thrombosis until he became a Fellow of the Royal College of Physicians [37]. Coronary artery disease remained virtually unrecognized as a cause of death until 1912, when Herrick described (in six patients) the clinical features of sudden obstruction of the coronary arteries, including the gross changes that occurred in the myocardium in the region of the infarct. He noted that, while previous attacks of angina had generally been experienced by the patient, fatal coronary arterial thrombosis might be the ﬁrst evidence of coronary disease [38]. In 1918, he republished his data and reported electrocardiographic studies conducted in patients with coronary artery thrombosis [39]. White commented that, in the mid 1920s, at Massachusetts General Hospital diagnoses of coronary artery thrombosis and myocardial infarction were rare among the autopsies performed [31]. He stated that he did not see his ﬁrst patient with a myocardial infarction until he was in his second year of practice in 1921. In 1923, Wearn wrote that ‘‘coronary thrombosis with infarction of the heart as a clinical entity is a condition which is generally classed among the rarities of medicine’’ [37]. The most famous instance of failure to recognize the signs and symptoms of fatal coronary arterial disease occurred in San Francisco on August 2, 1923, when Warren Harding, the 29th president of the United States, died following an acute myocardial infarction. His death was attributed to acute indigestion or

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(by the New York Times) to a ‘‘stroke of apoplexy.’’ By the late 1920s, however, coronary thrombosis—alias myocardial infarction—was a well-established diagnosis. Development of Modern Diagnostic Techniques In 1929, a German intern, Werner Forssmann, having heard of an experiment by Claude Bernard, threaded a catheter through his antecubital vein into his right atrium. His goal was to devise a technique to speed delivery of drugs to a patient and, in addition, to understand the mysteries of the heart and circulatory system [40,41]. Discouraged from pursuing his experiments by Sauerbruch, the Professor of Surgery, Forssmann became a urologist. Cournand became aware of Forssmann’s work and by 1941 had developed a technique for catheterizing the right heart in humans [42]. Zimmerman in 1950 and Seldinger in 1953 developed the techniques of left heart catheterization. In 1958, F. Mason Sones, Jr., accidentally injected the right coronary artery with contrast material producing the ﬁrst selective coronary angiogram performed in a human being. Louis Pasteur is credited with the statement ‘‘chance favors the prepared mind.’’ Sones not only recognized the potential value of his serendipitous observation but pursued development of the technique of selective coronary arteriography to make it a practical diagnostic technique. The presentation of his results during the 1959 meeting of the American Heart Association introduced the modern era of medical and surgical treatment of coronary artery disease [43].

NATURAL HISTORY OF PATIENTS WITH ANGINA PECTORIS Only 30 to 40% of 70-year-old individuals with anatomically signiﬁcant disease of one or more coronary arteries will be overtly symptomatic (with classical angina pectoris or evidence of a myocardial infarction on a resting electrocardiogram) [25,27]. Of those who have symptomatic CAD, about 37% of men and 65% of women will have angina pectoris as the initial manifestation of the disease. If death as an initial manifestation of symptomatic CAD is excluded, then about 40% of men and 70% of women with CAD will present with angina pectoris as their initial symptom [44,45] (Table 5). Since severe and/or intractable angina pectoris is the major indication for 75 to 95% of the CABGs performed in the United States, particularly in the elderly, an understanding of the natural history of those with angina pectoris must be the foundation for evaluating the eﬀectiveness of medical or surgical therapy of CAD.

Table 5 Distribution and Frequency of Initial Manifestations of Coronary Heart Disease in 492 Individuals from the Framingham Study Men Manifestation Angina pectoris Coronary insuﬃciency Myocardial infarction Death Total

Women

Total

Number

Percent

Number

Percent

Number

Percent

119 23 139 42 323

37 7 43 13 100

110 12 30 17 169

65 7 18 10 100

229 35 169 59 492

47 7 34 12 100

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Unfortunately, the natural history of angina pectoris is diﬃcult to document. Early studies by Herrick (1918) and by White (1926, 1931, 1943) were handicapped because investigators lacked the technology to determine the extent of disease in the coronary arteries during life [39,46–48]. In addition, patients with angina pectoris complicated by associated diseases such as hypertension, valvular heart disease, myocardial infarction, and congestive heart failure were often included with those who suﬀered from uncomplicated angina pectoris. In these early series the annual mortality of patients with angina pectoris ranged from 2.5 to 9.0%. [49]. In 1952, Block et al. [50] described 5- and 10-year survivals by age group for 6882 patients in whom a diagnosis of angina pectoris had been made. The study population included patients with cardiac enlargement, congestive heart failure, and myocardial infarction. Table 6 summarizes their results. Annual mortality (averaged over 10 years) for the entire group was 6.0%. Annual mortality was greatest during the ﬁrst year (15.3%) then decreased in subsequent years. Overall, 5-year survival for the group was 58%; 10year survival was 37%. Expected survivals in a general population of like ages would have been 87% at 5 years and 70% at 10 years. In 1971, Gordon and Kannel [44] reported the frequency with which coronary events occurred during a 14-year follow-up of 5209 people randomly sampled from a general population. One-hundred and ninety-seven persons developed angina pectoris as their initial manifestation of coronary artery disease. The risks of dying in this group of individuals varied with the severity of their symptoms. Annual mortality for those free of heart disease was 1/1000. For those in New York Heart Association (NYHA) class I, the risk of dying was 4/1000/year; for those in NYHA class II, the risk was 19/1000/year, and for those in classes III or IV, 43/1000/year. In 1972, Kannel and Feinleib [45] reported presentations and outcomes in 492 persons who ﬁrst developed coronary artery disease during the 14-year follow-up of a general population of 5127 individuals from the Framingham study (Table 5). Coronary angiography was not performed in these patients. Of the 492 people, 229 presented with angina pectoris. Two hundred of these manifested ‘‘uncomplicated’’ angina pectoris; that is, angina not complicated by myocardial infarction, coronary insuﬃciency, or coronary death. Forty percent of the men with uncomplicated angina and 40% of women z60 years of age with uncomplicated angina died within 8 years. Only 15% of women under age 60 with uncomplicated angina died during the 8 years. Annual mortality was 4% for men with uncomplicated angina pectoris. Over a

Table 6 Prognosis of Angina Pectoris: Survival Rates of Patients with Angina Pectoris According to Ages at Time of Diagnosis Percentage alive at Age group (years) <40 40–49 50–59 60–69 70–79 >80

Number of patients

5 Years

10 Years

112 935 2067 2046 572 34

66.1 65.2 61.0 55.4 42.8 26.5

46.5 43.1 37.2 29.0 16.4 13.0

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period of 5 years, myocardial infarction was relatively uncommon in women with angina pectoris (7%) but occurred in 24% of men. Half of the men over age 45 years with angina suﬀered a myocardial infarction within 8 years. While studies conducted in the 1950s and 1960s could relate the eﬀects of age, severity of symptoms, and presence of associated cardiac diseases with outcome in patients with angina pectoris, it was not until coronary arteriography became widely available that it was possible to correlate the natural history of these patients with the extent of their coronary disease. In 1972, Oberman [51] analyzed the course of 246 patients with angina but without associated cardiovascular disease or serious non-cardiovascular disease. All had undergone coronary arteriography between 1965 and 1970, a time period prior to the advent of aortocoronary bypass grafting in their institution. At 22 months, there were no deaths in patients with one-vessel disease and small hearts or in those with one-vessel disease and no electrocardiographic evidence of an old transmural infarction. The annual mortality for all patients with one-vessel disease was 2.0%. Annual mortality for patients with two-vessel disease was 13.0% and for three-vessel disease, 15.0%. The presence of an old myocardial infarction, a history of congestive heart failure, or an enlarged heart markedly increased the annual mortality in patients with angina pectoris. In 1974, Reeves et al. [49] analyzed the course of 705 patients who had undergone coronary arteriography prior to 1970. The annual mortality for the entire group was 6.5%. For one-vessel disease, annual mortality was 2.2%; for two-vessel disease, 6.8%; and for three-vessel disease, 11.4%. In 1983, Proudﬁt et al. [52] presented 15-year survivals for 598 patients with chest pain treated medically following angiography. All but 64 were male. Annual mortality averaged over 10 years was 5.4% with a 31% 15-year survival. Overall, the natural history of most patients with angina pectoris is poor with annual mortality rates for uncomplicated disease of 4 to 6%. However, angina pectoris taken by itself is a poor predictor of survival [53]. Individuals with single-vessel disease and angina pectoris uncomplicated by a history of transmural myocardial infarction, congestive heart failure, cardiomegaly, associated cardiovascular disease, or serious noncardiovascular disease appear to have annual mortality rates of 1% or less [49]. In Oberman et al.’s study, in the order of their importance, the independent predictors of increased annual mortality in patients with angina pectoris followed for 22 months were: heart size, stenosis of the left anterior descending artery, dyspnea on eﬀort with either paroxysmal nocturnal dyspnea or orthopnea, heart rate, stenosis of the left main coronary artery, stenosis of the left circumﬂex artery, and stenosis of the right coronary artery [51]. The need to identify subsets of patients with coronary artery disease was to assume greater importance as the outcomes of CABG and PTCA began to be evaluated.

EVOLUTION OF SURGICAL TREATMENT At about the time of Herrick’s report that sudden occlusion of a major coronary artery was not ‘‘almost universally fatal,’’ surgeons began their attempts to relieve the pain of angina pectoris. Franeois-Franck, in 1899, proposed removal of the cervical and ﬁrst thoracic ganglia. His intent was to accomplish a complete cure of certain cases of Grave’s disease, which were complicated by aortitis and angina [54]. Bilateral extirpation of the cervical sympathetic chain, together with removal of both thoracic ganglia for the treatment of angina pectoris, was ﬁrst performed by a Bucharest surgeon, Jonnesco, in 1916 [55].

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From 1916 through 1982, no less than 59 diﬀerent varieties of surgical procedures were performed for the treatment of coronary artery disease. The procedures ranged from those designed to interrupt the aﬀerent nerve pathways from the heart to those developed to replace the heart. These surgical approaches to coronary artery disease can be divided into four broad categories: extrapericardial procedures, techniques for indirect myocardial revascularization, direct revascularization of the coronary arteries, and cardiac replacement [41,56–58] (Table 7). A few of these procedures were performed only in experimental animals; some represented variations of a more basic concept; many were devised by more than one individual; most were performed in humans at one time or another often over a period of many years. Eventually, all but a few were found to be ineﬀective or minimally eﬀective. A major share of the credit for the development of modern coronary arterial surgery belongs to Claude Beck of Western Reserve University and to his persistent eﬀorts to prevent sudden death in patients with a heart ‘‘too good to die.’’ Beginning in 1935, he devised and applied numerous variations of his Beck I and Beck II operations. He noted that increases of arterial ﬂow of as little as 5 mL/min into anoxic areas of the myocardium could relieve the pain of angina pectoris and could aﬀord protection against a fatal heart attack [59,60]. About 10 years later, Arthur Vineberg of Montreal began advocating implantation of systemic arteries into the myocardium, thus beginning the era of indirect myocardial revascularization [61]. Two sentinel events in the 1950s made possible the modern era of myocardial revascularization. On May 6, 1953, the ability to operate on a quiet heart free of blood became a reality when John Gibbon successfully closed an arrial septal defect using a heart lung machine he and his wife had developed [62,63]. In 1958, F. Mason Sones, Jr., provided the means to accurately identify, localize, and quantify coronary artery lesions [43,64].

Table 7 Classification of Surgical Procedures Designed to Treat Coronary Artery Disease 1.

2.

3.

4.

Extrapericardial procedures A. Denervation procedures B. Procedures to decrease metabolic demand of myocardium C. Procedures to redirect blood ﬂow to coronary arteries Indirect myocardial revascularization procedures A. Cardio - pericardiopexy procedures B. Epicardial grafting procedures C. Procedures to increase retrograde ﬂow into native vessels D. Procedures to increase oxygen extraction E. Procedures to stimulate collateral development F. Myocardial channelization procedures G. Myocardial implant procedures Procedures for direct revascularization of the coronary arteries A. Angioplastic (endarterectomy) procedures B. Replacement grafting C. Bypass grafting Cardiac replacement A. Transplantation B. Mechanical heart

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Widespread application of the current techniques of direct myocardial revascularization began after the reports of Favoloro, Johnson, Urschel, and Kerth in 1969 [64–67]. The ﬁrst transplantation of a human heart was performed by Christiaan Barnard in South Africa in 1967 [68]. On September 16, 1977, Andreas Gruentzig, in Zurich, performed the ﬁrst balloon dilatation of a coronary artery in a human. The technique was referred to as percutaneous transluminal angioplasty (PTCA) and was quickly adopted as an alternative to CABG [41]. In the mid-1970s, 70,000 CABGs were performed annually in the United States [64]. By 1994, the number had grown to 318,000 per year [69]. As early as 1971, however, there were those who questioned the eﬃcacy of aortocoronary bypass grafting and the justiﬁcation for its widespread application. The objections and criticisms were based in part on the past history of failures and marginal results of surgical procedures intended to treat coronary artery disease, in part on what were considered to be the high risks inherent in coronary artery surgery and in part on the availability of techniques of medical management that presumably could yield results comparable or superior to those achieved by operation. These concerns led to performance of numerous controlled studies that compared the outcomes of medical and surgical therapy. The advent of PTCA led to additional randomized studies comparing PTCA with CABG and with medical treatment.

OUTCOME OF RANDOMIZED STUDIES Since 1972, ﬁve large randomized studies have compared the results of coronary arterial bypass plus medical therapy with intensive medical therapy of angina pectoris. Stable angina pectoris was the subject of three studies; unstable angina was the subject of two studies. More recently, two more randomized studies have compared outcomes in patients treated by PTCA and CABG. While various criticisms can be made of the design and conduct of these studies, it is important summarize their ﬁndings since the conclusions drawn from them have shaped the indications for CABG in patients of all ages. Early VA Studies In the mid-1960s, cardiologists and thoracic surgeons in the Veterans Administration developed a keen interest in evaluating current surgical procedures to revascularize the ischemic heart. Three operations were studied, each in increasing detail, employing randomization techniques: The Beck ‘‘poudrage’’ procedure, the Vineberg implant procedure, and direct revascularization procedures. Analyses of the Beck procedure did not reach the literature. In the study of the Vineberg procedure, a total of 146 patients (75 medical and 71 surgical) were randomized between 1966 and 1972. Thirty-day operative mortality was 12.3%. Visualization of the implant 1 year after operation was accomplished in half of the eligible patients. Fifty percent of the patients with single implants and 69% of those with double implants were found to have patent grafts. At 12 years, 41% of the medical group and 42% of the surgical group were alive. Eighty-one percent of the deaths in both the medical and surgical groups were due to cardiac disease. The degree of revascularization achieved by the implants did not improve survival. The study ended partly because of these ﬁndings and partly because of the shift to direct revascularization of the coronary arteries [70].

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VA Stable Angina Study Six-hundred and eighty-six patients were entered into the stable angina study between 1972 and 1974. Three-hundred and ﬁfty-four individuals were randomized to medical therapy; 332 were randomized to medical plus surgical therapy. Ninety-one patients had greater than 50% stenosis of the left main coronary artery (43 medical, 48 surgical). Fivehundred and ninety-ﬁve patients were ‘‘non–left main’’ (311 medical and 284 surgical). All patients were men. There were no age restrictions. The age range of those in the study was 27 to 68 years with a mean age of 50.5 years. Forty-four percent of the patients were less than 50 years old. Patients with all degrees of angina were accepted. There was no minimum ejection fraction set for selection. During 11 years of follow-up, 38% of the 354 patients assigned to medical treatment underwent bypass surgery. Twenty-two of those crossing over had left main coronary artery disease. At 11 years, survival for patients without signiﬁcant left main disease was 58% in both treatment groups. Survival between treatment groups of patients with one-vessel or three-vessel disease was not signiﬁcantly diﬀerent at either 7 or 11 years. At 11 years, survival for patients with two-vessel disease treated surgically was marginally worse than for their counterparts treated medically (55% vs. 69%; p = 0.045). Patients treated surgically for left main disease clearly did better than those treated medically (88% vs 65%, p = 0.016). Patients who were categorized as high risk by angiographic and/or clinical criteria had signiﬁcantly better survival with surgical treatment. Patients were classiﬁed as angiographically high risk if they had three-vessel disease and impaired left ventricular function. They were classiﬁed as clinically high risk if they had at least two of the following: resting ST depression, a history of myocardial infarction, or a history of hypertension. Survival at 11 years in the high clinical risk group was 49% for the surgical group and 36% for the medical group ( p = 0.015). In the low clinical risk group, survival at 11 years was 63% for the surgical group and 73% for the medical group ( p = 0.066). In the angiographic high-risk group, survival at 11 years was 50% for surgical patients and 38% for medical patients ( p = 0.026). In the angiographic low-risk group, the corresponding survival data were 61% and 68% ( p = 0.105). In the combined high angiographic and clinical risk group, survival at 11 years was 54% in the surgical group and 24% in the medical group ( p = 0.005). Corresponding survivals in the combined low angiographic and clinical risk group were 66% and 76% ( p = 0.092). The average annual mortality rates during the ﬁrst 7 years of the study were 3.3% for all surgically treated patients without left main disease and 4.0% for all medically treated patients without left main disease. During the next 4 years, the corresponding annual mortality rates were 4.8% and 3.5%. Thus, three groups of patients beneﬁted from surgical treatment: those with signiﬁcant left main disease; those with extensive coronary arterial disease associated with reduced ventricular function; and those who fell into clinical or angiographic high-risk categories. Quality of life was better in those patients treated surgically. At 5 years, 41% of surgical patients and 17% of medical patients reported marked improvement in symptoms. Twenty percent of the surgical patients and 42% of the medical patients described worsening symptoms. Over the 5-year period, the beneﬁts of surgery decreased, but at 5 years were still signiﬁcantly better than medically treated patients ( p = 0.0014). The incidence of nonfatal myocardial infarction was not signiﬁcantly diﬀerent between the two treatment groups. At 5-year follow-up, left ventricular function remained unchanged in both treatment groups [71–74].

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VA Unstable Angina Study Four-hundred and sixty-eight patients were entered into the unstable angina study between 1976 and 1982 (237 medical, 231 medical plus surgical). Three-hundred and seventyfour patients were identiﬁed as Type I (accelerated angina, rest angina, and recent-onset angina); 94 were identiﬁed as Type II (prolonged angina unrelieved by nitrates and accompanied by ST-segment changes on electrocardiogram). All patients were men. There were no age restrictions. The age range in the study was 32 to 73 years, with a mean age of 56 years. Patients with all degrees of angina were accepted. Patients with ejection fractions below 30% and those with left main lesions greater than 50%, recent myocardial infarction, or prior coronary artery surgery were excluded. At the end of 10 years, 50% of patients randomized to medical treatment had crossed over to surgery. At 10 years, survival was 61% for surgical patients and 62% for medical patients. At 5 years and 8 years, there was signiﬁcantly better survival for patients with three-vessel disease treated surgically (89% vs. 77% and 77% vs. 65%, respectively). At 10 years, however, the surgical advantage was no longer signiﬁcant (63% vs. 57%; p = 0.190). At 8 years, survival of patients with three-vessel disease and an ejection fraction of 58% or less was signiﬁcantly better in the surgical group (79.5% vs. 57.1%; p = 0.018). In contrast, survival at 8 years in those with one- or two-vessel disease and an ejection fraction greater than 58% was signiﬁcantly better with medical treatment (83.2% vs. 67.8%; p = 0.022). A major ﬁnding in this study was the eﬀect of surgical treatment on survival of patients with an ejection fraction between 30% and 58% if the crossovers from medicine to surgery were censored (counted as lost to follow-up at the time of crossover). When this was done, there was a strong advantage to surgical treatment throughout the 10 years of follow-up (59% vs. 43%; p = 0.007) [75]. Continued smoking was an independent predictor of death in the surgical group at 2, 5, and 10 years. At 10 years, New York Heart Association class III or IV, age, and diabetes mellitus were additional independent predictors of mortality in the surgical group. In the medically treated group, decreased ejection fraction and the number of vessels diseased were consistent, independent predictors of mortality. As in the stable angina study, quality of life was better in the surgical patients who had superior pain control, reduced medication requirements, and signiﬁcantly fewer new cardiovascular hospitalizations over the 10-year observation period ( p = 0.0001). At the end of 10 years, the number of nonfatal myocardial infarctions was not signiﬁcantly different between the treatment groups [76–79].

EUROPEAN CORONARY SURGERY STUDY GROUP Seven-hundred and sixty-eight patients were entered into the study between 1973 and 1976 (373 medical, 395 surgical). One patient was lost to follow-up before operation, leaving 394 surgical patients. All were men under the age of 65 years (mean age 50 years). Those with severe angina pectoris as well as those with ejection fractions below 50% or singlevessel disease were excluded from the study. Patients with left main lesions of 50% or more were included on a discretionary basis (31 medical, 28 surgical patients). Those assigned to medical treatment could cross over to the surgical group if they had unacceptable symptoms despite adequate medical therapy (24% did cross over within 5 years). All patients

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were followed for 5 years; 60% were followed for 6 years; 25% for 7 years; and 10% for 8 years. At 5 years, 92.4% of the surgical patients and 83.6% of the medical patients were alive ( p = 0.00025). In those patients with left main disease, there was a markedly increased 5-year survival with operation, but because of the small numbers, the diﬀerence was not signiﬁcant (81.7% vs. 67.9%; p = 0.11). Survival was markedly improved in the surgical group with three-vessel disease and also in the group with two- or three-vessel disease when it was associated with stenosis of 50% or greater in the proximal left anterior descending artery. An abnormal electrocardiogram, ST-segment depression of 1.5 mm or more during exercise, and the presence of peripheral vascular disease were each independent predictors of better survival with operation. Survival at 10 years in patients over the age of 53 years was signiﬁcantly better in the surgical group (72% vs. 57%; p = 0.007). Below age 53 years, age was not a signiﬁcant factor aﬀecting outcome between the two treatment groups. A conclusion drawn from the study was that the greatest beneﬁts of surgery occurred in the high-risk groups of patients. Surgery was unlikely to improve 5year survivals in patients with good left ventricular function, ST-segment depression less than 1.5 mm on exercise, a normal resting electrocardiogram, and absence of peripheral vascular disease. These conclusions closely resemble those reached in both the stable and unstable VA randomized studies [79–82]. Operation markedly improved the quality of life as measured by the percentage of patients free of angina or by the degree of increased exercise tolerance. As in other studies, these eﬀects diminished with time, although the advantage over medical treatment remained statistically signiﬁcant at 4 years for exercise performance ( p = 0.001) and throughout the study for relief of angina ( p = 0.001) [80]. Coronary Artery Surgery Study In 1973 the National Heart, Lung and Blood Institute organized a randomized trial designed to compare results of medical and surgical therapy in patients with coronary artery disease. The goal of the randomized trial was to test the hypthesis that coronary artery bypass surgery signiﬁcantly reduced the mortality rate and the incidence of myocardial infarction in patients with mild angina or in those who were asymptomatic after a myocardial infarction (but who had coronary artery disease documented by angiography) [82,83]. Between 1975 and 1979, 780 patients were entered into the study (390 medical, 390 surgical). Ninety percent of the patients were men. All enrollees were 65 years of age or less; the mean age was 51.2 years. Patients with angina more severe than Canadian Class II were excluded as were those with unstable angina, progressive angina, congestive heart failure, previous coronary bypass surgery, or serious coexisting illness. Patients with an ejection fraction <35% and those with left main lesions >70% were also excluded. Patients with a well-documented myocardial infarction more than 3 weeks before randomization were accepted into the study. Analyses were performed on the basis of treatment assigned [79,83]. At 8 years, 87% of the surgical patients and 84% of the medical patients were alive ( p = 0.14). However, in the subset of patients with ejection fractions below 50%, 84% of the surgical patients and 70% of the medical patients were alive at 7 years ( p = 0.012). When this subset of patients was analyzed by the number of vessels diseased, a signiﬁcant diﬀerence in survival was found only in those patients with three-vessel disease (88% in the

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surgical group, 65% in the medical group; p = 0.0094). There was no signiﬁcant diﬀerence between the medical and surgical treatment groups in the occurrence of nonfatal myocardial infarction. At 5 years, the crossover rate from medicine to surgery was 24% [82]. From the standpoint of quality of life at 5 years, the surgical group had signiﬁcantly less chest pain ( p<0.0001), fewer limitations of activity ( p<0.0001), and a lower requirement for beta-blockade ( p<0.0001). In the surgical group, treadmill exercise tests documented less exercise-induced angina, less ST-segment depression, and longer treadmill times [84]. National Cooperative Study Group: Unstable Angina Under the auspices of the National Heart, Lung and Blood Institute, a prospective, randomized study was initiated comparing intensive medical therapy with urgent coronary arterial bypass for the management of patients with unstable angina. Between 1972 and 1976, 288 patients were entered into the study (147 medical, 141 surgical). Eighty-two percent were men. All enrollees were under the age of 70 years. The patients had to have angina associated with transient ST-segment or T-wave changes on electrocardiogram. Ninety percent of the patients had rest pain while in the hospital. Although the patients had to have greater than 70% occlusion of at least one coronary artery to be eligible for randomization, 76% had multivessel coronary artery disease. Thirty percent of the individuals in the study had proximal left anterior descending arterial disease. Thus, the group corresponded to patients with Type II symptoms in the VA unstable angina study. Ejection fractions of 30% or less or greater than 50% narrowing of the left main coronary artery were reasons for exclusion as were a myocardial infarction within 3 months or serious illnesses other than coronary artery disease. At 65 months, there was no signiﬁcant diﬀerence in survival between surgical and medical patients (85% surgery vs. 84% medical). Forty-three percent of patients crossed over from medicine to surgery (34% of those in NYHA classes I and II and 60% of those in NYHA classes III and IV). Crossover occurred sooner in patients with more severe angina [85]. As was the case in the other randomized studies, quality of life was better in the surgical group. At the end of the ﬁrst year, severe angina was signiﬁcantly more common in the medical group in patients with one-vessel disease ( p < 0.05), two-vessel disease ( p < 0.01), and three-vessel disease ( p < 0.01). There was no signiﬁcant diﬀerence in the incidence of nonfatal myocardial infarction between the two treatment groups [86]. Emory Angioplasty Versus Surgery Trial The Emory Angioplasty versus Surgery Trial (EAST) study was designed to determine whether initial revascularization with angioplasty in patients with multivessel coronary disease was a viable alternative to bypass surgery on the basis of outcome at 3 years. Between 1987 and 1990, 5118 patients were screened. Exclusion criteria included left main disease, two or more total occlusions of the coronary vessels, an ejection fraction V25%, recent myocardial infarction (within 5 days), insuﬃcient symptoms, and life-threatening noncardiac illnesses. Advanced age was not a criterion. Three-hundred and ninety-two patients were randomized, 198 to PTCA and 194 to CABG. All had two- or three-vessel disease. The mean age of the PTCA patients was 61.8 years. The mean age of the CABG patients was 61.4 years; 74.7% of the PTCA patients and 72.7% of the CABG patients were men. Data were analyzed according to intention to treat.

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Operative mortality was 1% in both groups. In-hospital Q-wave myocardial infarctions were suﬀered by 10.3% of CABG patients and 3.0% of PTCA patients. Ten percent of the PTCA patients required CABG at the time of initial revascularization. Within 3 years 6.2% of the CABG group had died compared with 7.1% of the PTCA group ( p = 0.72). 19.6% of the CABG patients had suﬀered a Q-wave myocardial infarction compared with 14.6% of those treated by PTCA ( p = 0.21). During the 3-year follow-up, 1% of the CABG group and 22% of the PTCA group required CABG. Thirteen percent of the CABG group and 41% of the PTCA group required PTCA. In terms of quality of life, the CABG group had a better outcome than the PTCA patients. Twenty percent of those treated by PTCA were in Canadian Cardiovascular Society (CCS) classes II, III, or IV compared with 12% of those treated by CABG ( p = 0.039). Sixty-six percent of the PTCA group and 51% of the CABG group required antianginal medication ( p = 0.005). Median initial procedure costs (in 1987 dollars) for PTCA were $14,166 compared with $22,894 for CABG. At 3 years, the median costs for treating a PTCA patient totaled $19,059; those for a CABG patient totaled $23,572. Procedure costs included physician and hospital costs [87,88]. The Bypass Angioplasty Revascularization Investigation In 1987 the National Heart, Lung and Blood Institute initiated the Bypass Angioplasty Revascularization Investigation (BARI) study to test the hypothesis that, during a 5-year follow-up period, PTCA does not result in a poorer clinical outcome than does CABG in patients with multivessel coronary disease and severe angina or myocardial ischemia. Between 1988 and 1991, 1829 patients were randomized: 914 to CABG and 915 to PTCA. Mean age of the CABG patients was 61.1 years. That of the PTCA patients was 61.8 years. Seventy-three percent of the PTCA patients and 74% of the CABG patients were men. Data were analyzed according to the intention-to-treat principle. Operative mortality was 1.3% in the CABG group and 1.1% in the PTCA group; 4.6% of the CABG group and 2.1% of the PTCA group suﬀered a Q-wave myocardial infarction ( p = 0.004). 12.8% of those assigned to PTCA had additional revascularization procedures during the initial hospitalization; 6.3% of the PTCA patients required emergency CABG. Cumulative survival rates at 5 years were 89.3% for CABG patients and 86.3% for PTCA patients ( p = 0.19). Rates of survival free of Q-wave infarction at 5 years were 80.4% for those treated by CABG and 78.7% for those treated by PTCA ( p = 0.84). Cumulative rates of Q-wave infarction at 5 years were 11.7% for CABG and 10.9% for PTCA ( p = 0.45). During the 5-year follow-up, 54.5% of the PTCA patients required revascularization procedures compared with 8.0% of the CABG patients. Nineteen percent of the PTCA group required multiple revascularization procedures compared with 3.0% of the CABG group. Improvement in functional status (as measured by the Duke Activity Scale) was better in the CABG patients (5.6 units vs. 3.2 units; p = 0.04). Mean initial procedure cost for PTCA was $21,113 compared with $32,347 for CABG. At 5 years, the total mean costs for PTCA were $56,225 compared with $58,889 for CABG. A major ﬁnding in this study was the diﬀerence in survival at 5 years between treated diabetics assigned to PTCA and treated diabetics assigned to CABG (65.5% for PTCA patients vs. 80.6% for CABG patients; p = 0.003). The term treated diabetics referred to those requiring insulin or oral hypoglycemic agents. As is true in most studies, the overall

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survival at 5 years for diabetics was less than that for nondiabetics (73.1% vs. 91.3%) [12,88,89]. Overview While the general goal of each of the randomized trials summarized above was to compare the results of medical and surgical treatment of coronary arterial disease, it is clear that the individual studies diﬀered substantially in mortality data, study design, patient selection, and patient recruitment. It is nevertheless striking that there are a number of major conclusions for which there is substantial agreement among the studies: 1.

2. 3. 4.

5. 6.

7.

8.

9. 10.

11. 12.

Angina pectoris is not of itself an indication for CABG except for the quality of life. Surgical treatment for this purpose had a signiﬁcant advantage in each of the trials. CABG does not increase survival over that obtained by medical therapy for oneor two-vessel disease unless the patient falls into a high-risk category. CABG has a clear advantage over medical management in the treatment of signiﬁcant left main disease. CABG results in a signiﬁcantly increased survival when compared with medical management in patients with three-vessel disease and abnormal left ventricular function. CABG results in better survival than medical management in patients who are high risk by clinical or angiographic criteria, or a combination of both. Quality of life is uniformly better in the group treated by CABG. Exercise tolerance and freedom from angina are better in the surgical group. Requirements for medication and new hospitalizations for cardiovascular events are less in the surgical group. In those groups that beneﬁted from CABG, the beneﬁts, particularly as they concern quality of life, tend to decrease with time. Even so, the advantages of CABG continue for 5 to 10 years. When analyzed on the basis of intent-to-treat, there is no diﬀerence in 3- to 5year survival of patients randomized to PTCA or CABG as the initial treatment for multivessel disease. Over a 3- to 5-year period, there is no diﬀerence in the rate of Q-wave infarctions in patients initially randomized to PTCA or CABG. Patients undergoing PTCA as the initial treatment for multivessel disease require additional revascularization procedures much more frequently than those initially treated by CABG. Initial-costs of PTCA are lower than those of CABG, but at 5 years the total costs are about equal. Diabetics requiring insulin or oral hypoglycemic agents fare better with CABG than PTCA for multivessel coronary artery disease.

THE ELDERLY AS CANDIDATES FOR CABG The ﬁve randomized studies comparing CABG with medical treatment were conducted in the 1970s in a younger, primarily male population. Mean ages in the ﬁve studies varied from 50 to 56 years. Patient outcomes in that group were used to determine indications for

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surgery. The current population undergoing CABG, however, has a diﬀerent composition. It is older (mean age 65 years) and has a larger percentage of women (30%). Reports of outcomes following CABG in 70-, 80-, and even 90-year-olds are easily found in the literature but determining the beneﬁts of CABG in this group and establishing indications for operation in the elderly necessarily involves an appreciation of the nature and extent of CAD in the patient population at risk. Table 8 compares by age group the baseline characteristics of 21,573 patients undergoing cardiac catheterization for ischemic heart disease. Approximately half of these patients were managed medically. The remainder underwent either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). It is apparent that older patients present for operation with more advanced coronary disease, more complications from their heart disease, and a greater number of coexisting diseases [90]. The prevalence of angina pectoris in the general population in the United States is approximately 1%. Prevalence increases with increasing age, aﬄicting 9.2% of a general population 55 to 69 years old and 14.7% of a general population 70 to 88 years old ( p = 0.0002) [53]. Even so, the prevalence of ischemic heart disease increases more rapidly with age than does angina [3], indicating that CAD in the elderly is more likely to present with manifestations other than uncomplicated angina. Silent ischemia aﬀects about 30% of the population over 70 years of age in contrast to 10% of a population in its 50s [25,26,91–94]. Silent ischemia is not a benign event, even in the middle aged, but it is much more dangerous in the elderly. In Erikssen and

Table 8 Baseline Characteristics of Patients Undergoing Cardiac Catheterization for Ischemic Heart Disease 1/1/95 Through 12/31/98 (21,573 patients) Prevalence (in percentage) Factor Number of patients Female gender Severity of disease Left main disease 3-vessel disease EF >30% <50% Clinical indication myocardial infarction unstable angina stable angina Complications CAD Prior myocard infarction Hx congest heart failure Comorbidity Diabetes mellitus Cerebrovascular disease Periph vascular disease Chronic pulmonary disease Hypertension

<70 years

70–79 years

>80 Years

15 392 26.0

5198 36.4

983 44.2

6.3 18.1 20.5

11.3 22.9 23.4

13.9 24.3 22.2

27.1 28.4 32.1

25.5 34.0 29.7

31.8 37.8 21.3

49.5 10.5

53.5 20.3

59.1 30.5

17.4 4.2 5.7 7.3 48.8

20.4 8.7 8.8 12.4 56.9

18.4 11.5 11.7 13.5 57.7

Abbreviations: CAD = Coronary artery disease; EF = ejection fraction. Source: Ref. 90.

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Thaulow’s study of younger patients [91], there was 0.5% incidence of sudden death. Cardiac events occurred in 21 to 46% of younger patients with silent ischemia [92]. In a study by Aronow [95], the prevalence of sudden death and coronary events in octogenarians was 38 and 69%, respectively, during 43 months of follow-up. Myocardial infarction is not only more common in the elderly, but also it often goes unrecognized (39% of those over 65 vs. 27% of those under 65) [96,97]. Dyspnea rather than chest pain becomes the predominant symptom of an acute myocardial infarction in those over the age of 80 [98,99]. Compared with a younger population, the elderly also have a higher mortality after infarction (12 to 39% vs. 2.0 to 8.0%) and a higher incidence of complications secondary to the infarction [99,100]. Congestive heart failure (CHF) is more common in older individuals with an annual incidence rising from 2/1000 in men 45 to 64 years old to 8/1000 in those 65 to 74 years old, 14/1000 in those 75 to 84, and 54/1000 in those 85 to 94. Women over the age of 75 years have a similar or greater incidence. Mortality from CHF in those between the ages of 65 and 94 is 88% within 6 years [101]. The incidence of sudden death from CAD in a general population rises from 1.1/ 1000 in men 45 to 54 years old to 2.6/1000 in men 65 to 74 years old. In women, the respective incidences are 0.3/1000 and 1.2/1000. The percentage of coronary attacks (death and/or myocardial infarction) whose initial manifestation is sudden death increases from 13.6% in men 35 to 44 years old to 20% in men over 65. The probability of sudden death also increases with the duration of uncomplicated angina (2.6% at 2 years; 9.7% at 7 years). Males who have heart disease and are hypertensive, diabetic, and cigarette smokers represent an identiﬁable group who are at high risk for sudden death. The risk of sudden death over the age of 65 years is three to four times higher in men with CAD and two to seven times higher in women with CAD than it is in those without CAD [102,103]. Table 9 represents a composite of 34 non-randomized studies reported between 1982 and 1997 of patients who had undergone CABG. It compares the characteristics of a pop-

Table 9 Characteristics of Patients Undergoing Coronary Bypass Grafting: Comparison of Those <70 with Those >70 Years Old Prevalence (in percentage) Under 70 yrs old Factor Female gender NYHA IV Left main disease 3-vessel disease EF >30%, <50% Prior myocardial infarction Hx congestive heart failure Diabetes mellitus Cerebrovascular disease Peripheral vascular disease Urgent or emergent surgery

70 yrs old or older

Range

Mean

Range

Mean

13.0–38.7 23.0–56.0 7.0–20.9 40.8–78.0 19.7–42.0 35.0–62.0 3.0–33.6 4.0–28.0 XXX 4.4–13.0 6.0–41.0

28.3 44.8 13.1 49.0 24.6 57.4 9.7 16.1 6.0 4.4 9.5

24.6–46.0 20.0–63.0 3.4–35.0 27.0–90.0 22.0–66.0 22.8–68.5 7.0–67.0 3.0–60.0 6.4–21.0 4.2–26.0 7.0–56.8

27.8 36.7 16.4 61.9 33.3 53.6 17.1 12.6 9.0 5.4 17.3

Abbreviations: NYHA = New York Heart Association; EF = ejection fraction; Hx, History.

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ulation under age 70 with those of a population over 70. While there is considerable overlapping of data, it is apparent that those over 70 are more likely to have a history of CHF and a higher prevalence of left main disease, three-vessel disease, and impaired left ventricular function. In addition, more of the elderly are operated upon urgently or emergently, a circumstance that in itself will double or triple their operative mortality [104].

OUTCOME Eﬀectiveness of CABG in the elderly must be measured against the results of alternative treatments such as PTCA, maximal medical management, or routine symptomatic treatment. When costs are being compared, expenses of treatment over a period of years must be considered rather than just those of the initial episode. Mortality and morbidity are the obvious short-term measurements to be made. The critical long-term measurements are survival and quality of life. Survival must not only be measured against that of the general population of similar age, but against the projected survival of a population in which CAD was allowed to pursue its natural course. Quality of life includes measurements such as relief of symptoms, freedom from further coronary events, and improvement in functional capacity. Costs are of concern to patients, their families, and society as both a practical matter and a philosophical issue. Baseline Data Table 10 depicts both expected survivals for a general population age 60 years in 1940 and for individuals in a general population of selected ages in 1992. The same table also depicts the expected survivals of patients with angina pectoris prior to the advent of modern medical and surgical treatment. The data reported by White [48] and Block [50] excludes patients with valvular disease, but includes some patients with a history of myocardial infarction, congestive heart failure, hypertension, and diabetes. The data reported by Kannel [45] represents survivals of patients with uncomplicated angina pectoris; that is, patients without valvular disease, myocardial infarction, or the coronary insuﬃciency syndrome. While the data from White and Block are older (30s and 40s) than those from Kannel, the composition of their patient populations more closely approximates that of current populations undergoing CABG. The two sets of data represent the extremes of outcome against which the results of medical and surgical treatment can be evaluated. Operative Mortality Reported operative mortality following CABG in the elderly varies widely as a result of diﬀerences in patient selection. Advanced cardiac disease, high prevalence of associated diseases, and the need for urgent or emergency operation are the major factors that increase mortality in the elderly. Table 11 [104–110] is a composite of operative mortalities reported in various age groups undergoing elective or emergency operation. It is apparent that operative mortality increases with advancing age and the priority of the procedure. Performing CABG urgently or emergently in the elderly is associated with a very high operative mortality. Table 12, a compilation of data from Curtis et al. [106], Peterson et al. [107], and He et al. [111], lists the eﬀects of selected factors on operative mortality following CABG in the elderly. Again, performing CABG as an urgent or emergency proce-

1940 1992 1992 1992 1992 1992 1931 1927–1944 1949–1952 1944 1944

Source

Life Tables US Life Tables US Life Tables US Life Tables US Life Tables US Life Tables US White, Bland Block Kannel Barzilay Barzilay

60 50 60 70 80 80–89 56.5 58.8 z50, men 68 68

Age of population General population General population General population General population General population General population Natural Hx angina pectoris Natural Hx angina pectoris Nat Hx uncomplicated AP ND + CAD DM + CAD

Nature of population 98.2 99.5 98.8 97.3 94.0 92.0 89.3 84.7 100 — —

1 87.6 97.2 93.2 85.3 68.5 62.0 64.2 58.4 84.0 75.0 63.0

5

72.0 92.9 83.8 67.2 — — 39.8 37.1 58.0 55.0 39.0

10

53.3 86.6 71.5 46.1 — — 19.5 22.1 — 34.0 21.0

15

20 33.2 77.9 56.4 — — — 12.7 14.1 — — —

Percentage survival at speciﬁed intervals (yrs)

Abbreviations: CAD = Coronary artery disease; ND + CAD = nondiabetic patient with CAD treated either medically or surgically; DM + CAD = diabetic patient with CAD treated either medically or surgically; uncomplicated AP = angina pectoris uncomplicated by myocardial infarction, coronary insuﬃciency, or coronary death.

Reference year

Table 10 Survival Data: General Population, Natural History of Population with Angina Pectoris, Diabetic Population with CAD

372 Stemmer and Aronow

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Table 11 Summary of Reported Operative Mortality Following Coronary Artery Bypass by Age Groups 30-day Operative Mortality (%) Priority of operation

V50

<70

z70

z80

Overall Elective Urgent or emergent

0.6–3.0 0.4–0.7 2.2–4.8

1.0–5.2 0.6–1.6 4.9–5.1

1.8–12.0 1.0–4.2 4.1–22.2

2.0–24.0 0.0–8.0 8.8–28.6

dure clearly has the greatest adverse eﬀect on operative mortality. Dziuban [112], describing his group’s experience with 460 patients, found an operative mortality of 1.2% following elective CABG; 3.2% after urgent CABG, and 26% if the operation was performed as an emergency. In series in which the adverse factors listed in Table 12 were not signiﬁcantly higher in elderly patients, operative mortalities of 1.0 to 1.3% were reported in groups of patients with a mean age of 61 and 1.0 to 4.2% in those z70 year old [13,89,108,113]. Diabetes mellitus (DM) treated with insulin or oral hypoglycemic agents is associated with an increased 30-day mortality following CABG. Carson [114], reporting outcomes in 146,786 patients with a mean age of 65 years, found that operative mortality in those without DM was 2.7%. Thirty-day operative mortality (OM) with DM controlled by oral medications was 3.2% while OM in insulin-dependent diabetics was 4.6%. Morbidity After CABG Overall postoperative morbidity in the elderly can be as high as 65%. Nineteen percent of the complications are life threatening, while 30% of patients have two or more complications [115]. Table 13 summarizes morbidity following CABG [108–110,116,117–124]. It is apparent that the overall frequency of complications increases with age over 70 years. The most common minor complications over age 70 were cardiac arrhythmias. Atrial ﬁbrillation occurred in 10 to 40% of patients [109,113,125]. Major complications were

Table 12 Relative Effects of Selected Factors on 30-Day and 3-Year Morality Relative mortality Factor Urgent or emergent operation Cigarette smoking Chronic renal failure Hx myocardial infarction Cerebrovascular disease Congestive heart failure Peripheral vascular disease Age Female gender Pulmonary disease

30 days 4.50 2.69 2.42 2.33 2.22 1.77 1.42 1.37–3.50 1.19–2.90 0.96

Three years

2.38 1.70 1.73 1.33 1.33 1.33 1.11

374 Table 13

Stemmer and Aronow Summary of Reported Morbidity Following Coronary Artery Bypass by Age Groups Prevalence (%)

Complication Overall Cardiac Atrial arrhythmia Ventricular arrhythmia Perioperative MI Pulmonary Stroke Renal failure GI bleeding Sepsis Pneumonia Wound infection

V50

<70

>70

z80

0.6–26.0

16.0–20.0

20.0–58.0

54.0–73.0

— 6.0 1.8–6.0 3.7 0.0–2.4 1.2 — — — 2.5

4.0–8.0 — 0.9–7.0 41.0 0.7–2.0 0.3–3.5 0.9–1.6 0.0–1.2 3.4 2.5

11.0 — 0.0–9.9 — 1.3–6.5 0.9–3.5 1.8–4.3 1.2–1.4 4.4–6.5 5.4

19.0–42.0 6.0–8.0 1.4–13.0 20.0–36.0 1.3–5.6 6.3–19.0 — 7.0 14.0 3.9–5.0

suﬀered by 22 to 24% of those older than 70 years [120,125]. The most common major complications were myocardial infarction, pneumonia, and stroke. Carson [114], reporting morbidity, infection, and septicemia rates in 146,786 CABG patients with an average age of 65 years, noted that the risk of infection and other serious life-threatening complications was 36 to 38% higher in diabetics treated with insulin or oral agents even after adjusting for diﬀerences in risk factors. Survival Table 14 summarizes survival data from several authors [90,110,113,117,118,121,126–128]. Again, there is some variation as a result of atient selection, but it is clear that long-term survival following CABG of those 70 years old or older as well as those in their 80s closely

Table 14 Duration

Reported Survivals Following Coronary Artery Bypass by Author, by Year, and by Survival in percent

Ref (yr)

Age (yrs)

1 Year

3 Years

113 (94) 126 (95) 127 (85) 90 (02) 121 (88) 90 (02) 117 (94) 118 (90) 128 (97) 90 (02) 110 (92)

36 36 69 <70 >70 >70 >80 >80 >80 >80 82

98 93 98 91 92 89 90 87 87

93 90 95 88 88 77 76 78 77 77.4

5 Years 86 90 83 92 86 82 66 60 66 73

6–7 Years 85 80 85

47

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approximates that of a general population of like age (Table 10). It is also clear that survival of patients after CABG is markedly better than would have been the case if the angina had been allowed to pursue its natural course (Table 10). Although most authors have reported a higher operative mortality in women, long-term survival of women following CABG is at least as good as that of men in all age groups. [116] (Table 15). Increasing age, ejection fraction below 35%, severe wall motion abnormalities, endsystolic volume greater than 80 mL, and the presence of two or more associated medical conditions are predictors of decreased long-term survival [126,129]. Over age 65 years, 45% of late deaths are due to noncardiac causes. Below age 65 years, 29% of late deaths are due to noncardiac causes. Diabetics with CAD, particularly those requiring insulin or oral hypoglycemic agents, have a decreased long-term survival regardless of the method of treatment of their CAD. However, their survival is better with CABG than it is with either PTCA or medical management [89,130–134] (Table 16). Table 17 summarizes survival data following PTCA [87,88,117,131,135]. Immediate mortality following PTCA in the elderly is consistently lower than that following CABG. In controlled studies, 5-year survival following PTCA closely approximates that following CABG (except for TDM) [88,89,135]. Table 18 compares long-term survival following medical treatment of CAD with that following CABG in the elderly [110,127]. Although it is probable that, in these nonrandomized studies, patients treated medically were sicker than those treated surgically, the data that are available strongly suggest that elderly patients who undergo CABG fare better than their medical counterparts in terms of prolonged survival, relief of symptoms, and restoration of an active lifestyle. Cumulative 6-year survivals of 1491 patients 65 years old or older in the Coronary Artery Surgery Study (CASS) were 80% in the surgical group and 63% in the medical group [127]. Ko et al. [110] reported in 1992 that octogenarians treated by CABG had a better 3-year survival than those treated medically (77.2% vs. 55.2%). Peterson [107], describing Medicare data, noted that 1-year survival was 92.1% after CABG in 147,822 individuals 65 to 70 years old. Three-year survival was 86.9%. One- and 3-year survivals were 80.9% and 71.2% in 24,461 patients z80 years old.

Table 15 Reported Survivals Following Coronary Artery Bypass by Author, by Gender, and by Duration Survival in percent Ref (yr) 116 (93) Men

Women

Age (yrs) V45 46–54 55–64 65–74 z75 V45 46–54 55–64 65–74 z75

1 Year

3 Years

5 Years 92 94 90 83 69 96 98 87 84 77

6–7 Years

10 Years

15 Years

82 86 75 60 40 85 81 71 70 38

64 72 55 35 81 67 55 35 28

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Table 16 Reported Survivals of Diabetes with CAD by Author, by Year, and by Duration (Various Modes of Therapy) Survival in Percent Ref (yr)

Mean age (Yrs)

130 (94)

68

132 (91)

82

133 (93)

59

134 (91)

55

89 (97)

62

131 (96)

57 60

Study DM + CABG DM + MED ND + CABG DM + CABG ND + CABG DM + CABG ND + CABG DM + CABG TDM + CABG TDM + PTCA ND + PTCA DM + PTCA

1 Year

88 65

3 Years

95 92

83 — 98 96 93 88

97 93

95 90

5 Years 72 50 64 — 96 89 91 85 81 66 92 82

7 Years

10 Years

15 Years

48 24

24 18

76 63

64 41

94 81 86 74

87 74

Abbreviations: ND = nondiabetic; DM = diabetic; TDM = diabetic patients requiring insulin or oral hypoglycemic agents; +CABG-treated by coronary artery bypass; +PTCA- treated by balloon angioplasty.

Table 17 Reported Survivals Following PTCA or CABG by Author, by Year, by Duration, and by Treatment Survival in percent Ref (yr) 131 (96) 87 (94) 88 (96) 89 (97) 135 (94) 117 (94)

Mean age (yrs) 57 60 62 61 62 61 62 75 75 84 82

Study ND + PTCA DM + PTCA PTCA CABG PTCA CABG ND* + PTCA ND* + CABG PTCA CABG PTCA

1 Year

3 Years

5 Years

7 Years

9–10 Years

97.9 92.8 96.5 97.9 96.5 96.5

95.0 89.5 92.9 93.8 91.8 93.8

91.6 81.5

86.6 74.1

82.3 64.1

87.5 85.0 88.0 89.0

77.5 72.5 83.0 77.0

86.3 89.3 90.5 89.7 63.0 65.0 55.0 66.0

21.0 42.0

Abbreviations: ND = nondiabetic; PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass; ND* = Includes nondiabetic and diabetics not requiring insulin or oral hypoglycemic agents.

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Table 18 Reported Survivals Following CABG or Medical Management by Author, by Year, by Duration, and by Treatment Survival in percent Ref (yr) 127 (85)

110 (92)

1 Year

3 Years

5 Years

6 Years

CABG

93

90

83

MED MANAG

89

78

68

80 81 77 75 63 67 51 56

Age (yrs) z65 65–69 70–74 z75 z65 65–69 70–74 z75 81 83

Study

CABG MED MANAG

77 55

Abbreviations: CABG = coronary artery bypass; MED MANAG = medical management.

Graham [90], reviewing data from the Alberta, Canada registry, reported that patients in three age groups had better 4-year survival following CABG than they did following medical management (Table 19). In that study, those over 80 years of age beneﬁted most from CABG. Procedural mortality was not reported. Quality of Life As survival following treatment of ischemic heart disease has improved, measurement of the quality of the patient’s life following treatment has become a focus of increasing discussion. Evaluation of operative mortality, morbidity, and survival are readily addressed by objective measurements, but quality of life is less easily measured objectively. Investigators often use indirect measurements such as freedom from cardiac events, relief of pain, decreased requirements for medication, or fewer hospitalizations as evidence of a better quality of life. Attempts to develop objective direct measurements have involved use of instruments such as the Duke activity score index, the SF 36 health survey, the Rose questionnaire for angina, the Hospital Anxiety and Depression scale, the Nottingham

Table 19 Survival After Coronary Revascularization (APPROACH Data According to Ages and Treatment Modality) Age group (yrs) <70 70–79 z80

Number of patients 15 392 5198 983

Percentage survival at 4 years by treatment modality CABG

PCI

MED MANAG

95.0 87.3 77.4

93.8 83.9 71.6

90.8 79.1 60.3

Abbreviations: APPROACH = Alberta Provincial Project for Outcomes in Coronary Heart Disease; CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention. Source: Ref. 90.

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Health Proﬁle, the EuroQuol Questionnaire, and changes in the New York Heart Association or the Canadian Cardiac Society classiﬁcation [136–138]. Each requires patient self-assessment as well as the patient’s understanding of the questions, ability, and willingness to respond. Nevertheless, there is substantial data to indicate that both medical and surgical treatment improve the quality of patients’ lives. Freedom from Events Multiple authors have reported that at 5 years, 59 to 78% of elderly patients surviving CABG; 40 to 70% of those surviving PTCA; and 67% of those treated medically for CAD were free of recurrent cardiac events [128,135,139,140]. The term ‘‘cardiac events’’ usually included death or new Q-wave infarction, but in some publications it also included reoperation, arrhythmia, and stroke. Freedom from Angina Severe intractable angina is the most frequent indication for CABG in the elderly. After CABG, 62 to 94% of patients were found to be free of angina with follow-up ranging from 3 months to 8 years [12,110,118,122,127,135,140,141]. Fifty-ﬁve to 82% of elderly patients treated by PTCA and 29 to 51% of those treated medically were free of angina [12,87, 118,127,135,140,142]. Vogt. [142] reported that 85% of elderly patients treated by CABG were free of angina 6 to 12 months later compared with 55% of those treated by PTCA and 51% of those managed medically. In general, PTCA and medically treated patients were more likely to be taking antianginal medications than were the CABG patients. The advantages of surgical treatment over medical treatment seem to decrease slowly over time but were sustained for at least 10 years [141]. Post-treatment Myocardial Infarction The frequency of recurrent or late myocardial infarction 1 to 5 years after CABG in the elderly ranged from zero to 2%. Following PTCA, the frequency was 2 to 6%. After medical management, the frequency of a new myocardial infarction was as high as 28% [122,135,143]. Functional Status In terms of mobility, ability to care for themselves or live independently, the elderly clearly beneﬁt more from CABG than from medical management. When the high frequency of CABG following PTCA is considered, patients treated only by CABG probably have a better quality of life than do those treated only by PTCA. Ko [110] reported that CABG produced a signiﬁcant improvement in functional capacity lowering the NYHA classiﬁcation from an average of 3.4 preoperatively to 1.2 postoperatively. Medical management did not (2.8 to 2.5). Similarly, Mullany [118] found that 89% of the elderly undergoing CABG were returned to NYHA class 1 or 2. Preoperatively 97% of the patients were NYHA class 3 or 4. Krumholz. [143], evaluating 93 octogenarians following hospitalization for an acute myocardial infarction, found that 1 year later, 89% of those treated by CABG, 86% of those treated by PTCA, and 44% of those treated medically rated their quality of life as good or excellent. King [87] reported that 44.5% of patients treated by CABG and 47% of those treated by PTCA were able to engage in moderate or strenuous activity. Akins [128] commented that 86% of octogenarians who had undergone CABG were living at home or with their families. Krumholz et al. [143] found that 89% of octogenarians treated by CABG, 89% of those undergoing PTCA, and 55% of those treated medically for CAD were living independently. For comparison, earlier in this chapter the

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comment was made that half of the general population 85 years old or older still lived alone or with their spouses [21]. Several authors have attempted to measure quality of life objectively. Vogt. [142], measuring outcomes in 98 individuals older than 70, found that patients undergoing CABG were signiﬁcantly more able to engage in the basic and intermediate activities of daily living (ADL) than were those who underwent PTCA or medical therapy. Hlatky et al. [12] measured functional status following CABG or PTCA in a group of 934 patients with a mean age of 62 years. Employing the Duke Activity Status Index, he reported that improvement was signiﬁcantly better after CABG than after PTCA (7.0 vs. 4.4). Chocron et al. [141], using the Nottingham Health Proﬁle, found that 3 months after CABG, 92% of elderly patients reported improvement in their social activities; 89% in their energy; 80% in their physical mobility; and 79% in their pain. Speziale et al. [144], using a questionnaire that evaluated ﬁve areas of activity, reported the results at 3 years from 203 patients treated by CABG, 107 patients treated medically, and 107 normal patients. Mean age was 60 years. The surgical patients scored signiﬁcantly better than the medical patients, but both treatment groups scored signiﬁcantly worse than the normals.

COSTS From the data presented, it is apparent that CABG and/or PTCA cannot only extend the life of elderly patients with CAD, but also they can prevent further myocardial injury, restore function, and increase the quality of life. Costs, however, are a valid consideration as these procedures are performed in increasing numbers of the elderly. Peterson et al. [107] noted that the rate of CABGs performed in those aged 65 to 70 grew from 38.1/ 10,000/year in 1987 to 42.1/10,000/year in 1990. The rate in octogenarians grew from 7.2/ 10,000/year in 1987 to 12.0/10,000/year in 1990. The total number of bypass operations performed in octogenarians is expected to increase from 8000 in 1990 to more than 30,000 by 2050 at an in-hospital cost that will exceed $1.2 billion in 1990 dollars. In 1990 dollars, the mean hospital cost for a CABG performed in patients 65 to 70 years old was $21,700; for those in their 80s the mean cost was $27,200 [107]. The increased costs for CABG in the elderly result primarily from longer hospital stays and more intensive treatment rather than from the procedure itself. In turn, the prolonged stays are due to the presence and severity of coexisting disease, the generally more advanced stage of CAD at the time of operation, and the increased frequency of postoperative complications in the elderly. Smith et al. [145], reviewing economic outcomes in 1114 patients undergoing CABG, found that lower ejection fractions, higher age, congestive heart failure, presence of unstable angina, cardiomegaly, stroke, renal disease, and diabetes requiring insulin were signiﬁcant patient factors that predicted higher costs. Lower age, higher ejection fractions, absence of diabetes, no prior PTCA, and male sex predicted earlier hospital discharge. Comparative costs of PTCA and CABG are also valid considerations. It is generally accepted that the initial costs for PTCA are signiﬁcantly less than the costs of CABG (35 to 84% less) [12]. Over a period of time, however, the total cost of PTCA approaches that of CABG because of more frequent hospitalizations, more frequent revascularization procedures, and a greater cost for medications. Hlatky [12] concluded that over a 3- to 5year period, balloon angioplasty has a signiﬁcant cost advantage over CABG in patients with two-vessel disease. In patients with three-vessel disease, the costs were similar. In diabetics with CAD, bypass surgery was more cost eﬀetive than angioplasty.

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As the number of cardiac revascularization procedures performed in progressively older patients continues to increase and the cost of health-care continues to escalate, the question of cost eﬀectiveness of these procedures in the elderly has become a topic of discussion among health planners. The TIME investigators (Switzerland) [136] noted that individuals older than 75 years represent the fastest growing segment of the population. They pointed out that more than one-third of the total health-care expenditures are consumed by this group of individuals in whom coronary artery disease is the most prominent cause of morbidity and mortality. Sollano [138] studied the cost eﬀectiveness of CABG surgery versus medical management in 224 patients 80 years of age or older. Survival and quality of life were evaluated post-treatment. Cost per quality-adjusted life-years saved was calculated. In the group undergoing CABG the cost per year was $10,424, well within the benchmark of $50,000 per year considered to be cost eﬀective for a number of other treatments. They concluded that performance of CABG surgery in octogenarians was highly cost eﬀective.

INDICATIONS FOR CABG IN THE ELDERLY Compared with cardiac disease in the younger population, CAD in the elderly is more likely to be associated with severe complications and a higher mortality from those complications. Age, in itself, has been shown repeatedly to be an independent predictor of an increased operative mortality. Thus, the elderly face greater risks in the perioperative period while at the same time the durability of long-term beneﬁts is necessarily limited. Nevertheless, conclusions drawn from the randomized studies together with data from multiple nonrandomized studies of coronary revascularization in the elderly have led to generally accepted indications for CABG in older patients. As summarized by Aronow [146], they are: 1. 2. 3.

4.

5. 6. 7.

Signiﬁcant left main disease. Signiﬁcant three-vessel disease, especially in the presence of a decreased left ventricular ejection fraction and ischemia. Signiﬁcant two- or three-vessel disease, a decreased left ventricular ejection fraction, and signiﬁcant stenosis of the proximal left anterior descending coronary artery. ST-segment depression on resting ECG plus at least two of the following—New York Heart Association (NYHA) functional class III or IV, history of MI, history of hypertension, or all three without ECG changes. Signiﬁcant two- or three-vessel disease and exercise-induced ischemic ST-segment depression of 1.5 mm or greater. Clinical evidence of CHF during ischemic episodes with ischemic but viable myocardium. Unacceptable symptoms despite optimal medical management.

SUMMARY Coronary angioplasty or bypass is being performed for increasing numbers of patients in their seventh, eighth, ninth, and even tenth decades of life. Both silent and overt CAD are

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more common in the population over 65. Because CAD in the elderly presents more often in an atypical manner, diagnosis of the disease is frequently delayed. As a result, the elderly typically face the operation with a higher prevalence of complications of their CAD. Myocardial infarction, impaired myocardial function, and congestive heart failure are more frequent in the elderly. CABGs are performed more frequently as emergencies in older individuals, particularly those z80. Nevertheless, it is clear from recent reports that elective CABG can be performed with operative mortalities in the 1.0 to 4.0% range even in 70- and 80-year-olds. Survival of the elderly treated by CABG approximates that of a general population of like age and is markedly superior to that achieved by medical management. It is also true that CABG in older individuals improves the quality of life over and above that observed following alternative methods of treatment, particularly medical management. While the costs of performing CABG in the elderly are higher than they would be for a younger population, it is not clear that these costs are higher in the long run than they would be for nonoperative treatment with its associated costs of repeated interventions and hospitalizations. Greater eﬀorts directed toward detection of ischemic heart disease in the older population and performance of earlier, elective surgery could signiﬁcantly reduce both the mortality and disability associated with CAD in the elderly. Delay in operation until the patient has a complication of CAD, particularly a myocardial infarction, has a markedly adverse outcome in both the short and the long term.

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3.

4. 5.

6.

7.

8.

9.

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15 Percutaneous Coronary Intervention in the Elderly Charles L. Laham, Mandeep Singh, and David R. Holmes, Jr. Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A.

The numbers of older (age over 65 years) and old (those over age 80 years) patients with coronary artery disease (CAD) are increasing in our society at a tremendous rate. Indeed, there has been unsurpassed growth in the elderly population in the last 10 to 15 years. Within a decade, one-sixth of the population, representing 45 million people, will be over the age of 65 [1], with half of those being over age 75 and some 25% of those over the age of 80. The elderly have a high prevalence (about 60%) of signiﬁcant atherosclerotic CAD in at least one coronary vessel, with many becoming symptomatic enough to require deﬁnitive treatment [2]. Patients older than 65 now constitute over half of all patients undergoing coronary revascularization procedures at major medical centers [3–6]. Unfortunately, many studies of revascularization for symptomatic coronary artery disease in the past have either excluded patients over the age of 70 to 75 or have insuﬃcient numbers to draw eﬀective conclusions. There is a high proportion of extensive disease, greater medical comorbidities, and poorer success rates leading to higher complication/ death rates in the elderly, both with percutaneous coronary intervention [6–8] and with coronary artery bypass surgery (CABG) [9]. These factors make the decision to perform coronary revascularization challenging. With the rapid evolution of percutaneous coronary intervention (PCI) techniques, one must continually reevaluate PCI’s applicability in the setting of older, sicker patients so as to better advise of its relative beneﬁt versus alternative treatment strategies.

BASIS FOR INTERVENTION IN THE ELDERLY Recent studies have shown that elderly patients with symptomatic coronary artery disease have poorer long-term and event-free survival with medical therapy alone compared with revascularization [10,11]. The large observational APPROACH study, set in the mid1990’s (6000 patients with CAD over age 70, about 1000 patients over age 80) noted agerelated diﬀerences in adjusted 4-year survival in the elderly with medical treatment (MED) compared with PCI and CABG as follows: aged <70 MED = 90.5%, PCI = 93.8%, CABG = 95.0%; aged 70 to 79 MED = 79.1%, PCI = 83.9%, CABG = 87.3%; aged 389

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>80 MED = 60.3%, PCI = 71.6%, CABG = 77.4% [10]. Elderly patients in general did poorer with medical therapy, but this trend seemed to worsen with increasing age. Graham et al. and others [10,12] have shown that beneﬁts of revascularization in carefully selected elderly patients are more pronounced. In addition to frequent symptoms, some 50% of medically treated patients will be admitted with an acute coronary event, a trend that can be favorably impacted with timely revascularization therapy [11]. Other factors in the elderly limit the overall utility of medications as a primary option for therapy: their ischemia is often refractory to medication, leading to frequent maximization of medical therapy [13]. Elderly patients have a fair degree of medication intolerance (due to peptic ulcer disease/other gastrointestinal conditions) as well as cognitive impairment that can lead to less compliance with medications than younger patients [14–16]. Undoubtedly, for a multitude of reasons, older patients tend to downplay their symptoms and delay seeking care; when they do present with active coronary ischemia, they are more likely to do so late, with signs of severe congestive heart failure (CHF), acute myocardial infarction, and/or cardiogenic shock [7]. It is these very subsets of elderly who are shown to carry a poorer prognosis with medical therapy in the absence of revascularization [17,18]. Together with a high prevalence of chronic symptomatic ischemia, a high burden of atherosclerosis, and many medical comorbidities, active CAD can be a tremendously disabling problem in the elderly, one that often prompts patients to consider the more deﬁnitive beneﬁts oﬀered by revascularization therapy.

CHARACTERISTICS OF THE ELDERLY PERCUTANEOUS CORONARY INTERVENTION POPULATION Elderly subjects undergoing PCI are generally sicker than younger ones due to a higher prevalence of comorbid medical conditions [5,19,20]. Patients over age 65 frequently have hypertension and diabetes leading to more advanced CAD, peripheral vascular disease, and cerebrovascular disease [5,19,20]. Older patients have a greater burden of coronary atherosclerosis associated with a relatively high percentage of prior myocardial infarction, prior history of PCI’s and/or CABG, and resultant lower ejection fraction (EF) [5,13,19,21,22]. Based on a multicenter registry study, CHF is common in the elderly and comparatively rare in younger patients: only 4% of patients younger than 65 have had congestive heart failure versus some 9% over 65 years and 20% over age 75 [13]. In addition, there is a higher percentage of women undergoing PCI over age 75 (40–50%) compared with those younger than 65 (21%), a factor that alone trends toward a higher need for subsequent revascularization procedures [20]. The presence of many adverse risk predictors in the elderly has a major impact on the lesion’s suitability for PCI and is inherent in their higher procedural risk. There is a high incidence of multivessel CAD in patients with lower EFs. One study noted that 50% of patients over the age of 75 versus 33% of younger patients have multivessel disease, with some 13% of those over age 80 having left main coronary disease [23]. Thus, in the early balloon era, only 31% of patients in their 80s were considered suitable candidates for angioplasty due to diﬀuse extensive CAD [23,24]. With the rise of better PCI techniques such as stenting and/or debulking, interventions for many of these advanced ‘‘type C’’ lesions are now routine, but the modiﬁed AHA/ACC characteristics still predict poorer overall shortand long-term success in this setting [25].

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As a consequence of more extensive disease, elderly patients are often more unstable upon presentation for intervention than younger patients, not uncommonly having had prior silent infarctions [26]. They have a higher frequency of class III/IV angina, which is present during intervention in as many as 70% of patients over 65 and in an even higher number of those over age 80, compared with less than 50% of younger patients [5,13,19– 22,27].

OUTCOMES OF BALLOON ANGIOPLASTY IN THE ELDERLY Initial results in elderly patients undergoing angioplasty in the early 1980s showed relatively low acute success rates, higher procedural complications, and higher mortality [13,19]. The results have been age-dependent, with those over age 75 having poorer outcomes than younger patients [13,19,20–22,28,29]. Elderly patients who underwent angioplasty at the Mayo Clinic between 1980 to 1989 showed procedural mortality of 1.2% for patients below age 75 but 6.7% for those over age 75 [5]. This is in keeping with other large centers during the same period [30]. In a large Medicare database of some 20,000 patients, Jollis et al. reported in-hospital mortality rates of 7% in patients over age 80 with angioplasty [31]. With lower proﬁle balloons, perfusion balloons, in-lab monitoring of anticoagulation status, increasing operator experience, and occasional use of bailout stenting, angioplasty success had signiﬁcantly improved by the early 1990s to an acceptable level of 88 to 93% [30,32] in elderly patients with single-vessel disease, but was still lower in the oldest subjects. From 1990 to 1992 (compared to the 1980s), results of angioplasties performed at Mayo Clinic showed a 50% drop in hospital mortality to 0.8% in patients aged 65 to 74 and to 3% in those over age 75 [32]. The rate of complications had also fallen during this time period, with procedural infarction rates in those over age 65 falling to 2.2% (vs. 3.9% previously) and emergency bypass rates of 0.65% (vs. 5.5%). Other medical complications post-procedure have also been a particular concern in the elderly. After angioplasty, Maiello and colleagues [33] described a 1.1% rate of renal insuﬃciency and a 5.4% rate of need for transfusion in patients over 70. As a result, the elderly tend to have longer hospital stays, although this may be favorably altered by careful attention to the amount of contrast dye used, better preprocedural hydration, less aggressive anticoagulant dosing, and the use of smaller caliber equipment.

PREDICTORS OF POOR EARLY OUTCOME WITH ANGIOPLASTY IN THE ELDERLY The strongest predictor of hospital death in the elderly is the presence of extensive or multiple-vessel coronary disease [34]. Maiello and colleagues showed a high success rate, approaching 100% in patients over the age of 75 in single-vessel angioplasty versus a success rate in multiple-vessel treatment of only 52% [35]. The overall procedural success rate depends on the additive number of vessels treated. Calciﬁed coronary artery lesions have deﬁnitely been predictors of failed angioplasty procedures in the past and, even in contemporary practice with stenting, are associated with poorer long-term event-free survival [25,36] due to a higher subsequent need for repeat revascularization procedures.

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LONG-TERM OUTCOMES IN THE ELDERLY FOLLOWING ANGIOPLASTY The long-term results after a successful angioplasty in the elderly have shown consistent improvement. By the early 1990s Buﬀet [28] and Thompson [5] had shown 4-year survivals of 83 and 86%, respectively. The overall long-term survival rates were not signiﬁcantly different between those over and those under 75 years of age. However, there was less satisfactory event-free survival in patients over 75 years in these series [5–28] that was probably due less to restenosis than to progression of their underlying advanced atherosclerotic disease. Restenosis rates have been quite similar, in the 31 to 44% range, with angioplasty in patients over 80 years, older patients between 65 and 79, and in younger patients [20,37–40]. The strongest predictor of event-free survival in the elderly postangioplasty is the extent of CAD. DeJaegere [41] reported an 81% event-free survival postangioplasty in patients over age 70 with single-vessel disease versus 45% in patients with multivessel disease. The extent of disease also was a multivariate risk predictor in a prior review of the Mayo Clinic angioplasty experience in the elderly [34]. Other predictors of long-term eventfree survival were the left ventricular systolic function, the presence of unstable angina and the number of noncardiac medical problems [31,32,34,38–42]. Clearly, there is a wide variation in risk in angioplasty patients: this is most true in the elderly. The number of adverse risk factors present greatly impacts the long-term risk of death or myocardial infarction. In a Mayo Clinic series with risk stratiﬁcation by the number of risk predictors, we noted that elderly patients undergoing angioplasty with three-vessel CAD, recent CHF, and two other concomitant medical problems had 3-year survival rates free of myocardial infarction of only 66%, while in the absence of these factors, it was 96% [34].

ELDERLY PATIENTS WITH MULTIVESSEL DISEASE: ANGIOPLASTY VERSUS SURGERY Some authors have suggested that the reduced event-free survival seen in the elderly may relate to the frequency of incomplete revascularization with angioplasty, but others believe it indirectly reﬂects the greater extent of active coronary disease in this population [34,41,42], associated with more coronary risk factors. Nonetheless, the relative lack of complete and durable revascularization achieved with angioplasty for multivessel disease in the elderly is a prime reason why many elderly patients will ultimately require surgery [43]. This was one of the major ﬁndings in the elderly subset of the largest randomized multivessel coronary angioplasty versus bypass study, the BARI (Bypass Angioplasty Revascularization Investigation) trial, which enrolled patients from 1988 to 1991 [44]. No signiﬁcant diﬀerence in 30-day mortality (1.7% in each) was noted in the 709 patients aged 65 to 80 who were randomized, although many patients with angioplasty required repeat revascularization and some ultimately had CABG. Only the subset with diabetes in all age groups showed higher mortality with angioplasty versus bypass surgery, and this is deﬁnitely a consideration in elderly patients undergoing angioplasty in lieu of CABG [45]. The rate of strokes with CABG was signiﬁcantly higher in the elderly than with angioplasty [44]. Since the prohibitively high revascularization rates with angioplasty seen in the overall population in BARI (52% vs. 6% with CABG at 5 years), stenting has become the preferred therapy. Importantly, even in the present era, not all lesions are suitable for stenting, and some may

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still be better treated with balloon angioplasty; hence these results are still clinically relevant in as many as 25 to 30% of PCI involving the elderly, particularly in small vessels, branch vessels, or those with heavy calciﬁcation.

CONTEMPORARY PERCUTANEOUS CORONARY INTERVENTION: STENTING IN THE ELDERLY The approval of balloon expandable stainless steel stents by the FDA in June, 1993 was a tremendous breakthrough in percutaneous revascularization [46,47]. It eliminated most of the threatened/abrupt vessel closure following dilation and thus avoided the Q-wave infarctions and/or salvage emergency coronary bypass seen in as many as 5 to 10% of patients. It signiﬁcantly improved the restenosis rate from 30% to 20% in fairly short/focal lesions, reducing the need for repeat interventions [47]. Stenting was initially hindered by increased vascular access site complications due to bulky equipment and the use of warfarin anticoagulation. This has greatly improved since the combined use of aspirin/thienopyridine therapy [48], together with smaller 6 French (2 mm) guiding catheters, better wire technology, and lower proﬁle, better designed, more ﬂexible stents. These improvements have enhanced the suitability of stenting complex AHA/ACC lesion types such as calciﬁed lesions and chronic total occlusions. Thus, the elderly with more extensive and higher grade lesions are now treatable in many instances by percutaneous intervention with stenting. The above revolution in PCI with the introduction of stenting comes with three caveats: in many complex and some simple coronary lesions, the delivery of the stent still depends on pretreatment with either prior balloon dilatation or debulking atherectomy; the ‘‘superior’’ angiographic appearance of stented lesions has led to their usage in small arteries, calciﬁed vessels, thrombus-ﬁlled lesions in acute infarction, and in vessels previously thought too extensively diseased for intervention; stenting has introduced the new problem of in-stent restenosis, which has become more frequent with the other two features mentioned. Another issue that has improved the suitability of PCI in high-risk patients has been the availability of glycoprotein IIB/3A inhibitors of platelet function. It has extended the beneﬁts of PCI/stenting to high-risk thrombotic lesions in those with an acute coronary syndrome with/without cardiogenic shock and has even led to usage of multivessel stenting in patients with diabetes [49] who previously had prohibitively high restenosis rates. The only downside to the rapid evolution in interventional procedures is that it has made it diﬃcult to clearly establish an evidenced-based population study of contemporary PCI versus CABG in the elderly. Indeed, a prospective randomized trial of 3 years duration may be based on outdated methods by the time it is reported, although it may still lead to long-lasting changes in treatment guidelines based on these ‘‘older’’ methods.

RESULTS OF CORONARY STENTING IN THE ELDERLY Coronary stenting has become the dominant revascularization mode in the elderly in those with one- and two-vessel disease and, occasionally, in those with three-vessel CAD felt to be too high risk for CABG. In the early stenting era, Yokoi et al [50] reported initial successful stent results to be lower in those over 75 years compared with younger patients for the Palmaz-Schatz stent (86% vs. 95%) with associated higher hospital mortality (4.1% vs. 1.2%). By the mid 1990s, the procedural success rate with lower proﬁle, more deliverable

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stents had improved to 90.8% and 90.2% in two series by Chevalier and Batchelor [51,52] of 142 and 7472 octogenarians, respectively, but with poorer results compared to younger patients’ success rates of 95.5%. Overall in-hospital mortality was still around 3.5% and combined death/infarction and stroke risks were 5.2%; stenting was associated with better procedural success rates, lower need for repeat revascularization but higher vascular complication rates [51]. Overall procedural success with stenting has increased compared with results from the early series and now ranges between 90 and 97% success rates at major medical centers [53–55]. A recent National Heart, Lung and Blood Institutes (NHLBI) Dynamic Registry study of PCIs from 1997 to 1999 [56] compared 307 patients over 80 years of age (oldest), 1776 patients aged 65 to 79 (older), and 2537 patients under 65 years (youngest). Successful procedural treatment of all lesions attempted was lower in those over versus those under age 80 (84% vs. 92 to 93%) despite similar IIB/IIIA receptor inhibitor use (26 to 29%), similar stent rates (72 to 73%) and similar rates of rotational atherectomy (5.2 to 7.2%). Accounting for the varied success in the oldest patients (versus the older and the youngest) was a higher burden of coronary disease with more vessels (two or more in 15% vs. 9.4% vs. 9.4%), more lesions (2 or more in 39.1% vs. 34.2% vs. 29.0%), and more graft vessels (8.5% vs. 8.3% vs. 3.9%) treated. Complication rates included higher stroke rates in those over age 80 (1.0% vs. 0.5% older vs. 0.2% younger), higher in-hospital mortality (4.6% vs. 2.2% vs. 0.6%) and more nonfatal myocardial infarctions (6.2% vs. 3.1% vs. 2.2%). One-year survival, although lower with increasing age, was identical to the age-expected mortality rates of the general population, suggesting that successful revascularization in the elderly is beneﬁcial [56].

LONG-TERM RESULTS OF STENTING IN THE ELDERLY The earliest study that included a large number of elderly patients undergoing stenting with ﬁrst-generation stents reported increased angiographic restenosis rates in 137 patients aged 75 and older compared with 2551 younger individuals (47% vs. 28%) [55]. The presence of more advanced coronary disease in those over versus those under aged 75 years was evidenced by higher rates of stenting in multiple vessels (44% vs. 27%), left main (7.35 vs. 1.5%), ostial lesions (15.5 vs. 7%) and more frequent use of rotational atherectomy for debulking of calciﬁed lesions in the elderly (notably, all factors in restenosis). Other studies by Chauhan et al. [53] in 300 octogenarians, Abizaid et al. [54] in over 700 patients over age 70, and Alfonso et al. [57] in 378 patients over age 65 years have all shown similar clinical restenosis rates when compared to younger patients, but higher in-hospital mortality rates (1.3 to 3.0% in those over age 80 vs. 0.2 to 0.7% in younger patients), higher procedural infarction rates (7 to 10% vs. 2%), higher bleeding and vascular complications (5% vs. 1.0%), and higher subsequent 1-year mortality (5 to 9% vs. 1 to 2%). Many studies with coronary interventions in the past have shown that late events are related mostly to repeat revascularization; despite similar restenosis rates, patients over 75 are less likely to undergo repeat revascularization, possibly due to less aggressive late treatment [58].

PREDICTORS OF STENTING OUTCOME IN THE ELDERLY In a landmark study reﬂecting current practice in PCI, Klein [59] examined 8828 octogenarians undergoing intervention with predominant stenting (75%) in the 100,000 patient ACC-National Cardiovascular Data Registry from 1998 to 2000. The most important factor

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identiﬁed as a predictor of in-hospital death in the elderly was the presence of an acute myocardial infarction within 6 h of PCI. For those over age 80, treated in a nonemergency fashion, the overall mortality was only 1.4% (vs. 13.8% for intervention in the setting of acute infarction), with low stroke rates (0.34%) and infrequent renal failure (1.5%), though a notable degree of vascular complications (3.0%). The overall success rate was 93%, with slightly lower success in those with acute infarctions (91% vs. 94%). Other predictors of increased procedural mortality in octogenarians, if present (vs. if not present), included decreased EF, acute renal failure (29% vs. 3.2%), peripheral vascular disease with vascular complications (8.2% vs. 3.3%), procedural Q-wave infarction (17.4% vs. 3.7%), and stroke (17% vs. 3.3%). Predictors of higher mortality were 2 to 3 times as frequent with acute myocardial infarction. Other studies have identiﬁed the presence of multivessel disease, CHF, left main disease, thrombus, vein graft treatment, cardiogenic shock, chronic renal failure, prior myocardial infarction, prior CABG as additive predictors of poor outcome in PCI in the elderly in the stent era [6,7]. A listing of factors associated with adverse procedural outcome with PCI are listed in Table 1.

PERCUTANEOUS INTERVENTION FOR ACUTE INFARCTION IN THE ELDERLY The GUSTO-I trial was one of the ﬁrst to recognize the survival advantage of rapid restoration of normal levels of coronary blood ﬂow in the infarc-related artery. Reperfusion therapy was introduced with thrombolytic agents, but it became apparent that, in the elderly, particularly those over age 75, thrombolysis resulted in worrisome levels of disabling and/or fatal strokes, negating some of the survival beneﬁts of opened arteries [60]. The risk appeared to be higher with tissue plasminogen activator (TPA) therapy than with streptokinase, leading to preferential use of the latter in the elderly. As angioplasty and, later stenting techniques, became accepted therapy in chronic stable angina, their use as primary therapy in acute infarction in the elderly was tested in a number of small studies. Initial success rates varied widely and ranged between 61 and 92%, depending on age and the presence/absence of multivessel disease, left ventricular dysfunction, bleeding complications, and other comorbidites.

Table 1 Factors Predicting Adverse Outcome and/or Mortality with Percutaneous Coronary Revascularization in the Elderly Baseline characteristics Age over 80 Numerous comorbid illnesses Frail health Prior CABG Prior myocardial infarction Cardiogenic shock Acute myocardial infarction Chronic renal failure Peripheral vascular disease Congestive heart failure

Procedural issues Decreased EF Respiratory failure/intubation Multivessel disease Left main coronary disease Intra-coronary thrombus Saphenous vein graft disease Acute renal failure post PCI Q-wave infarction post PCI Stroke post-PCI Vascular access complication

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Holmes and colleagues [61] noted a trend toward improved overall 30-day mortality (5% vs. 14.3%) and lower overall 30-day combined mortality, disabling stroke, or reinfarction (10 vs. 20%) in 119 patients aged 70 to 79 treated with primary balloon angioplasty during acute infarction compared with 105 given thrombolysis in the Gusto-IIB trial. The only randomized trial of reperfusion therapy for acute infarction speciﬁcally in the elderly was recently reported by de Boer et al. [62]. This study of 87 patients over age 75 years randomized 46 patients to PCI versus 41 patients to streptokinase therapy. Of the 41 patients who actually received PCI (two had bypass, two medical treatment, one died preangiography), 90% had a successful result, with 51% receiving stents. The results were dramatic, with in-hospital mortality (7% vs. 20%), 30-day mortality rates (7% vs. 22%), 1-year mortality (13% vs. 41%), stroke risk (1% vs. 7%) and reinfarction rates (2% vs. 15%) showing signiﬁcant advantages of PCI over thrombolysis. Certainly, these results suggest that PCI will become the favored therapy for acute infarction therapy in the elderly once multicenter trials are conducted to conﬁrm these ﬁndings.

ACUTE INTERVENTION IN CARDIOGENIC SHOCK COMPLICATING MYOCARDIAL INFARCTION IN THE ELDERLY The SHOCK (Should we emergently revascularize Occluded Coronaries for cardiogenic shock) Trial suggested a survival advantage with rapid revascularization for younger patients with cardiogenic shock [63]. Unfortunately, there was a trend toward poorer outcome in those over age 75 who were revascularized versus those receiving aggressive medical treatment, which included use of an intra-aortic balloon pump (75% vs. 53% 30-day morality). A portion of this trial occurred during an era of lower stent use and also may not be reﬂective of contemporary use of IIB/IIIA receptor inhibitors. Three more recent observational studies of acute intervention in the elderly for cardiogenic shock have suggested signiﬁcant survival advantages with stenting. The large GRACE Investigation (Global Registry of Acute Coronary Events) of 583 patients (April 1999 to June 2001) shows overall mortality rates of 59%, with rates of only 35% in those treated with stenting [18]. The two smaller studies have shown similar beneﬁts, but have attributed much of the eﬀect to synergy between use of stents and the use of abciximab. In 96 and 113 patients respectively, Chan [64] and Giri [65] noted angiographic success rates (TIMI-3 ﬂow) of 85% in the abciximab-stenting patients versus lower rates (64–67%) with stenting alone, angioplasty plus abciximab and angioplasty alone. Mortality in the abciximab-stenting groups was 13 to 22% (vs. 36–38% in both angioplasty groups and 36–52% mortality in the stent only groups), indicating signiﬁcant beneﬁt in these high-risk patients. Although the momentum is building toward a preferred role for acute interventions in elderly patients with acute cardiogenic shock, one must await randomized multicenter trials to make ﬁrm recommendations. In an elderly patient with minimal prior comorbidities, PCI with stenting in acute cardiogenic shock may be a consideration, whereas it may not be appropriate in a frail patient with numerous health concerns.

MULTIVESSEL STENTING RESULTS IN THE ELDERLY With the advent of better stenting strategies, better techniques/devices to address higher risk ACC/AHA Type C lesions and the rise of antiplatelet therapies, outcomes with PCI have

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improved in general [66]. Thus PCI has become an attractive, if not preferential, alternative to bypass surgery, especially in candidates not favorable for or desiring CABG. The questions are whether it is appropriate to perform multivessel stenting in the elderly and what are the beneﬁts/problems versus CABG? A number of contemporary trials of multivessel stenting compared with CABG for extensive disease have been reported. The largest trial, ARTS (Arterial Revascularization Therapy Study), randomly assigned 1205 patients (600 to PCI vs. 605 to CABG) [67]. The results in the nondiabetics showed low 1-year mortality in both assigned therapies (1.6% PCI vs. 2.8% CABG), with an overall 76% event-free survival at 18 months with stents compared to 88% with CABG ( p < 0001). Some 11.7% of PCI-assigned patients (vs. 2.9% CABG patients) required subsequent PCI while 3.9% later underwent CABG (vs. 0.6% CABG patients). Although CABG showed signiﬁcantly better symptom-free survival, the stenting results were much more favorable than those at a similar follow-up stage in the BARI angioplasty subset [45], despite 70% of patients having complex type B2/C lesions. Results in the 208 randomized diabetic patients were not as attractive with PCI as with CABG (63% vs. 84% event-free survival at 18 months), possibly related to the low 3.5% rate of abciximab use in this high-risk subset. In contrast, it was possibly the 28% use of abciximab and the higher procedural CABG mortality (5.7% vs. 0.9%) that allowed multivessel stenting to show a better 18-month survival rate than CABG (96.9% vs. 92.5%; p < 0.02) in the ERACI-2 trial (Argentine Randomized Study) of multivessel therapy options [68]. In the 225-patient PCI arm versus a similar-sized CABG arm, there was also a lower long-term rate of infarction (2.3% vs. 6.6%; p < 0.02), but the rate of repeat revascularization with PCI versus CABG patients was 16.8% compared to 4.8%. The randomized Stent or Surgery (SoS) trial, with 500 CABG patients and 488 multivessel PCI patients, also showed a high rate of 2-year repeat procedures of 21% in the PCI group versus 6% in the CABG patients [69]. The low surgical mortality rate of 2% was in keeping with some 50% of patients having stable angina; the mortality rate in patients with unstable angina in the ERACI trial was 7.9%. Perhaps one of the most relevant trials to date in the elderly and in high-risk patients was the recently reported AWESOME trial (Angina With Serious Operative Mortality Evaluation). It enrolled 454 medically refractory veterans from 1995 to 2000 with one or more high-risk characteristics: age over 70 years, cardiac shock needing intra-aortic balloon pumping, EF <35%, prior CABG, and recent infarction [70]. With 222 patients receiving multivessel stenting and 232 receiving CABG—and at least 50% over age 67—it showed low 30-day (5% vs. 3%), 6-month (10% vs. 6%), and 3-year mortalities (21% vs. 20%) with CABG versus PCI, respectively. Thus, elderly patients who are high risk due to one or more of the above risk factors may be able to avoid the longer recovery of CABG and live just as long with multivessel stenting.

OPTIONS FOR REVASCULARIZATION IN THE ELDERLY From early in the revascularization era, a deﬁnite role for CABG has emerged in higher risk patient groups based on its consistent beneﬁcial eﬀect on long-term survival and in reducing anginal symptoms [10,45,71–73]. The success of CABG versus PCI in the elderly has been attributed mostly to CABG’s greater eﬃcacy at achieving complete revascularization of all or most aﬀected vessel territories in the setting of multivessel CAD, left main CAD, advanced AHA/ACC lesion class, and/or lower EF [9,43,71–75]. Whereas balloon angio-

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plasty in the 1980s and early 1990s was an accepted therapy for single-vessel disease [76,77], the frequent problem of restenosis, as demonstrated by 5-year revascularization rates exceeding 50% in BARI, has limited its widespread application in multivessel disease, particularly in the presence of diabetes [44,45]. CABG has been utilized as a viable revascularization option in older patients with extensive CAD because past studies with PCI, even with stenting, have shown frequent recurrent angina leading to repeat PCIs and ultimate need for CABG in up to 20% of patients [44,45,52–54,67,69,70]. Unfortunately, CABG surgery in the elderly is not entirely a benign procedure. The overall mortality rate of CABG in a 1990 Medicare database of nearly 24,500 patients over age 80 was higher compared with patients aged 65 to 70, with poorer in-hospital mortality (11.5% vs. 4.4%), 1-year mortality (19.3% vs 7.9%), and 3year mortality (28.8% vs. 13.1%) rates [78]. Many elderly patients are also at substantial risk of perioperative myocardial infarction, pneumonia, renal failure, prolonged mechanical ventilation, and neurological events, with rates between 2 and 10% [44,79]. Given these risks, in addition to cognitive impairments seen in 60% short term and some 20% long term post-CABG in the elderly [80–82], many patients will not regain their previous level of function and, thus, suﬀer a loss in their quality of life [79]. Some elderly patients, particularly those who have extensive CAD, a recent or prior myocardial infarction, prior revascularization, or additional comorbidities, will have even higher potential morbidity and mortality with CABG. The search for a viable alternative to CABG has continued to make steady progress. Recent PCI studies with predominant stent use demonstrate comparable or slightly better survival with PCI versus CABG but have still failed to avoid the subsequent need for

Table 2 Factors Favoring Better Revascularization Results with Either Percutaneous Coronary Intervention or Coronary Artery Bypass Surgery in the Elderly Patient characteristics Percutaneous intervention better Age over 80 Numerous comorbid illnesses Frail health/limited life expectancy Major depression Poor motivation to rehabilitate Morbid obesity/severe COPD

Coronary bypass better Diabetes (extensive disease) No major comorbid illnesses Active lifestyle/expect longevity Dedicated to lifestyle changes Great motivation to rehabilitate Thin, athletic in past

Angiographic characteristics Percutaneous intervention better

Coronary bypass better

Focal/limited 1- or 2-vessel CAD Good left ventricular function AHA/ACC Type A, B1 lesion Bifurcation: risk to small branch Crossable total occlusion

3-vessel CAD/left main CAD Poor left ventricular function AHA/ACC Type B2, C lesion Bifurcation: risk to large branch Uncrossable occlusion/large area of ‘‘jeopardized’’ tissue Stable CAD Goal: survival/symptom relief

Acute MI/cardiogenic shock Procedure goal: symptom relief

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additional revascularization in the PCI group, especially in the setting of diabetes [67–70]. The question, when deciding upon the most suitable revascularization modality, is whether the higher procedural morbidity/mortality with CABG is justiﬁed by the 20% lower 5-year need for repeat revascularization compared with PCI. In the setting of numerous comorbidities or frailty, elderly patients may be better served wit‘h moderate-duration symptomatic improvement oﬀered by PCI, as many are less likely to gain the reported superior long-term survival oﬀered by CABG in younger patients. Indeed, one issue many studies fail to recognize when reporting poorer long-term survival in the elderly after either CABG or PCI is that the long-term survival with a successful revascularization modality is not very diﬀerent compared to others of similar age [7,78]. Factors favoring preferential attempts at PCI with stenting compared to those favoring CABG in the elderly are listed in Table 2. The challenge in the near future will be to further deﬁne the role for PCI versus CABG, especially in the elderly and patients with extensive CAD and signiﬁcant comorbidities. Drug-eluting stents, by promising a solution to the problem of restenosis, may well provide the opportunity [46] for multivessel PCI to surpass CABG as the preferred revascularization therapy in general and in the elderly in particular.

GOALS OF REVASCULARIZATION IN THE ELDERLY One drawback of comparing results of angioplasty and PCI in the elderly versus younger patients is that there is often a diﬀerent emphasis on the goals of the procedure. More often, elderly patients are poor surgical candidates with the palliative goal of reducing symptoms whereas younger patients are freer to consider the options: either the most eﬀective procedure that will avoid the need for future procedures versus the one that will interfere the least with their active lifestyle. The options in the elderly are often less applicable or consist of picking the ‘‘better’’ of two ‘‘unappealing’’ therapy alternatives. In summary, results employing PCI with stenting and careful use of IIB/IIIA inhibitors have advanced interventional methods to a degree where stenting may be the preferred revascularization option in the oldest and/or sickest patients. Hopefully, clinical trialists will soon develop suitable studies to speciﬁcally address revascularization issues in the elderly, recognizing their unique needs.

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Laham et al. Singh M, Lennon RJ, Holmes DR Jr, Bell MR, Rihal CS. Correlates of procedural complications and a simple integer risk score for percutaneous coronary intervention. J Am Coll Cardiol 2002; 40:387–393. Holmes DR Jr, Berger PB, Garratt KN, Mathew V, Bell MR, Barsness GW, Higano ST, Grill DE, Hammes LN, Rihal CS. Application of the New York State PTCA mortality model in patients undergoing stent implantation. Circulation 2000; 102:517–522. Singh M, Mathew V, Garratt KN, Berger PB, Grill DE, Bell MR, Rihal CS, Holmes DR Jr. Eﬀect of age on the outcome of angioplasty for acute myocardial infarction among patients treated at the Mayo Clinic. Am J Med 2000; 108:187–192. Gersh BJ, Kronmal RA, Schaﬀ HV, Frye RL, Ryan TJ, Myers WO, Atherarn MW, Gosselin AJ, Kaiser GC, Killip T III. Coronary arteriography and coronary artery bypass surgery: morbidity and mortality in patients 65 years or older: a report from Coronary Artery Surgery Study. Circulation 1983; 67:483–491. Graham MM, Ghali WA, Faris PD, Galbraith D, Norris CM, Knudtson MLfor the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) Investigators. Survival After Coronary Revascularization in the Elderly. Circulation 2002; 105: 2378–2384. The TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease(TIME): a randomized trial. Lancet 2001; 358:951–957. Bell MR, Gersh BJ, Schaﬀ HV, Holmes DR Jr, Fisher LD, Alderman EL, Myers WO, Parsons LS, Reeder GS. Eﬀect of completeness of revascularization on long-term outcome of patients with three-vessel disease undergoing coronary artery bypass surgery. A report from the Coronary Artery Surgery Study(CASS) Registry. Circulation 1992; 86:446–457. Kelsey SF, Miller DP, Holubkov R, Lu AS, Cowley MJ, Faxon DP, Detre KM. Results of percutaneous transluminal coronary angioplasty in patients greater than or equal to 65 years of age (from the 1985 to 1986 National Heart, Lung, and Blood Institute’s Coronary Angioplasty Registry). Am J Cardiol 1990; 66:1033–1038. Backes RJ, Gersh BJ. The treatment of coronary artery disease in the elderly. Cardiovasc Drugs Ther 1991; 5:449–455. Gurwitz JH, Col NF, Avorn J. The exclusion of the elderly and women from clinical trials in acute myocardial infarction. JAMA 1992; 268:1417–1422. Nolan L, O’Malley K. Prescribing for the elderly. Part I: Sensitivity of the elderly to adverse drug reactions. J Am Geriatr Soc 1988; 36:142–149. Dauerman HL, Goldberg RJ, Malinski M, Yarzebski J, Lessard D, Gore JM. Outcomes and early revascularization for patients > or = 65 years of age with cardiogenic shock. Am J Cardiol 2001; 87:844–848. Dauerman HL, Goldberg RJ, White K, Gore JM, Sadiq I, Gurﬁnkel E, Budaj A, Lopez de Sa E, Lopez-Sendon J for the Global Registry of Acute Coronary Events (GRACE) Investigators. Revascularization, stenting, and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. Am J Cardiol 2002; 90:838–842. Mock MB, Holmes DR Jr, Vlietstra RE, Gersh BJ, Detre KM, Kelsey SF, Orszulak TA, Schaﬀ HV, Piehler JM, Van Raden MJ. Percutaneous transluminal coronary angioplasty (PTCA) in the elderly patient: experience in the National Heart, Lung, and Blood Institute PTCA Registry. Am J Cardiol 1984; 53:89C–91C. Macaya C, Alfonso F, Iniguez A, Zarco P. Long-term clinical and angiographic follow-up of percutaneous transluminal coronary angioplasty in patients greater than or equal to 65 years of age. Am J Cardiol 1990; 66:1513–1515. Ten Berg JM, Bal ET, Gin TJ, Ernst JM, Mast EG, Ascoop CA, Defauw JJ, Plokker HW. Initial and long-term results of percutaneous transluminal coronary angioplasty in patients 75 years of age and older. Cathet Cardiovasc Diagn 1992; 26:165–170. Voudris V, Antonellis J, Salachas A, Ifantis G, Sionis D, Margaris N, Koroxenidis G. Coronary angioplasty in the elderly: immediate and long-term results. Angiology 1993; 44:933–937.

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16 Exercise Training in Older Cardiac Patients Philip A. Ades University of Vermont College of Medicine, Fletcher-Allen Health Care, Burlington, Vermont, U.S.A.

The goals of exercise training in older coronary populations are to decrease cardiac disability, cardiac-related symptoms, and to extend disability-free survival. Compared with younger patients with coronary heart disease (CHD), older patients have higher rates of disability and mobility limitations and a diminished exercise capacity [1–3]. Coronary artery disease in the elderly is also characterized by a greater severity of angiographic disease [4], more severe and more diﬀuse left ventricular systolic dysfunction [5], and increased levels of peripheral vascular and left ventricular stiﬀness, also termed ‘‘diastolic dysfunction,’’ compared with younger cardiac patients [6]. The higher rate of diastolic dysfunction results in the fact that dyspnea is a more common symptom than chest pain in many older patients suﬀering a myocardial infarction [7,8]. Compared with older men, older women with CHD have a higher prevalence of chronic heart failure, a greater prevalence of coronary risk factors, and a more complex clinical course [9]. Despite the fact that primary prevention has resulted in a lower prevalence of CAD in the elderly, the rapidly increasing size of the older population is such that the absolute number of older patients with CHD is increasing [10,11]. Cardiac rehabilitation exercise training designed to decrease disability in older CHD patients should come to play an increasingly important role as the size of the older CHD population continues to grow.

CARDIAC DISABILITY The Social Security Administration has no guidelines or deﬁnitions for cardiac disability for patients over the age of 65 years, because at this age disability pensions are simply converted to ‘‘old-age’’ pensions [12]. In practice, disability in older CHD patients is deﬁned by limitations in physical activity, mobility, and ability to perform activities of daily living, with an underlying psychological component. Data from the Framingham Disability Study provides insight into the eﬀects of various coronary heart disease manifestations on disability and mobility in older populations [1]. The Framingham Disability Study included 2576 participants and yielded a quantitative assessment of levels of physical and social disability, in older adults, based upon self-reported information. The 405

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measures of disability were primarily based upon three questions: ‘‘Are you able to walk up and down stairs to the second ﬂoor without help?’’ ‘‘Are you able to walk a half mile without help?’’ and ‘‘Are you able to do heavy work around the house, like shoveling snow or washing windows, walls, or ﬂoors without help?’’ The presence of any negative responses determined a component of physical disability. In general, at a given age, women were more likely to report disability than men, and the presence of coronary heart disease was a major predictor of activity limitations in both men and women (Table 1). In the 55- to 69-year age group, 49% of men and 67% of women with CHD were disabled as compared with 9% of men and 25% of women without CHD. In coronary patients over the age of 70 years with symptoms of angina pectoris or chronic heart failure, disability was reported by over 80% of women and 55% of men. The presence of CHD in the ‘‘older-old’’ was particularly ominous, with estimated disability rates of up to 76% in men 75 years of age and older. Other studies on this topic are complementary to the Framingham study. In the Medical Outcomes Study, angina was related to the total physical activity score in older patients, although past myocardial infarction was not [13]. Chirikos and Nickel studied 976 men and women hospitalized for acute coronary syndromes (myocardial infarction or unstable angina). By multivariate analysis, they found that the presence of cardiac disease, in particular angina pectoris, was predictive of disability at 6, 18, and 24 months of followup [14]. In a subsequent analysis, they found that angina was more disabling in older women than older men, supporting the ﬁndings of the Framingham study [2]. Data from our laboratory provides further insight into the determinants of physical functional capacity in older coronary patients [15]. A group of 51 men and women over the age of 65 years with established chronic coronary heart disease underwent comprehensive evaluations with exercise echocardiography, measurement of peak aerobic capacity, strength, and body composition along with detailed clinical histories, and self-reported

Table 1 Framingham Disability Study by Age and Coronary Disease Status Age (55 to 69 years) Percent with disability

Age (70 to 88 years) Percent with disability

No CAD or CHF Women Men

25% 9%

49% 27%

Coronary heart disease Women Men

67% 49%

79% 49%

Angina pectoris Women Men

67% 57%

84% 56%

Chronic heart failure Women Men

80% 43%

88% 57%

Abbreviation: CHF = chronic heart failure. Source: Adapted from Ref. 1.

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measures of physical function and mental depression. Univariate predictors of physical function score included peak aerobic capacity, depression score, handgrip strength, gender, and comorbidity score. [16]. By mulitivariate analysis, the only independent predictors of physical function score were peak aerobic capacity and depression score. Left ventricular systolic function, which varies inversely with infarct size, was not related to physical function score [15]. In summary, the presence of clinical CHD is a powerful predictor of disability and mobility limitations in the elderly. Disability rates are highest in women, the older-old, and in the presence of angina pectoris, chronic heart failure, and mental depression.

AEROBIC TRAINING Again, the goals of exercise training in older coronary populations are to decrease cardiac disability and to extend disability-free survival. This is accomplished by a program that will increase aerobic capacity, muscle strength, and ﬂexibility and that will provide associated psychosocial and perceptual beneﬁts. Exercise training programs also need to take into account commonly associated comorbidities that can alter the modalities and intensities of the exercise stimulus that is required. These include, but are not limited to, chronic heart failure, arthritis, chronic lung disease, diabetes, osteoporosis, and peripheral and cerebrovascular disease. In middle-aged coronary patients and in patients with chronic heart failure, reduced cardiovascular ﬁtness (peakVO2) is a primary clinical predictor of impaired physical function and of clinical survival [17,18]. Furthermore, training-induced changes in peak aerobic capacity are associated with a lower mortality for patients with the greatest training eﬀect [19]. Meta-analyses of randomized trials of cardiac rehabilitation, including over 4000 patients, document a 25% decreased mortality over an average follow-up of 3 years after cardiac rehabilitation [20,21]. These studies are limited, however, by the inclusion of few patients over the age of 65 and the fact that over 80% of the subjects were male. Most of these studies antedated current thrombolytic and interventional approaches to acute myocardial infarction as well as the many interventions available for secondary prevention, such as lipid lowering, antiplatelet therapy, beta-adrenergic blockade, and angiotensinconverting-enzyme inhibitors. The Cochrane Database systematic review of cardiac rehabilitation in 2001 extends these ﬁndings to contemporary populations, although these remain primarily middle-aged patients [22]. In older coronary patients, there are no deﬁnitive randomized clinical trial data assessing whether exercise conditioning prolongs life. Therefore, the goals of rehabilitation in the elderly need to focus on improving physical functioning and extending disabilityfree survival. It should be noted, however, that a large observational study, the British Regional Heart Study of almost 6000 men with established CHD, found that regular lightto-moderate physical activity was associated with a lower 5-year all-cause mortality [23]. Secondarily, exercise rehabilitation plays an important role in coordination of coronary risk factor therapy, including management of hypertension, lipid abnormalities, insulin resistance, and obesity [24]. The cardiac rehabilitation literature and clinical experience of rehabilitation centers clearly support the safety and eﬃcacy of exercise training regimens in older coronary patients [3,25–28]. Compared with younger coronary patients, older patients are signiﬁcantly less ﬁt at entry into a rehabilitation program 1 to 3 months after suﬀering a major coronary event, such as myocardial infarction or coronary bypass surgery [3]. However,

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after 3 months of aerobic conditioning, older coronary patients derive a similar relative training beneﬁt as younger patients, with peak VO2 increasing 16 to 20%, eﬀectively distancing themselves from mobility limitations and disability (Fig. 1). Training programs have been extended to a year and longer with long-term maintenance of exercise-related beneﬁts [27,29]. The eﬀects of aerobic exercise training programs on submaximal exercise response in older coronary patients is more relevant to the performance of daily activities than the maximal exercise response. In a study of 45 older coronary patients, mean age 69 F 6 years, subjected to a 3-month aerobic conditioning program, submaximal indices of exercise performance were closely studied [30]. Training eﬀects were assessed during an exhaustive submaximal exercise protocol, with patients exercising at a steady intensity of 80% of a previously measured peak aerobic capacity. Outcome measures included endurance time, serum lactate, perceived exertion, heart rate, blood pressure, and expired ventilatory measures. Exhaustive endurance time increased by more than 40% after conditioning, with associated decreases in serum lactate, perceived exertion, minute ventilation, heart rate, and systolic blood pressure during relatively steady-state exercise. Respiratory exchange ratio during steady-state exercise, an indicator of substrate utilization, decreased, indicating a shift toward greater use of free fatty acids as a more eﬃcient metabolic fuel. Activities that were exhaustive before training became sustainable for extended periods of time at a lower perceived exertion. The mechanisms of physiological adaptations to aerobic exercise conditioning in the elderly may diﬀer somewhat from those seen in younger (i.e., middle-aged) coronary patients. In younger patients, physiological responses to training include both peripheral adaptations (skeletal muscle and vascular), which result in a widened arteriovenous oxygen diﬀerence at maximal exercise [31,32], and cardiac adaptations, which include increases in cardiac dimensions, stroke work, cardiac output, and afterload-corrected indexes of left ventricular function [33–36]. In older coronary patients, coronary and peripheral vascular

Figure 1 Peak aerobic capacity (VO2 max) before and after conditioning in older and younger patient groups. * = p < 0.001 compared with preconditioning. (Reprinted with permission from Ref. 15.)

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disease are superimposed on ‘‘age-related’’ increases in left ventricular and arterial wall thickness and stiﬀness [6,37,38] that may reduce their adaptability to remodeling. We found that, after 3 months of intensive aerobic conditioning in 60 older coronary patients (mean age 68F 5 years, range 62-82 years), conditioning-induced adaptations were localized almost exclusively to the periphery [39]. Peak exercise cardiac output, hyperemic calf blood ﬂow, and vascular conductance were unaﬀected by the conditioning program. In contrast, at 3 and 12 months, arteriovenous oxygen diﬀerence at peak exercise was increased in intervention subjects but not in age-matched controls, explaining the 16% increase in peak aerobic capacity. Histological analysis of skeletal muscle documented a 34% increase in capillary density and a 23% increase in oxidative enzyme capacity after 3 months. After 12 months, an increase in individual ﬁber area was seen compared with baseline measures. Thus, even after 12 months of aerobic exercise, in contrast with middle-aged coronary patients, we saw no discernible improvements in cardiac output or calf blood ﬂow. It is acknowledged, however, that the absolute amount of exercise performed by older coronary patients is less than that performed by younger patients, and this may potentially confound comparisons of physiological response to training by age group. Practical issues related to the implementation of exercise training programs in older coronary patients include the frequent need for training regimens to be adjusted to accommodate the presence of comorbidities such as arthritis, diabetes, and peripheral vascular disease. The least ﬁt individuals are often unable to sustain exercise for extended periods and do well with repeated intermittent brief bouts of exercise (often termed ‘‘interval training’’) that are gradually extended. Some authors recommend longer term exercise programs for the elderly, partly related to their low baseline functional capacity [29]. It should be noted, however, that even patients who use canes and walkers can perform an exercise test, and can train on a treadmill with surround bars or on a cycle ergometer. Despite the documented value of exercise regimens in older patients and the low baseline measures of functional capacity, older coronary patients are far less likely than younger patients to participate in cardiac rehabilitation [40]. Our data documented a 21% participation rate in cardiac rehabilitation for patients over the age of 62 years who recently suﬀered a coronary event and who lived within 1 of the rehabilitation center, compared with a 4% participation rate in younger patients [40]. By far the most powerful predictor of cardiac rehabilitation participation in the clinical setting was the strength of the primary physician’s recommendation for participation as described by the patient. The physician’s recommendation was scored from 1 to 5, ranging from no encouragement to participate (a score of 1) to a strong encouragement to participate (a score of 5). When the recommendation was weak (1–3), a 2% participation rate was noted, compared to a strong recommendation for participation (score of 4–5), where a 66% participation rate was noted. Older women had a lower participation rate than men (15% vs. 25%; p=0.06); his was primarily related to lower physician recommendation scores for women than men [41]. Other factors weighing against participation for women include more comorbid conditions, greater diﬃculty with transportation, lower likelihood of being married, and higher likelihood of having a dependent spouse at home.

RESISTANCE TRAINING Resistance training has been advocated as a particularly useful intervention in older coronary patients for several reason [42–44]. First and foremost, even ‘‘normal’’ aging is

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associated with a signiﬁcant loss of muscle mass and strength, related both to diminished activity proﬁles and to decreased rates of muscle protein synthesis that actually being in middle age [42,45–47]. Furthermore, in healthy community living elders and institutionalized octogenarians, resistance training has been demonstrated to improve walking endurance, muscle mass, and strength [48,49]. In coronary patients, aging-related musculoskeletal abnormalities are superimposed upon activity restrictions related to chronic disease [50], and diminished muscle mass and strength, termed ‘‘sarcopenia,’’ is even more severe. In a study that focused upon resistance training in older CAD patients who had recently suﬀered a myocardial infarction, relative increases in strength were found to be similar to increases seen in younger CAD patients [43]. In older women with chronic CHD, where the negative eﬀects of age, gender, and chronic disease all result is a severe loss of strength and function [15], the eﬀects of strength training have recently been studied [51]. Brochu et al. assessed the eﬀects of 6 months of resistance training on strength, endurance, and on a performance test designed to assess physical function during practical household activities in 30 older women, mean age 71F5 years [52]. Compared with patients randomized to a control group, strength-trained women increased strength, endurance, and capacity to perform a wide range of household activities such as carrying groceries and climbing stairs. The increase in strength after resistance training correlated with improvements in the overall physical function score (Fig. 2). From a practical point of view, the onset of upper body resistance training should be delayed until 3 months after coronary bypass surgery to allow for full sternal healing, whereas it can commence as soon as 1 month post–myocardial infarction after performance of a satisfactory baseline exercise tolerance test. The resistance training program should include training of the leg extensor muscles to assist with walking and stair climbing,

Figure 2 Association between percent changes in total Continuous Scale Physical Functional Performance test score (CS-PFP) and percent changes in maximal strength on the bench press before and after strength training in older women with coronary heart disease. (Reprinted from Ref. 15.)

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and upper body training to aid in the lifting and pushing required for the performance of daily household activities. Training is based upon the performance of a single repetition maximal lift (1-RM) supplemented by a Borg scale for perceived exertion [53]. Patients begin their resistance training with 8 to 10 repetitions of each exercise at 40 to 50% of their 1-RM for a given exercise and gradually increase exercise intensity, as tolerated, to 50 to 80% of updated 1-RMs.

SCREENING AND IMPLEMENTATION Optimally, older coronary patients begin exercise training only after a careful screening process, which should include an electrocardiographically monitored exercise tolerance test, strength measures, and a clinical review including an analysis of disease severity and questionnaire or interview-derived data regarding physical and psychosocial function. Diagnostic categories appropriate for consideration of cardiac rehabilitation exercise training in older cardiac patients include myocardial infarction, stable angina pectoris, coronary bypass surgery, percutaneous coronary revascularization (angioplasty, stenting, rotoblador etc), valve replacement, and chronic heart failure. Exercise modalities should include options for aerobic exercise, resistance exercise, and ﬂexibility. Aerobic choices include treadmills, a walking course, cycles, airdynes, rowers, etc. Aerobic exercise is often guided by an exercise heart rate range and/or scales of perceived exertion such as the Borg scale. A gradual increment of exercise heart rate from 60 to 65% of maximal attained heart rate to higher levels of up to 85% is balanced against the greater risk of injury at higher levels and past demonstration of measurable beneﬁts even with low levels of exercise [54]. It has been observed that older coronary patients are less likely to exercise to a physiological maximum at their baseline exercise test than younger patients; therefore, strict adherence to an exercise heart rate range is often inappropriate [3]. As mentioned above, utilization of a perceived exertion scale is a useful guide to exercise intensity in these patients. Duration of the exercise stimulus can begin with very brief, intermittent bouts of exercise, gradually increasing to 20 to 25 min or longer. Special considerations in the elderly include that training regimens often need to be adjusted to accommodate the presence of comorbidities. For example, patients with hip arthritis may do better with cycling or rowing exercise to avoid the weight bearing of treadmill walking. However, walking is generally a preferred modality due to its direct relevance to daily activities. Finally, it should be noted that, for many elders, ﬂexibility, or lack thereof, can be an exercise-limiting factor. Flexibility exercises can be as simple as 5 to 10 min of stretching per day to more complex protocols of yoga and ti-chi. Gender Issues Healthy older women have lower levels of habitual physical activity and physical functioning than older men, explained in part by lower strength and muscle mass [55–57]. Older women with coronary artery disease further curtail their activities due to apprehension regarding the safety of speciﬁc physical activities, which compounds their deconditioning. Following a coronary event, women have lower ﬁtness levels than men, yet are less likely to be referred to an exercise-based rehabilitation program by their physicians [41]. This may relate in part to the older age of women after infarction, compared with men, or to higher rates of angina pectoris, but is most likely related to physican misunderstanding regarding

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the beneﬁts of rehabilitation in the most severely debilitated patients. Women make similar improvements in aerobic ﬁtness and in muscular strength compared with men in rehabilitation programs [41,43]. The current model of cardiac rehabilitation was developed primarily in middle-aged male coronary patients in the 1960s and 1970s. The diﬀering clinical proﬁle of women in cardiac rehabilitation may require a diﬀerent model relevant to their older age, increased prevalence of comorbid conditions, more prominent cardiac risk factor proﬁles, higher rates of depression, higher risk of recurrent coronary events, and diﬀering personal preferences [58–61]. Supervised Versus Home Exercise Only 15% of eligible patients in the United States receive cardiac rehabilitation services, with the lowest participation rates noted in older patients [24,40]. In many cases, cardiac rehabilitation programs are not geographically available, whereas in other cases, patients are unable to travel or formal rehabilitation is not recommended by the primary physician. While cardiac rehabilitation services have classically been delivered on site at an established exercise training facility, a need to expand preventive cardiology services to include the majority of eligible patients in a cost-eﬀective manner necessitates a redeﬁnition of this classical model. The development of alternate approaches to delivery of cardiac rehabilitation services is an ongoing process, with a goal of expanding the base of patients who receive services, at the lowest possible health-care cost. Older patients tend to require a more ‘‘hand-on’’ approach early in the rehabilitative process, but often can transition to a home program with appropriate follow-up. Case management, that is, evaluation and management of the exercise program and risk factors for the individual patient by a nurse ‘‘case manager,’’ allows for the individualization of preventive care in health-care delivery systems that focus on eﬃciency and outcomes. Exercise programs can be individualized, with moderate and highrisk patients referred to a rehabilitation program for closer supervision and monitoring.

PREVENTIVE CARDIOLOGY Exercise plays an adjunctive role in the management of blood lipid levels, weight control, and blood pressure control. In older coronary populations, exercise rehabilitation has metabolic beneﬁts that includes improved blood lipid values, decreased body fat, improved glucose tolerance, and lower blood pressure, along with decreased measures of depression and

Table 2 Noncardiac Benefits of Exercise in Older Coronary Patients Eﬀect Increased HDL cholesterol (+8–10%) Decreased triglycerides (10–25%) Decreased body fat (1–2%) Improved glucose tolerance Lowered blood pressure (5–7 mmHg systolic) Diminished depression and anxiety

Ref. 28,62 28,62 63 64 28,65,66

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anxiety (Table 2) [28,62–66]. These measures constitute important outcome measures for older CHD patients engaging in therapeutic exercise. Pharmacological therapy for these conditions is often indicated and can be coordinated in the cardiac rehabilitation setting. The beneﬁts in older coronary patients of lipid-lowering, smoking-cessation angiotensinconverting-enzyme inhibition, antiplatelet agents, and beta-adrenergic blockade have all been demonstrated in appropriately selected populations [67,68].

FUTURE DIRECTIONS As the older cardiac population continues to grow in size and complexity, much research remains to be done. The eﬀects of aerobic and resistance-training protocols on measures of physical functioning need to be better studied in older coronary populations, with inclusion of patients disabled by angina or chronic heart failure. Whether training regimens can improve physical functioning in the most severely disabled patients is of particular importance, although preventing disability in the less severely aﬀected ‘‘younger-old’’ is also a priority. Eﬀects of exercise regimens on other important outcomes, including lipid levels, blood pressure measures, insulin levels, body composition, and body fat distribution, need to be further studied to better deﬁne expected beneﬁts of rehabilitation. Finally, whether training regimens can aﬀect the economics of health care is crucial, especially if costly hospitalizations and/or home-care services can be minimized. In summary, the older coronary population is a highly disabled group, yet quite heterogeneous as to physical functioning and disease severity. Exercise rehabilitation training programs have been demonstrated to be safe and to improve aerobic ﬁtness capacity and muscular strength. Exercise training may, in fact, reverse and prevent cardiac disability. Thus cardiac rehabilitation can pay great medical, social, and economic dividends in the older coronary population.

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17 Aortic Valve Disease in the Elderly Wilbert S. Aronow and Melvin B. Weiss Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A.

AORTIC STENOSIS Etiology and Prevalence Valvular aortic stenosis (AS) in elderly patients is usually due to stiﬀening, scarring, and calciﬁcation of the aortic valve leaﬂets. The commissures are not fused as in rheumatic AS. Calciﬁc deposits in the aortic valve are common in elderly patients and may lead to valvular AS [1–7]. Aortic cuspal calcium was present in 295 of 752 men (36%), mean age 80 years, and in 672 of 1663 women (40%), mean age 82 years (6). Of 2358 patients, mean age 81 years, 378 (16%) had valvular AS, 981 (42%) had valvular aortic sclerosis (thickening of or calciﬁc deposits on the aortic valve cusps with a peak ﬂow velocity across the aortic valve V1.5 m/s), and 999 (42%) had no valvular AS or aortic sclerosis [7]. Calciﬁc deposits in the aortic valve were present in 22 of 40 necropsy patients (55%) aged 90 to 103 years [2]. Calcium of the aortic valve and mitral annulus may coexist [1–3,8,9]. In the Helsinki Aging study, calciﬁcation of the aortic valve was diagnosed by Doppler echocardiography in 28% of 76 patients aged 55 to 71 years, in 48% of 197 patients aged 75 to 76 years, in 55% of 155 patients aged 80 to 81 years, and in 75% of 124 patients aged 85 to 86 years [5]. Aortic valve calciﬁcation, aortic sclerosis, and mitral annular calcium (MAC) are degenerative processes [1,2,10–12], accounting for their high prevalence in an elderly population. Otto et al. [11] demonstrated that the early lesion of degenerative AS is an active inﬂammatory process with some similarities to atherosclerosis, including lipid deposition, macrophage and T-cell inﬁltration, and basement membrane disruption. In a prospective study of 571 unselected patients, mean age 82 years, 292 patients (51%) had calciﬁed or thickened aortic cusps or root [13]. A serum total cholesterol z200 mg/dL, a history of hypertension, diabetes mellitus, and a serum high-density lipoprotein cholesterol <35 mg/dL were more prevalent in elderly patients with calciﬁed or thickened aortic cusps or root than in elderly patients with normal aortic cusps and root [13]. In the Helsinki Aging Study, age, hypertension, and a low body mass index were independent predictors of aortic valve calciﬁcation [14]. In 5201 patients older than 65 years of age in the Cardiovascular Health Study, independent clinical factors associated with degenerative aortic valve disease included age, male gender, smoking, history of 417

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hypertension, height, and high lipoprotein (a) and low-density lipoprotein cholesterol levels [12]. In 1275 elderly patients, mean age 81 years, AS was present in 52 of 202 patients (26%) with 40 to 100% extracranial carotid arterial disease (ECAD) and in 162 of 1073 patients (15%) with 0 to 39% ECAD [15]. In 2987 elderly patients, mean age 81 years, symptomatic peripheral arterial disease was present in 193 of 462 patients (42%) with AS and in 639 of 2525 patients (25%) without AS [16]. In 290 patients, mean age 79 years, with valvular AS who had follow-up Doppler echocardiograms, elderly patients with MAC had a greater reduction in aortic valve area/ year than elderly patients without MAC [17]. Signiﬁcant independent risk factors for progression of valvular AS in 102 patients, mean age 76 years, who had follow-up Doppler echocardiograms were cigarette smoking and hypercholesterolemia [18]. Palta et al. [19] also found that cigarette smoking and hypercholesterolemia accelerate the progression of AS. These and other data suggest that aortic valve calcium, MAC, and coronary atherosclerosis in elderly patients have similar predisposing factors [11–21]. A retrospective analysis of 180 elderly patients with mild AS who had follow-up Doppler echocardiograms at z2 years showed that signiﬁcant independent predictors of the progression of AS were male gender, cigarette smoking, hypertension, diabetes mellitus, a serum low-density lipoprotein cholesterol z125 mg/dL at follow-up, a serum high-density lipoprotein cholesterol <35 mg/dL at follow-up, and use of statins (inverse association) [22]. Novaro et al. [23], in a retrospective analysis of 174 patients, mean age 68 years with mild-to-moderate AS, also reported that statin therapy reduced the progression of AS. The frequency of AS increases with age. Valvular AS diagnosed by Doppler echocardiography was present in 141 of 924 men (15%), mean age 80 years, and in 322 of 1881 women (17%), mean age 81 years [24]. Severe valvular AS (peak gradient across aortic valve of z50 mmHg or aortic valve area <0.75 cm2) was diagnosed in 62 of 2805 elderly patients (2%) [24]. Moderate valvular AS (peak gradient across aortic valve of 26 to 49 mmHg or aortic valve area of 0.75 to 1.49 cm2) was present in 149 of 2805 elderly patients (5%) [24]. Mild valvular AS (peak gradient across aortic valve of 10 to 25 mmHg or aortic valve area z1.50 cm2) occurred in 252 of 2805 elderly patients (9%) [24]. In 924 elderly men, mean age 80 years, AS was present in 36 of 236 African Americans (15%), in 19 of 135 Hispanics (14%), and in 86 of 553 whites (16%) [24]. In 1881 elderly women, mean age 81 years, AS was present in 84 of 494 African Americans (17%), in 33 of 188 Hispanics (18%), and in 205 of 1199 white women (17%) [24]. In 501 unselected patients aged 75 to 86 years in the Helsinki Aging Study, critical AS was present in 3% and moderate-to-severe AS in 5% of the 501 elderly patients [5]. Pathophysiology In valvular AS, there is resistance to ejection of blood from the left ventricle (LV) into the aorta, with a pressure gradient across the aortic valve during systole and an increase in LV systolic pressure. The pressure overload on the LV leads to concentric LV hypertrophy, with an increase in LV wall thickness and mass, normalizing systolic wall stress, and maintenance of normal LV ejection fraction and cardiac output [25,26]. A compensated hyperdynamic response is common in elderly women [27]. Elderly patients with a comparable degree of AS have more impairment of LV diastolic function than do younger patients [28]. Coronary vasodilator reserve is more severely impaired in the subendocardium in patients with LV hypertrophy caused by severe AS [29].

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The compensatory concentric LV hypertrophy leads to abnormal LV compliance, LV diastolic dysfunction with reduced LV diastolic ﬁlling, and increased LV end-diastolic pressure, further increased by left atrial systole. Left atrial enlargement develops. Atrial systole plays an important role in diastolic ﬁlling of the LV in patients with AS [30]. Loss of eﬀective atrial contraction may cause immediate clinical deterioration in patients with severe AS. Sustained LV hypertrophy eventually leads to LV chamber dilatation with decreased LV ejection fraction and, ultimately, congestive heart failure (CHF). The stroke volume and cardiac output decrease, the mean left atrial and pulmonary capillary pressures increase, and pulmonary hypertension occurs. Elderly patients with both obstructive and nonobstructive coronary artery disease (CAD) have an increased incidence of LV enlargement and LV systolic dysfunction [31]. In a percentage of elderly patients with AS, the LV ejection fraction will remain normal and LV diastolic dysfunction will be the main problem. In 48 elderly patients with CHF associated with unoperated severe valvular AS, the LV ejection fraction was normal in 30 patients (63%) [32]. The prognosis of patients with AS and LV diastolic dysfunction is usually better than that of patients with AS and LV systolic dysfunction, but is worse than that of patients without LV diastolic dysfunction [32,33]. Symptoms Angina pectoris, syncope or near-syncope, and CHF are the three classic manifestations of severe AS. Angina pectoris is the most common symptom associated with AS in elderly patients. Coexistent CAD is frequently present in these patients. However, angina pectoris may occur in the absence of CAD as a result of an increase in myocardial oxygen demand with a reduction in myocardial oxygen supply at the subendocardial level. Myocardial ischemia in patients with severe AS and normal coronary arteries is due to inadequate LV hypertrophy with increased LV systolic and diastolic wall stresses causing decreased coronary ﬂow reserve [34]. Syncope in patients with AS may be caused by reduced cerebral perfusion following exertion when arterial pressure drops because of systemic vasodilatation in the presence of a ﬁxed cardiac output. LV failure with a decrease in cardiac output may also cause syncope. In addition, syncope at rest may be caused by a marked reduction in cardiac output secondary to transient ventricular ﬁbrillation or transient atrial ﬁbrillation or transient atrioventricular block related to extension of the valve calciﬁcation into the conduction system. Coexistent cerebrovascular disease with transient cerebral ischemia may contribute to syncope in elderly patients with AS. Exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema may be caused by pulmonary venous hypertension associated with AS. Coexistent CAD and hypertension may contribute to CHF in elderly patients with AS. Atrial ﬁbrillation may also precipitate CHF in these patients. CHF, syncope, or angina pectoris was present in 36 of 40 elderly patients (90%) with severe AS, in 66 of 96 elderly patients (69%) with moderate valvular AS, and in 45 of 165 elderly patients (27%) with mild valvular AS [35]. Sudden death occurs mainly in symptomatic valvular AS patients [32,35–38]. It may also occur in 3% to 5% of asymptomatic patients with AS [36,38]. Marked fatigue and peripheral cyanosis in patients with AS may be caused by a low cardiac output. Cerebral

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emboli causing stroke or transient cerebral ischemic attack, bacterial endocarditis, and gastrointestinal bleeding may also occur in elderly patients with AS.

Signs A systolic ejection murmur heard in the second right intercostal space, down the left sternal border toward the apex, or at the apex is classiﬁed as an aortic systolic ejection murmur (ASEM) [3,4,39,40]. An ASEM is commonly heard in elderly patients [1,3,39], occurring in 265 of 565 unselected elderly patients (47%) [3]. Of 220 elderly patients with an ASEM and technically adequate M-mode and two-dimensional echocardiograms of the aortic valve, 207 (94%) had aortic cuspal or root calciﬁcation or thickening [3]. Of 75 elderly patients with an ASEM, valvular AS was diagnosed by continuous-wave Doppler echocardiography in 42 patients (56%) [40]. Table 1 shows that an ASEM was heard in 100% of 19 elderly patients with severe AS, in 100% of 49 elderly patients with moderate AS, and in 95% of 74 elderly patients with mild AS [4]. However, the ASEM may become softer or absent in patients with CHF associated with severe AS because of a low cardiac output. The intensity and maximal location of the ASEM and transmission of the ASEM to the right carotid artery do not diﬀerentiate among mild, moderate, and severe AS [3,4,40]. The ASEM may be heard only at the apex in some elderly patients with AS. The apical systolic ejection murmur may also be louder and more musical than the basal systolic ejection murmur in some elderly patients with AS. The intensity of the ASEM in valvular AS increases with squatting and by inhalation of amyl nitrite and decreases during the Valsalva maneuver. Prolonged duration of the ASEM and late peaking of the ASEM best diﬀerentiate severe from mild AS [3,4,40]. However, the physical signs do not distinguish between severe and moderate AS (Table 1) [4,40]. A prolonged carotid upstroke time does not diﬀerentiate between severe and moderate AS in elderly patients [4]. A prolonged carotid upstroke time was palpable in 3% of elderly patients with mild AS, in 33% of elderly patients with moderate AS, and in 53% of elderly patients with severe AS (Table 1) [4]. Stiﬀ noncompliant arteries may mask a prolonged carotid upstroke time in elderly patients with severe AS. The pulse pressure

Table 1 Correlation of Physical Signs of Valvular Aortic Stenosis with the Severity of Aortic Stenosis in Elderly Patients Severity of aortic stenosis Physical sign ASEM Prolonged duration ASEM Late-peaking ASEM Prolonged carotid upstroke time A2 absent A2 decreased or absent

Mild (n = 74)

Moderate (n = 49)

Severe (n = 19)

95% 3% 3% 3% 0% 5%

100% 63% 63% 33% 10% 49%

100% 84% 84% 53% 16% 74%

Abbreviations: ASEM = aortic systolic ejection murmur; A2 = aortic component of second heart sound. Source: Adapted from Ref. 4.

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may also be normal or wide rather than narrow in elderly patients with severe AS because of loss of vascular elasticity. An aortic ejection click is rare in elderly patients with severe AS because of loss of vascular elasticity. An aortic ejection click is rare in elderly patients with AS because the valve cusps are immobile [4,40]. An absent or decreased A2 occurs more frequently in elderly patients with severe or moderate AS than in patients with mild AS (Table 1) [4,40]. However, an absent or decreased A2 does not diﬀerentiate between severe and moderate AS [4,40]. The presence of atrial ﬁbrillation, reversed splitting of S2, or an audible fourth heart sound at the apex also does not diﬀerentiate between severe and moderate AS in elderly patients [40]. The presence of a third heart sound in elderly patients with AS usually indicates the presence of LV systolic dysfunction and elevated LV ﬁlling pressure [41].

Electrocardiography and Chest Roentgenography Table 2 shows that echocardiography is more sensitive than electrocardiography in detecting LV hypertrophy in elderly person with AS [4]. Rounding of the LV border and apex may occur as a result of concentric LV hypertrophy. Poststenotic dilatation of the ascending aorta is commonly seen. Calciﬁcation of the aortic valve is best seen by echocardiography or ﬂuoroscopy. Involvement of the conduction system by calciﬁc deposits may occur in elderly patients with AS. In a study of 51 elderly patients with AS who underwent aortic valve replacement, conduction defects occurred in 58% of 31 patients with MAC and in 25% of 20 patients without MAC [9]. In another study of 77 elderly patients with AS, ﬁrst-degree atrioventricular block occurred in 18% of patients, left bundle branch block in 10% of patients, intraventricular conduction defect in 6% of patients, right bundle branch block in 4% of patients, and left axis deviation in 17% of patients [42]. Complex ventricular arrhythmias may be detected by 24-h ambulatory electrocardiograms in patients with AS. Elderly patients with complex ventricular arrhythmias associated with AS have a higher incidence of new coronary events than elderly patients with AS and no complex ventricular arrhythmias [43].

Echocardiography and Doppler Echocardiography M-mode and two-dimensional echocardiography and Doppler echocardiography are very useful in the diagnosis of AS. Of 83 patients with CHF or angina pectoris and a systolic

Table 2 Prevalence of Electrocardiographic and Echocardiographic Left Ventricular Hypertrophy in Elderly Patients with Mild, Moderate, and Severe Valvular Aortic Stenosis Severity of valvular aortic stenosis

Electrocardiographic LVH Echocardiographic LVH Source: Adapted from Ref. 4.

Mild (n = 74)

Moderate (n = 49)

Severe (n = 19)

11% 74%

31% 96%

58% 100%

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precordial murmur in whom severe AS was diagnosed by Doppler echocardiography, AS was not clinically diagnosed in 28 patients (34%) [44]. Echocardiography can detect thickening, calciﬁcation, and reduced excursion of aortic valve leaﬂets (3). LV hypertrophy is best diagnosed by echocardiography [4]. Chamber dimensions and measurements of LV end-systolic and end-diastolic volumes, LV ejection fraction, and assessment of global and regional LV wall motion give important information on LV systolic function. Doppler echocardiography is used to measure peak and mean transvalvular gradients across the aortic valve and to identify associated valve lesions. Aortic valve area can be calculated by the continuity equation using pulsed Doppler echocardiography to measure LV outﬂow tract velocity, continuous-wave Doppler echocardiography to measure transvalvular ﬂow velocity, and two-dimensional long-axis view to measure LV outﬂow tract area [45,46]. Aortic valve area can be detected reliably by the continuity equation in elderly patients with AS [46]. Figures 1 through 5 illustrate two-dimensional echocardiographic ﬁndings (Figs. 1 and 3), continuous-wave Doppler echocardiographic ﬁndings (Figs. 2 and 4), and simultaneous LV and femoral arterial pressure tracings (Fig. 5) in elderly patients with severe valvular AS. Shah and Graham [47] reported that the agreement in quantitation of the severity of AS between Doppler echocardiography and cardiac catheterization was greater than 95%. Patients with a peak jet velocity z4.5 m/s had critical AS, and those with a peak jet

Figure 1 Two-dimensional echocardiographic image from a parasternal long-axis view of a 93year-old female with aortic stenosis and moderately depressed left ventricular function showing a ﬁbrotic aortic valve and mitral annular calciﬁcation. PS-LAX = parasternal long-axis view; RV = right ventricular cavity; LV = left ventricular cavity; IVS = interventricular septum; PW = posterior wall; CA ANUL = mitral annulus calciﬁcation; LA = left atrium; AO = aorta.

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Figure 2 Continuous-wave Doppler recording of the velocity proﬁle across the aortic valve in the same patient shown in Figure 1. A 52-mmHg gradient across the aortic valve is measured using the Bernoulli equation. Indexed aortic valve area measured by the continuity equation using Doppler data = 0.5 cm2/m2.

velocity<3.0 m/s had noncritical AS. Slater et al. [48] demonstrated a concordance between Doppler echocardiography and cardiac catheterization in the decision to operate or not to operate in 61 of 73 patients (84%) with valvular AS. In 75 patients, mean age 76 years, with valvular AS, the Bland-Altman plot showed that four of the 75 patients (5%) had disagreement between cardiac catheterization and Doppler echocardiography that was outside the 95% conﬁdence limits [49]. Cardiac catheterization was performed in 105 patients in which Doppler echocardiography demonstrated an aortic valve area V0.75 cm2 or a peak jet velocity z4.5 m/s, consistent with critical AS [50]. Doppler echocardiography was 97% accurate in this subgroup. Cardiac catheterization was performed in this study in 133 patients with noncritical AS. Doppler echocardiography was 95% accurate in this subgroup. Although most elderly patients do not require cardiac catheterization before aortic valve surgery, they require selective coronary arteriography before aortic valve surgery. Patients in whom Doppler echocardiography shows a peak jet velocity between 3.6 and 4.4 m/s and an aortic valve area > 0.8 cm2 should undergo cardiac catheterization if they have cardiac symptoms attributable to AS [47]. Patients with a peak jet velocity between 3.0 and 3.5 m/s and a LV ejection fraction <50% may have severe AS, requiring aortic valve replacement, and should undergo cardiac catheterization [47]. Patients with a peak jet velocity between 3.0 and 3.5 m/s and a LV ejection fraction >50% probably do not need aortic valve replacement but should undergo cardiac catheterization if they have symptoms of severe AS [47].

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Figure 3 Two-dimensional echocardiographic image obtained in the same patient in Figures 1 and 2 from a short-axis parasternal view in which the aortic valve oriﬁce is mapped, yielding, an indexed area of 0.4 cm2/m2.

Natural History Ross and Braunwald [36] found that the average survival rate was 3 years after the onset of angina pectoris in patients with severe AS. Ross and Braunwald [36] reported that the average survival rate after the onset of syncope in patients with severe AS was 3 years. Ross and Braunwald [36] demonstrated that the average survival rate after the onset of CHF in patients with severe AS was 1.5 to 2 years. Patients with symptomatic severe valvular AS have a poor prognosis [35–38,51]. At the National Institutes of Health, 52% of patients with symptomatic severe valvular AS not operated on were dead at 5 years [37,38]. At 10-year follow-up, 90% of these patients were dead. At 4-year follow-up of patients aged 75 to 86 in the Helsinki Aging Study, the incidence of cardiovascular mortality was 62% in patients with severe AS and 35% in patients with moderate AS [52]. At 4-year follow-up, the incidence of total mortality was 76% in patients with severe AS and 50% in patients with moderate AS [52]. In a prospective study, at 19-month follow-up (range 2 to 36 months), 90% of 30 patients with CHF associated with unoperated severe AS and a normal LV ejection fraction were dead [32]. At 13-month follow-up (range 2 to 24 months), 100% of 18 patients with CHF associated with unoperated severe AS and an abnormal LV ejection fraction were dead [32]. Table 3 shows the incidence of new coronary events in elderly patients with no, mild, moderate, and severe AS. Independent risk factors for new coronary events in this study were prior myocardial infarction, AS, male gender, and increasing age [35]. In this

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Figure 4 Continuous-wave Doppler recording of the velocity proﬁle across the aortic valve in an elderly patient with aortic stenosis and normal left ventricular systolic function. The indexed aortic valve area is 0.5 cm2/m2 by both Gorlin’s formula and the Doppler continuity equation. The peak gradient across the aortic valve by Bernoulli’s equation is 81 mmHg, a value higher than that recorded in Figure 2 for the same indexed aortic valve area.

prospective study, at 20-month follow-up of 40 elderly patients with severe AS, CHF, syncope, or angina pectoris was present in 36 of 37 patients (97%) who developed new coronary events and in none of 3 patients (0%) without new coronary events [35]. At 32month follow-up of 96 elderly patients with moderate valvular AS, CHF, syncope, or angina pectoris was present in 65 of 77 patients (84%) who developed new coronary events and in 1 of 19 patients (5%) without new coronary events [35]. At 52-month follow-up of 165 elderly patients with mild AS, CHF, syncope, or angina pectoris was present in 40 of 103 patients (39%) who developed new coronary events and in 5 of 62 patients (8%) without new coronary events [35]. In a prospective study of 981 patients, mean age 82 years, with aortic sclerosis and of 999 patients, mean age 80 years, without valvular aortic sclerosis, elderly patients with aortic sclerosis had at 46-month follow-up a 1.8 times higher chance of developing a new coronary event than those without valvular aortic sclerosis [7]. Otto et al. [53] also reported in 5621 men and women z65 years of age that AS and aortic sclerosis increased cardiovascular morbidity and mortality. Kennedy et al. [54] followed 66 patients with moderate AS diagnosed by cardiac catheterization (aortic valve area 0.7 to 1.2 cm2). In 38 patients with symptomatic moderate AS and 28 patients with minimally symptomatic moderate AS, the probabilities of avoiding death from AS were 0.86 for patients with Symptomatic As and 1.0 for patients with minimally symptomatic moderate AS at 1-year follow-up, 0.77 for patients

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l

Figure 5 Simultaneous left ventricular and femoral artery pressure recordings obtained in the same patient in Figure 4 conﬁrming a large gradient across the aortic valve with a maximum value of 81 mm Hg (instantaneous pressure). Fem. Art. = femoral artery pressure tracing; LV = left ventricular pressure tracing.

with symptomatic AS and 1.0 for patients with minimally symptomatic AS at 2 years, 0.77 for patients with symptomatic AS and 0.96 for patients with minimally symptomatic AS at 3 years, and 0.70 for patients with symptomatic AS and 0.90 for patients with minimally symptomatic AS at 4 years [54]. During 35-month mean follow-up in this study, 21 patients underwent aortic valve replacement. Hammermeister et al. [55] followed 106 patients with unoperated AS in the Veterans Administration Cooperative Study on Valvular Heart Disease for 5 years. During followup, 60 of 106 patients (57%) died. Multivariate analysis demonstrated that measures of the severity of the AS, the presence of CAD, and the presence of CHF were the important predictors of survival in unoperated patients. Studies have demonstrated that patients with asymptomatic severe AS are at low risk for death and can be followed until symptoms develop [56–59]. Turina et al. [56] followed

Table 3 Incidence of New Coronary Events in Older Persons with No, Mild, Moderate, and Severe Valvular Aortic Stenosis

Age (years) Follow-up (months) New coronary events Source: Adapted from Ref. 35

No AS (n = 1,496)

Mild AS (n = 165)

Moderate AS (n = 96)

Severe AS (n = 40)

81 49 41%

84 52 62%

85 32 80%

85 20 93%

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17 patients with asymptomatic or mildly symptomatic AS. During the ﬁrst 2 years, none died or had aortic valve surgery. At 5-year follow-up, 94% were alive and 75% were free of cardiac events. Kelly et al. [57] followed 51 asymptomatic patients with severe AS. During 17-month follow-up, 21 (41%) of the patients became symptomatic. Only 2 of the 51 patients (4%) died of cardiac causes. In both patients, death was preceded by the development of angina pectoris or CHF. Pellikka et al. [58] observed that 113 of 143 patients (79%), mean age 72 years, with asymptomatic severe AS were not initially referred for aortic valve replacement or percutaneous aortic balloon valvuloplasty. During 20-month follow-up, 37 of 113 patients (33%) became symptomatic. The actuarial probability of remaining free of cardiac events associated with AS, including cardiac death and aortic valve surgery, was 95% at 6 months, 93% at 1 year, and 74% at 2 years. No asymptomatic person with severe AS developed sudden death while asymptomatic. Rosenheck et al. [59] followed 126 patients with asymptomatic severe AS for 22 months. Eight patients died and 59 patients developed symptoms necessitating aortic valve replacement. Event-free survival was 67% at 1 year, 56% at 2 years, and 33% at 4 years. Five of the 6 deaths from cardiac disease were preceded by symptoms. Of the patients with moderately or severely calciﬁed aortic valves whose aortic jet velocity increased by 0.3 m/s or more within 1 year, 79% underwent aortic valve replacement or died within 2 years of the observed increase. When patients with low-gradient AS due to abnormal LV ejection fraction are considered for aortic valve replacement, failure to respond to dobutamine and large preoperative LV end-systolic and end-diastolic volumes are poor prognostic signs [60,61].

Medical Management Prophylactic antibiotics should be used to prevent bacterial endocarditis in patients with AS regardless of severity, according to American Heart Association guidelines [62]. Patients with CHF, exertional syncope, or angina pectoris associated with moderate or severe AS should undergo aortic valve replacement promptly. Valvular surgery is the only deﬁnitive therapy in these elderly patients [63]. Medical therapy does not relieve the mechanical obstruction to left ventricular outﬂow and does not relieve symptoms or progression of the disorder. Patients with asymptomatic AS should report the development of symptoms possibly related to AS to the physician immediately. If signiﬁcant AS is present in asymptomatic elderly patients, clinical examination and an electrocardiogram and Doppler echocardiogram should be performed at 6-month intervals. Nitrates should be used with caution in patients with angina pectoris and AS to prevent the occurrence of orthostatic hypotension and syncope. Diuretics should be used with caution in patients with CHF to prevent a decrease in cardiac output and hypotension. Vasodilators should be avoided. Digitalis should not be used in patients with CHF and a normal LV ejection fraction unless needed to control a rapid ventricular rate associated with atrial ﬁbrillation.

Aortic Valve Replacement Aortic valve replacement is the procedure of choice for symptomatic elderly patients with severe AS. Other Class I indications for aortic valve replacement in elderly patients with severe AS include patients undergoing coronary artery bypass graft (CABG) surgery or surgery on the aorta or other heart valves [64].

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The bioprosthesis has less structural failure in elderly patients than in younger patients and may be preferable to the mechanical prosthetic valve for AS replacement in the elderly due to the anticoagulation issue [65, 66]. Patients with mechanical prostheses need anticoagulant therapy indeﬁnitely. Patients with porcine bioprostheses require anticoagulant therapy for 3 months after hospital discharge and then may be treated with antiplatelet therapy alone unless the patient has atrial ﬁbrillation, abnormal LV ejection fraction, previous thromboembolism, or a hypercoagulable condition [64,67]. Arom et al. [68] performed aortic valve replacement in 273 patients aged 70 to 89 (mean age 75 years), 162 with aortic valve replacement alone, and 111 with aortic valve replacement plus CABG surgery. Operative mortality was 5%. Late mortality at 33-month follow-up was 18%. Actuarial analysis showed at 5-year follow-up that overall survival was 66% for patients with aortic valve replacement alone, 76% for patients with aortic valve replacement plus CABG, and 74% for a similar age group in the general population. A United Kingdom heart valve registry observed in 1100 patients aged z80 years (56% women) who underwent aortic valve replacement that the 30-day mortality was 6.6% [69]. The actuarial survival was 89% at 1 year, 79% at 3 years, 69% at 5 years, and 46% at 8 years. The survival of patients with severe AS, LV ejection fraction<35%, and a low transvalvular gradient at 1 year and at 4 years was 82% and 78%, respectively, in 39 patients, mean age 73 years, who underwent aortic valve replacement versus 41% and 15%, respectively, in 56 patients, mean age 75 years, in a control group [70]. Aortic valve replacement is associated with a reduction in LV mass and in improvement of LV diastolic ﬁlling [71–73]. Hoﬀman and Burckhardt [74] performed a prospective study in 100 patients who had aortic valve replacement. At 41-month follow-up, the yearly cardiac mortality rate was 8% in patients with electrocardiographic LV hypertrophy and repetitive ventricular premature complexes z2 couplets per 24 h during 24-h ambulatory monitoring and 0.6% in patients without either of these ﬁndings. If LV systolic dysfunction in patients with severe AS is associated with critical narrowing of the aortic valve rather than myocardial ﬁbrosis, it often improves after successful aortic valve replacement [75]. In 154 patients, mean age 73 years, with AS and LV ejection fraction V35% who underwent aortic valve replacement, the 30-day mortality was 9%. The 5-year survival was 69% in patients without signiﬁcant CAD and 39% in patients with signiﬁcant CAD. NYHA functional class III or IV was present in 58% of patients before surgery versus 7% of patients after surgery. Postoperative LV ejection fraction was measured in 76% of survivors at a mean of 14 months after surgery. Improvement in LV ejection fraction was found in 76% of patients [75].

Balloon Aortic Valvuloplasty Aortic valve replacement is the procedure of choice for symptomatic elderly patients with severe AS. In a Mayo Clinic study, the actuarial survival of 50 elderly patients, mean age 77 years, with symptomatic severe AS in whom aortic valve replacement was refused (45 patients) or deferred (5 patients) was 57% at 1 year, 37% at 2 years, and 25% at 3 years [76]. Because of the poor survival in this group of patients, balloon aortic valvuloplasty should be considered when operative intervention is refused or deferred. On the basis of the available data, balloon aortic valvuloplasty should be considered for elderly patients with symptomatic severe AS who are not candidates for aortic valve surgery and possibly for patients with severe LV dysfunction as a bridge to subsequent valve surgery [77–79].

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AORTIC REGURGITATION Etiology and Prevalence Acute aortic regurgitation (AR) in elderly patients may be due to infective endocarditis, rheumatic fever, aortic dissection, trauma following prosthetic valve surgery, or rupture of the sinus of Valsalva, and causes sudden severe LV failure. Chronic AR in elderly patients may be caused by valve leaﬂet disease (secondary to any cause of AS, infective endocarditis, rheumatic fever, congenital heart disease, rheumatoid arthritis, ankylosing spondylitis, following prosthetic valve surgery, or myxomatous degeneration of the valve) or by aortic root disease. Examples of aortic root disease causing chronic AR in elderly patients include association with systemic hypertension, syphilitic aortitis, cystic medial necrosis of the aorta, ankylosing spondylitis, rheumatoid arthritis, Reiter’s disease, systemic lupus erythematosus, Ehler-Danlos syndrome, and pseudoxanthoma elasticum. Mild or moderate AR was also diagnosed by Doppler echocardiography in 9 of 29 patients (31%) with hypertrophic cardiomyopathy [80]. Margonato et al. [81] linked the increased prevalence of AR with age to aortic valve thickening. The prevalence of AR increases with age [81–83]. In a prospective study of 450 unselected patients, mean age 82 years, AR was diagnosed by pulsed Doppler echocardiography in 39 of 114 men (34%) and in 92 of 336 women (27%) [83]. Severe or moderate AR was diagnosed in 74 of 450 elderly patients (16%). Mild AR was diagnosed in 57 of 450 elderly patients (13%). In a prospective study of 924 men, mean age 80 years, and 1881 women, mean age 82 years, valvular AR was diagnosed by pulsed Doppler recordings of the aortic valve in 282 of 924 men (31%) and in 542 of 1881 women (29%) [24].

Pathophysiology The primary determinants of AR volume are the regurgitant oriﬁce area, the transvalvular pressure gradient, and the duration of diastole [84]. Chronic AR increases LV ventricular end-diastolic volume. The largest LV end-diastolic volumes are seen in patients with chronic severe AR. LV stroke volume increases to maintain the forward stroke volume. The increased preload causes an increase in LV diastolic stress and the addition of sarcomeres in series. This results in an increase in the ratio of the LV chamber size to wall thickness. This pattern of LV hypertrophy is called eccentric LV hypertrophy. Primary myocardial abnormalities or ischemia due to coexistent CAD depress the contractile state. LV diastolic compliance decreases, LV end-systolic volume increases, LV end-diastolic pressure rises, left atrial pressure increases, and pulmonary venous hypertension results. When the LV end-diastolic radius-to-wall thickness ratio rises, LV systolic wall stress increases abnormally because of the preload and afterload mismatch [26,85]. Additional stress then decreases the LV ejection fraction response to exercise [86]. Eventually, the LV ejection fraction, forward stroke volume, and eﬀective cardiac output are decreased at rest. We demonstrated that an abnormal resting LV ejection fraction occurred in 8 of 25 elderly patients (32%) with CHF associated with chronic severe AR [87]. In patients with acute severe AR, the LV cannot adapt to the increased volume overload. Forward stroke volume falls, LV end-diastolic pressure increases rapidly to high levels [88], and pulmonary hypertension and pulmonary edema result. The rapid rise of the LV end-diastolic pressure to exceed the left atrial pressure in early diastole causes

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premature closure of the mitral valve [89]. This prevents backward transmission of the elevated LV end-diastolic pressure to the pulmonary venous bed. Symptoms Patients with acute AR develop symptoms due to the sudden onset of CHF, with marked dyspnea and weakness. Patients with chronic AR may remain asymptomatic for many years. Mild dyspnea on exertion and palpitations, especially on lying down, may occur. Exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and edema are common clinical symptoms when LV failure occurs. Syncope is rare. Angina pectoris occurs less often in patients with AR than in patients with AS and may be due to coexistent CAD. However, nocturnal angina pectoris, often accompanied by ﬂushing, diaphoresis, and palpitations, may develop when the heart rate slows and the arterial diastolic pressure falls to very low levels. Most patients with severe AR who do not have surgery die within 2 years after CHD develops [90]. Signs The AR murmur is typically a high-pitched blowing diastolic murmur that begins immediately after A2. The diastolic murmur is best heard along the left sternal border in the third and fourth intercostal spaces when AR is due to valvular disease. The murmur is best heard along the right sternal border when AR is due to dilatation of the ascending aorta. The diastolic murmur is best heard with the diaphragm of the stethoscope with the person sitting up, leaning forward, and holding the breath in deep expiration. The severity of AR correlates with the duration of the diastolic murmur, not with the intensity of the murmur. Grayburn et al. [91] heard an AR murmur in 73% of 82 patients with AR and in 8% of 24 patients without AR. Saal et al. [92] heard an AR murmur in 80% of 35 patients with AR and in 10% of 10 patients without AR. Meyers et al. [93] heard an AR murmur in 73% of 66 patients with AR and in 22% of 9 patients without AR. Table 4 shows that an AR murmur was heard in 95% of 74 elderly patients with severe or moderate AR diagnosed by pulsed Doppler echocardiography, in 61% of 57 elderly patients with mild AR, and in 3% of 319 elderly patients with no AR [83]. In patients with chronic severe AR, the LV apical impulse is diﬀuse, hyperdynamic, and displaced laterally and inferiorly. A rumbling diastolic murmur (Austin Flint) may be heard at the apex, with its intensity decreased by inhalation of amyl nitrite. A short basal

Table 4 Correlation of Aortic Regurgitation Murmur with Severity of Aortic Regurgitation in Elderly Patients with Chronic Aortic Regurgitation AR murmur Severe or moderate AR (n = 74) Mild AR (n = 57) No AR (n = 319) Source: Adapted from Ref. 83.

95% 61% 3%

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systolic ejection murmur is heard. A palpable LV rapid ﬁlling wave and an audible S3 at the apex are usually found. Physical ﬁndings due to a large LV stroke volume and a rapid diastolic runoﬀ in patients with severe AR include a wide pulse pressure with an increased systolic arterial pressure and an abnormally low diastolic arterial pressure, an arterial pulse that abruptly rises and collapses, a bisferiens pulse, bobbing of the head with each heart beat, booming systolic and diastolic sounds heard over the femoral artery, capillary pulsations, and systolic and diastolic murmurs heard over the femoral artery when compressing it proximally and distally.

Electrocardiography and Chest Roentgenography The electrocardiogram may initially be normal in patients with acute severe AR. Roberts and Day [94] showed in 30 necropsy patients with chronic severe AR that the electrocardiogram did not accurately predict the severity of AR or cardiac weight. Using various electrocardiographic criteria, the prevalence of LV hypertrophy varied from 30% (RV6>RV5) to 90% (total 12-lead QRS voltage >175 mm). The P-R interval was prolonged in 28% of patients, and the QRS duration was z0.12 s in 20% of patients [94]. The chest x-ray in patients with acute severe AR may show a normal heart size and pulmonary edema. The chest x-ray in patients with chronic severe AR usually shows a dilated LV, with elongation of the apex inferiorly and posteriorly and a dilated aorta. Aneurysmal dilatation of the aorta suggests that aortic root disease is causing the AR. Linear calciﬁcations in the wall of the ascending aorta are seen in syphilitic AR and in degenerative disease.

Echocardiography and Doppler Echocardiography M-mode and two-dimensional echocardiography and Doppler echocardiography are very useful in the diagnosis of AR. Two-dimensional echocardiography can provide information showing the etiology of the AR and measurements of LV function. Eccentric LV hypertrophy is diagnosed by echocardiography if the LV mass index is increased with a relative wall thickness <0.45 [95–97]. Echocardiographic measurements reported to predict an unfavorable response to aortic valve replacement in patients with chronic AR include LV end-systolic dimension >55 mm [98]. LV shortening fraction <25% [98], LV diastolic radius-to-wall thickness ratio >3.8 [99], LV end-diastolic dimension index >38 mm/m2 [2,99], and LV ventricular end-systolic dimension index >26 mm/m2 [2,99]. Grayburn et al. [91] showed that pulsed Doppler echocardiography correctly identiﬁed the presence of AR in 57 of 57 patients (100%) with z2+ AR and in 22 of 25 patients (88%) with 1+ AR. Saal et al. [92] demonstrated that pulsed Doppler echocardiography identiﬁed the presence of AR in 34 of 35 patients (97%) with documented AR. Continuous-wave Doppler echocardiography has also been shown to be very useful in diagnosing and quantitating AR [100,101]. AR is best assessed by color ﬂow Doppler imaging [102]. Figure 6 illustrates two-dimensional echocardiographic and color Doppler ﬁndings in an elderly patient with chronic severe AR. Figure 7 illustrates continuous-wave Doppler ﬁndings in the elderly patient with chronic severe AR shown in Figure 6.

Figure 6 Two-dimensional echocardiographic image from an apical four-chamber view in an elderly patient with severe aortic insufficiency, showing a large diastolic aliasing color Doppler jet in the left ventricular outflow tract. AI = aortic insufficiency; LV = left ventricular cavity; MV = mitral valve leaflets; LA = left atrium; RA = right atrium. (See color insert.)

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Figure 7 Continuous-wave Doppler recording of the velocity proﬁle across the aortic valve in the same patient shown in Figure 6. A holosystolic decrescendo high-velocity proﬁle is recorded from the left ventricular outﬂow tract, characteristic of aortic insufficiency. AI = aortic insufficiency. (See color insert.)

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Natural History The natural history of chronic AR is signiﬁcantly diﬀerent than the natural history of acute AR. Patients with acute AR should have immediate aortic valve replacement because death may occur within hours to days. In one study of patients with hemodynamically signiﬁcant chronic AR treated medically, 75% were alive at 5 years after diagnosis [51,103]. Of patients with moderate-to-severe chronic AR, 50% were alive at 10 years after diagnosis [51,103]. The 10-year survival rate for patients with mild-to-moderate chronic AR was 85 to 95% [51,104]. In another study of 14 patients with chronic severe AR who did not have surgery, 13 (93%) died within 2 years of developing CHF [90]. The mean survival time after the onset of angina pectoris is 5 years [103]. During 8-year follow-up of 104 asymptomatic patients with chronic severe AR and normal LV ejection fraction, 2 patients (2%) died suddenly, and 23 patients (22%) had aortic valve replacement [105]. Of the 104 patients, 19 (18%) had aortic valve replacement because of cardiac symptoms and 4 patients (4%) had aortic valve replacement because of the development of LV systolic dysfunction in the absence of cardiac symptoms. Multivariate analysis showed that age, initial end-systolic dimension, and rate of change in endsystolic dimension and resting LV ejection fraction during serial studies predicted the outcome. In a prospective study, at 24-month follow-up (range 7 to 55 months) of 17 patients, mean age 83 years, with CHF associated with unoperated severe chronic AR and a normal LV ejection fraction, 15 patients (88%) were dead [87]. At 15-month follow-up (range 8 to 21 months) of 8 patients, mean age 85 years, with CHF associated with unoperated severe chronic AR and an abnormal LV ejection fraction, 8 patients (100%) were dead [87].

Medical and Surgical Management Asymptomatic patients with mild or moderate AR do not require therapy. However, prophylactic antibiotics should be used to prevent bacterial endocarditis in patients with AR, according to AHA guidelines [62]. Echocardiographic evaluation of LV end-systolic dimension should be performed yearly if the measurement is less than 50 mm, but every 3 to 6 months if the LV end-systolic dimension is 50 to 54 mm. Aortic valve replacement should also be considered when the LV ejection fraction approaches 50% before the decompensated state [84]. Patients with asymptomatic, chronic severe AR should be treated with hydralazine [106], nifedipine [107], or preferably angiotensin-converting-enzyme therapy [108] to decrease the LV volume overload. Infections should be treated promptly. Systemic hypertension increases the regurgitant ﬂow and should be treated. Drugs that depress LV function should not be used. Arrhythmias should be treated. Patients with AR due to syphilitic aortitis should receive a course of penicillin therapy. Prophylactic resection should be considered in patients with Marfan’s syndrome when the aortic root diameter exceeds 55 mm [109]. Bacterial endocarditis should be treated with intravenous antibiotics. Indications for aortic valve replacement in patients with AR due to bacterial endocarditis are CHF, uncontrolled infection, myocardial or valvular ring abcess, prosthetic valve dysfunction or dehiscence, and multiple embolic episodes [110–112].

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CHF should be treated with sodium restriction, diuretics, digoxin if the LV ejection fraction is abnormal, vasodilator therapy, and aortic valve replacement. Angina pectoris should be treated with nitrates. Patients with acute severe AR should undergo aortic valve replacement immediately. Patients with chronic severe AR should have aortic valve replacement if they develop symptoms of CHF, angina pectoris, or syncope [105]. Aortic valve replacement should also be performed in asymptomatic patients with chronic severe AR if they develop LV systolic dysfunction [105]. Table 5 shows Class I American College of Cardiology/ American Heart Association indications for aortic valve replacement in patients with chronic severe AR [64]. These indications include NYHA functional class III or IV symptoms and LV ejection fraction z50% at rest; NYHA functional class II symptoms and LV ejection fraction z.050% at rest but with progressive LV dilatation or decreasing LV ejection fraction at rest on serial studies or decreasing eﬀort tolerance on exercise testing; asymptomatic or symptomatic patients with a resting LV ejection fraction of 25% to 49%; and patients undergoing CABG or surgery on the aorta or other valves [64]. Elderly patients undergoing aortic valve replacement for severe AR have an excellent postoperative survival if the preoperative LV ejection fraction is normal [113–115]. If LV systolic dysfunction was present for less than 1 year, patients also did well postoperatively. However, if the person with severe AR has an abnormal LV ejection fraction and impaired exercise tolerance and/or the presence of LV systolic dysfunction for longer than 1 year, the postoperative survival is poor [113–115]. After aortic valve replacement, women exhibit an excess late mortality, suggesting that surgical correction of severe chronic AR should be considered at an earlier stage in women [116]. The operative mortality for aortic valve replacement in elderly patients with severe AR is similar to that in elderly patients with aortic valve replacement for valvular AS. The mortality rate is slightly increased in patients with infective endocarditis and in those patients needing replacement of the ascending aorta plus aortic valve replacement. The bioprosthesis is preferable to the mechanical prosthetic valve for aortic valve replacement in elderly patients as in elderly patients with valvular AS [65,66]. Patients with porcine bioprostheses require anticoagulant therapy for 3 months after hospital discharge and then may be treated with antiplatelet therapy alone unless they have atrial ﬁbrillation, abnormal LV ejection fraction, previous thromboembolism, or a hypercoagulable state [64,66]. Table 5 American College of Cardiology/American Heart Association Class I Indications for Aortic Valve Replacement in Persons with Chronic Severe Aortic Regurgitation 1. Patients with New York Heart Association functional Class III or IV symptoms and a resting LV ejection fraction z50% 2. Patients with New York Heart Association functional Class II symptoms and a resting LV ejection fraction z50% but with progressive LV dilatation or decreasing LV ejection fraction at rest on serial studies or decreasing eﬀort tolerance on exercise testing 3. Patients with Canadian Heart Association functional Class II or greater angina pectoris with or without coronary artery disease 4. Symptomatic or asymptomatic patients with a resting LV ejection fraction of 25% to 49% 5. Patients undergoing coronary artery bypass surgery or surgery on the aorta or other heart valves Source: Modiﬁed from Ref. 64.

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In a prospective study, aortic valve replacement in 38 patients with severe AR normalized LV chamber size and mass in two-thirds of patients undergoing surgery [117]. At 9-month follow-up after AR replacement, 58% of patients had a normal LV enddiastolic dimension and 50% of patients had a normal LV mass. During further follow-up (18 to 56 months postoperatively), 66% of patients had a normal LV end-diastolic dimension and 68% of patients had a normal LV mass. The LV end-diastolic dimension normalized in 86% of patients with a preoperative LV end-systolic dimension V55 mm. A preoperative LV end-systolic dimension >55 mm was present in 81% of patients with postoperative persistent LV dilatation [117].

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Karp RB. Role of surgery in infective endocarditis. Cardiovasc Clin 1987; 17(3):141–162. Cobbs CG, Gnann JW. Indications for surgery. In: Sande MA, Kaye D, Root RK, eds. Endocarditis. New York: Churchill Livingstone, 1984:201–212. Bonow RO, Picone AL, McIntosh CL, Jones M, Rosing DR, Maron BJ, Lakatos E, Clark RE, Epstein SE. Survival and functional results after valve replacement for aortic regurgitation from 1976 to 1983: impact of preoperative left ventricular function. Circulation 1985; 72:1244– 1256. Bonow RO. Noninvasive evaluation: prognosis and timing of operation in symptomatic and asymptomatic patients with chronic aortic regurgitation. In: Cohn LH, DiSesa VJ, eds. Aortic Regurgitation: Medical and Surgical Management. New York: Marcel Dekker, 1986:55–86. Turina J, Milincic J, Seifert B, Turina M. Valve replacement in chronic aortic regurgitation. True predictors of survival after extended follow-up. Circulation 1998; 98:II-100–II-107. Klodas E, Enriquez-Sarano M, Tajik AJ, Mullany CJ, Bailey KR, Seward JB. Surgery for aortic regurgitation in women. Contrasting indications and outcomes compared with men. Circulation 1996; 94:2472–2478. Roman MJ, Klein L, Devereux RB, Kligﬁeld P, Niles NW, Hochreiter C, Isom OW, Borer JS. Reversal of left ventricular dilatation, hypertrophy, and dysfunction by valve replacement in aortic regurgitation. Am Heart J 1989; 118:553–563.

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18 Mitral Regurgitation, Mitral Stenosis, and Mitral Annular Calcification in the Elderly Melvin D. Cheitlin University of California, San Francisco, San Francisco, California, U.S.A.

Wilbert S. Aronow Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A.

ETIOLOGY Mitral Stenosis The etiology of mitral stenosis (MS) in the elderly as in the young patient is chronic rheumatic heart disease. There is a small incidence of mitral annular calciﬁcation with such exuberant atherosclerotic encroachment from the annulus into the base of the left ventricle such that the mitral oriﬁce is decreased, producing some degree of mitral stenosis, most often not severe. With the marked decrease in the incidence of acute rheumatic fever in the United States over the last half century, the prevalence of mitral stenosis in those people under age 40 born and raised in the United States with chronic rheumatic heart disease and mitral stenosis or mitral regurgitation has markedly decreased, so that mitral stenosis in this population is seen predominantly in the elderly patient, frequently the older patient who has had earlier mitral valve surgery. Since rheumatic fever is still very common in eastern Europe, Asia, Latin and South America, and Africa, most of the younger patients with mitral stenosis we see in the United States were born and raised in these countries. Mitral Regurgitation In the elderly patient mitral valve disease, especially mitral regurgitation (MR), is more frequently seen than aortic valve disease, although aortic stenosis is much more often the reason for valve surgery in this age group [1]. Mitral regurgitation has numerous etiologies (Table 1) [2]. The most frequent etiologies in elderly patients are myxomatous degeneration (mitral valve prolapse), functional MR due to left ventricular dilatation, coronary artery disease, rheumatic heart disease, and mitral annular calciﬁcation. Since mitral annular calciﬁcation is seen predominantly in the elderly patient and poses problems beyond 443

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Table 1 Etiologies of Mitral Regurgitation 1. 2. 3. 4. 5. 6. 7.

Rheumatic heart disease Mitral valve prolapse (myxomatous degeneration)a Infective endocarditisa Left ventricular dilatation (left ventricular failure) Idiopathic rupture of chordae tendinaea Trauma, penetrating and nonpenetratinga Coronary artery disease a. Transient ischemiaa b. Myocardial infarction c. Ruptured papillary musclea 8. Connective tissue diseases (lupus erythematosus, Marfan disease) 9. Mitral annular calciﬁcation 10. Postmitral valvotomya 11. Valve dehiscencea 12. Paraprosthetic MR 13. Degeneration of a bioprosthetic valve a

Etiologies where clinical picture may be that of acute MR.

those related to volume overload, a detailed discussion of this topic will be presented separately at the end of the chapter.

PATHOPHYSIOLOGY Mitral Stenosis The major pathology is that of commissural fusion and fusion and shortening of the chordae tendinae. Later there is increasing ﬁbrosis and calciﬁcation of the valve leaﬂets. Therefore, the obstruction to diastolic ﬂow across the mitral valve can be due to the narrowed mitral oriﬁce caused by commissural fusion, to the thickening and calciﬁcation of the leaﬂets so that they do not open without a pressure gradient in spite of open commissures or obstruction due to a subvalvular component caused by fused, shortened chordae tendinae. In these latter two instances, commissurotomy will not relieve the obstruction and valve replacement is necessary. The normal mitral valve oriﬁce is f5.0 cm2. With a normal stroke volume there is no obstruction to diastolic ﬂow until the valve area is reduced to f2.0 cm2. When the valve area reaches about 1.0 cm2, there is suﬃcient obstruction at resting ﬂow rates to result in a diastolic gradient across the mitral valve, so the left atrial pressure as well as pulmonary venous and pulmonary capillary pressures rise enough to cause pulmonary congestive symptoms [3]. The obstruction and pressure gradient between the left atrium and left ventricle in diastole accelerates the blood through the narrowed oriﬁce, causing the turbulence and vortex formation that generates the characteristic low-frequency diastolic murmur. The loudness of the murmur is related to the magnitude of the pressure gradient and to the volume of blood accelerated across the obstructed valve as well as to the nearness of

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the chamber in which the murmur is generated (here the left ventricle) to the ear. Since the left ventricular apex pushes the chest wall in systole creating the point of maximal impulse (PMI), this is where the murmur is best heard. As left atrial pressure rises, pulmonary capillary pressure rises and overcomes the colloid osmotic pressure in the pulmonary capillary bed, leading to increasing congestion in the interstitial areas of the lung and ﬁnally to pulmonary edema. As left atrial pressure rises, there is a pari passu rise in right ventricular systolic pressure, increasing afterload on the right ventricle, right ventricular hypertrophy, and, ﬁnally, right ventricular failure. In 10 to 15% of cases there is a marked increase in pulmonary artery pressure and pulmonary vascular resistance due to edema pressure on the interstitial small arteries and vasoconstriction probably mediated by pulmonary artery endothelial release of vasoconstrictive amines such as endothelin. Eventually, with right ventricular failure, there is a decrease in cardiac output, and signs of right ventricular failure with increased central venous pressure, edema, and even ascites [3]. As left atrial pressure rises, the left atrium enlarges resulting in atrial ﬁbrillation that may occur relatively early in the course of mitral stenosis. With atrial ﬁbrillation, stasis of blood, especially in the left atrial appendage, as well as endocardial changes [4] that promote platelet activation and release of thrombogenic substances, result in atrial clotting and form the basis for the high incidence of systemic thromboemboli, the most important of which is embolic stroke that is so common in mitral stenosis [5]. Hemoptysis occurs in these patients as pulmonary venous pressure increases, opening collaterals for run-oﬀ to the bronchial veins. These protrude into the lumen of the bronchi and, when rupture occurs, cause hemoptysis [3]. Ortner’s syndrome (paralysis of the left vocal cord) can occur with the recurrent laryngeal nerve, which hooks around the ligamentum arteriosus being stretched by the enlarging left pulmonary artery and left atrium [6].

Mitral Regurgitation Mechanism of Regurgitant Orifice Formation The development of MR depends on the formation during systole of a regurgitant oriﬁce. There are a number of mechanisms by which this can occur. Dilatation of the left ventricular os (including the mitral annulus) is seen in any cause of left ventricular failure with left ventricular dilatation. The valve itself remains normal, but the area of the mitral opening is too great to be closed by coaptation of the leaﬂets. There is also displacement of the papillary muscles and more lateral tension in systole on the leaﬂet edges, thus restricting leaﬂet motion [7]. A similar problem occurs with ischemia and myocardial ﬁbrosis where the mural leaﬂet is held from coapting with the anterior leaﬂet. Other mechanisms of regurgitant oriﬁce formation are loss of leaﬂet tissue and ﬁbrosis, retraction of leaﬂet tissue as is seen in rheumatic heart disease, or tearing of the leaﬂet as in infective endocarditis, seen also in penetrating and nonpenetrating trauma. Finally, there can be loss of infravalvular support as seen in chordal and papillary muscle rupture. With myxomatous leaﬂets, mitral valve prolapse occurs where there may be coaptation of the leaﬂets early in systole, but as the left ventricle empties and becomes smaller, the redundant leaﬂet is displaced back above the mitral annulus into the left atrium, and at some point a regurgitant oriﬁce is created [8]. With myocardial infarction and ﬁbrosis of the papillary muscle and its origin from the left ventricular wall, as

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systole progresses the mitral valve leaﬂets prolapse toward the left atrium and a regurgitant oriﬁce forms. With annular calciﬁcation, the os of the left ventricle is prevented from constricting during systole and the mural leaﬂet can be immobilized, preventing it from coapting with the anterior leaﬂet. Pathophysiology Causing Symptoms Acute MR The pathophysiology of MR depends on the severity of the leak (regurgitant volume) and the rapidity with which the MR occurred. With sudden chordal or leaﬂet rupture or valve dehiscence, a sudden low-resistance runoﬀ in systole from the left ventricle develops. If the regurgitant oriﬁce is large, the regurgitant volume will be large. The total left ventricular stroke volume is now divided into the stroke volume going out of the aorta (eﬀective forward stroke volume) and the blood regurgitating back into the left atrium (regurgitant volume). The left ventricle in this situation empties rapidly during systole. Since much of the regurgitant volume goes into the left atrium against low resistance, the left ventricle faces a decreased afterload early in systole, permitting it to empty more easily and achieving a smaller end-systolic volume and a higher ejection fraction [3]. The increased blood coming into the left atrium during systole results in a higher ‘‘V’’ wave. With the next diastole, the blood coming from the pulmonary veins adds to the regurgitant blood thus increasing the left ventricular end-diastolic volume. The FrankStarling mechanism increases the next left ventricular stroke volume so that the regurgitant volume can be maintained as well as the eﬀective forward stroke volume. In acute MR, the sudden increase in left ventricular end-diastolic volume resisted by the unprepared left ventricle and unstretched pericardium results in a marked rise in left ventricular ﬁlling pressure. With the increased ﬁlling pressure the left atrial and pulmonary capillary pressure is increased causing pulmonary congestion and pulmonary edema. With the rise in left atrial pressure there is a sudden increase in afterload on the right ventricle, which may dilate and rapidly fail [3]. Chronic MR With gradually increasing regurgitant volume, there is stimulus and time for remodeling of the left ventricle and eccentric hypertrophy to occur. As the ventricle dilates, left ventricular hypertrophy (LVH) occurs so that the wall does not become thinner, preventing an increase in left ventricular wall tension. The ventricle remains compliant and the pericardium stretches to keep the left ventricular ﬁlling pressure and left atrial pressure normal. The dilated more compliant left atrium limits the height of the ‘‘V’’ wave to 30 to 35 mmHg. The left ventricular ﬁlling pressure remains normal until the left ventricle fails, at which time the ﬁlling pressure rises. Since the left ventricle is contracting against a lower afterload, the ejection fraction remains normal or even higher than normal. As the left ventricular end-diastolic diameter increases, eventually the wall tension and afterload increases and the ejection fraction begins to fall [9]. At this stage, even with the ejection fraction still ‘‘within normal limits,’’ there has been a decrease in myocardial contractility. When the left atrial mean pressure rises, there is increased afterload on the right ventricle and eventually right ventricular failure. Here, right ventricular failure is very late in the course of the natural history. Age Modiﬁes the Pathophysiology of MR In the elderly there is decreased compliance of the left ventricle [10] as well as LVH which leads to a further, more rapid increase in left ventricular ﬁlling pressure given the volume load present in MR. With the increased aortic stiﬀness present in the elderly [11], there is increased left ventricular im-

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pedance to ejection and increased left ventricular afterload leading to earlier decompensation of the left ventricle in MR.

CLINICAL PICTURE Mitral Stenosis Symptoms For many years the patient may remain asymptomatic. In the elderly, many patients have had a previous intervention, either surgical or balloon valvotomy. In elderly patients, pulmonary congestion almost always results in progressive dyspnea on exertion and eventually orthopnea and paroxysmal nocturnal dyspnea. Wall tension and enlargement of the left atrium lead to the development of atrial ﬁbrillation and the increased danger of systemic emboli, especially stroke [3]. Frequently the ﬁrst symptoms occur with the onset of atrial ﬁbrillation or, in the young patient, during the course of pregnancy [3]. With decreasing right ventricular function, the patient may have fewer symptoms and signs of pulmonary congestion and more problems with decreased exercise tolerance. Eventually the clinical picture is dominated by the signs and symptoms of right heart failure, pedal edema, engorged neck veins, and ﬁnally ascites and the stasis cyanosis of low cardiac output. Signs The murmur of mitral stenosis is a characteristic low-pitched, rumbling diastolic murmur best heard at the apex. With ﬂexible valve leaﬂets, the ﬁrst heart sound is loud and even palpable and there is an opening snap after the S2 in early diastole. The second heart sound may be increased and even palpable if the pulmonary artery pressure is elevated. With severe pulmonary hypertension, a diastolic blowing murmur of pulmonic insuﬃciency may be heard along the left-sternal border, indistinguishable from the murmur of aortic regurgitation (Graham-Steele murmur). With right ventricular hypertrophy, there may be a precordial lift. With right heart failure, a systolic murmur along the left sternal border of tricuspid regurgitation may be present, as well as an elevated central venous pressure, hepatomegaly, edema, and even ascites [3]. Age Modiﬁes Signs and Symptoms of Mitral Stenosis In the elderly, symptoms may be far advanced before the patient recognizes that they are in trouble. Elderly patients may accept shortness of breath and decreased exercise tolerance as an inevitable consequence of ‘‘getting older.’’ Also, accompanying comorbidities, such as chronic obstructive pulmonary disease, may be accepted as the cause of the increasing symptoms. In the elderly patient, the antero-posterior diameter of the chest is frequently increased so that the left ventricle no longer contacts the chest wall. Also dilatation of the right ventricle may move the left ventricle posteriorly away from contact with the chest wall. Since the lowfrequency murmur does not conduct well through the blood of the right ventricle, the murmur may be inaudible [3]. Sometimes rolling the patient into the left lateral position can bring the left ventricle into contact with the chest wall and make the murmur detectable with the bell of the stethoscope over the point of maximal impulse. Also increasing the heart rate and cardiac output with exercise increases the diastolic gradient across the mitral valve and makes the murmur louder. Since the elderly are more likely to have a ﬁbrotic, calciﬁed valve, the ﬁrst heart sound may not be loud and the opening snap may be absent. In these patients the mitral stenosis may be truly silent and the patient simply looks like a patient in heart failure.

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Laboratory Findings and Diagnosis The classic ﬁndings on a chest x-ray are those of right ventricular dilatation, prominence of the pulmonary artery and pulmonary veins, especially with redistribution to the upper lung ﬁelds. There is also a double density behind the right cardiac silhouette protruding beyond the right heart border of left atrial enlargement, and a ﬁlling in below the main pulmonary artery segment in the AP view of the left atrial appendage. In the lateral ﬁlm at times calciﬁcation of the mitral valve can be seen, better on ﬂuoroscopy. The classic ﬁndings on ECG are left atrial abnormality and right ventricular hypertrophy. In the elderly, atrial ﬁbrillation is common. The restricted opening of the mitral valve can be seen in the 2-D echocardiogram and the mitral oriﬁce can be planimetered. The increased diastolic velocity across the mitral valve is measured by Doppler and the diastolic gradient is calculated by the formula [12] Gradient ¼ 4V2 The severity of the mitral stenosis can be calculated from the diastolic half-time [13] and the mitral oriﬁce area from the continuity equation [14] Mitral valve area ¼

LV outflow tract area velocity Velocity across mitral valve

or by the proximal isovelocity surface area (PISA) method [15] Mitral area ¼

Flowð2pr2 Þ Velocity across mitral valve;

where r is determined from the Nyquist limit. There are several echocardiographic scores [16,17], which by looking at the thickness and mobility of the leaﬂets, the degree of leaﬂet and commissural calciﬁcation, and subvalvular chordal fusion, can reliably identify those patients who will beneﬁt from balloon or surgical valvotomy and those patients who should have valve replacement. Mitral Regurgitation Symptoms Acute MR With sudden development of severe MR, there is no time for compensatory eccentric hypertrophy or enlargement of the left atrium, so the patient frequently develops severe shortness of breath, orthopnea, PND, early pulmonary edema, and even right heart failure. Since the left atrium is not dilated, it is unusual for the patient to be in atrial ﬁbrillation [18]. Chronic MR The patient may remain asymptomatic for years. Eventually the earliest symptom may be a decrease in exercise tolerance rather than dyspnea on exertion since with left ventricular dysfunction the forward stroke volume may decrease with exercise. Later shortness of breath, orthopnea, PND, and left heart failure occur. Finally, right heart failure is very late in the course of the disease [19]. The elderly patient may deny symptoms thinking that decreased exercise tolerance is due to aging and shortness of breath is due to pulmonary disease. Also, with a gradual decrease in the patient’s ability to exercise, symptoms may be avoided by decreasing the level of activity so that the patient may have very severe MR and still deny symptoms.

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Signs Acute MR With acute MR the PMI may not be displaced but is hyperactive, especially compared to the radial pulse that may be rapid rising and abbreviated. If the regurgitant oriﬁce is very large, pressure in the left atrium and left ventricle may approach equality, in which case the murmur may be short or even absent. These patients are usually extremely dyspneic or in pulmonary edema [18]. With posterior leaﬂet prolapse, the regurgitant jet may be directed anteriorly and superiorly so that the murmur may be heard well at the base as well as the apex. With anterior leaﬂet prolapse, the jet is directed posteriorly and is well heard in the back. The murmur of acute MR may be confused with that of aortic stenosis but with a PVC, the post-extrasystolic beat results in a murmur that does not get louder, unlike that of the post-extrasystolic beat in aortic stenosis. With rapid ﬁlling of the left ventricle, there is frequently an S3, and since the rhythm is usually sinus rhythm, an S4. Chronic MR With chronic MR, the left ventricle is dilated and the PMI is displaced laterally and sustained. With the PMI and carotid pulse felt simultaneously, instead of the PMI collapsing before the carotid pulse, with LVH the PMI collapses after the carotid pulse. The pansystolic murmur of MR, best heard at the apex, is ﬂat throughout systole. Since the regurgitation continues throughout all of left ventricular systole, there are no isovolumic contraction or relaxation phases and the murmur classically buries the ﬁrst and second heart sounds [19]. In patients where the regurgitant oriﬁce does not form until the ventricle is ejecting, such as in mitral valve prolapse, nonejection click or clicks may be present as the leaﬂet prolapses and suddenly is stopped in its motion. Since the regurgitant oriﬁce continues to enlarge as the ventricle empties, the murmur starts after the click, crescendos in loudness, and incorporates the second sound [20]. With the marked increase in diastolic blood ﬂow across the mitral valve, there may be a short diastolic rumble and an S3 sound. Atrial ﬁbrillation is common in the elderly patient with signiﬁcant MR. Other signs and symptoms may be related to the etiology of the MR. For instance, with MR secondary to a dilated left ventricle, the ﬁndings of cardiomyopathy may be present with an S3 and S4 gallop. Fever and immunoembolic signs may be present in patients with infective endocarditis, physical signs of connective tissue diseases such as Marfan disease, or a history of trauma, angina, or acute myocardial infarction. Laboratory Findings and Diagnosis Chest x-Ray Since there is no time for atrial or ventricular remodeling, in acute MR the heart may not be enlarged on the chest x-ray. Pulmonary congestion and edema are commonly seen. With chronic severe MR the left atrium and ventricle are dilated and appear enlarged on the chest x-ray. With chronic MR, occasionally the left atrium can become extremely dilated so that it touches the right lateral chest wall compressing the right lower lung. ECG With acute MR, the ECG may be normal, except for sinus tachycardia, or have only nonspeciﬁc ST-T wave changes. With chronic MR, LVH, left atrial abnormality, and atrial ﬁbrillation are common. Echocardiography The regurgitant volume and size of the regurgitant oriﬁce can be estimated by Doppler echocardiography. The eﬀect of the MR on the size and function of the cardiac chambers can also be evaluated. With acute severe MR, there is frequently pulmonary hypertension, which can be estimated by identifying a tricuspid regurgitant jet

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that allows estimation of the pulmonary artery systolic pressure [21]. The direction of the MR regurgitant jet as well as multiple views on TEE can reliably show which scallops of the mitral leaﬂets are prolapsing and deﬁne the anatomical and functional mechanism causing the MR; and it is necessary for planning the surgical procedure [22]. Recently, Thomas and colleagues [23] developed an MR index using six echoDoppler ﬁndings, three related to the regurgitant volume and three to the eﬀect on the cardiac chambers. The index correlated well with regurgitant fraction and other measures of MR severity and identiﬁed patients with severe MR with a 90% sensitivity, a 88% speciﬁcity, and a 79% positive predictive value.

NATURAL HISTORY OF MITRAL STENOSIS AND MITRAL REGURGITATION IN THE ELDERLY Mitral Stenosis A patient over age 65 with mitral stenosis who has not already had a commissurotomy will have had mild mitral stenosis for many years or may have progressed to moderate mitral stenosis. Others have progressed to severe mitral stenosis by valvular ﬁbrosis and calciﬁcation. Many have had mitral stenosis diagnosed at an early age and, if symptomatic, had a valvotomy or valve replacement. Once mitral stenosis becomes symptomatic, the course usually is to become progressively more symptomatic, going through the pulmonary congestive phase, then the right heart failure phase, and ﬁnally the low cardiac output stage to death [3]. Since valvotomy or valve replacement has been available for a half century, it is unusual to see an elderly person with severe mitral stenosis who has not had at least one attempt at valvotomy. Mainly in patients newly arrived in the United States do we see elderly patients with previously unrecognized severe mitral stenosis.

Mitral Regurgitation The natural history of patients with MR depends on the acuteness of onset, severity, and etiology of MR. With MR caused by ischemia or myocardial infarction, the prognosis is poor unless there is minimal myocardial damage and the ischemic muscle can be revascularized and the valve made competent [24]. With endocarditis the cause of the MR, the course depends on the infecting organism and the complications seen with infective endocarditis. If trauma is the etiology, the damage to the heart and other organs determines the course. Acute Mitral Regurgitation How large the regurgitant volume is when the acute MR occurs will determine the symptomatic state of the patient. In the elderly patient, the stiﬀer left ventricle results in a higher ﬁlling pressure for a given volume overload. With a single chord rupture, there may be minimal to moderate regurgitation and the patient may not exhibit the clinical picture of acute MR. With severe MR as is seen with rupture of several primary chords or with rupture of the papillary muscle tip, the classic clinical picture of acute MR is seen and the patient frequently presents with pulmonary edema, culminating in early demise [18].

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With the decrease in afterload, the ventricle empties in systole to a greater extent than normal and the ejection fraction increases. With myocardial dysfunction, the left ventricular end-diastolic and end-systolic volumes increase and the ejection fraction begins to fall, at times into the normal range [9]. The decrease in ejection fraction in this case still identiﬁes myocardial dysfunction that has a negative eﬀect on prognosis even after surgical correction of the MR [25]. Although in one study a relatively high incidence of sudden death has been reported in patients with acute MR due to ﬂail leaﬂets [26], this has not been conﬁrmed because in that study coronary artery disease could not be ruled out as the etiology. [27]. After a period of time, remodeling of the left atrium and left ventricle allows the ﬁlling pressure to fall and the eﬀective forward stroke volume to be maintained. The patient may become less symptomatic and the clinical picture may become that of chronic MR. Chronic Mitral Regurgitation Patients with chronic MR can remain asymptomatic for many years with good exercise tolerance. At some point, the volume load on the left ventricle combined with increasing afterload due to the ventricle becoming more spherical and increasing its radius results in myocardial dysfunction. The course becomes that of increasing symptoms and death, usually from congestive heart failure [19].

TREATMENT OF MITRAL STENOSIS AND MITRAL REGURGITATION IN THE ELDERLY Mitral Stenosis Balloon Valvotomy for Mitral Stenosis In elderly patients with mild-to-moderate MS who have good or acceptable exercise tolerance consistent with their age and not interfering with their life, controlling volume overload, the ventricular rate if in atrial ﬁbrillation, and anticoagulation with warfarin because of the high risk of systemic embolization is the best approach. If the patient develops symptoms that do not respond to gentle diuresis and rate control with betablockers or calcium channel blockers, valvotomy should be considered. If the valve is ﬂexible, with minimal calciﬁcation, no left atrial thrombus and no more than mild (grade 2 or less) MR, the patient is a candidate for valvotomy [28]. At the present time with experienced operators, balloon valvotomy is the treatment of choice rather than open commissurotomy [29,31]. With balloon valvotomy, the success rate of increasing the valve area to 1.5 cm2 or greater, eﬀectively doubling the valve area, is high—about 90%, even in valves with a high echo score [32]. Preexisting MR is a risk factor predicting poor outcome [32,33]. The presence of commissural calcium is related to the development of MR after balloon valvotomy and with calciﬁcation of the valve there is less chance that the valve can be opened to z1.5 cm2 and less improvement in symptoms. Iung and colleagues [30] reported results of balloon valvotomy in 1514 patients, 45 F 15 years of age. Twenty-ﬁve percent had calciﬁed valves. A good result, deﬁned as opening the mitral valve to 1.5 cm2 or more without creating 2+ or greater MR, was obtained in 1348 (89%) patients. Important predictors of a good result were younger age, echo score V8, and relatively large predilation valve area. Palacios and colleagues [31] reported 327 patients with balloon valvotomy. There were seven in-hospital deaths. The follow-up period was 20 F 12 months. The echo score, which evaluates the anatomical suitability for

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valvotomy using the Wilkins scoring system [16], was determined. Patients with an echo score >8 compared to those V8 were older (64 F 11 years vs. 48 F 14 years) had more atrial ﬁbrillation (65% vs. 40%), more valve calciﬁcation (81% vs. 29%), and more previous surgical commissurotomy (30% vs. 16%). Event-free survival was 79 F 10% for those with echo score <8 vs. 39 F 18% with echo score z8. There is a limited experience with valvotomy in patients over age 65 to 70. Le Feuvre and colleagues [34] reported 234 patients who had a balloon valvotomy, only 28 (10%) z70 years old. Compared to younger patients, the 70 years and older patients had a higher percentage of NYHA Class III and IV (84% vs. 67%), and higher echo scores (9.3 F 2.1 vs. 8.0 F 1.6), meaning they were less suitable for valvotomy. They also had more atrial ﬁbrillation (61% vs. 36%), more complications (27% vs. 9%), and a higher 30-day mortality (12% vs. 0.8%). The success rate in opening the valve was similar in both groups. Long-term survival without cardiac events (death, cerebrovascular accidents, another intervention) depends on the patient’s age as well as comorbidity. In general, the older the patient and the more comorbidity, the shorter the survival. Meneveau and colleagues [35] reported 532 patients after balloon valvotomy (Table 2). The event-free survival was age-dependent. The anatomical form of the mitral valve was the second important factor in event-free survival. Given the fact that a calciﬁed valve is unfavorable for valvotomy, in those very symptomatic patients with calciﬁed valves believed to be too great a risk for surgery, balloon valvotomy can be palliative, achieving a moderate increase in valve area at low procedural risk and with improvement of symptoms in the majority of patients. [36]. Patients with echo scores that make them unsuitable for balloon valvotomy and rejected for surgery because of frailty or comorbidity can beneﬁt from balloon valvotomy. Sutaria and colleagues [37] reported 80 patients over age 70 years of age. Fifty-ﬁve were considered unsuitable for surgery. There was a 95% success rate in opening the valve. One year later, 28 of the 55 unsuitable patients (51%) had improved at least one NYHA Class and 14 (25%) at 5 years. Of the 25 with suitable valves, 16 (64%) had achieved this outcome at 1 year and 9 (36%) at 5 years. Shaw and colleagues [38] reported similar results in 20 patients 70 years of age and older. The absence of commissural calciﬁcation is a signiﬁcant predictor of the frequency of achieving a mitral valve opening of 1.5 cm2

Table 2 Long-Term Follow-Up of 532 Patients with Balloon Valvotomy Event-free survival

3 years

5 years

7.5 years

Entire group 84% 74% 52% Age V65 80% 70% 45% Age >65 52% 38% 17% The anatomical form of the mitral valve was the second important factor in event-free survival 3 years 5 years 7.5 years Favorable anatomy (Echo score of 1) Intermediate anatomy (Echo score of 2) Unfavorable anatomy (Echo score of 3) Source: From Ref. 35.

92%

84%

70%

86%

73%

34%

45%

25%

16%

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without creating severe MR. Sutaria and colleagues [39] reported that calciﬁcation of one or more commissures predicts a<50% chance of achieving a valve area of z1.5 cm2. Its inﬂuence is greatest in valves with an echo score of V8. Those with commissural calciﬁcation grade of 0/1 had a signiﬁcantly larger number of patients with improvement in symptoms and achieving a valve area of 1.5 cm2 (67%) than those with a grade of 3/4 (46%). [39]. If the echo score is >8, the degree of commissural calciﬁcation is less important. In patients age 80 and older, there is limited experience. Sutaria and colleagues [40] reported 20 octogenarians (age range 80 to 89) with balloon valvuloplasty, all functional Class II to IV, 14 unﬁt for surgery. The mitral valve area was increased by 106% from 0.81 F 0.3 to 1.67 F 0.8 cm2. Eight patients attained a valve area of z1.5 cm2 and 16 an area z1.2 cm2. Eighty percent improved at least 1 NYHA functional class. Since many elderly patients with mitral stenosis have had a previous surgical commissurotomy, the question arises whether balloon valvotomy could be successful if restenosis occurs. Iung and colleagues [41] reported the results of balloon valvotomy in 232 patients, mean age 47 F 14 years, who had undergone a surgical commissurotomy 16 F years before. Eighty-one of these patients had valve calciﬁcation and bilateral commissural fusion. One patient died (0.4%), MR>2/4 developed in 4% and 82% achieved an immediate valve area of z1.5 cm2 without signiﬁcant MR. Predictors of a poor result were age ( p<0.001), smaller initial valve area ( p = 0.01), and use of a double-balloon technique ( p=0.015), indicating that results in the elderly would not be as good. In the 175 patients with follow-up, 8-year survival without operation and in NYHA Class I and II was 48 F 5% and in those with good immediate results, 58 F 6%. Surgical Management of Mitral Valve Disease The management of mitral valve disease in the 65 to 75 age group is not much diﬀerent than in younger patients, except that older patients have more comorbidity, which increases the mortality and morbidity of surgery. Over age 75, there is a marked increase in surgical mortality and morbidity related to limited cardiac, renal, and pulmonary reserves. Since prolongation of life is not as likely in this age group, other therapeutic goals must justify surgery such as improvement in quality of life (QOL) and return to independent lifestyle. Surgery in an unacceptably symptomatic patient should not be denied on the basis of age alone, and a patient who is symptomatically doing well should not be subjected to surgery with its higher mortality and morbidity. Mitral Stenosis Open commissurotomy should be considered when the valve is ﬂexible enough to open when the commissures are released, there is minimal MR, but the subvalvular apparatus is obstructive, when there is thrombus in the left atrium, especially in the body of the left atrium, that remains after 2 to 3 months of anticoagulation, which would make balloon valvotomy hazardous [28]. At surgery, the subvalvular structures can be separated, the commissures opened, and the valve preserved. If not, the valve can be replaced. Cotrufo and colleagues [42] reported 540 consecutive mitral stenosis patients, 340 with mitral commissurotomy and 240 with a bileaﬂet valve replacement. Hospital mortality was 2% in each group (Table 3). Late mortality was lower in the open commissurotomy group (1%) than in the valve replacement group (3%). With the exception of a greater incidence of reoperation, long-term results were better in the open commissurotomy group. This is consistent with many other studies that found that mitral valve repair is preferable to replacement [43,44]. Mitral Regurgitation With the present techniques, most patients with MR (except those with extensive loss of ﬂexible leaﬂet tissue) can have the valve repaired successfully,

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Table 3 Mitral Commissurotomy Versus Mitral Valve Replacement Commissurotomy 10-year survival rate Freedom from reop Freedom from emboli Freedom from hemorrhage

98.7 88.1 93.7 99.3

F F F F

1% 2% 2% 0.5%

Valve replacement 93.7 97.7 83.9 98.4

F F F F

3% 1% 7% 1%

Source: From Ref. 42.

but the selection of patients and the expertise of the surgeon are critical factors for success [44]. MR due to rheumatic heart disease is characterized by ﬁbrosis and retraction of the leaﬂet edges as well as chordal shortening and fusion [45]. Repair is least successful in this group and selection of the proper patients for repair is essential. Most MR in the elderly is caused by myxomatous redundant leaﬂets, and these are ideal candidates for valve repair. With ischemic MR or a dilated left ventricle and left ventricular os, annuloplasty, with or without an annular ring is frequently suﬃcient to create a competent valve [46]. However, restricted leaﬂet motion can make the repair less predictable. Contraindications for repair are loss of leaﬂet area, extreme leaﬂet thickening, or calciﬁcation of leaﬂets or commissures [44]. Some surgeons have suggested that calciﬁcation of the annulus or leaﬂets does not preclude successful valve repair. Grossi and colleagues [47] reported the results of mitral valve repair in 558 patients. Debridement of calciﬁcation in annulus and/or leaﬂets was necessary in 64 (11.5%) patients. Freedom from reoperation at 10 years was 88.1% for debrided patients and 82.6% for those not needing debridement. When good annulus and leaﬂet mobility can be achieved in calciﬁed valves, calcium debridement allows durable valve repair. Patients with a small mitral annulus or multiple leaﬂet defects have a small probability of being successfully repaired. Patients with small left ventricular cavities, most often seen in elderly women, have a high incidence of postoperative systolic anterior motion and left ventricular outﬂow tract obstruction [44]. Patients with mitral valve prolapse involving the posterior leaﬂet have the most success with repair. However, recently there have been reports of successful repair of anterior leaﬂet prolapse [48,49]. For the best results, patient needs a careful evaluation by TEE and an experienced surgeon. Because the expected lifespan after surgery is shorter for the elderly patient at the time of surgery, there is an advantage of bioprosthetic valves over mechanical valves in older patients since anticoagulation is not necessary in the absence of atrial ﬁbrillation. The frequency of atrial ﬁbrillation in elderly patients with moderate-to-severe chronic MR lessens the advantage because these patients require anticoagulants to prevent systemic emboli [28]. There is evidence that valve degeneration occurs much more slowly in the elderly than in younger patients. In one study, the rate of primary structural deterioration in patients over age 65 was 0.95% per patient-year [50]. For this reason, in patients over 65 years of age, the preferred valve is a bioprosthetic valve. Dalrymple-Hay and colleagues [43] reported 329 patients with MR due to myxomatous degeneration, mean age 65.5 years with valve repair in 169 and valve replacement in 160 patients. Operative mortality occurred in 4 (1.2%), all in those with valve replacement. Actuarial survival at 1, 5, and 10 years was 94 F 1.4%, 77 F 2.9%, and 41 F 5.8%, with survival in patients with repair signiﬁcantly better ( p<0.05) than with valve replacement.

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Reoperation was required in 10 (6%) of those with valve repair and in 13 (8%) of those with valve replacement. Increased age, worse left ventricular function, the type of operation (repair vs. replacement), and left ventricular size all were signiﬁcantly associated with poorer survival. Lee and colleagues [51] reported 614 patients with valve surgery for severe MR, 190 aged 70 and older and 424 under age 70. In the older patients, there was signiﬁcantly more myxomatous disease, coronary disease, worse left ventricular function, and worse NYHA Class III to IV symptoms. Operative mortality in both young and old patients was low (3.5% vs. 3.7%). In the older patients, 7-year survival was lower than in the young (49 F 6% vs. 72 F 3%) as were overt heart failure (74 F 3% vs. 44 F 7%) and complicationrelated deaths (78 F 3% vs. 57 F 7%). However, both young and old patients who were NYHA Class I with an EF >40% had the same freedom from complication-related death (93 F 3% in the younger vs. 90 F 7% in the elderly). These ﬁndings support the approach to early surgery once symptoms occur and before the EF begins to fall, especially if valve repair is possible. There is good evidence that valve repair or replacement for MR improves the quality of life (QOL). Goldsmith and colleagues [52], in a prospective study of 61 consecutive patients with severe MR, mean age 64 F 12 years, who had mitral valve repair [40] or replacement [21] obtained QOL scores using the short form (SF) 36-questionnaire before and 3 months after surgery. There was signiﬁcant improvement in 7 out of 8 QOL parameters in those with repair and in 3 out of 8 in those with valve replacement. Patients with EF z50% improved in 7 out of 8 parameters. Those with impaired function or endsystolic dimensions of z45 mm showed no improvement in any of the parameters. These ﬁndings support the importance of early surgery before a decline in left ventricular function. Grossi and colleagues [53] studied 278 patients with mitral valve repair aged 70 and older (mean age 75.2 years). Concomitant procedures were done in 72.3%, with over half having coronary revascularization. Mortality was lower in those with isolated mitral valve repair than in those with concomitant revascularization (6.5% vs. 17%). With an additional valve procedure, the mortality was 13.2%. Long-term mortality was excellent with freedom from cardiac death in 100% of those with isolated mitral valve repair, lower in those with a concomitant procedure (79.7%; p=0.006), and freedom from reoperation in 91.2%. Valve replacement is performed in more elderly patients for aortic valve than for mitral valve disease, most often calciﬁc aortic stenosis, and operative mortality is lower than with mitral valve replacement [54,55]. Helft and colleagues [50] reported 110 patients, 65 and older (mean 73.4 years), with bioprosthetic valve replacement, 71 with aortic, 32 with mitral, and 7 with both. Follow-up was 8.5 years. At 5 years the actuarial survival was 79.6% and at 10 years 62.4%. Of the 44 patients who died, over half (52.3%) died from non-valve-related causes. Reoperation was needed in 13 patients (11.8%), 10 for structural deterioration, with one death (7.7%). Anticoagulation for atrial ﬁbrillation was needed in 26%, with 6.4% developing severe bleeding (2.9% per patient-year). Similar results have been reported in octogenarians [56–58]. With MR due to ischemia, operative and late mortality is higher than with MR due to myxomatous degeneration [24]. Operative mortality is also higher when the ejection fraction is 30% or lower. Hausmann and colleagues [24] reported 337 patients with ischemic MR and mitral valve repair or replacement (Table 4). The goal of surgery in patients with ischemic MR is to reduce the MR to no more than Grade 1. A frequent problem with ischemia and 1 to 3 + MR is whether to simply revascularize the patient or also make the mitral valve more competent, usually with a annuloplasty.

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Table 4 Surgery for Ischemic Mitral Regurgitation Op mort EF Type of operation n Op mort 10–30% Valve repair 140 12.1% 33.3% Valve replace 197 14.2% 30.3% When MR reduced to Grade 0–1 patient survival best

EF >30% 8.4% 11.0%

Actuarial survival rate 2 yr 75.4% 78.6% 81.0%

5 yr 66.8% 73.4% 78.4%

7 yr 61.7% 67.2% 77.2%

Source: From Ref. 25.

Tolis and colleagues [59] had 49 patients, men aged 66.3 years with advanced ischemic heart disease, 1 to 3 + MR (62% had 2–3+ MR), and an ejection fraction of 10 to 30% (mean 22.4%). In-hospital mortality was 2% and the mean degree of MR went from 1.73 down to 0.54 ( p<0.05). The NYHA class decreased from 3.3 to 1.8 ( p<0.05) and the EF rose from 22% to 31.5% ( p< 0.05). The 1-, 3-, and 5-year survivals were 88%, 65%, and 50%. They concluded that in such patients revascularization was suﬃcient and that improvement in MR and EF occur from improved left ventricular function and size after revascularization. Aklog and colleagues [46] reported 136 patients mean age 70.5 years with ischemic heart disease and more severe 3+ MR with a mean EF of 38.1%. Operative mortality was 2.9%. They found the intraoperative TEE underestimated the degree of MR and the postoperative TTE revealed that 40% of the patients still had 3+ MR, 51% improved to 2+ MR, and only 9% had 0 to 1+ MR. They conclude that ischemic MR required more than just revascularization, usually concomitant annuloplasty. Others have reported beneﬁt in terms of symptoms and improved survival in patients with severe left ventricular dysfunction and MR not only due to coronary artery disease but in cardiomyopathy and chronic valvular regurgitation [60, 61].

MITRAL ANNULAR CALCIFICATION Mitral annular calcium (MAC) is a chronic degenerative process that is common in elderly persons, especially women. The amount of calcium may vary from a few spicules to a large mass behind the posterior cusp, often extending to form a ridge or ring encircling the mitral leaﬂets, occasionally lifting the leaﬂets toward the left atrium. Sphincter function loss of the mitral annulus and mechanical stretching of the mitral leaﬂets can cause improper coaptation of the leaﬂets during systole, resulting in MR [62]. Although the calciﬁc mass may immobilize the mitral valve, actual calciﬁcation of the leaﬂets is rare. In persons with severe MAC, the calciﬁcation may extend inward to involve the underside of the leaﬂets. Mitral stenosis may result from severe calciﬁc deposits within the mitral annulus protruding into the oriﬁce [63]. Calciﬁc deposits may extend from the mitral annulus into the membranous portions of the ventricular septum, involving the conduction system and causing rhythm and conduction disturbances [64]. Although the annular calcium is covered with a layer of endothelium, ulceration of this lining can expose the underlying calciﬁc deposits, which may serve as a nidus for platelet-ﬁbrin aggregation and subsequent thromboembolic episodes [65,66]. In patients with endocarditis associated with

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MAC, the avascular nature of the mitral annulus predisposes to periannular and myocardial abscesses [66,67].

Prevalence MAC is a degenerative process that increases with age and occurs more frequently in women than in men [65,68]. In a prospective study of 1797 unselected elderly persons in a long-term health-care facility, mean age 81 F 8 years (range 60 to 103 years), with technically adequate M-mode and two-dimensional echocardiograms of the mitral valve, MAC was present in 665 of 1243 women (53%) and in 194 of 554 men (35%) [69]. Table 5 shows the prevalence of MAC with increasing age in elderly men and elderly women [70].

Predisposing Factors Because calciﬁc deposits in the mitral annulus, in the aortic valve cusps, and in the epicardial coronary arteries are commonly associated in elderly persons and have similar predisposing factors, Roberts [71] suggested that MAC and aortic cuspal calcium are a form of atherosclerosis. MAC and aortic cuspal calcium may coexist [62,65,68,71–73]. Breakdown of lipid deposits on the ventricular surface of the posterior mitral leaﬂet at or below the mitral annulus and on the aortic surfaces of the aortic valve cusps is probably responsible for the calciﬁcation [62]. Increased left ventricular systolic pressure due to aortic valve stenosis increases stress on the mitral apparatus and may accelerate development of MAC [62,65,74]. Tricuspid annular calcium and MAC may also coexist and have similar predisposing factors [75]. Systemic hypertension increases with age and predisposes to MAC [62,65,66,68,69]. Persons with diabetes mellitus also have a higher prevalence of MAC than nondiabetic persons [62,72,73]. MAC occurs in the teens in persons with serum total cholesterol levels >500 mg/dL [76]. Waller and Roberts [77] suggested that hypercholesterolemia predisposes to MAC. The prevalence of hypercholesterolemia with a serum total cholesterol z200 mg/dL was higher in elderly persons with MAC than in elderly persons without MAC [73]. Roberts [71] also stated that MAC is rare in older persons residing in areas of

Table 5 Prevalence of Mitral Annular Calcium with Increasing Age in Elderly Men and Elderly Women Mitral Annular Calcium Men Age (years) 62–70 71–80 81–90 91–100 101–103

n 4/22 13/42 44/75 19/22 —

Source: Adapted from Ref. 70.

Women (%) (18) (31) (59) (86) —

n 7/35 40/116 146/226 56/63 3/3

(%) (20) (34) (65) (89) (100)

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the world where serum total cholesterol levels are <150 mg/dL. However, Nair and colleagues [72] found no signiﬁcant diﬀerence in mean serum total cholesterol levels between persons younger than 60 years with MAC and a control group. Roberts and Waller [78] found that chronic hypercalcemia predisposes to MAC. Patients undergoing dialysis for chronic renal insuﬃciency have an increased prevalence of MAC [78–80]. MAC has also been found to be a marker of left ventricular dilatation and decreased left ventricular systolic function in patients with end-stage renal disease on peritoneal dialysis [81]. Cardiac calcium in patients with chronic renal failure has been attributed to secondary hyperparathyroidism [82]. Nair and colleagues [72] demonstrated a similar mean serum calcium, a higher mean serum phosphorus, and a higher mean product of serum calcium and phosphorus in patients younger than 60 years with MAC than in a control group. However, Aronow and colleagues [73] observed no signiﬁcant diﬀerence in mean serum calcium, serum phosphorus, or product of serum calcium and phosphorus between elderly persons with and without MAC. By accelerating the rate of rise of left ventricular systolic pressure, hypertrophic cardiomyopathy predisposes to MAC [62]. Kronzon and Glassman [83] diagnosed MAC in 12 of 18 patients (67%) older than 55 years with hypertrophic cardiomyopathy and in 4 of 28 patients (14%) younger than 55 years with hypertrophic cardiomyopathy. Nair and colleagues [84] found MAC in 12 of 42 patients (27%) with hypertrophic cardiomyopathy. Their patients with both MAC and hypertrophic cardiomyopathy were older than their patients with hypertrophic cardiomyopathy and no MAC. Motamed and Roberts [85] demonstrated MAC in 30 of 100 autopsy patients (30%) with hypertrophic cardiomyopathy older than 40 years and in none of 100 autopsy patients (0%) younger than 40 years with hypertrophic cardiomyopathy. Aronow and Kronzon [86] diagnosed MAC in 13 of 17 older persons (76%) with hypertrophic cardiomyopathy and in 176 of 362 older persons (49%) without hypertrophic cardiomyopathy. Elderly men and women with MAC have a higher prevalence of coronary artery disease [87–89], of peripheral arterial disease [89,90], of extracranial carotid arterial disease (ECAD) [89,91], and of aortic atherosclerotic disease [89] than elderly men and women without MAC. MAC has also been shown to be associated with thoracic aorta calcium in patients with systemic hypertension [92]. Diagnosis Calciﬁc deposits in the mitral annulus are J, C, U, or O-shaped and are visualized in the posterior third of the heart shadow [65,93,94]. MAC may be diagnosed by chest x-ray ﬁlms or by ﬂuoroscopy [56]. However, the procedures of choice for diagnosing MAC are Mmode and two-dimensional echocardiography. Posterior MAC (Fig. 1) is diagnosed by M-mode echocardiography when a band of dense echoes is recorded anterior to the left ventricular posterior wall and moving parallel with it [95]. These echoes end at the atrioventricular junction and merge with the left ventricular posterior wall on echocardiographic sweep from the aortic root to the left ventricular apex. Anterior MAC (Fig. 1) is diagnosed by M-mode echocardiography when a continuous band of dense echoes is observed at the level of the anterior mitral leaﬂet in both systole and diastole [95]. These echoes are contiguous with the posterior wall of the aortic root. Calciﬁcation may extend from the mitral annulus throughout the base of the heart and into the mitral and aortic valves.

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Figure 1 M-mode echocardiogram with scan from the aortic root to the left ventricular apex in a patient with both anterior and posterior mitral annular calcium. AOC = aortic calcium; AMAC = anterior mitral annular calcium; PMAC = posterior mitral annular calcium.

Figure 2 Two-dimensional echocardiogram long-axis view depicting mitral annular calcium (MAC). LA = left atrium; LV = left ventricle; RV = right ventricle; AO = aorta; AML = anterior mitral leaﬂet.

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Figures 2 and 3 are two-dimensional echocardiograms showing increased echogenicity and brightness of the mitral annulus characteristic of MAC. Using multiple echocardographic views, MAC may be classiﬁed as mild, moderate, or severe [96]. The echo densities in mild MAC involve less than one-third of the annular circumference (<3 mm in width) and are usually restricted to the angle between the posterior leaﬂet of the mitral valve and the left ventricular posterior wall. The echo densities in moderate MAC involve less than two-thirds of the annular circumference (3–5 mm in width). The echo densities in severe MAC involve more than two-thirds of the annular circumference (>5 mm in width), usually extending beneath the entire posterior mitral leaﬂet with or without making a complete circle. In a blinded prospective study, MAC was diagnosed by M-mode and two-dimensional echocardiography in 55% of 604 unselected elderly patients in a long-term healthcare facility [94]. The diagnosis of MAC by chest x-ray ﬁlms using a lateral chest x-ray in addition to the posterior-anterior or anterior–posterior chest x-ray had a sensitivity of 12%, a speciﬁcity of 99%, a positive predictive value of 95%, and a negative predictive value of 47%. Patients with radiographic MAC were more likely than patients without radiographic MAC to have a more severe form of the disease, with signiﬁcant MR, functional MS, or conduction defects. However, patients with echocardiographically severe MAC and signiﬁcant MR, functional MS, or conduction defects may have no evidence of MAC on chest x-ray ﬁlms. Figure 4 shows C-shaped calciﬁcation of the mitral annulus. Figure 5 illustrates J-shaped calciﬁcation of the mitral annulus.

Figure 3 Two-dimensional echocardiogram four-chamber view of a patient with mitral annular calcium (MAC). LA = left atrium; RA = right atrium; RV = right ventricle; LV = left ventricle; AML = anterior mitral leaﬂet; PML = posterior mitral leaﬂet.

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Figure 4 Posterior-anterior chest X-ray in a patient with C-shaped calciﬁcation of the mitral annulus (arrows).

Chamber Size Patients with MAC have a higher prevalence of left atrial enlargement [62,66,68,70,72,96] and left ventricular enlargement [68,72,96] than patients without MAC. In a prospective study of 976 elderly patients (526 with MAC and 450 without MAC), left atrial enlargement was 2.4 times more prevalent in patients with MAC than in the group without MAC [66].

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Figure 5 Posterior-anterior chest X-ray in a patient with J-shaped calciﬁcation of the mitral annulus (arrow).

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Atrial Fibrillation Patients with MAC also have a higher prevalence of atrial ﬁbrillation than patients without MAC [65,66,68,70,96,97]. Table 6 shows that the prevalence of atrial ﬁbrillation was increased 12, 5, and 2.8 times in patients with MAC than in patients without MAC [68,96,97]. Conduction Defects Because of the close proximity of the mitral annulus to the atrioventricular node and the bundle of His, patients with MAC have a higher prevalence of conduction defects, such as sinoatrial disease, atrioventricular block, bundle branch block, left anterior fascicular block, and intraventricular conduction defect, than patients without MAC [64,65,74,96]. The calciﬁc deposits may also extend into the membranous portions of the interventricular septum involving the conduction system, or may even extend to the left atrium, interrupting interatrial and intra-atrial conduction. In addition, MAC may be associated with a sclerodegenerative process in the conduction system. Nair et al. [96] showed in their prospective study that patients with MAC had a higher incidence of permanent pacemaker implantation because of both atrioventricular block and sinoatrial disease than patients without MAC. Mitral Regurgitation MAC is thought to generate systolic murmurs by the sphincter action loss of the annulus and the mechanical stretching of the mitral leaﬂets causing MR and from vibration of the calciﬁed ring or vortex formation around the annulus. Table 7 shows that the prevalence of apical systolic murmurs of MR in patients with MAC ranged from 12% to 100% in diﬀerent studies [65,68,95,98–101]. Table 8 states the prevalence of MR diagnosed by Doppler echocardiography in patients with MAC [97,101–103]. The prevalence of MR associated with MAC ranged from 54% to 97% in the Doppler echocardiographic studies [101–103]. Figure 6 illustrates severe MR due to MAC diagnosed by color Doppler echocardiography. The greater the severity of MAC, the greater the severity of MR associated with MAC. Moderate-to-severe MR was diagnosed by Doppler echocardiography in 33% of

Table 6 Prevalence of Atrial Fibrillation in Patients With and Without Mitral Annular Calcium (MAC) Atrial ﬁbrillation MAC

Framingham Study [18] Patients younger than 61 years [58] Patients older than 60 years (mean age 81 F 8) [62]

No MAC

n

(%)

n

(%)

20/162 11/107

(12) (10)

53/5532 2/107

(1) (2)

225/1028

(22)

85/1120

(8)

Relative risk 12 5 2.8

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Table 7 Prevalence of Apical Systolic Murmurs of Mitral Regurgitation (MR) in Patients with Mitral Annular Calcium Prevalence of MR murmur (%)

n Korn et al. [16] Schott et al. [32] Hammer et al. [2] Fulkerson et al. [7] Savage et al. [18] Nair et al. [57] Aronow et al. [22] Aronow et al. [63] a

14/14 10/14 2/4 72/80 26/132 17/104 129/293 43/100

(100) (71)a (50) (90) (12) (16) (44) (43)

MAC due to noninﬂammatory calciﬁc disease.

51 patients with MAC by Labovitz and colleagues [103] and in 22% of 1028 patients with MAC by Aronow and colleagues [97]. Kaul and colleagues [102] diagnosed severe MR in 7% of their 29 patients with MAC. Kaul and colleagues [102] also concluded from their study that MR in patients with MAC is caused by a reduced sphincteric action of the mitral annulus, with MAC preventing the posterior annulus from contracting and assuming a ﬂatter shape during systole. Mitral Stenosis An apical diastolic murmur may be heard in patients with MAC as a result of turbulent ﬂow across the calciﬁed and narrowed annulus (annular stenosis). Table 9 shows that the prevalence of apical diastolic murmurs of MS in patients with MAC ranged from 0% to 25% in diﬀerent studies [68,95,98,100,101,103,104]. Table 9 also indicates that MS associated with MAC was diagnosed by Doppler echocardiography in 8% of 51 patients by Labovitz and colleagues [103], in 6% of 100 patients by Aronow and Kronzon [101], and in 8% of 1028 patients by Aronow et al. [97]. Figure 7 illustrates MS due to MAC diagnosed by Doppler echocardiography. The reduction of mitral valve oriﬁce in patients with MAC is due to the annular calcium and to decreased mitral excursion and mobility secondary to calcium at the base of

Table 8 Prevalence of Mitral Regurgitation Diagnosed by Doppler Echocardiography in Patients with Mitral Annular Calcium MR

Labovitz et al. [64] Aronow et al. [63] Kaul et al. [60] Aronow et al. [62] a

Moderate-to-severe MR

n

(%)

n

(%)

28/51 54/100 28/29 —

(55) (54) (97)a —

17/51 18/100 — 224/1028

(33) (18) — (22)

Severe mitral regurgitation in 2 of 29 patients (7%).

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Figure 6 Color Doppler echocardiographic ﬁndings in a patient with mitral annular calcium and severe mitral regurgitation (MR). LA = left atrium; RA = right atrium; RV = right ventricle; LV = left ventricle. (See color insert.)

Table 9 Prevalence of Apical Diastolic Murmurs of Mitral Stenosis and of Mitral Stenosis in Patients with Mitral Annular Calcium Prevalence of MS murmu

Simon and Liu [52] Korn et al. [16] Schott et al. [32] Hammer et al. [2] Savage et al. [18] Nair et al. [57] Aronow et al. [22] Labovitz et al. [64] Aronow et al. [63] Aronow et al. [62] a

Prevalence of MS by Doppler echocardiography

n

(%)

n

(%)

5/59 3/14 2/14 1/4 2/132 7/104 28/293 0/51 6/100 —

(8) (21) (14)a (25) (2) (7) (10) (0) (6) —

— — — — — — — 4/51 6/100 83/1028

— — — — — — — (8) (6) (8)

MAC due to noninﬂammatory calciﬁc disease.

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Figure 7 Continuous-wave Doppler tracing across a stenotic mitral valve oriﬁce due to mitral annular calcium. Peak diastolic gradient = 12 mmHg. Pressure halftime = 200 ms. Mitral valve area = 1.1 cm2.

the leaﬂets [101]. The commissures are fused in rheumatic MS but are not fused in MS associated with MAC. The mitral leaﬂet margins in MAC may be thin and mobile, and the posterior mitral leaﬂet may move normally during diastole. However, Doppler echocardiographic recordings show increased transvalvular ﬂow velocity and prolonged pressure halftime and, therefore, smaller mitral valve oriﬁce in patients with MS, regardless of the etiology. Bacterial Endocarditis Bacterial endocarditis, with a high incidence of Staphylococcus aureus endocarditis, may complicate MAC [12,65,66]. Patients with MAC associated with chronic renal failure are especially at increased risk for developing bacterial endocarditis [99]. The calciﬁc mass erodes the endothelium under the mitral valve, which is exposed to transient bacteremia. The avascular nature of the mitral annulus interferes with antibiotics reaching a nidus of bacteria, predisposing to periannular and myocardial abscesses and, consequently, to a poor prognosis [12,105]. Burnside and DeSanctis [105] therefore recommended prophy-

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lactic antibiotics to prevent bacterial endocarditis in patients with MAC. Nair and colleagues [68] observed at 4.4-year mean follow-up no signiﬁcant diﬀerence in incidence of bacterial endocarditis in 99 patients younger than 61 years with MAC compared to a control group of 101 patients. However, Aronow and colleagues [66] demonstrated at 39month mean follow-up a 3% incidence of bacterial endocarditis in 526 elderly patients with MAC and a 1% incidence of bacterial endocarditis in 450 elderly patients without MAC. On the basis of these data, prophylactic antibiotics should be used to prevent bacterial endocarditis in patients with MAC, according to American Heart Association guidelines [106]. Cardiac Events In a prospective study of 107 patients (8 lost to follow-up) younger than 61 years with MAC and 107 (6 lost to follow-up) age- and sex-matched control subjects, Nair and colleagues [96] demonstrated at 4.4-year mean follow-up that patients with MAC had a higher incidence of new cardiac events than control subjects (Table 10). In a prospective study of 526 elderly patients with MAC and 450 elderly patients without MAC, Aronow and colleagues [66] found at 39-month mean follow-up that the incidence of new cardiac events (myocardial infarction, primary ventricular ﬁbrillation, or sudden cardiac death) was also higher in elderly patients with MAC than in elderly patients without MAC (Table 10). Mitral Valve Replacement Nair and colleagues [107] reported that mitral valve replacement can be accomplished in patients with MAC with morbidity and mortality similar to that in patients without MAC. Following mitral valve replacement, subsequent morbidity and mortality during 4.4-year mean follow-up were also similar in patients with and without MAC.

Table 10

Incidence of New Cardiac Events in Patients With and Without Mitral Annular Calcium Cardiac events MAC Follow-up

Nair et al. [58] Total cardiac death Sudden cardiac death Congestive heart failure Mitral or aortic valve replacement Aronow et al. [23] cardiac eventsa if: Atrial ﬁbrillation Sinus rhythm All patients a

No MAC

n

(%)

31/99 12/99 41/99 9/99

(31) (12) (41) (9)

2/101 1/101 6/101 0/101

62/90 157/436 219/526

(69) (36) (42)

22/41 106/409 128/450

n

(%)

Relative risk

(2) (1) (6) (0)

15.5 12.0 6.8 —

(54) (26) (28)

1.3 1.4 1.5

Years

39 months

Myocardial infarction, primary ventricular ﬁbrillation, or sudden cardiac death.

468

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Cerebrovascular Events Although the increased prevalence of atrial ﬁbrillation, MS, MR, left atrial enlargement, and congestive heart failure predisposes patients with MAC to thromboembolic stroke, some investigators consider MAC a marker of other vascular disease causing stroke rather the primary embolic source [108]. In a retrospective study of 110 elderly patients with chronic atrial ﬁbrillation, 44 (40%) had documented thromboembolic stroke [109]. In this study, the prevalence of MAC was not signiﬁcantly diﬀerent in elderly patients with thromboembolic stroke (80%) or without thromboembolic stroke (65%) (relative risk = 1.2). However, six prospective studies have demonstrated an increased incidence of new cerebrovascular events in patients with MAC than in patients without MAC (Tables 11–13) [66,96,97,110–112] ranging from a relative risk of 1.5 up to 5.0. Aronow and colleagues studied the incidence of new thromboembolic stroke at 44month mean follow-up in 310 unselected elderly patients in a long-term health-care facility with chronic atrial ﬁbrillation [97] (Table 12). MS and the severity of MR were diagnosed by Doppler echocardiography in this study [97]. In elderly persons with chronic atrial ﬁbrillation, MAC increased the incidence of new thromboembolic stroke 2.1 times if MS was associated with MAC, 1.7 times if 2-4+ MR was associated with MAC, and 1.4 times if 0-1 + MR was present.

Table 11 Incidence of New Cerebrovascular Events in Patients With and Without Mitral Annular Calcium Cerebrovascular events MAC Follow-up Nair et al. [58] TE cardiovascular events Benjamin et al. [69] stroke Aronow et al. [23] TE stroke if: Atrial ﬁbrillation Sinus rhythm All patients Boston Area Anticoagulation Trial for Atrial Fibrillation [70], ischemic stroke Aronow et al. [47], TE stroke if: 40–100% ECD 0–39% ECD TIA if 40–100% ECD 0–39% ECD

No MAC

n

(%)

n

(%)

Relative risk

4.4 years

10/99

(10)

2/101

(2)

5.0

8 years

22/160

(14)

51/999

(5)

2.7

45/90 59/436 104/526 10/129

(50) (14) (20) (8)

14/41 38/409 52/450 5/291

(34) (9) (12) (2)

1.5 1.6 1.7 4.0

52/101 88/365

(51) (24)

16/49 47/413

(33) (11)

1.5 2.2

8/101 11/365

(8) (3)

3/49 3/413

(6) (1)

1.3 3.0

39 months

2.2 years

45 months

Abbreviations: TE = thromboembolic; ECD = extracranial carotid arterial disease; TIA = cerebral transient ischemic attack.

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469

Table 12 Incidence of New Thromboembolic Stroke at 44-Month Mean Follow-Up in Elderly Patients With Chronic Atrial Fibrillation Thromboembolic stroke (%) Atrial Atrial Atrial Atrial

ﬁbrillation, no MAC (n = 85) ﬁbrillation with mitral stenosis due to MAC (n = 42) ﬁbrillation with MAC and 2–4 + mitral regurgitation (n = 90) ﬁbrillation with MAC and 0–1 + mitral regurgitation (n = 93)

(35) (74) (59) (48)

Abbreviation: MAC = mitral annular calcium. Source: Adapted from Ref. 97.

Table 13 shows the incidence of new thromboembolic stroke at 44-month mean follow-up in 1838 unselected older persons, mean age 81 years, in a long-term health-care facility with sinus rhythm [97]. In elderly persons with sinus rhythm, MAC increased the incidence of new thromboembolic stroke 3.6 times if MS was associated with MAC, 3.1 times if 2-4+ MR was associated with MAC, and 2.7 times if 0-1+ MR was present. Using the multivariate Cox regression model, independent risk factors for new thromboembolic stroke in this study were prior stroke (risk ratio = 2.4), MAC (risk ratio = 2.6), atrial ﬁbrillation (risk ratio = 3.0), and male gender (risk ratio = 1.6). There was a higher prevalence of MAC in elderly patients with 40 to 100% ECAD (67% of 150 patients) than in elderly patients with 0 to 39% ECAD (47% of 778 patients) [112]. The increased prevalence of signiﬁcant ECAD contributes to a higher stroke rate. Thrombi of the mitral annulus also contribute to thromboembolic stroke in elderly patients with MAC [112,113]. In addition, MAC is associated with aortic atheromatous disease [89], complex intra-aortic debris [114], and thoracic aorta calcium [92] which could contribute to thromboembolic stroke. Some patients with MAC who experienced thromboembolic events also had a mobile component that was associated with the thromboembolic events [115]. There was no signiﬁcant diﬀerence in the association of MAC with prior stroke between elderly whites and elderly African Americans, between elderly whites and elderly Hispanics, and between elderly African Americans and elderly Hispanics [116]. Since patients with MAC and atrial ﬁbrillation or sinus rhythm have a higher incidence of thromboembolic stroke than patients without MAC, antithrombotic therapy should be considered in patients with MAC and no contraindications to antithrombotic therapy. In

Table 13 Incidence of New Thromboembolic Stroke at 44-Month Mean Follow-Up in Elderly Patients With Sinus Rhythm Thromboembolic Stroke (%) Sinus Sinus Sinus Sinus

rhythm, no MAC (n = 1035) rhythm with mitral stenosis due to MAC (n = 41) rhythm with MAC and 2–4 + mitral regurgitation (n = 134) rhythm with MAC and 0–1 + mitral regurgitation (n =625)

Abbreviations: MAC = mitral annular calcium. Source: Adapted from Ref. 97.

(9) (32) (28) (24)

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the Boston Area Anticoagulation Trial for Atrial Fibrillation study, warfarin reduced the incidence of thrombembolic stroke in patients with MAC by about 90% [117,118]. Until data from prospective, randomized studies evaluating the eﬃcacy and risk of antithrombotic therapy in patients with MAC are available, patients with MAC associated with either atrial ﬁbrillation, MS, or moderate-to-severe MR should be considered for treatment with warfarin if they have no contraindications to anticoagulant therapy. The INR should be maintained between 2.0 and 3.0. The eﬃcacy of antiplatelet therapy in patients with MAC is unknown.

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96. Nair CK, Thomson W, Ryschon K, Cook C, Hee TT, Sketch MH Sr. Long-term follow-up of patients with echocardiographically detected mitral anular calcium and comparison with ageand sex-matched control subjects. Am J Cardiol 1989; 63:465–470. 97. Aronow WS, Ahn C, Kronzon I, Gutstein H. Association of mitral annular calcium with new thromboembolic stroke at 44-month follow-up of 2,148 persons, mean age 81 years. Am J Cardiol 1998; 81:105–106. 98. Korn D, DeSanctis RW, Sell S. Massive calciﬁcation of the mitral annulus: A clinicopathologic study of fourteen cases. N Engl J Med 1962; 267:900–909. 99. Schott CR, Kotler MN, Parry WR, Segal BL. Mitral annular calciﬁcation: Clinical and echocardiographic correlations. Arch Intern Med 1977; 137:1143–1150. 100. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of murmurs of mitral stenosis and mitral regurgitation with presence or absence of mitral anular calcium in persons older than 62 years in a long-term health care facility. Am J Cardiol 1987; 59:181–182. 101. Aronow WS, Kronzon I. Correlation of prevalence and severity of mitral regurgitation and mitral stenosis determined by Doppler echocardiography with physical signs of mitral regurgitation and mitral stenosis in 100 patients aged 62 to 100 years with mitral anular calcium. Am J Cardiol 1997; 60:1189–1190. 102. Kaul S, Pearlman JD, Touchstone DA, Esquival L. Prevalence and mechanisms of mitral regurgitation in the absence of intrinsic abnormalities of the mitral leaﬂets. Am Heart J 1989; 118:963–972. 103. Labovitz AJ, Nelson JG, Windhorst DM, Kennedy HL, Williams GA. Frequency of mitral valve dysfunction from mitral anular calcium as detected by Doppler echocardiography. Am J Cardiol 1985; 55:133–137. 104. Simon MA, Liu SF. Calciﬁcation of the mitral valve annulus and its relation to functional valvular disturbance. Am Heart J 1954; 48:497–505. 105. Burnside JW, DeSanctis RW. Bacterial endocarditis on calciﬁcation of the mitral anulus ﬁbrosus. Ann Intern Med 1972; 76:615–618. 106. Dajani AS, Taubert KA, Wilson W, Bolger AF, Boyer A, Ferrieri P, Gewitz MH, Shulman ST, Nouri S, Newburger JW, Hutto C, Pallasch TJ, Gage TW, Levison ME, Peter G, Zuccaro G Jr. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997; 96:358–366. 107. Nair CK, Biddle P, Kaneshige A, Cook C, Rysehon K, Andersen A, Sketch MH Sr. Mitral valve replacement in patients with mitral anular calcium [abstr]. Chest 1991; 100(suppl): 109S. 108. Sherman DG, Dyken ML, Fisher M, Harrison MJG, Hart RG. Cerebral embolism. Chest 1986; 89:82S–98S. 109. Aronow WS, Gutstein H, Hsieh FY. Risk factors for thromboembolic stroke in elderly patients with chronic atrial ﬁbrillation. Am J Cardiol 1989; 63:366–367. 110. Benjamin EJ, Plehn JF, D’Agostino RB, Belanger AJ, Comai K, Fuller DL, Wolf PA, Levy D. Mitral annular calciﬁcation and the risk of stroke in an elderly cohort. N Engl J Med 1992; 327:374–379. 111. Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The eﬀect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial ﬁbrillation. N Engl J Med 1990; 323:1505–1511. 112. Stein JH, Soble JS. Thrombus associated with mitral valve calciﬁcation. A possible mechanism for embolic stroke. Stroke 1995; 26:1697–1699. 113. Eicher J-C, Soto F-X, DeNadai L, Pessencourt O, Falcon-Eicher S, Giroud M, Louis P, Wolf JE. Possible association of thrombotic, nonbacterial vegetations of the mitral ring–mitral annular calcium and stroke. Am J Cardiol 1997; 79:1712–1715. 114. Rubin DC, Hawke MW, Plotnick GD. Relation between mitral annular calcium and complex intraaortic debris. Am J Cardiol 1993; 71:1251–1252. 115. Shohat-Zabarski R, Paz R, Adler Y, Vaturi M, Jortner R, Sagie A. Mitral annulus calciﬁ-

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Cheitlin and Aronow cation with a mobile component as a possible source of embolism. Am J Geriatr Cardiol 2001; 10:196–198. Aronow WS, Ahn C, Kronzon I, Gutstein H. Association of mitral annular calcium with prior thromboembolic stroke in older white, African-American, and Hispanic men and women. Am J Cardiol 2000; 85:672–673. Aronow WS. The eﬀect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial ﬁbrillation. Letter to the Editor. N Engl J Med 1991; 325:130. Singer DE, Hughes RA, Gress DR, Sheehan MA, Oertal LB, Maraventano SW, Blewett DR, Rosner B, Kistler JP. The eﬀect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial ﬁbrillation (reply to letter to the editor). N Engl J Med 1991; 325:131.

19 Endocarditis in the Elderly Thomas C. Cesario and David A. Cesario University of California, Irvine, Irvine, California, U.S.A.

Encocarditis is a disease with variable manifestations. In the preantibiotic era, endocarditis predominately occurred in the third and fourth decades [1], but numerous publications have now provided an increasing awareness of the growing proportion of older individuals aﬄicted with this disease. The ﬁrst comprehensive account of endocarditis in the English literature was provided by William Osler [2]. Generally thought to be a result of the infections of platelet ﬁbrin deposition on the endocardial surface [3,4] of previously damaged heart valves, the manifestations of endocarditis are many and the consequences great; however, it is acknowledged that certain organisms may infect normal heart valves. A number of prior reviews have crystallized the classic nature of this disease for the clinician. King and Harkness [5] have provided one such survey of the general nature of this disease process. The overall incidence of endocarditis worldwide was estimated to be 60 per million per year [6], with the majority of cases typically seen in males [5]. The changing age incidence of this process is reviewed here. In the past, the most common predisposing factor for infection of the endocardium had been rheumatic heart disease. Of all cases, 25 to 60% occurred on valves damaged by the consequences of rheumatic fever [5]. Other predisposing factors included congenital heart disease (10–20% of cases), mitral valve prolapse, prosthetic valves, and degenerative processes occurring on the valves. Traditionally, the viridans streptococci, other strains of streptococci, and the staphylococci have accounted for the majority of cases of bacterial endocarditis [7] occurring in all age groups [8]. According to King and Harkness, endocarditis can lead to clinical manifestations in four ways: (1) constant bacteremia; (2) local invasion; (3) peripheral embolization; and (4) circulating immune complexes. These lead to the classic signs and symptoms associated with endocarditis, including changing murmurs, skin manifestations, embolic episodes, and splenomegaly. Treatment depends on identiﬁcation of the appropriate organism, generally by culture of the blood, and selection of an antibiotic to which the organism is susceptible. In some cases surgery is indicated. Earlier overviews of endocarditis reﬁned the character of endocarditis in the postantibiotic era. Rabinovich et al. [9] reviewed the cases of bacterial endocarditis occurring over a 40-year period at the university hospitals in Iowa. They conﬁrmed the male predominance of the disease and that rheumatic heart disease was the major predisposing factor over the 477

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years, accounting for 68.2% of all cases. Congenital heart disease was the second most common identiﬁable predisposing factor, accounting for 13.1% of the cases; however, no identiﬁable heart disease was found in 16.3% of the cases. a-Hemolytic streptococci accounted for 61.4% of the cases. Fever was present in every case, skin manifestations (petechiae) in 48% of the cases, clubbing in only 15%, and splenomegaly in 43%. As for laboratory values, hematuria was present in 28% of the patients and anemia in 78%. Complications reported included embolic episodes in 55 of the 337 individuals and congestive heart failure in 25. The immediate fatality rate since 1950 was 30% for the total group, and the authors signiﬁcantly noted that ‘‘age by itself did not seem to have any eﬀect on the fatality rate.’’ A year later, Lerner and Weinstein [10] published one of the best-known endocarditis series reported in the modern era. They described 100 patients seen at the New England Medical Center in Boston. They clearly documented the rising age of patients with endocarditis occurring after the studies of Kelson and White [1] and appreciated that 60% of these individuals were over the age of 50. They again noted 56% of the patients were infected with streptococci (27% viridans streptococci) and 23% with staphylococci (20% with Staphylococcus aureus). In reviewing the underlying heart disease predisposing to endocarditis, these authors noted no antecedent cardiac disorder could be ascertained in 39% of the cases. Of those in whom an underlying cardiac diagnosis seemed apparent, Lerner and Weinstein reported that rheumatic heart disease was most common (40%), followed by congenital heart disease (10%) and arteriosclerotic disease (3%). They emphasized that many elderly patients with endocarditis had no knowledge of antecedent cardiac disease. In reviewing the clinical features of the disease, these authors reported 97% of the patients were febrile, 85% had murmur, 29% had petechiae, 44% had splenomegaly, and 30% had at least one episode of major embolic phenomenon. Hematuria was found in 26% of the cases, anemia in 50%, and elevated erythrocyte sedimentation rates in 90%. These authors pointed out that mortality rate did not seem aﬀected much by age until the eighth decade of life. Of the eight patients who were 70 or older, seven succumbed to illness. In 1971, Cherubin and Neu [11] reported a 30-year experience with endocarditis at Presbyterian Hospital in New York City. They reviewed the records of 656 cases of infective endocarditis seen between 1938 and 1967. They again appreciated the increasing mean age of the patients, from 31 years in 1938 to 52 years of age in 1966, and described the impact of social change on the epidemiological characteristics of endocarditis. Thus, they reported an increase in staphylococcal and fungal valvular infections secondary to increasing narcotic usage. Similarly, they appreciated a rising incidence of enterococcal disease despite the fact that Streptococcus viridans remained the most common causative organism for bacterial endocarditis. Rheumatic fever was the most common predisposing factor for bacterial endocarditis (38.5% of cases) in this study, followed by congenital heart disease (5.8% of the cases). They commented that ‘‘the older the patient the less frequent is an antecedent history of valvular heart disease.’’ These authors noted an increase in aortic valve disease, a slight decrease in mitral valve disease, and a marked decline in combined aortic-mitral disease. In 1978, Garvey and Neu [12] reported the occurrence of endocarditis at ColumbiaPresbyterian Hospital for the years 1968 to 1973. Those years saw 154 patients admitted to that institution, with a total of 165 episodes of endocarditis. In this series, the mean age of the patients rose a further 3 years, to 55 years. Infection on prosthetic valves accounted for 20.6% of the cases, but in the cases of natural valve endocarditis, aortic involvement exceeded mitral involvement (39–35%). Rheumatic fever was again the most common predisposing factor, followed by congenital heart disease, although 65% of the cases for

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whom information was available had no known underlying cardiac process. Streptococci were the most common organisms producing natural valve endocarditis; however, enterococci accounted for 6.5% of the cases and S. aureus for 16%. Negative blood cultures were found in 11% of the patients. In 84% of the cases of natural valve endocarditis, fever was appreciated and murmurs were found in 96%. Elevated erythrocyte sedimentation rates (ESR) were noted in 86% of the cases. Major emboli occurred in 55 of the 107 cases of natural valve bacterial endocarditis, and congestive heart failure was seen in half the patients in this series. One-fourth of the cases died, but half of these were lost because the true diagnosis was not recognized. In 1980, Lowes et al. [13] published the experience of St. Bartholomew’s Hospital, London, over the years 1966 to 1975. These authors followed 60 patients. As found by authors before them, the age of the patients increased over reports from the preantibiotic era; thus, 45% of the cases occurred in patients over the age of 50. The male–female ratio was 1:5 to 1:0. The predominant underlying heart disease was rheumatic in nature (35%), followed by congenital lesions (22%); however, no underlying disease was found in 30%. Clinically only two-thirds of the patients reported fever, but congestive heart failure, cutaneous manifestations, and splenomegaly occurred in almost half the individuals. In this period echocardiography was introduced, and six patients were described in whom this procedure localized the process. Blood cultures were positive in 86% of the patients from whom samples were taken, and streptococci accounted for nearly two-thirds of the isolates. Enterococci were reported in seven instances (13%). The overall mortality in this series was 20%, but these authors suggested mortality was much higher in patients over 40 (25% vs. 10% in younger patients). In 1981, Von Reyn et al. [14] surveyed endocarditis at the Beth Israel Hospital in Boston between the years 1970 and 1977. They reported 104 instances in 94 patients and noted the advanced age of the patients (57 years mean age), the short duration of symptoms (27 days mean), and the high incidence of underlying valvular heart disease (66%). The highest percentage of cases occurred on the mitral valve (40%). Most of the cases were due to viridans streptococci, and only 5% were culture negative. In additional, 13% of the patients had nosocomial endocarditis, 12% had prosthetic valve infections, and 18% required surgery. A total of 86% of the cases were febrile, 86% had murmurs, and 32% had splenomegaly. The overall mortality was 15% in this series. M-mode echocardiography was done in 32 patients, six of whom were demonstrated to have vegetations. In 1993, Watanakunakorn and Burkett [15] reported on 210 cases of endocarditis from a large community teaching hospital. They noted that the largest percentage of their patients were in the age group between 60 and 70 years of age. Almost 46% of their non-IVDU patients had no underlying valve disease. Thirty of the 210 cases of endocarditis in their series were nosocomial and the most frequently encountered organism responsible for the endocarditis was Staphylococcus aureus (48.6% of non-prosthetic-valve infection in patients who were not intravenous drug users). Fever (66.2%), chills (42.6%), and malaise (39.9%) were the most common symptoms in this group and 81.1% had murmurs. Twenty-eight percent of their cases occurred in individuals with atherosclerotic valves and only 7% in patients with valves damaged by rheumatic fever. Twenty seven of their cases occurred in individuals with prosthetic valves. In 1995, Hogevik et al. [16] described the epidemiological aspects of endocarditis in a Swedish population. They pointed out the incidence of endocarditis was more than six times greater in the age group over 70 than in the age group under 70, and the median age of their patients was 69 years. Forty-four percent of their patients had no previous history of

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valvular disease, but rheumatic fever was the predisposing factor in 186 of the episodes and 15% of the cases occurred in patients with prosthetic valves. Fever and fatigue were again the most common symptoms. Most importantly they noted that the risk of embolization was less in the group >70 years of age as compared to the group <70. In this series, streptococci were encountered slightly more often than staphylococci. Thus, a summary of some of the major reviews of endocarditis occurring over the last 65 years shows several changing trends. Perhaps most striking has been the advancing age of the patients, which was an almost universal ﬁnding. In addition, most of these extensive reviews found fever and murmurs to be very frequent in endocarditis patients and anemia and elevated erythrocyte sedimentation rates to be common. Other manifestations, including cutaneous ﬁndings, splenomegaly, and neurological ﬁndings, occurred in half or less of the cases. Rheumatic heart disease remained a common predisposing factor but many of the more recent cases occurred in individuals with no known valvular problems. Streptococci, especially viridans streptococci, was the most frequent etiological agent identiﬁed. Several summaries [17–19] of endocarditis in the most recent years have noted the disease remains present (incidence of 1.7 to 6.2 cases/110,000 person years) but describe degenerative and mitral valve prolapse as the most common predisposing cardiac condition for native valve endocarditis. Streptococci and staphylococci still remained the most common causes of native valve endocarditis. Since the early descriptions of Osler, various authors have focused on age-related diﬀerences in the disease process. Kerr [20], in his classic monograph, noted that Gibson in 1896 remarked on the modiﬁed character of the disease in old age. Kerr himself suggested that, as the population aged, arteriosclerotic valvular heart disease would become a signiﬁcant antecedent cardiac lesion for bacterial endocarditis. In the later part of this review, we focus on the surveys of endocarditis reported in the English literature that have examined the speciﬁcs of endocarditis in the elderly. This provides a basis for determining diﬀerences between the disease in the general population, as described earlier, and older individuals. In 1940, Bayles and Lewis [21] reported 28 cases of endocarditis diagnosed at autopsy in people over the age of 40. The authors noted the majority of cases occurred on valves damaged by rheumatic fever but that 25% of the cases occurred on arteriosclerotic valves. They commented on the similarity of the clinical features between younger and older patients, but noted the greater subtlety of the disease in the older group. In the same year, Willis [22] described the occurrence of endocarditis in an 82-year-old. In 1945, Zeman and Siegal [23] reported 27 cases of bacterial endocarditis in patients over the age of 60. They emphasized that the features of endocarditis in the older population were more likely classiﬁed as acute. The features of acute disease have generally implied a more aggressive course with a shorter duration of symptoms. To some authors, acute disease has suggested the occurrence of infection on presumably normal valves, generally caused by S. aureus, Streptococcus pneumoniae, or group A h-hemolytic streptococci. In recent years, the use of the terms ‘‘acute’’ and ‘‘subacute’’ endocarditis have not been as popular. Zeman and Siegal also stressed the diagnostic diﬃculties encountered in older patients with bacterial endocarditis because of the frequent occurrence of other underlying disease processes. In 1949, Traut et al. [24] reported 94 cases of bacterial endocarditis in patients over 45 years of age diagnosed at Cook County Hospital over the years 1935 to 1946. The vast majority of these (61%) occurred on valves damaged by rheumatic fever, but ﬁve occurred on atherosclerotic valves. They emphasized the infrequency of the disease in older people. In an autopsy series, Wallach et al. [25] described 13 cases of bacterial endocarditis super-

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imposed on rheumatic valves and 17 cases imposed on valves without rheumatic disease, all of which occurred in patients over the age of 50. These authors noted that the disease in the older patients was more often incidental, not directly related to the cause of death. They further noted that the older patients more frequently had underlying genitourinary infections or other diseases (diabetes mellitus) and more often had sclerotic changes in the valves. A year later, Anderson et al. [26] emphasized the occurrence of endocarditis in older patients from St. Thomas’ Hospital in London. They reviewed 14 cases (18.4% of the total cases) seen from 1946 to 1954 occurring in people older than 60 years. In this group, mortality was higher (50%) versus the entire group of patients with endocarditis seen at their hospital (31%). The patients included 10 with S. viridans infection and 4 with either negative cultures or no cultures. Virtually all patients had evening temperatures of 100jF or higher, and all had murmurs; 43% of the patients had splenomegaly, and the same number had cutaneous manifestations. They commented that endocarditis was ofter missed in the elderly because it was not generally realized that the disease could occur in this age group, that the disease in the aged was less severe, and that several criteria usually associated with endocarditis were not necessarily found in the aged. Somewhat later, Gleck [27] described 10 cases of endocarditis occurring in patients over age 55. He noted that in addition to dental extractions and skin infections, genitourinary tract manipulations were precipitating events in the elderly. The subjects of this report were six men and four women. Although three patients had typical features of endocarditis, another three patients presented with changes in mental status or depression; one patient presented with liver disease, one with uremia, one with anorexia and weight loss, and one with stroke. At least two patients had maximum daily temperatures below 100jF. Of the atypical patients, four died. In the same year, Hartman and Myers [28] noted 7 of 20 patients with endocarditis to be over the age of 60. Of the seven, four were female, ﬁve were infected by S. viridans, one by staphylococcus, and one by enterococcus. Of these patients, four had rheumatic heart disease and three had arteriosclerotic disease; two patients died. These authors suggested enterococcal endocarditis was common in the older patient. Cummings et al. [29] in 1960 noted that 18 of 55 patients with endocarditis were over age 50. Of these patients, 13 died (72%), as opposed to 10 of 37 below this age (27%). Of the patients, 10 were females and, in all but three, murmurs were described. Of all patients, 27% had splenomegaly, but only half were reported to have fever. Streptococcal infections were seen in six patients, and in one Proteus vulgaris was isolated from the blood. The rest had negative cultures or no cultures were drawn. Uwaydah and Weinberg [30], in 1965, noted the changing pattern of endocarditis. They reviewed 100 total patients seen at the Massachusetts General Hospital in Boston. In their series, 38% of the cases were over the age of 60, and half of these had infection superimposed on arteriosclerotic or calciﬁed valves. They commented on the declining incidence of rheumatic fever as a predisposition for endocarditis in the older patient. In this series, 37% of the young patients died, but 68% of the older group expired. In 1973, Habte-Gabr et al. [31] reported 57 patients over the age of 60 with endocarditis seen at the University of Iowa Hospital between 1940 and 1971. They noted endocarditis in the elderly had gradually increased. The male–female incidence was 4:1. They commented that, although all the patients were febrile, half complained of weight loss, confusion, or other symptoms. These authors noted that the signs and symptoms were similar between younger and older patients. Of all patients, 27% had negative cultures; however, the

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most common organisms isolated from the older age group included a-hemolytic streptococcus (40%), other streptococci (23%), and staphylococci (23%). Of the patients who were treated, 56% survived. These authors stressed the varied presentation of endocarditis in the elderly, especially the prevalence of central nervous system complaints and uremia as presenting symptoms. The diﬃculty of making the true diagnosis in the elderly was emphasized. Watanakunakorn and Tan [32] reported 19 of 33 cases of staphylococcal endocarditis occurring in people over the age of 60. Presenting complaints were often nonspeciﬁc, such as anorexia and mental deterioration. Highlighting a modern risk factor for endocarditis, two patients were infected from indwelling intravenous catheters. In 10 patients, the diagnosis was established antemortem from blood cultures, but in the others it was established at autopsy or by direct culture of surgically removed valves. All but four patients were febrile. Only 2 of the 10 in whom the diagnosis was made antemortem survived. At autopsy, the mitral valve was the source of the infection in 13 of the 16 cases and atherosclerosis was the predisposing cardiac condition in 8 of 16 cases. This same group of authors also reported 20 patients with S. viridans endocarditis seen at the University of Cincinnati Medical Center [33] who were older than age 60. The presenting complaints of these patients were generally weakness, fatigue, and weight loss. All patients had fever, all had cardiac murmurs (40% had splenomegaly and 60% had cutaneous lesions). In 55% of the patients, the disease involved the mitral valve, in 30% the aortic valve, and in 15% both valves. Of these patients, 85% were alive 2 years after treatment, and it appeared survival was similar to that in a younger group of patients with the same disease. Later, Appleﬁeld and Hornick [34] conducted a retrospective analysis of patients admitted to the University of Maryland Hospital between the years 1950 and 1970 with a diagnosis of endocarditis. Of 29 patients, 21% fulﬁlled the criteria for endocarditis and were 60 years of age of older. Among these older individuals, pyrexia of unknown origin was the presenting complaint in 48% of the cases; however, 45% presented with neurological ﬁndings, including delirium. In 10 patients, no murmur was detected. In 18 individuals, aortic valve disease predisposed to infection, and in 10 mitral valve disease was preexistent. Staphylococci accounted for 24% of the cases and streptococci for 41% (including three cases of enterococcal disease), but in 29% of the cases (eight cases in all) no organism was isolated. Of this group, 72% died, but 48% had received antimicrobial therapy judged to be inappropriate. Thell et al. [35] presented data on 42 cases of endocarditis occurring in subjects over 60 years and conﬁrmed by autopsy or surgery. In this series, ﬁve cases of right-sided endocarditis were reported. The most common organisms isolated were staphylococci (33% of the cases), followed by streptococci (24% of the cases). In 37% of the cases, no underlying heart disease was found, but aortic valve disease was most common in those in whom an underlying process could be identiﬁed. This included calciﬁc aortic disease. These authors stressed that the diagnosis of endocarditis was suspected in only 38% of the cases despite the fact that fever was present in 94% of the cases in whom it was recorded and murmurs in 68% of the patients. Robbins et al. [36] also contributed to our understanding of endocarditis in the elderly. They reviewed 56 cases of infective endocarditis in patients 65 years of age and older. In this group, 93% were febrile, 86% had murmurs, and 36% had peripheral stigmata. They appropriately divided the cases into community-acquired and nosocomially acquired cases. Of a total of 41 community-acquired cases of endocarditis, 71% were found due to

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streptococci, including six cases of Streptococcus faecalis; eight cases (20%) were due to staphylococci. Among 15 nosocomially acquired cases, three were due to S. faecalis, seven to staphylococci (six attributed to S. aureus) and three to fungi. Of the total cases, ﬁve were caused by undetermined bacteria. Underlying diseases found to predispose to natural valve endocarditis in this series included six cases of rheumatic heart disease, three cases of calciﬁc aortic valve disease, and 16 cases of atherosclerotic disease. Complications occurred in 34 individuals (64% of the patients) who developed congestive heart failure and in 20 patients (35%) who had neurological abnormalities. All patients tested had an elevated erythrocyte sedimentation rate, and two-thirds were anemic. The overall mortality in this series was 45%. Terpenning et al. [37] compared infective endocarditis in patients over the age of 60 (53 episodes) to the disease in patients 40 to 60 years of age and to patients under 40 years of age (55 episodes). The percentages of cases caused by streptococci and staphylococci were approximately equal, but infection due to enterococci, Streptococcus bovis, and coagulasenegative staphylococci were more common in the older age group. Strikingly, 23% of the cases in the older patients were nosocomially acquired. The proportion of cases associated with various types of underlying heart disease was similar in all three groups, but the highest percentage of cases in all age groups was associated with no known underlying disease. A slightly greater percentage of the elderly group had prosthetic valves. Clinical manifestations were also similar in the various age groups, with fever present in over 80% of all individuals included regardless of age. Confusion was slightly more common in the older age group, and new or changing murmurs were present more often in the younger groups. Errors in diagnosis were signiﬁcantly more common in the older age group. Echocardiograms were read as showing vegetations in 56.8% of the group under 40, 47.8% of the group 40 to 60 years of age, and 43.7% of the group over 65 years of age. The aortic valve was the most common valve infected overall, but the mitral valve was more often the site of infection in the elderly (54.7%). In the youngest age group, the tricuspid was most often infected because of the higher incidence of intravenous drug use as a predisposing factor in the process. Major neurological events were slightly more common in the elderly, and pulmonary embolic events were more frequent in the younger group. Overall mortality was signiﬁcantly more common with increasing age, reaching 45% in the oldest group. In 1994, Durack et al. [38] described new criteria for the diagnosis of endocarditis incorporating the ﬁndings of echocardiography. This reﬁned the method of establishing the diagnosis of endocarditis. Using these new criteria, Weiner et al. [39] reported on endocarditis in the elderly and compared the ﬁndings with those in younger patients. The utilization of transesophageal echocardiography by these authors provided an interesting tool for the comparison between the older and younger age groups. They reported on 106 episodes of endocarditis and divided them into three groups; those under age 50, those between 50 and 70, and those over 70 years of age. The median age of all the cases was 59 years. S. viridans and staphylococci were the most common causative organisms in all age groups. While no signiﬁcant diﬀerences were found between the age groups with respect to the source of the infection or the type of organism responsible, elderly patients more often had degenerative and calciﬁed lesions or prosthetic valves. Vegetations were smaller in the two older groups. Fever (55%) and leukocytosis (25%) were less common in those over 70 as opposed to those under 50. The outcome in the older patients, however, was no worse than in the younger group. Embolic events were again more common in the younger group. Selton-Suty et al. [40] also described the clinical and bacteriological characteristics of endocarditis in the elderly. They reported on a total of 114 patients with endocarditis. They

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divided the patients into two groups; those over 70 years of age and those under 70. These authors also utilized the newer echocardiographic criteria. While streptococci were again the most common causative organisms in both age groups, these authors thought older patients had a greater number of infections related to organisms normally inhabiting the gastrointestinal tract. Fever was common in both age groups (>80%). Again, these authors noted that elderly patients had a higher percentage of infections occurring on prosthetic valves (52% vs. 25%) and less often experienced embolic complications (8% vs. 28%). The mortality in the older age group was higher, however, than in the younger age group (28% vs. 13%). In 1998, Gagliardi et al. [41] compared the features of native valve endocarditis in elderly patients with similar features in younger individuals using the Duke criteria. They carefully divided the age groups into those over 64 years of age and those between the ages of 29 and 60. Most importantly, they did not include intravenous drug users. They found the clinical features of the disease in the two age groups to be very similar, only in the duration of hospital stay was there a statistically signiﬁcant diﬀerence, older patients having a longer period of hospitalization. Neither the nature of the predominant organisms (streptococci and staphylococci) nor the incidence of fever and mortality diﬀered signiﬁcantly. Mitral valve involvement remained more common than aortic valve involvement in older patients while the reverse was true in the younger age group. A year later, Netzer et al. [42] reported their experience from a Swiss referral hospital. They conﬁrmed many of the ﬁndings of Gagliardi et al., but found that older patients were more prone to complications after valvular surgery, splenomegaly was more common in the younger group, and there was a statistically signiﬁcant diﬀerence in mortality with old patients dying more often as a complication (25% in all). In summary, endocarditis is an evolving process that is becoming increasingly a disease of older patients. This is in part related to a declining incidence of rheumatic fever as a predisposing factor in younger patients, leaving degenerative disease as a relatively more common underlying factor. Thus older individuals constitute a greater percentage of cases. Older patients, because of more frequent hospitalizations, may be more likely to develop nosocomial infections of the sclerotic valves. Furthermore, the greater frequency of genitourinary procedures in the older patient means the older patient may be at greater risk for infection with enterococci. The major clinical manifestations in older patients are likely to be similar. Thus older patients still commonly have fever and some form of murmur. Peripheral manifestations (petechiae, splinter hemorrhages, Osler nodes, Janeway lesions, etc.) should be found in frequencies about equal to that generally observed in other age groups and observed in the past. It is of interest that more recent studies have suggested that older patients are less prone to embolic complications. Common laboratory features of the disease (i.e., anemia, elevated erythrocyte sedimentation rate, and hematuria) appear to be observed in the elderly with equal frequency. Confusion should be more likely in the older patient, since this is often a nonspeciﬁc response in the elderly to any physiological stress and should always force a search for infections, including endocarditis. With regard to mortality, the data appear to be conﬂicting at least regarding natural valve endocarditis. However, higher mortality rates have been suggested in the older population [43,44]. This must be extrapolated to the individual situation, however. An otherwise healthy older person with viridans streptococci on a prolapsed mitral valve may be at no greater risk of death than a younger person. In contrast, a more mature individual with underlying disease and a more diﬃcult organism to eradicate (enterococci and methicillin-resistant coagulase-negative staphylococci) may indeed experience a higher risk of dying from the endocarditis. Finally, in the

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older patient it is clear the diagnosis is more diﬃcult because clinicians are less apt to consider it until greater damage is done. The diagnosis of endocarditis in the older adult is probably no less diﬃcult to establish if it is considered. Blood cultures taken before empirical antibiotics, especially if endocarditis is a consideration, are certainly helpful. Echocardiography [43] in the older patient is clearly a useful diagnostic maneuver and transesophageal echocardiography is especially valuable. The treatment of endocarditis in the older patient is similar to that in the younger individual [9]. Care must be exerted in the older individual when using potentially toxic agents (aminoglycosides), and greater attention must be paid to renal function, toxicity monitoring, drug levels, and so on. In treating any case of endocarditis, serum cidal levels should be monitored and attempts made to keep serum levels, especially peak levels, at 1:8 or greater. An overall summary of endocarditis in older patients has been reported by Dhawan [44]. Suggested regimens for the treatment of endocarditis are listed in Table 1 and are derived from Dhawan [44], Wilson [45], and Mylonakis et al. [17]. Prophylaxis for bacterial endocarditis in older patients is identical to that recommended for younger patients [44,46].

Table 1

Regimens for the Treatment of Endocarditis

Etiology Natural valve endocarditis S. viridans Enterococci

Staphylococci Coagulase-positive (methicillin-sensitive) Coagulase-negative (methicillin-resistant) Fastidious Gram-negative rods (e.g., HACEKb Organisms) Prosthetic valve endocarditis Coagulase-negative or-positive (methicillin-resistant)

Treatment Penicillin G, 10 to 20 million U/day (divided dose) Ampicillin, 12 g/day or Vancomycina (500 to 1000 mg BID, and gentamicin, 3 mg/kg/day (divided dose)

Nafcillin, 12 g/day (divided dose) Vancomycina, 500–1000 mg twice per day Ceftriaxone, 2g/day

Vancomycina, 500–1000 mg twice per day, + gentamicin, 3 mg/kg/day, + rifampin, 300 mg every day (orally)

Duration (weeks)

4 4 to 6

6 6 6

6 (ﬁrst 5 days only)

All doses are intravenous unless otherwise indicated. a b

Vancomycin 30 mg/kg per 24 h in two divided doses not to exceed 2 g in 24 h unless serum levels are monitored. HACEK (Hemophilus parainﬂuenza, H. aphrophilus, H. paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikinella corrodens, and Kingella kingae).

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14. 15. 16. 17. 18. 19. 20.

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Kelson SR, White PD. Notes on 250 cases of subacute bacterial (streptococci) endocarditis studied and treated between 1927 and 1939. Ann Intern Med 1945; 22:40–60. Osler W. Gulstonian lectures on malignant endocarditis. Lancet 1885; 1:415–418, 459–464, 505–508. Durack TT, Beeson PB. Experimental bacterial endocarditis. Colonization of sterile vegetations. Br J Exp Pathol 1972; 53:44–50. Freedman LR, Valone J. Experimental infective endocarditis. Prog Cardiovasc Dis 1979; 22: 169–180. King K, Harkness J. Infective endocarditis in the 1980s. Med J Aust 1986; 144:536–540, 588–594. Freedman LR. Infective Endocarditis and Other Intravascular Infections. New York: Plenum, 1982. Finland M, Barnes W. Changing etiology of bacterial endocarditis in the antibacterial area. Ann Intern Med 1970; 72:341–348. Cantrell M, Yoshikawa T. Infective endocarditis in the aging patient. Gerontology 1984; 30: 316–326. Rabinovich S, Evans J, Smith I, January L. A long term view of bacterial endocarditis: 337 cases 1924 to 1963. Ann Intern Med 1965; 63:185–198. Lerner P, Weinstein L. Infective endocarditis in the antibiotic era. N Engl J Med 1966; 274: 199–206, 259–266, 323–330, 388–393. Cherubin C, Neu H. Infective endocarditis at the Presbyterian Hospital in New York City from 1938–1967. Am J Med 1971; 51:83–96. Garvey G, Neu H. Infective endocarditius an evolving disease: a review of endocarditis at Columbia Presbyterian Medical Center 1968–1973. Medicine (Baltimore) 1978; 57:105–127. Lowe J, Williams G, Tabaqchali S, Hill I, Hamer J, Houang E, Sahw E, Rees G. Ten years of infective endocarditis at St. Bartholomews Hospital: analysis of clinical features and treatment in relation to prognosis and mortality. Lancet 1980; 1:133–136. Von Reyn CF, Levy B, Arbeit R, Friedland G, Crumpacker C. Infective endocarditis: an analysis based on strict case deﬁnitions. Ann Intern Med 1981; 94:505–518. Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital 1980–1990: a review of 210 episodes. Medicine 1993; 72:90–102. Hogevik H, Olaison L, Andersson R, Lindberg J, Alestig K. Epidemiologic aspects of infective endocarditis in an urban population. Medicine 1995; 74:324–339. Mylonakis E, Calderwood SB. ‘‘Infective endocarditis in adults. ’’ N Engl J Med 2002; 345: 1318–1330. Mauri L, de Lemos J, O’Gara P. ‘‘Infective Endocarditis’’. Curr Problems Cardiol 26:562–610. Eykyn SJ. ‘‘Endocarditis: basics.’’ Heart 2001; 86:476–480. Kerr A. In: Puller RL, ed. Subacute Bacterial Endocarditis. Springﬁeld, IL: Charles C Thomas, 1955, No. 274 American Lecture Series, Monographs on Bannerstone Division of American Lectures in Internal Medicine. Bayles T, Lewis W. Subacute bacterial endocarditis in older people. Ann Intern Med 1940; 13: 2154–2163. Willis F. Cardiac clinic. LXX. Clinic on subacute bacterial endocarditis aﬄicting an aged patient. Proc Staﬀ Mtg Mayo Clin 1940; 15:270–272. Zeman F, Siegal S. Acute bacterial endocarditis in the aged. Am Heart J 1945; 29:597–610. Traut E, Carter J, Gumbiner S, Hench R. Bacterial endocarditis in the elderly, a report of 94 autopsied cases. Geriatrics 1949; 4:205–210. Wallach J, Gless M, Lukasler L, Angust A. Bacterial endocarditis in the aged. Ann Intern Med 1954; 42:1206–1213. Anderson J, Staﬀurth J. Subacute bacterial endocarditis in the elderly. Lancet 1955; 2:1055– 1713.

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27. Gleck WJ. Diagnostic aspects of subacute bacterial endocarditis in the elderly. Arch Intern Med 1959; 102:761–765. 28. Hartman T, Meyers W. Occurrence of bacterial endocarditis in older inﬁviduals. Geriatrics 1959; 14:374–379. 29. Cummings V, Furman S, Dunst M, Rubin I. Subacute bacterial endocarditis in the older age group. JAMA 1960; 172:137–141. 30. Uwaydah M, Weinberg A. Bacterial endocarditis—a changing pattern. N Engl J Med 1965; 273:1231–1234. 31. Habte-Gabr E, January L, Smith I. Bacterial endocarditis: the need for early diagnosis. Geriatrics 1973; 28:166–170. 32. Watanakunakorn C, Tan J. Diagnostic diﬃculties of staphylococcal endocarditis in geriatric patients. Geriatrics 1973; 28:168–173. 33. Tan J, Watanakunakorn C, Terhune C. Streptococcus viridans endocarditis: favorable prognosis in geriatric patients. Geriatrics 1973; 28:68–73. 34. Appleﬁeld M, Hornick R. Infective endocarditis in patients over age 60. Am Heart J 1974; 88: 90–94. 35. Thell R, Martin F, Edwards J. Bacterial endocarditis in subjects 60 years of age and older. Circulation 1975; 51:174–182. 36. Robbins N, DeMaria A, Miller M. Infective endocarditis in the elderly. South Med J 1980; 73: 1335–1338. 37. Terpenning M, Buggy B, Kauﬀman C. Infective endocarditis: clinical features in young and elderly patients. Am J Med 1987; 83:626–634. 38. Durack D, Lukes A, Bright D. Duke in endocarditis service. New criteria for diagnosis of infective endocarditis: utilization of speciﬁc echocardiographic ﬁndings. Am J Med 1994; 96: 200–209. 39. Werner G, Schulz R, Fuchs J, Andreas S, Prange H, Ruschewski W, Kreuzer H. Infective endocarditis in the elderly in the era of transesophageal echocardiography: clinical features and prognosis compared to younger patients. Am J Med 1996; 100:90–97. 40. Selton-Suty C, Hoen B, Grentzinger A, Houplon P, Maignan M, Julliere Y, Danchin N, Canton P, Cherrier F. Clinical and bacteriologic characteristics of endocarditis in the elderly. Heart 1997; 77:260–263. 41. Gagliardi J, Nettles R, McCarty D, Sanders L, Corey GR, Sexton D. Native valve infective endocarditis in elderly and younger adult patients: comparison of Clinical Features and outcomes with use of the Duke criteria and the Duke endocarditis database. Clin Infect Dis 1998; 26:1165–1168. 42. Netzer R, Zollinger E, Seiler C, Cerny A. Native valve infective endocarditis in elderly and younger patients: comparism of clinical features and outcomes with use of the Duke criteria. Clin Infect Dis 1999; 28:933–935. 43. Melvin ET, Berger M, Lutzker L. Non-invasive methods for detection of valve vegetations in infective endocarditis. Am J Cardiol 1981; 47:271–278. 44. Dhawan V. Infective endocarditis in elderly patients. Clin Infect Dis 2002; 34:806–812. 45. Wilson W, Karchman A, Dajani A, Taubert K, Bayer A, Kaye D, Bisno A, Ferrieri P, Shulman S, Durack D. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci and HACEK microorganisms. JAMA 1995; 274:1706–1713. 46. Dijani A, Taubert K, Wilson W, Bolger A, Bayer A, Ferrieri P, Gewitz M, Shulman S, Nouri S, Newburger J, Hulto C, Pallasch T, Gage T, Levism M, Peter G, Zuccaro G. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997; 96:358–366.

20 Cardiomyopathies in the Elderly John Arthur McClung, Wilbert S. Aronow, and Robert N. Belkin Westchester Medical Center/New York Medical College, Valhalla, New York, U.S.A.

Michael Nanna Albert Einstein College of Medicine, Bronx, New York, U.S.A.

The true prevalence of cardiomyopathy in the elderly may be underestimated because of the low sensitivity of the clinical criteria, particularly in milder cases. Data from Framingham demonstrate that the incidence of heart failure is 10% in patients older than 80 as compared to only 1% in patients who are in their sixth decade [1]. Approximately one-third of those identiﬁed expire within 2 years of diagnosis. The annual incidence in men aged 85 to 95 years was noted to be 4.4% with a doubling of incidence noted with each 10 years of age, making heart failure the leading primary diagnosis in hospitalized elderly patients [1,2]. This chapter focuses on the nonischemic causes for cardiomyopathy encountered commonly in the elderly.

DIASTOLIC DYSFUNCTION Diastolic dysfunction is especially prevalent in the elderly and accounts for a very high morbidity [3]. Of patients identiﬁed as having congestive failure by the Framingham study, more than 50% had a left ventricular ejection fraction >50% [4]. Mortality, although lower than that noted for patients with diminished ejection fraction, remained four times greater than that of age- and sex-matched controls. A recent study of 269 elderly patients with congestive heart failure revealed that LV ejection fraction was normal in 63% [5]. An analysis of 83 patients with clinical heart failure and LV ejection fractions z45% participating in the V-HeFT trial demonstrated that exercise tolerance in this population was only slightly better than that for patients with lower ejection fractions [6]. The pathophysiology of diastolic dysfunction combines delayed relaxation, impairment of left ventricular ﬁlling, and decreased compliance of the ventricle [7]. Delayed relaxation, or more properly prolonged systolic contraction, can be induced by any substance that will increase the pressure or volume load to the ventricle, such as angiotensin II or ADH. Whereas delayed relaxation represents a compensatory adjustment to loading phenomena, impaired relaxation with secondary reduction in ventricular ﬁlling constitutes active diastolic pathology that relates to a speciﬁc underlying cause. It is important to 489

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recognize that diastolic dysfunction is, to some extent, a function of aging per se, perhaps related to an increase in cellular apoptosis over time [8,9]. This tendency toward diastolic dysfunction with aging has been demonstrated to be reversible with exercise in an animal model [10]. As a result, the clinician must be able to diﬀerentiate between what could be a result of normal sedentary aging and abnormal deterioration in ventricular compliance. Pathologically, diastolic dysfunction with normal left ventricular systolic dysfunction is associated with coronary artery disease (see Chaps. 9 to 16), restrictive cardiomyopathy, and both primary and secondary hypertrophic cardiomyopathy.

RESTRICTIVE CARDIOMYOPATHY Restrictive cardiomyopathy results from increased stiﬀness of the left ventricular myocardium, generally as a result of inﬁltrative disease [11]. As the inﬁltrative disorder is often biventricular, right-sided signs often predominate. Disturbances in conduction as well as dysrhythmia can also be common [12–15]. Clinical ﬁndings are often similar to pericardial constriction and care is required in order to establish the correct diagnosis [16]. Etiology In contrast to younger patients, idiopathic restrictive myopathy is not only rare in the elderly, but also carries a better prognosis [17]. Similarly, Lo¨ﬄer’s endocarditis is extremely rare in older populations [18]. Amyloidosis constitutes the most common etiology in the elderly, followed by other inﬁltrative processes such as cardiac sarcoid, carcinoid, hemochromatosis, and systemic sclerosis [8,19]. The broader use of both chest radiotherapy and anthracyclines in elderly patients with cancer leaves these patients at risk for the development of restrictive cardiomyopathy secondary to endomyocardial ﬁbrosis [20]. Amyloid inﬁltration of the atria is extremely common in the elderly and has been documented in 91% of subjects of advanced age in a recent histological study [21]. Primary amyloidosis, manifesting as a clinical syndrome with cardiac involvement, however, is considerably less common. The incidence of primary amyloidosis has been estimated to be between 6.1 and 10.5 per million person-years with the median age of presentation to medical attention being roughly 74 years [22]. Diastolic dysfunction associated with primary amyloidosis may result directly from the presence of monoclonal immunoglobulins rather than requiring the presence of the amyloid deposit itself. A recent study demonstrates that diastolic dysfunction similar to that observed in patients with cardiac involvement can be replicated in mice simply by the systemic infusion of light chains isolated from patients with cardiac amyloidosis [23]. The ventricular cavities are generally normal or small in size; however, mild dilatation can be noted (Fig. 1). The atria are characteristically dilated and in some cases may present with thrombi in the appendages [20]. Only 25% of patients with primary amyloidosis present with congestive heart failure, while about one-sixth present with orthostatic hypotension [19]. Median survival in patients presenting with congestive heart failure is 6 months. One of the key prognostic variables is left ventricular wall thickness. Median survival is 2.4 years for patients presenting with normal ventricular dimensions and falls to 0.4 years for those with signiﬁcant left ventricular hypertrophy [24,25]. Prognosis is also reduced in patients presenting with shortened deceleration time and an increase in E to A ratio as measured by Doppler echocardiography (Fig. 2) [26]. Dysrhythmia associated with amyloidosis

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Figure 1 Two-dimensional echocardiogram from a parasternal long-axis view in an elderly patient with cardiac amyloidosis shows a hypertrophic interventricular septum with the characteristic ‘‘sparkling’’ appearance of the septal myocardium. RV = right ventricle; IVS = interventricular septum; AO = aorta; LA = left atrium; MV = mitral valve; LV = left ventricle; PW = posterior wall.

Figure 2 LV diastolic waveforms obtained with pulsed Doppler echocardiography in an elderly patient with cardiac amyloidosis show increased flow velocity of early peak (E) and decreased maximal velocity of the late peak as a result of atrial systole (A).

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ranges from node dysfunction and bundle branch blocks to life-threatening ventricular dysrhythmia and is also related to the severity of the disease process as demonstrated by the above indices [27]. Familial amyloidosis, although responsible for only 10% of cases, also presents in the elderly. This autosomal dominant disorder is indistinguishable from primary amyloidosis by clinical criteria and requires identiﬁcation of the variant protein by immunochemical modalities. Accurate diagnosis is important primarily because of the more favorable prognosis for survival that is roughly twice that of primary amyloidosis [28]. Cardiac sarcoidosis is associated with interstitial inﬂammation resulting in abnormal diastolic function [29]. Incidence and prevalence of cardiac involvement remains largely unknown with only a minority of patients presenting in their elder years. Cardiac involvement can apparently be frequently subclinical with studies demonstrating between ﬁve and eight times as many patients presenting with cardiac inﬁltration at necropsy as had been previously diagnosed clinically [30,31]. As many as half the patients presenting with sarcoidosis can have electrocardiographic abnormalities; however, the precise signiﬁcance of these ﬁndings is unknown [32]. Sudden death is the most common cause of mortality in patients presenting with cardiac sarcoid as a result of either complete heart block or malignant tachyarrhythmia [33]. The mean age of patients presenting with carcinoid syndrome has been reported to be 64 years with a range extending up to 83 years [34]. Up to half of the cases present with carcinoid heart disease as a late complication [35]. The majority of cases present with tricuspid regurgitation with additional ﬁbrotic involvement of the pulmonic valve and the right ventricular endocardium. Presentation and Diagnosis Restrictive myopathies often present with generalized ﬁndings of fatigue, peripheral edema, paroxysmal nocturnal dyspnea, orthopnea, dyspnea, and occasionally ascites. Chest pain can occur in patients presenting with amyloidosis [36]. Similar clinical presentations require that this diagnosis be diﬀerentiated from pericardial constriction. This is accomplished largely by a combination of clinical history with echocardiographic and Doppler ﬁndings, cardiac MRI, and hemodynamic observations. Similar to pericardial constriction, restrictive myopathy often presents with a prominent y descent in the jugular venous pulse, a positive Kussmaul’s sign, an enlarged and pulsatile liver, ascites, and pedal edema. The presence of a third heart sound can serve to help diﬀerentiate restriction from constriction, which classically presents with a pericardial knock. The presence of pulmonary alveolar congestion on chest radiography favors restriction over constriction. The classic echocardiographic presentation of amyloid heart disease includes left ventricular hypertrophy with characteristic sparkling of the myocardium [37]. Mitral inﬂow velocities in patients with diastolic dysfunction vary depending upon the extent of the disease. E/A ratios customarily in the elderly become less than one in most individuals. The ﬁrst sign of diastolic dysfunction is often pseudonormalization of the Doppler spectral display in which the E/A ratio once again becomes greater than one associated with increasing prominence of the diastolic ﬁlling velocity in the pulmonary vein [38,39]. Active restrictive physiology results in a very steep, high-velocity mitral E wave with a short deceleration time, followed by a very small or absent A-wave [20]. B-natriuretic peptide assay has recently been used to enhance the diagnosis of diastolic dysfunction in patients who present with normal systolic function on echocardiography [40].

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Thickening of the pericardium, which is common in pericardial constriction, is absent in patients with restrictive cardiomyopathy on cardiac MRI. At cardiac catheterization, the end-diastolic pressures can be equalized in both restrictive and constrictive physiology; however, it is rare for the pre-a pressure to fall toward zero in patients with restriction. In some patients, endomyocardial biopsy may be necessary for diagnosis [41]. Treatment Speciﬁc therapy for patients with restrictive myopathy is poorly understood [42]. Drug therapy has been primarily aimed at the presumed cause of the disorder [7]. In patients in which tachycardia appears to play a major role, the use of beta blockade, some calcium channel blockers, and occasional digoxin has been advocated. Angiotensin-converting-enzyme inhibitors have been used in order to both reduce pressure and volume load as well as assist in ventricular remodeling at the microstructural level [7]. Diuretics reduce preload and improve exercise tolerance [43]. Nitrates similarly decrease preload as well as potentially abbreviate systole which could assist in the augmentation of diastolic ﬁlling [44,45]. Coumadin may be indicated in those patients who present with atrial appendage thrombus on transesophageal echocardiography. Drugs such as amiodarone may be necessary in order to maintain sinus rhythm and enhance cardiac output in patients who develop atrial ﬁbrillation [20]. Pacing may be requisite for patients who develop conduction system disease [46].

HYPERTROPHIC CARDIOMYOPATHY Hypertrophic cardiomyopathies are common in the elderly. In some series, more than 80% of patients presenting to the hospital with newly diagnosed hypertrophic obstructive cardiomyopathy (HOCM) were older than 50 years and more than 40% were older than 60 years [47,48]. Hypertensive hypertrophic cardiomyopathy is characteristically found in older populations. Whereas older males and females demonstrate generally equal prevalence of obstructive cardiomyopathy, hypertensive hypertrophic cardiomyopathy appears to predominate in females [48,49]. Hypertrophic cardiomyopathy in older adults needs to be diﬀerentiated from the septal bulge or ‘‘sigmoid septum’’ commonly seen in older patients without any other evidence of myocardial hypertrophy [50]. The bulge is caused by an increased angulation of the interventricular septum which can result in as much as a twofold increase in LV outﬂow tract velocity following amyl nitrate. A recent echocardiographic study has documented that, although demonstrating an increase in fractional shortening comparable to patient with hypertrophic cardiomyopathy, subjects with septal bulge had no decrease in enddiastolic dimension, no evidence of anterior malposition, and normal wall thickness apart from the basal septum, suggesting that this constitutes a separate physiological entity [51]. Hypertrophic Obstructive Cardiomyopathy HOCM has an autosomal dominant inheritance pattern with many diﬀerent mutations, some of which are speciﬁc for phenotypic expression at an older age [52,53]. Although disease severity can vary depending upon the type of mutation, phenotypic expression varies to such a degree as to currently render the type of mutation a poor indicator of prognosis on

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a case-by-case basis [54,55]. The histological pattern of HOCM has been demonstrated to be distinctly diﬀerent from the hypertrophy associated with hypertension [56]. Elderly patients diagnosed with HOCM present with an increased severity of symptoms compared to younger individuals; however, the progression of the disease appears to be slower [48,57,58]. The annual mortality for the elderly patient with HOCM has been reported to be only 2.6% compared with 5.9% in younger patients, and does not appear to be demonstrably diﬀerent from that of age- and sex-matched controls [49,59]. The predominant symptom noted by multiple authors is dyspnea with between one-third and one-half of elderly patients presenting with chest pain [49,58,60,61]. Presentation in NYHA class III or IV heart failure has been noted to increase the annual mortality rate to 36% [49]. Between 20 and 30% complain of syncope or presyncope, while some authors report palpitations in as many as half [49,58,59]. Classic physical ﬁndings include the presence of carotid pulsus bisferiens, a fourth heart sound, and a systolic ejection murmur at the left sternal margin that becomes more prominent with the Valsalva maneuver and less audible with isometric exercise [62,63]. The bisferiens pulse may be less noticeable in older patients as a result of increased atherosclerosis in the peripheral vasculature [58,64]. Both atrial ﬁbrillation and hypertension have been reported to be more commonly associated with the diagnosis in the elderly, and are also associated with decreased survival [59,65]. Electrocardiographic presentation in the older adult includes the presence of atrial abnormality, LVH, and bundle branch block; however, the anterior Q waves that are typical of HOCM in the young are only rarely seen [59,66]. Echocardiographic ﬁndings in the older patient with HOCM, similar to younger patients, include left ventricular hypertrophy, systolic anterior motion of the anterior leaﬂet of the mitral valve, and increased LV outﬂow tract velocity (Figs. 3 to 12) [64]. Left ventricular cavity shape in the elderly appears to be more oval than that of younger patients with HOCM [59]. In addition, mitral annular calciﬁcation is much more common in older patients presenting with HOCM, with prevalence rates reported to be anywhere between 30 and 100% [67–70]. As a result, the mechanism for outﬂow tract obstruction may depend more on the posterior displacement of the septum and less on the anterior displacement of the mitral apparatus than it does in younger patients. Beta-adrenergic blocking agents and non-dihydropyridine calcium channel blockers, particularly verapamil, have been shown to reduce symptoms in patients with HOCM; however, no clear eﬀect on mortality has been documented [62,71]. As in patients with coronary disease, hypersensitivity to beta-adrenergic stimulation accompanied by precipitous clinical deterioration occurs in patients who are abruptly withdrawn from betablockers [72]. Patients who do not respond to beta-blockade can have a salutary response to large doses of verapamil [73]. Disopyramide in doses of 600 to 800 mg daily has also been demonstrated to decrease symptoms in selected patients [62]. All of these agents are relatively contraindicated in patients with conduction system disease in the absence of cardiac pacing. Positive inotropic agents such as digoxin and load-reducing agents such as nitrates, diuretics, and dihydropyridine calcium channel blockers are relatively contraindicated because of their ability to increase the gradient across the LV outﬂow tract [48,66,70]. Dysrhythmia requires special attention in this patient population. Atrial ﬁbrillation is associated with a diminished long-term prognosis and requires anticoagulation [74]. Ventricular dysrhythmia poses a more vexing problem. A recent trial has demonstrated that ventricular tachycardia or ﬁbrillation appears to be the primary mechanism for sudden death in patients carrying a diagnosis of hypertrophic cardiomyopathy [75]. In these cases, implantable deﬁbrillators were found to be eﬃcacious in the treatment of these rhythms and

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Figure 3 Systolic frame of a two-dimensional echocardiogram from an apical view in a 91-yearold female with hypertrophic cardiomyopathy of the elderly, showing extensive mitral annulus calcification and prominent systolic anterior motion of the mitral valve with near obliteration of the LVOT.SAM = Systolic anterior motion of the mitral valve leaflets. MAC = mitral annulus calcification.

the prevention of sudden death. Mean age in this patient population, however, was 40 F 16 years with more than half the sample size being less than 41 years of age. In addition, it is not clear how many of these subjects presented with HOCM and how many had hypertensive hypertrophic cardiomyopathy, although the mean age suggests that HOCM might have been the prevailing diagnosis. A subsequent trial demonstrated that LV wall thickness is directly related to the risk of sudden death and may, therefore, be an indicator of the need for AICD placement [76]. Once again, however, the mean age was only 47 years with the mean age being youngest (31 years) for the patients with the thickest walls. As a result, it is unclear at this time how much prescriptive relevance these data have for the older patient with obstructive myopathy. These ﬁndings in combination with other observations (vide infra), however, like the appearance of complex ventricular dysrhythmia in the elderly patient with hypertrophic cardiomyopathy, does in fact suggest a negative prognosis in comparison to patients in whom they do not appear and should be considered for cardioverter deﬁbrillator placement. DDD pacing for patients with HOCM who have not responded to medical therapy has been associated with variable results [77–79]. Maron et al. demonstrated a signiﬁcant reduction in outﬂow tract velocity in all subjects; however this did not translate into improved functional capacity for any subgroup except for elderly patients over the age of 65 years [80]. As such, pacing may be of some beneﬁt to older adults with HOCM who do not respond well to medical therapy.

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Figure 4 Early systolic frame from a two-dimensional parasternal long axis view in the same patient illustrated in Figure 1, showing a prominent septal bulge and systolic anterior motion of the mitral valve. RV = right ventricular cavity. IVS = interventricular septum. Ao = aortic root. LV = left ventricular cavity. LA = left atrium. PW = posterior wall. MAC = mitral annulus calcification. SAM = systolic anterior motion of the mitral valve leaflets.

In patients who continue to demonstrate class III or IV symptoms despite medication and pacing, surgery or transcatheter septal ablation must be considered. Older studies have described symptomatic improvement in as many as 80 to 90% of patient over 65 years of age undergoing surgical myectomy [26,58]. Operative mortality, however, has been observed to more than triple in patients over 65 years of age when myectomy is combined with coronary artery bypass surgery [81]. The concurrent presence of severe mitral annular calciﬁcation may require mitral valve surgery as well [74]. More recent data from a threepatient subset of patients with HOCM and mitral annular calciﬁcation undergoing myectomy (mean age = 61 years) suggests that the myomectomy alone may signiﬁcantly reduce the amount of MR such that mitral surgery may be unnecessary [82]. Initial 1-year follow-up of patients with HOCM as old as 83 years undergoing transcatheter septal ablation with ethanol has been favorable [83]. Therefore, this procedure appears to be an acceptable alternative to surgical intervention in selected cases. Hypertensive Hypertrophic Cardiomyopathy of the Elderly Hypertensive hypertrophic cardiomyopathy (HHC) was ﬁrst described by Topol and colleagues, who reported on 21 elderly patients in 1985 [84]. There has been signiﬁcant concern as to whether or not this description represents a genuinely diﬀerent pathophysiological entity from other hypertrophic myopathies [85]. More recent study has suggested that the cell cycle is actively deranged in patients (mean age 61 years) with nonhypertensive

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Figure 5 Color Doppler flow display superimposed on the same systolic frame from a parasternal long axis view shown in Figure 2, demonstrating turbulent LVOT flow. Abbreviations as in Figure 2.

Figure 6 CW Doppler obtained from interrogation of the LVOT flow in the same patient illustrated in Figure 1, demonstrating a large increase of LVOT velocity (maximum = 6 m/s) and a Bernoulliderived gradient of 170 mmHg.

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Figure 7 M-mode echocardiogram at the mitral valve level in an elderly patient with obstructive hypertrophic cardiomyopathy. During midsystole, a smooth anterior motion at the mitral valve is noted. The mitral valve assumes a flattened curve appearance as it approaches the septum, and the contact with the septum is facilitated by the posterior motion of the septum. Mitral annular calcification is present behind the posterior leaflet. IVS = interventricular septum; RV = right ventricular cavity; MV = mitral valve; CA ANNUL = mitral annular calcification.

cardiomyopathy compared to patients with hypertensive LVH [86]. Similarly, therapy with captopril was associated with regression of ventricular hypertrophy in hypertensive patients, but not in nonhypertensive patients with cardiomyopathy. As such, the pathophysiology of the two groups of patients appears to be diﬀerent. Patients with HHC may represent a hybrid of pathology that superimposes aspects of hypertensive left ventricular hypertrophy on a genetic predisposition to primary hypertrophic cardiomyopathy [87]. In contradistinction to HOCM, sudden death in this patient population appears to be rare, while prognosis for survival in general appears to be better [84]. Patients with hypertensive hypertrophic cardiomyopathy classically present with ﬂash pulmonary edema in the absence of prior symptoms [48]. Although frequently presenting with a chronic history of hypertension, the extent of the blood pressure elevation often does not correlate with the severity of the ventricular hypertrophy [84]. The ﬁndings on physical examination are somewhat similar to HOCM and feature the absence of neck vein distension, a palpable S4, a left ventricular heave, and a systolic ejection murmur [88]. The echocardiogram demonstrates severe left ventricular hypertrophy with hyperdynamic contractility and cavity obliteration, left atrial dilatation, and delayed opening of the mitral valve. Concentric LVH is more commonly seen than asymmetric septal hypertrophy and SAM is present in less than one-third of cases [48,84,85]. Medical therapy for patients with HHC is similar to that of patients with HOCM, with the exception that the need for diuretic therapy may be somewhat greater as a result of recurrent episodes of pulmonary edema.

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Figure 8 Diastolic frame of a two-dimensional echocardiogram from a parasternal long-axis view in an elderly patient with hypertrophic cardiomyopathy shows a small LV chamber, a hypertrophic interventricular septum (IVS), a fibrotic mitral valve (MV), and a calcified mitral annulus (Ca).

Figure 9 Two-dimensional apical four-chamber systolic still frame from an elderly patient with obstructive hypertrophic cardiomyopathy shows hypertrophy of the interventricular septum (IVS), a small LV cavity, fibrotic mitral valve (MV) leaflets, and a calcified mitral annulus (Ca).

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Figure 10 LV diastolic waveforms obtained with pulsed Doppler echocardiography in an elderly patient with hypertrophic cardiomyopathy show reduced maximal flow velocity of early peak (E), slow deceleration of early diastolic flow velocity (from E to F), prolongation of early filling components (from D to F) at the expense of diastasis, and increased maximal velocity of the late peak as a result of atrial systole (A).

DILATED CARDIOMYOPATHY Idiopathic dilated cardiomyopathy is primarily a disease of ventricular muscle, with increased LV or biventricular volumes, without an appropriate increase in ventricular septal or free wall thickness, and with depression of LV systolic function [89]. Other etiological factors that can cause diﬀuse LV systolic dysfunction must be excluded [90]. In a large cohort of 554 unselected men and 1243 women aged >60 years in a long-term healthcare facility, the prevalence of idiopathic dilated cardiomyopathy was 1% for both sexes [91]. In the same cohort, the prevalence of abnormal LV ejection fraction (<50%) was 29% in men and 21% in women. Approximately 10% of patients with dilated cardiomyopathy are older than 65 [91–95]. The diagnosis of dilated cardiomyopathy can be conﬁrmed by echocardiography (Figs. 13 to 15), and by pulsed Doppler echocardiography (Fig. 16) in elderly patients. Figure 15 shows a large apical thrombus that can complicate this condition. Coronary angiography should be considered in patients with dilated cardiomyopathy and chest pain. Transthoracic coronary echocardiography has been proposed as a useful method for distinguishing between ischemic and nonischemic dilated cardiomyopathy [96]. Symptoms Symptoms due to dilated cardiomyopathy include fatigue and weakness resulting from decreased cardiac output, exercise intolerance, dyspnea due to pulmonary congestion, chest

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Figure 11 Color Doppler flow display from a patient with obstructive hypertrophic cardiomyopathy shows turbulent flow in the LVOT and mild mitral regurgitation (MR). (See color insert.)

pain, and syncope. Symptoms due to systemic or pulmonary emboli may also occur. Physical examination reveals moderate-to-severe cardiomegaly and audible third and fourth heart sounds. Signs of LV or biventricular failure may be present. Fuster et al. reported 104 patients at the Mayo Clinic with idiopathic dilated cardiomyopathy followed for 6 to 20 year [94]. Of these 104 patients, 73% had congestive heart failure at the time of diagnosis, and 96% had congestive heart failure at follow-up. Systemic emboli were present in 4% of the patients at the time of diagnosis and in 18% of the patients at follow-up. Systemic thromboembolism developed in 8 of 24 patients (33%) with atrial ﬁbrillation and in 11 of 80 patients (14%) with sinus rhythm ( P = NS). Systemic thromboembolism developed in 18% of patients who did not receive anticoagulant therapy and in none of those who did ( p = 0.05). Of 104 patients, 80 (77%) had died at follow-up. two-thirds of the deaths having occurred within 2 years. Roberts et al. reported that 148 of 152 necropsy patients (97%) with idiopathic dilated cardiomyopathy had clinical evidence of chronic congestive heart failure [95]. Sudden death was the initial manifestation in 114 of 152 patients (75%), and in most patients it became intractable and caused death. The mean duration from the onset of chronic congestive heart failure to known death in 120 patients was 54 months. The cause of death was chronic congestive heart failure in 58% of patients, sudden death in 27% of patients, pulmonary

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Figure 12 Continuous-wave Doppler recording obtained in the LV outflow tract of an elderly patient with obstructive hypertrophic cardiomyopathy. Note the increased late-systolic LV outflow tract velocity, which translates to a peak LVOT gradient of 81 mmHg. In diastole, a characteristic aortic insufficiency velocity pattern is noted.

Figure 13 M-mode echocardiogram at the mitral valve level in an elderly patient with dilated cardiomyopathy shows thinning of the interventricular septum (IVS), a markedly dilated LV cavity (LV), and increased E point septal separation. RV = right ventricle; MV = mitral valve; PW = posterior wall.

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Figure 14 Diastolic frame of a two-dimensional echocardiogram from a parasternal long-axis view in an elderly patient with dilated hypertrophic cardiomyopathy shows thinning of the interventricular septum (IVS) and a large LV cavity (LV). RV = right ventricle; AO = aorta; MV = mitral valve; PW = posterior wall; LA = left atrium.

Figure 15 Two-dimensional apical two-chamber view in an elderly patient with dilated cardiomyopathy shows a large apical thrombus. LV = left ventricle; IW = inferior wall; MV = mitral valve.

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Figure 16 LV diastolic waveforms obtained with pulsed Doppler echocardiography in an elderly patient with dilated cardiomyopathy show increased flow velocity of early peak (E), fast deceleration of early diastolic flow velocity from (E to F), shortening of early diastolic filling component from (D to F) with visible diastasis, and decreased maximal velocity of the late peak as a result of atrial systole (A).

emboli in 9% of patients, and other in 6% of patients. Clinical evidence of pulmonary emboli was present in 39% of patients. Clinical evidence of systemic emboli was present in 20% of patients. Of 131 patients, 79 (60%) had either clinical or necropsy evidence, or both, of pulmonary or systemic emboli. Falk et al., studying 25 patients with nonischemic dilated cardiomyopathy who were not receiving anticoagulant therapy, demonstrated that a left ventricular thrombus was present on initial echocardiogram in 11 patients (44%), developed during 21.5 months of follow-up in an additional four patients (16%), and disappeared in two patients (8%) during follow-up [97]. Systemic thromboembolism developed in 5 of 25 patients (20%) during follow-up. Of the ﬁve thromboembolic events, four occurred in patients with echocardiographic evidence of a left ventricular thrombus. These ﬁve patients with thromboembolic events were treated with warfarin. No further embolic events occurred in these patients at 15 months of follow-up. Congestive heart failure in patients with dilated cardiomyopathy should be treated with salt restriction, diuretics, and angiotensin-converting-enzyme inhibitor therapy. Digoxin has been demonstrated to reduce the number of hospital admissions due to heart failure; however, its eﬀect on total mortality appears to be neutral [98]. Recently, the eﬀect of digoxin on clinical outcome was found to be identical even at low serum digoxin levels (0.5 to 0.9 ng/mL) [99]. Beta-blockade has now been shown unequivocally to be associated with improvement in symptoms, quality of life, exercise capacity, ejection fraction, and survival [100–103]. Other investigators have demonstrated beneﬁcial eﬀects of spironolactone,

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allopurinol, and AT1 blockade [104–106]. The role of anticoagulants in the patient population presenting with sinus rhythm and LV dysfunction is unclear, with some sources suggesting this for severe LV dysfunction. There is no evidence that antiarrhythmic drugs prolong life or prevent sudden cardiac death in patients with dilated cardiomyopathy; however there appears to be a role for AICD therapy in patients with an ischemic etiology [107]. Cardiac resynchronization therapy has been shown to be of value in reducing symptoms and improving exercise capacity in patients with advanced heart failure, a wide QRS complex, and evidence of contraction dyssynchrony [108].

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21 Thyroid Heart Disease in the Elderly Steven R. Gambert, Charles R. Albrecht, and Myron Miller Sinai Hospital of Baltimore, Johns Hopkins University School of Medicine Baltimore, Maryland, U.S.A.

INTRODUCTION The cardiovascular manifestations of thyroid disease are well documented and often lead to clinical diagnosis. Although the eﬀect of severe thyroid disease has been increasingly researched and expanded upon since the early nineteenth century, recent studies have increased our understanding of the molecular and cellular basis for the cardiovascular changes occurring in thyroid disease. The hymodynamic changes associated with both hyper- and hypothyroidism have been measured and continue to be an area of research eﬀort. The effects of subclinical stages of thyroid disease on the cardiovascular system and the potential beneﬁts of treatment at this early disease stage are reported with increasing frequency in the literature. This review will address recent progress in deﬁning the mechanism of action of thyroid disease on the heart as well as subsequent hemodynamic changes, clinical consequences, and treatment options.

HYPERTHYROIDISM Clinical Findings Classic ﬁndings of hyperthyroidism include heat intolerance, irritability, emotional lability, nervousness, muscle weakness, menstrual abnormalities, loss of weight, increased appetite, tremor, hyperactive reﬂexes, increased sweating, and fatigue [1]. The majority of hyperthyroid elderly persons, however, present most frequently with tachycardia, fatigue and weight loss. In one prospective study, atrial ﬁbrillation and anorexia were the only ﬁndings more commonly noted in an elderly population as compared to a younger population [1]. Hemodynamic alterations include an increased resting heart rate, blood volume, left ventricular mass, stroke volume, and ejection fraction. Subsequent clinical manifestations involving the cardiovascular system may include palpitations, tachycardia, widened pulse pressure, atrial ﬁbrillation, congestive heart failure, and angina. These latter problems are more common in the elderly and result from the increase in oxygen demand placed on the 511

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aged heart by excessive amounts of the thyroid hormones thyroxine (T4) and triiiodothyronine (T3) and subsequent increased metabolic demands by both the heart and other body organs. Mechanisms of Action The mechanisms of action of T3, the more active cellular form of thyroid hormone, include both stimulation of transcriptional processes and cellular membrane activity. The manifestations of hyperthyroidism resemble an increased adrenergic state. For this reason, an increased sensitivity to adrenergic stimulation in hyperthyroidism has been proposed. Although hyperthyroidism does aﬀect various components of the adrenergic system and a synergistic eﬀect has been reported between thyroid hormone and epinephrine, recent data have not supported the role of an increased sensitivity to catecholamines as the sole cause of the cardiovascular manifestations of hyperthyroidism. Early studies have suggested an adrenergic contribution secondary to the observation that sympathetic blockade could relieve thyroid storm and alterations in cardiovascular function [2,3]. Also, sympatholytic agents, speciﬁcally beta-adrenergic blockers, have been and continue to be eﬀective in reducing many of the cardiovascular manifestations of hyperthyroidism [4–7]. Several mechanisms have been proposed to explain the synergism between catecholamines and thyroid hormone, including an increase in the number of adrenergic receptor sites, an increase in the sensitivity of adrenergic receptors, an increase in tissue levels of free catecholamines, and thyroid stimulation of adrenergic nerve terminals [8,9]. Recent data have supported a positive or upregulation of beta-1-adrenergic receptors in hyperthyroidism while several other components of the adrenergic-receptor complex are negatively or downregulated, such that the net eﬀect on the sensitivity of the heart to adrenergic stimulation in hyperthyroidism remains normal [10–12]. Despite an apparent increase in adrenergic activity in hyperthyroid patients, catecholamine concentrations in thyrotoxic patients are normal to low in the serum, and normal rates of epinephrine and norepinephrine secretion by the adrenals have been demonstrated [13–16]. Currently, the physiological basis for the eﬀect of hyperthyroidism on the heart seems to be shifting away from the sympathetic system to direct cellular mechanisms and transcriptional actions of thyroid hormone. Although thyroid hormone has a direct eﬀect on the cardiovascular system by modulating the rate of transcription of multiple genes, T3 also exerts an eﬀect on the cellular membrane. Thyroid hormone was ﬁrst shown to exert a direct eﬀect on myocardial tissue when T4 was incubated with fragments of cardiac tissues from chicken embryos resulting in an increased rate of contraction. Several studies using cardiac muscle, specifically cat papillary muscles, demonstrated an increase in heart rate, isometric tension, and velocity of muscle shortening in the presence of thyroid hormone, in the absence of adrenergic tissue, and in the presence of depletion or blockage of catecholamines [17,18]. The rapid increase in cardiac output following an intravenous infusion of T3 supports a direct eﬀect of T3 on cellular membranes [19]. Extranuclear eﬀects include alterations of various membrane channels and subsequent changes in calcium, sodium, and potassium as mediated through the ATPase system, notably Na,K-ATPase. This increase in concentration leads to short-term increases in both inotropy and chronotropy [20–25]. The increase in myocyte contractile function in the presence of T3 is due to alterations of multiple cell membrane enzyme systems, including a direct eﬀect on myocyte sarcolemmal transduction [22]. Not only are there alterations in solute transport (calcium and sodium), but there is also

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a modulation of mitochondrial respiration, changes in several kinases that may promote signal transduction pathways, and several relevant thyroid hormone binding sites distinct from nuclear binding sites [24]. In autoimmune-mediated hyperthyroidism, myocardial tissue pathology reveals ﬁbroblast inﬁltration and degenerative changes. Patients with resulting cardiomyopathy have been found to have antibody receptor binding to thyrotropin-stimulating-hormone (TSH) receptors in the human heart [26]. The results of these studies support a role for a nongenomic or direct eﬀect of thyroid hormone on cardiovascular function. Since several of the membrane channel proteins are upregulated at a nuclear level by thyroid hormone, the boundaries of the genomic and nongenomic actions of thyroid hormone are not clear. Thyroid hormone action is reported throughout the literature to be mediated predominately by binding to nuclear receptors, and this mechanism has been recently reviewed [27]. In brief, T4 and T3 rapidly cross membranes due to their lipophilic nature and possibly through speciﬁc transport channels. Thyroid hormone enters the nucleus and binds with high aﬃnity to thyroid hormone receptors. These are either activated as a homodimer or bind to a second steroid hormone receptor and become activated as a heterodimer [28,29]. These, in turn, bind to target gene thyroid response elements in various conﬁgurations leading to transcriptional activity [26,30–32]. The multiple hemodynamic changes reported in hyperthyroidism may be explained by the transcriptional changes of several genes. Thyroid-hormone-responsive target genes include both regulatory and structural genes. These include transcriptional modulation of myosin heavy-chain alpha, myosin heavy-chain beta, making up the thick ﬁlament of cardiac myocytes, sarcoplasmic reticulum calciumATPase, Na,K-ATPase, phospholamban, voltage-gated potassium channels, adenylyl cyclase types V and VI, and the Na,Ca-exchanger [33–39]. The activation of the myosin heavy-chain alpha gene results in an increase in muscle ﬁber velocity and, theoretically, in increased myocardial contractility. The dominant component in human myoﬁbril proteins is myosin heavy-chain beta which is repressed [32,33], making the exact contribution of these structural proteins to human cardiovascular manifestations of thyroid disease less certain. Another indirect genomic action of thyroid hormone is the alteration in function of the sarcoplasmic reticulum, including sarcoplasmic reticulum calcium-ATPase and phospholamban. In hyperthyroid heart disease, the release of calcium and subsequent reuptake by the sarcoplasmic reticulum, which determines systolic contractile function as well as diastolic relaxation, is altered. This process favors an increase in myocardial contractility (inotropy) and an improvement in diastolic relaxation. Upregulation of sarcoplasmic reticulum calcium-ATPase and changes in the phosphorylation of phospholamban can increase contractility as well as diastolic relaxation, and may account for the hemodynamic changes in thyroid disease [35–37]. Considerable research is being conducted to further elucidate the contribution of each of the multiple mechanisms by which thyroid hormone exerts its inﬂuence on the cardiovascular system. Hemodynamic Changes The pathophysiology of the changes in cardiac function associated with thyroid disease are multifactorial and still under investigation. The associated hemodynamic changes of increased heart rate, blood volume, systemic vascular resistance, left ventricular stroke volume, ejection fraction, and cardiac output have been well deﬁned [30,40]. It is currently believed that the high cardiac output state associated with hyperthyroidism results from peripheral hemodynamic changes as well as direct changes in myocardial contractility.

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Cardiac contractility is also increased secondarily because of an increase in peripheral oxygen consumption and metabolic demands associated with excess thyroid hormone. Tachycardia is frequently associated with hyperthyroidism. Initially, this was felt to be associated with an altered responsiveness to adrenergic input. More recent data support a direct eﬀect of thyroid hormone on pacemaker activity through the S-A node [41]. An increased venous return secondary to a decreased systemic vascular resistance, activated renin-angiotensin-aldosterone system, and subsequently increased blood volume contribute to the increase in preload reported in hyperthyroid states [30,31,40,42–44]. Although these ﬁndings are certainly contributory to the augmented cardiac output associated with hyperthyroidism, cardiac contractility is increased in cardiac myocytes removed from peripheral eﬀects [17,18]. Systemic vascular resistance is decreased directly by thyroid hormone’s action on smooth-muscle cells as evidenced by invasive measurement after coronary artery bypass surgery [19]. Afterload is reduced in hyperthyroid patients as a result of direct arterial smooth muscle relaxation, which leads to an improvement in stroke volume and subsequently cardiac output. A recent review separated steady and pulsatile components of afterload and hypothesized that pulsatile components of arterial load actually compensate for the reduction in systemic vascular resistance noted in hyperthyroidism. These data cast doubt on the simpliﬁed notion of a single factor such as systemic vascular resistance controlling the observed decrease in ventricular afterload in the hyperthyroid patient [40]. Echocardiographic data have become available to further deﬁne the cardiac changes in hyperthyroidism. Speciﬁcally, it has been demonstrated that diastolic function improves as evidenced by increased isovolumic relaxation and left ventricular ﬁlling in hyperthyroid patients [45]. These alterations in hemodynamic parameters may explain many of the signs and symptoms of hyperthyroidism and help us better understand many of the cardiac complications associated with hyperthyroidism. Cardiac Complications Cardiac complications are the leading cause of death even after successful treatment of hyperthyroidism [46]. Electrocardiographic changes commonly associated with hyperthyroidism include repolarization abnormalities, atrial and ventricular extrasystolic beats, sinus tachycardia, and atrial ﬁbrillation. Other electrocardiographic ﬁndings include ischemia, left ventricular hypertrophy by voltage criteria, and varying degrees of heart block [47– 49]. Throughout the literature there continues to be debate as to whether hyperthyroidism by itself, even without preexisting structural heart disease, can cause the abnormalities frequently seen in the hyperthyroid patient. A recent electrophysiological study demonstrated that the atrial eﬀective refractory period as well as the atrial conduction delay noted in hyperthyroid patients is arrhythmogenic and could in itself account for the predisposition of hyperthyroid patients to develop atrial ﬁbrillation without prior presence of preexisting structural disease [50]. Previous echocardiographic studies, however, have demonstrated that patients with hyperthyroidism and atrial ﬁbrillation are much more likely to have atrial enlargement than those persons with hyperthyroidism in sinus rhythm [51]. Another recent review demonstrated that although most, if not all, of the cardiovascular manifestations associated with hyperthyroidism are reversible with therapy, long-term follow-up reveals an excess cardiovascular and cerebrovascular mortality. This is thought to be most likely due to an increased incidence of supraventricular dysrhythmias [52]. Atrial ﬁbrillation occurs in 5 to 15% of hyperthyroid patients. It is notable that a recent study questioning the usefulness

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of thyroid function testing in new-onset atrial ﬁbrillation found that less than 1% of these patients had hyperthyroidism [53]. However, testing is indicated even if the yield is low because multiple studies have shown that treatment of hyperthyroidism may lead to reversion to sinus rhythm; correction of hyperthyroidism is usually recommended before aggressively proceeding with cardioversion for atrial ﬁbrillation [54,55]. Although atrial ﬁbrillation secondary to hyperthyroidism is reported to carry a risk of systemic embolism independently of other risk factors for embolization, this risk has not been adequately quantiﬁed [39,55]. The hemodynamic changes associated with the hyperthyroid state can uncover previously compensated congestive heart failure and coronary artery disease. Exertional dyspnea and congestive heart failure can result from hyperthyroidism without underlying structural abnormalities in persons of all age groups [31,39]. One possibility is that despite the increase in contractility and other increased hemodynamic parameters in hyperthyroidism, there is an inadequate cardiac reserve to allow a further increase in cardiac function during periods of stress [56]. A second possible explanation is that the known cardiac hypertrophy that occurs with hyperthyroidism (as evidenced by an increase in left ventricular mass index) leads to systolic dysfunction. This is consistent with hyperthyroid cardiomyopathy and is completely reversible with treatment [57,58]. Hyperthyroidism can lead to an acute left ventricular dysfunction that mimics ischemic coronary artery disease. This disorder is rapidly reversible with treatment and is termed ‘‘myocardial stunning’’ because of the reversibility of the disease [59]. The clinical entity of resistance to thyroid hormone may lead to multiple changes that are consistent with hyperthyroidism, including increased heart rate, cardiac output, and stroke volume. Cardiac symptoms such as palpitations and signs such as tachycardia and atral ﬁbrillation were observed less frequently in one series of patients with resistance to thyroid hormone. The authors concluded that this syndrome was associated with an incomplete response to thyroid hormone in the heart [60]. While this syndrome is thought to be distinct from other syndromes of thyroid dysfunction, clinical ﬁndings may be symptomatically treated with beta-blockers because of the lower likelihood of developing cardiac complications in this subset of patients. Subclinical Hyperthyroidism Subclinical hyperthyroidism is deﬁned as a serum TSH below the lower limit of normal, usually less than 0.1 mU/L with normal T4 and T3 levels in the absence of clinical features [55]. Recent data have led to an increased understanding of subtle changes that may occur in subclinical hyperthyroidism, including altered heart rate, left ventricular mass index, increased systolic function, and impaired diastolic function [61]. Several large studies have been published that have shown an increased risk of atrial ﬁbrillation in patients with subclinical hyperthyroidism. One recent retrospective study reported that the risk of atrial ﬁbrillation was ﬁve times more likely in patients with subclinical hyperthyroidism, similar to that found in patients with overt hyperthyroidism [57,62–64]. An increase in the number of cardiac L-type Ca2+++ channels by up to threefold has been reported in patients who are subclinically hyperthyroid, a probable mechanism for the increased rate of atrial ﬁbrillation [65]. Treatment at this early stage of hyperthyroidism is controversial secondary to the low rates of progression to overt hyperthyroidism. A recent long-term study of patients with untreated subclinical hyperthyroidism demonstrated an increase in both cardiovascular and all-cause mortality [66]. When these data are coupled with the ﬁndings of self-reported

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ratings of diminished quality of life and a higher rate of osteopenia in persons with subclinical hyperthyroidism, it is reasonable to consider earlier, more aggressive treatment, especially in individuals who already manifest these changes [55,67]. Management of Hyperthyroid-Associated Cardiac Disease Cardiac ﬁndings such as palpitations, sinus tachycardia, and even tachyarrhythmias appear to be well tolerated in most hyperthyroid people, rarely produce an immediate crisis, and in most cases are amenable to conservative treatment pending correction of the hyperthyroid state itself. While radioactive iodine is an excellent treatment for the underlying hyperthyroid state, especially in the elderly patient, the time to onset of action can be weeks to months. If an immediate eﬀect is needed, Lugol’s solution may be administered after an initial dose of antithyroid medication such as propylthiouracil or methimazole. Iodine rapidly reduces circulating levels of thyroid hormone by blocking essential steps in thyroid hormone production. However, propylthiouracil or methimazole must be used in conjunction with the iodine to inhibit thyroid hormone synthesis, and to prevent the possibility of a thyroid nodule or diﬀuse toxic goiter from converting the iodine to thyroid hormone and eﬀectively worsening the hyperthyroid state [31,39]. In patients who are unstable with signs of cardiac compromise, intravenous betablockers rapidly decrease heart rate and may reduce the conversion of T4 to T3 by approximately 15%. If the patient presents with congestive heart failure, diuretics are still the mainstay of treatment. Digoxin is of use in patients with hyperthyroid-mediated congestive heart failure, although there may be a Na-K-ATPase-mediated resistance to its action [31]. Initial treatment of atrial ﬁbrillation should be tailored to correcting the hyperthyroidism because of the high rate of spontaneous cardioversion once thyroid hormone concentrations are normalized [54]. Most of these conversions take place within 3 weeks of becoming euthyroid and no spontaneous conversions occur if atrial ﬁbrillation is still present after 4 months of euthyroidism or if atrial ﬁbrillation was present for more than 13 months before becoming euthyroid. Patients who remain in atrial ﬁbrillation beyond 16 weeks or return to the euthyroid state are candidates for cardioversion. The decision to anticoagulate has not been elucidated in the case of hyperthyroidassociated atrial ﬁbrillation in any randomized controlled trials. However, it has been recommended that older patients with comorbid hypertension, congestive heart failure, left atrial enlargement, left ventricular dysfunction, or other conditions increasing the risk of systemic embolization, or those patients with longer duration of atrial ﬁbrillation, should be anticoagulated. On the contrary, it is probably not necessary to anticoagulate young patients without comorbid conditions or with a short duration of atrial ﬁbrillation [39,55,68]. Hyperthyroidism increases the sensitivity to the anticoagulant eﬀect of warfarin, resulting in a greater lowering of coagulation factors II and VII and greater increase in prothrombin ratio and partial thromboplastin time [69]. When warfarin is used, the dose should keep the International Normalization Ratio (INR) between 2.0 and 3.0 and continue until euthyroidism has been restored and there is a return to normal sinus rhythm [70].

HYPOTHYROIDISM Hypothyroidism, deﬁned as an elevated serum TSH along with serum T4 or free T4 below the lower limit of normal, is relatively common in the general population with a well-

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established relationship to gender and age. The incidence of hypothyroidism in women is three to four times that of men and there is a clear increase in prevalence with advancing age so that it is found in 15 to 20% of women over the age of 75 years and 4 to 7% of elderly men. The American Thyroid Association now recommends that all persons over 50 have annual screening for thyroid hormone abnormalities after studies have shown the cost-beneﬁt of such practice [71]. Cardiovascular manifestations of hypothyroidism occur as a consequence both of the eﬀects of thyroid hormone deﬁciency on the myocardium and of dyslipidemia on arterial vasculature. Histologically, swelling of the myoﬁbrillar elements, interstitial ﬁbrosis, basophilic degeneration, and tissue edema have been described [72]. There appears to be deposition of mucopolysaccharide, likely reﬂecting the decline in certain enzymes necessary for the breakdown of these substances. Electron microscopic studies reveal thickening of the capillary basement membrane similar to that observed in diabetes mellitus and in persons of advanced age [73,74]. Numerous other ultrastructural changes have been described, including loss of mitochondrial cristae. At the organ level, the heart in persons with hypothyroidism may be dilated, pale, and ﬂabby as a result of myxedematous inﬁltration, but there is no evidence of hypertrophy [75]. Pericardial eﬀusion may be present. Thyroid Hormone Deficiency and Cardiovascular Function Perhaps the most widely accepted change that has been noted in the setting of hypothyroidism is a reduction in myocardial contractility. Using isolated right ventricular papillary muscles from hypothyroid cats and dogs, a decrease was noted in isometric tension and the rate of tension development. The time taken to reach peak tension increased at all muscle lengths, and isotonic force-velocity relations shifted downward and to the left, supporting a depressed contractile state [76,77]. In all animal studies reported, congestive heart failure was not noted despite signiﬁcant reductions in circulating levels of thyroid hormone. It has been postulated that decreased myocardial contractility in hypothyroidism may result from a reduction in the thyroid-adrenergic relationship, with either a diminished response to a given amount of catecholamine or a reduced amount of free catecholamine available to interact at the cardiac receptor site. Studies have reported an increase, decrease, and no change in cardiovascular sensitivity to catecholamine stimulation in the setting of hypothyroidism [78–81]. Levels of norepinephrine in myocardial tissue of hypothyroid cats were not reported to be aﬀected by thyroid status [76], and thus it appears unlikely that a lower level of catecholamine exposure to the cardiac receptor is the cause of signiﬁcant cardiac eﬀects. Studies have shown a reduction in h-adrenergic receptor activity in atria from hypothyroid rats and an increase in a-receptor activity in the same tissue [82]. This reduction in the number and/or aﬃnity of h-receptors in cardiac tissue could result in a depressed myocardial response. Because contractile function is depressed in isolated papillary muscles from hypothyroid rats [76], thyroid hormone deﬁciency seems to have a direct eﬀect and is responsible for at least a component of the cardiovascular change induced by the hypothyroid state. The rate of calcium uptake and calcium-dependent ATP hydrolysis by isolated cardiac myocytes is reduced in the setting of hypothyroidism and may be a mechanism for decreased myocardial contractility [83]. A reduction in myocyte calcium ATPase activity of the sarcoplasmic reticulum has been described in both rat and mouse models ofhypothyroidism [84–86], although not in a rabbit model [86].

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The bradycardia that often occurs in hypothyroidism is thought to result from the lack of thyroid stimulation of sinoatrial node cells [87], further impacted by a reduction in sympathoadrenal stimulation. A decreased rate of diastolic repolarization and prolonged action potential duration has also been described. The hemodynamic changes seen in hypothyroidism are opposite those seen in hyperthyroidism and are less likely to be associated with overt clinical ﬁndings. Systemic vascular resistance is increased, heart rate is decreased, isovolumic relaxation time is increased, and there is decrease in ejection fraction, blood volume, and cardiac output [39,45,86]. An increase in systemic vascular resistance, decrease in heart rate, and decrease in the reninangiotensin-aldosterone system combined with a slowed diastolic relaxation lead to a decrease in preload and subsequent decrease in stroke volume. Thus, the functional consequence of decreased ventricular contractility, ventricular ﬁlling, and stroke volume is reduced cardiac output. Changes in blood lipoprotein composition in hypothyroidism have implications on atherogenesis. Short-term hypothyroidism is associated with an increase in plasma lipoprotein (a); T3 therapy rapidly lowered lipoprotein (a) together with apolipoprotein B and LDL cholesterol. These ﬁndings support the hypothesis that thyroid hormone is capable of regulating plasma lipoprotein (a) and apolipoprotein B in a parallel manner. Elevated concentrations of lipoprotein (a) in combination with LDL cholesterol may be involved in the increased risk of cardiovascular disease which is associated with hypothyroidism [88]. Changes in LDL receptor activity are signiﬁcantly correlated with changes in LDL cholesterol, but not changes in lipoprotein (a). The LDL receptor pathway appears to be involved in the catabolism of lipoprotein (a) to a limited extent [89]. Hypothyroidism has been associated with elevated levels of total and HDL cholesterol, total/HDL cholesterol ratio, apolipoprotein AI, and apolipoprotein E. The increase in apolipoprotein AI without a concomitant increase in apolipoprotein AII suggests a selective elevation of HDL2. These eﬀects were found to be reversible with treatment of the hypothyroidism [90]. Pulse-wave analysis from recordings at the radial artery in patients with hypothyroidism demonstrate increased augmentation of central aortic pressures and central arterial stiﬀness. These alterations lead to hypertension and increased cardiac afterload and, along with hypothyroid-associated endothelial dysfunction, contribute to increased cardiovascular risk. These abnormalities are reversed by appropriate thyroid hormone replacement [91]. Clinical Manifestations of Hypothyroidism Clinically evident cardiac manifestations of hypothyroidism occur only in association with a signiﬁcant reduction in the levels of circulating thyroid hormone. Studies using oxygen consumption as a corollary of thyroid hormone status have reported few cardiac symptoms in otherwise healthy persons until oxygen requirements decline by 75%. This is highly variable, however. Many persons with hypothyroidism have coexisting medical conditions that compromise the cardiovascular system and may lower the threshold for cardiac problems. The reduced requirement for oxygen by the hypothyroid myocardium may be protective against angina. In fact, angina may develop only after therapy with thyroid hormone has been initiated. Symptoms due to the eﬀect of hypothyroidism on the heart include dyspnea on exertion and easy fatigability. Less frequent are complaints of orthopnea, paroxysmal nocturnal dyspnea, and angina. Physical ﬁndings often present in patients with hypothyroidism

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include bradycardia, narrowed pulse pressure, mild hypertension, distant heart sounds, and evidence of cardiomegaly. Reduced cardiac output with resultant decrease in glomerular ﬁltration rate can lead to renal sodium retention and peripheral edema in the absence of congestive heart failure. In general, there is no change in the jugular venous pressure. In patients with severely diminished thyroid function, however, inﬁltrative cardiomyopathy, evidence of peripheral edema or nonpitting edema of the lower extremities, pleural eﬀusion, and even ascites may be noted and can produce a clinical picture suggesting congestive heart failure. The presence of nonpitting edema should be a suspicion that hypothyroidism is present. The electrocardiogram may be normal in the presence of hypothyroidism but more often there is bradycardia, prolonged QT interval, ﬂattening or inversion of the T-wave, particularly in lead II, and low-amplitude P, QRS complex, and T-waves [92]. These ﬁndings may result from a direct eﬀect of thyroid hormone deﬁciency, but can also be the result of a pericardial eﬀusion that may accompany hypothyroidism. Although uncommon, incomplete and complete right bundle branch block occur with greater frequency [93]. Ventricular arrhythmias may be seen, including the ventricular tachycardia of the torsades de pointes syndrome. With replacement therapy, these changes return to normal and may even precede the return to normal of other clinical features of the disease. The echocardiogram in hypothyroidism demonstrates features of decreased left ventricular contractility with increased systolic time interval and prolongation of isovolumic relaxation time. Small pericardial eﬀusions may be present in as many as 50% of hypothyroid patients but do not aﬀect cardiac function [94,95]. Studies suggest that in the absence of other coexisting diseases, congestive heart failure is an extremely uncommon ﬁnding in hypothyroidism [96]. In the setting of shortness of breath, pleural eﬀusions, cardiomegaly, and other symptoms, it is often diﬃcult to distinguish CHF from what has been termed myxedema heart, a cardiomyopathy resulting from insuﬃcient quantities of thyroid hormone that is reversible with thyroid hormone replacement. The absence of pulmonary congestion, diminished plasma volume, high protein content of pleural or pericardial eﬀusions, and normal resting venous, atrial, pulmonary artery, and right ventricular end-diastolic pressures is highly suggestive of myxedema itself. Exercise results in an increase in cardiac output and ejection fraction in persons with myxedema in contrast to the impaired response in those with congestive failure [97,98]. The hemodynamic changes associated with hypothyroidism appear to respond to thyroid hormone, but they are not very responsive to diuretic and digoxin therapy. Since in many persons both conditions occur together, there is a great deal of variability in clinical response. An increase in the risk for coronary heart disease has been associated with hypothyroidism. Decreased measures of thyroid function and serum HDL have been observed to be more common in patients with coronary artery disease [99]. Treatment of hypothyroidism with hormone replacement has been observed to protect against the angiographic progression of coronary artery disease, perhaps due to metabolic eﬀects of thyroid hormone on plaque progression [100]. Subclinical Hypothyroidism Large population surveys have identiﬁed a signiﬁcant proportion of individuals who have serum levels of TSH above the accepted upper limit of normal but in whom serum con-

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centrations of total and free T4 as well as total and free T3 are normal, and overt symptoms of hypothyroidism are usually mild or absent. This syndrome has been termed subclinical hypothyroidism, is most commonly found in women above the age of 60, and has been observed in 15 to 20% of women over the age of 75 years [101–106]. There is evidence that systolic and diastolic contractility are decreased in patients with subclinical hypothyroidism [61]. These changes may have little functional signiﬁcance in the resting state but symptoms can develop during cardiopulmonary exercise. The altered contractility and clinical response to exercise are corrected with thyroid hormone treatment [107–109]. Although subclinical hypothyroidism has been associated with a prolongation of the QT interval, little has been reported regarding its clinical consequences. A study of 1922 patients indicated that subclinical hypothyroidism was not associated with an adverse cardiovascular risk proﬁle [110]. The relationship between subclinical hypothyroidism and/or autoimmune thyroid disease and coronary heart disease (CHD) was evaluated in a Japanese population. Ninety-seven patients diagnosed as having CHD by a coronary angiogram (CHD group) and 103 healthy subjects matched for age, sex, and body mass index (control group) were included in the study. Thyroid function, thyroid autoantibodies, and serum lipid concentrations were measured in the CHD and control groups. The CHD group exhibited signiﬁcantly decreased levels of serum free T3 and free T4 and signiﬁcantly increased serum TSH levels as compared with the control group, indicating a signiﬁcant decrease in thyroid function in the CHD patients. Serum HDL cholesterol levels were signiﬁcantly decreased in the CHD group [99]. Among elderly residents of a nursing home, 6% were found to have subclinical hypothyroidism and, of these, 83% had dyslipidemia and 56% had evidence of coronary artery disease in contrast to a 16% incidence of coronary artery disease in euthyroid residents [111]. Women with hypercholesterolemia have an increased liklihood of having coexisting subclinical hypothyroidism [112]. Patients with subclinical hypothyroidism have been found to have a relative increase in LDL-lipoprotein and decrease in HDL lipoprotein with a corresponding higher prevalence of ischemic heart disease [113]. In a large group of elderly women with evidence of aortic atherosclerosis, 13.9% were found to have subclinical hypothyroidism and, in those women with with a history of myocardial infarction, 21.5% had subclinical hypothyroidism [101]. The presence of subclinical hypothyroidism was accompanied by a high prevalence of both aortic atherosclerosis and myocardial infarction, with an even higher prevalence in those who also had detectable thyroid antimicrosomal antibodies. A higher rate of adverse events, including reocclusion, has been observed after percutaneous coronary intervention in patients with subclinical hypothyroidism [114]. An increase in factor VII activity has been found in a study of patients with subclinical hypothyroidism, raising the possibility of a hypercoagulable state that may lead to an increased risk of thromboembolism [115]. Treatment with L-thyroxine has resulted in improved systolic and diastolic function, improvement in left ventricular ejection fraction with exercise, and decrease in systemic vascular resistance [61,113,116]. L-thyroxine treatment has also resulted in decrease in total and LDL cholesterol, increase in serum high-density lipoproteins, and decrease in lowdensity lipoproteins and apolipoprotein b [109,117,118]. A recent meta-analysis has further demonstrated a modest, but eﬀective, reduction in total and LDL cholesterol in treated cases of subclinical hypothyroidism [119]. There are no substantive data as yet to indicate that early treatment of subclinical hypothyroidism with thyroid hormone replacement will be eﬀective in reducing the risk for subsequent development of atherosclerosis or coronary artery disease.

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Myxedema Coma Myxedema coma is an extreme, life-threatening form of hypothyroidism that occurs almost exclusively in the elderly, usually in association with infection, severe trauma, or cold exposure, or following administration of sedatives, tranquilizers, or narcotics. Cardiac manifestations include bradycardia, hypotension, and shock. The electrocardiogram, in addition to bradycardia, will usually show low-voltage and T-wave ﬂattening. Serum CK is often markedly elevated and the clinical picture may resemble that of a myocardial infarction.

Management of Hypothyroidism Younger persons or those with no evidence of cardiovascular compromise may be started on L-thyroxine in an initial dose of 25 Ag daily. Because so many elderly persons with hypothyroidism may have underlying cardiovascular abnormalities, initiation of thyroid hormone replacement therapy in this population should begin with a smaller dose of Lthyroxine (i.e., 12.5 Ag daily). The use of diuretic therapy and digoxin should be reserved for persons in whom there is clear evidence of coexisting congestive heart failure. The starting dose should be increased by 12.5- to 25-Ag increments at 4- to 6-week intervals, realizing that both age and hypothyroidism prolong the half-life of L-thyroxine. Because it takes approximately ﬁve half-lives to reach a steady state, laboratory monitoring of serum TSH is necessary to avoid too rapid a rise in dosing. Dose adjustments are made until the level of serum TSH has declined to within the normal range or the patient develops signs of toxicity. In general, elderly persons who are hypothyroid require a replacement dose of between 75 and 100 Ag daily compared to an approximate dose of 100 to 125 Ag for younger persons. Lthyroxine is the preferred thyroid hormone for replacement because T3 exerts a ‘‘burst’’ eﬀect on the myocardium and is less well tolerated. It also has a shorter half-life, thereby having a less equilibrated metabolic proﬁle. Combination therapies also share the disadvantage of T3, a component in all these medications. In individuals who have severe ischemic cardiac disease, it may be diﬃcult to return the patient to the euthyroid state without provoking cardiac symptoms. However, in a study of hypothyroid patients who had known symptomatic coronary artery disease, treatment resulted in either no change or an improvement in symptoms in 84% of the patients with only 16% exhibiting an increase in symptoms [120]. An attempt should be made to maximize the antianginal regimen, including administration of h-blockers, vasodilators, and calciumchannel blockers. If this approach fails, the patient should undergo evaluation for the possibility of angioplasty or coronary artery bypass surgery [121]. The patient with myxedema coma should be cared for in an intensive-care-unit setting; treatment should be started promptly, with an initial intravenous dose of 300 to 500 Ag of Lthyroxine. Once there is evidence of a clinical response, such as rise in body temperature and heart rate, the daily dose of L-thyroxine should be reduced to 25 to 50 Ag orally and further adjusted slowly by monitoring the serum TSH [122,123].

CONCLUSIONS Thyroid hormone has multiple eﬀects on the cardiovascular system, acting through a variety of mechanisms. Clinically, these eﬀects are manifest in patients with hyper and hypo-

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22 Heart Failure Dalane W. Kitzman Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

Jerome L. Fleg National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

EPIDEMIOLOGY AND RISK FACTORS Over the past three decades, death rates for cardiovascular disease have declined dramatically in the United States and other western countries. In contrast, the prevalence and incidence of heart failure (HF) have increased steadily over this period [1]. Between 1979 and 1999, hospital discharges for HF in the United States nearly tripled in women and more than doubled in men [1]. The national prevalence of HF is approximately 4.8 million, with about 550,000 new cases occuring yearly. Heart failure prevalence and incidence increase markedly with age. For instance, in the Framingham Heart Study, the incidence of HF increased approximately ﬁvefold from the age of 40 to 70 years [2]. HF is predominantly a disorder of the elderly; over 80% of HF patients are z65 years old. In the community-based Rochester Community Project, the mean age of patients who developed new HF in Olmstead County, Minnesota, was 76 years, and nearly 50% were z80 years [3]. HF is the leading cause of hospitalization in Medicare beneﬁciaries, consuming $3.6 billion in 1998 [4]. Even within the older age group, HF prevalence increases with age. In the Cardiovascular Health Study (CHS), a population-based observational study of cardiovascular risk conducted in four U.S. communities and exclusively examining persons who were zage 65, HF prevalence increased in women from 4.1% at age 70 to 14.3% at age 85 (Fig. 1); HF prevalence was higher in men but with a similar age trend (7.8% increasing to 18.4%) [50]. During 6 years of follow-up, the incidence of HF in CHS was 10.6/1000 person-years at age 65 and was 42.5/1000 person-years at age z80 years [6]. HF incidence was greater in men than in women. In the Framingham study, although men are substantially more likely than women to develop HF before age 65, the ratio of men to women approached unity after this age [6]. In the Framingham study, CHF incidence declined from 31 to 40% in women but remained unchanged in men from 1950 to 1969 and during the 1990s. [7,8]. The prevalence and incidence of HF were similar in African Americans and whites in CHS [5,6]. 529

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Figure 1 Prevalence of congestive heart failure vs. age in elderly men (dark bars) and women (light bars) in the Cardiovascular Health Study. Even in an older cohort such as this, CHF prevalence increased with age. (Adapted from Ref. 5.)

Major factors in the increasing prevalence and incidence of HF are the growing proportion of elderly Americans with chronic hypertension and coronary heart disease (CHD), the two most common antecedent conditions. In addition to age, several common risk factors for HF have been identiﬁed in older populations. Over 75% of HF patients have antecedent hypertension. Recent studies in older populations have found that pulse pressure, an index of arterial stiﬀness, is the strongest blood pressure predictor of HF [9,10]. Coronary heart disease, especially prior myocardial infarction, and degenerative aortic valvular disease are potent predictors of HF in the elderly. Male sex, obesity, and diabetes were independent predictors of HF in CHS [6] in the New Haven cohort of the Established Population for Epidemiological Studies of the Elderly (EPESE) [10]. Additional predictors of HF in CHS were prior stroke, atrial ﬁbrillation, renal dysfunction, reduced ankle–arm index, increased C-reactive protein, left ventricular hypertrophy (LVH), and reduced forced expiratory volume [6]. There has been growing recognition over the past two decades that a substantial proportion of HF patients, mostly elderly, have preserved systolic LV function. This condition has been presumptively termed diastolic HF. Reports from population-based studies such as Framingham [11], CHS [5], Olmsted County [3], and the Strong Heart Study of American Indians [12] all suggest that at least half of all elderly HF patients have preserved LV systolic function. In the subset of patients z90 years old, about two-thirds had LV ejection fraction z50% [3]. In each of these studies, there was a strong female predominance among DHF cases. In CHS, women represented 67% of diastolic HF cases but only 39% of systolic HF cases [5]. Therefore, the typical proﬁle of a HF patient in the community, an elderly woman with preserved LV ejection fraction and systolic hypertension, diﬀers markedly from the typical patient in the HF literature, a middle-aged man with prior myocardial infarction and severely reduced systolic LV function (Table 1) [13].

Heart Failure Table 1

531

Heart Failure in Older Versus Middle-Aged Patients

Characteristic

Elderly

Middle-Aged

Prevalence Gender

6–18% Predominantly women

Etiology

Hypertension

LV systolic function Comorbidities

Normal Multiple

<1% Predominantly men Coronary heart disease Impaired Few

Abbreviations: LV: left ventricular. Source: Adapted from Ref. 148.

PROGNOSIS The morbidity and mortality of older HF patients are perhaps the highest of any chronic cardiovascular disorder. In the Olmstead County study, cumulative mortality was 24% at 1 year and 65% at 5 years [3]. Mortality increases markedly with age; in a database of 66,547 consecutive ﬁrst-time admissions for HF in Scotland, 1-year case fatality rate increased from 14% in patients below age 55 to 58% in those older than 84 [14]. In community-based individuals 65 to 74 years of age, 10-year mortality was 50% in women and >70% in men [15]. Among elderly persons hospitalized for HF, the prognosis is even worse, with 5-year mortality >70%; mortality was similar in whites and blacks [16]. This age-associated increase in HF mortality observed in numerous studies appears multifactorial. Contributing factors include a generalized reduction in functional reserve, the multiple morbidities seen in elderly patients, and underutilization of medications. Recent data, however, suggest a modest improvement in survival [7,14]. In Framingham, 5-year age-adjusted mortality declined from 70% to 59% in men and from 57% to 45% in women between 1950 to 1969 and during the 1990s [7]. Mortality from diastolic HF, although substantially higher than in age-matched controls, is about half that reported for systolic HF; in Framingham, the respective annual mortality rates were 8.9% and 19.6% [11]. Nearly identical results were seen in CHS (Fig. 2) [17]. In elderly patients hospitalized for HF, however, survival appears similar for those with diastolic versus systolic HF [18–20]. An important observation in CHS was that, given the higher prevalence of diastolic than systolic HF among the community-based elderly, the population-attributable mortality from diastolic HF equals or exceeds that for systolic HF in this age group [17]. Predictors of higher mortality in older HF patients resemble those in younger patients and include male sex, LV dilation, and systolic dysfunction, diabetes, renal dysfunction, hyponatremia, reduced peak oxygen consumption, and recent hospitalization [16,17,21,22]. Morbidity from HF is also very high in the elderly. Between 30% and 50% of older patients hospitalized for HF will be rehospitalized within 3 to 6 months [23–25]. This high hospitalization rate translates into poor quality of life and high health-care costs. Prior admission within 1 year, prior HF, diabetes, and serum creatinine >2.5 mg/dL at discharge predicted readmission in a Medicare database [21]. In contrast to mortality, readmission rates appear comparable between HF patients with preserved versus reduced systolic

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Figure 2 Survival of patients in the Cardiovascular Health Study. Control = nested case controls without heart failure; DHF = heart failure with a normal ejection fraction; Asx LVD = reduced ejection fraction with no symptoms of heart failure; SHF = systolic heart failure. (Modiﬁed from Ref. 17.)

function. Other adverse outcomes, such as myocardial infarction and stroke, are common in older HF patients.

PATHOPHYSIOLOGY Given the multiple age-associated changes in cardiovascular and noncardiovascular structure and function, and the numerous morbid conditions that often accompany aging, it would not be surprising if the pathophysiology of HF diﬀered in elderly versus younger patients. The limited speciﬁc comparative data that exist, particularly the substantially higher prevalence of HF with preserved systolic LV function in older as opposed to younger HF patients, support the notion of diﬀerential pathophysiology. Normal aging is accompanied by a mild concentric thickening of the LV myocardium and reduced early diastolic relaxation and ﬁlling rates [26,27]. Both of these may derive in part from the age-associated increase in arterial stiﬀness [28]. These ﬁndings are similar to those seen in younger hypertensive patients and provide a substrate more prone to development of diastolic HF. In addition, reduced chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation occur with advancing age [29–31]. The reduced maximal heart rate response to aerobic exercise is a major contributor to the nearly 10% per decade decline in peak oxygen consumption (VO2) [32,33]. Reduced maximal stroke volume, reﬂecting reduced inotropic and lusitropic reserves, also contribute to the predilection to HF in older individuals [30,33,34].

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Several noncardiovascular aging changes also contribute to an increased HF susceptibility among the elderly (Table 2). These include reduced glomerular ﬁltration rate and ability to excrete a sodium load, increased ventilation perfusion mismatching in the lung, reduced ventilatory capacity, and impaired central nervous system autoregulation. Many of the morbidities of elderly HF patients are actually exaggerations of these ageassociated physiological changes. Examples include systolic hypertension, LV hypertrophy, renal dysfunction, and restrictive lung disease. Together, the age-associated changes in CV and non-CV structure and function and the multiple comorbid diseases that occur with advancing age serve to increase susceptibility for developing HF, intensify symptoms, and complicate management. Despite these pathophysiological age diﬀerences in the substrate for HF, relatively few studies have speciﬁcally compared younger versus older HF patients in this regard. In 128 consecutive patients admitted with HF, Cody et al. [35] observed a reduced heart rate and increased systemic vascular resistance at rest in older patients and a reduced heart rate response to tilt. Plasma norepinephine increased with age whereas no consistent age trends were seen for plasma renin activity or urinary aldosterone. A reduction of glomerular ﬁltration rate and ﬁltration fraction and increases in renal vascular resistance and serum creatinine levels were observed at older ages [35]. In a comparison of HF outpatients >75 years old to those <65 years, Dutka, et al. [36] observed that the older group had substantially smaller ventricles, higher fractional shortening, higher Doppler A-wave velocity, lower E/A ratio, and longer deceleration time than the younger group. These ﬁndings of better systolic function and impaired diastolic performance in the older group are noteworthy because all patients in this study were required to have fractional shortening <28%, indicating, LV systolic dysfunction. These investigators conﬁrmed higher levels of plasma norepineprine in older patients but observed lower plasma renin, angiotensin, and atrial natriuretic peptide than in younger patients. Of note, 30% of the older group but none of the younger group had atrial ﬁbril-

Table 2

Comorbidities in Older Heart Failure Patients

Condition Renal dysfunction Chronic lung disease Cognitive dysfunction Depression, social isolation Postural hypotension, falls Urinary incontinence Sensory deprivation Nutritional disorders Polypharmacy Frailty

Implications Worsens symptoms, prognosis; exacerbated by diuretics, ACE inhibitors Worsens symptoms, prognosis; contributes to uncertainty about diagnosis/volume status Interferes with dietary, medication, activity compliance Worsens prognosis, interferes with compliance Exacerbated by vasodilators, diuretics, beta-blockers Aggravated by diuretics, ACE inhibitors (cough) Interferes with compliance Exacerbated by dietary restrictions Compliance issues, drug interactions Worsens symptoms and quality of life; exacerbated by hospitalization; increased fall risk

Abbreviations: ACE: angiotensin-converting enzyme. Source: Adapted from Ref. 148.

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lation, similar to the observation by Wong et al. [37]. Although Clark and Coats observed no age-associated decline in peak exercise oxygen consumption (VO2) in 68 HF patients with mean LV ejection fraction of 22% [38], others have reported greater reduction of aerobic capacity in elderly HF patients than in middle-aged HF patients [39]. As previously discussed, a majority of older HF patients have preserved systolic function [3,5,11,12]. This syndrome is relatively uncommon in younger HF patients and represents the most stark diﬀerence in HF as it commonly presents in older versus younger populations. Compared to systolic HF, there is a relative dearth of information regarding the pathophysiology of diastolic HF. Exercise intolerance, manifested as exertional dyspnea and fatigue, is the primary symptom in chronic HF with either a reduced or a normal ejection fraction. Three separate studies have now demonstrated that diastolic HF patients have severely reduced exercise capacity as measured objectively by peak VO2 during exercise and that their exercise intolerance is just as severe as that of age-matched systolic HF patients (Fig. 3) [40–42]. Understanding the mechanisms of reduced oxygen consumption in elderly diastolic HF patients could provide important insight into potential therapy. Using invasive cardiopulmonary exercise testing, it was demonstrated that diastolic HF patients have a reduced ability to increase stroke volume via the Frank-Starling mechanism despite severely increased LV ﬁlling pressure indicative of diastolic dysfunction (Fig. 4) [40]. This resulted in severely reduced exercise cardiac output and early lactate formation and was a signiﬁcant independent contributor to the severely reduced exercise capacity and associated chronic exertional symptoms [40]. Another study indicated that decreased aortic distensibility, probably due to the combined eﬀects of aging- and hypertension-induced thickening and remodeling of the thoracic aortic wall, is an important contributor to exercise intolerance in chronic diastolic HF. Compared to age-matched healthy subjects, patients with diastolic HF had increased pulse

Figure 3 Peak exercise oxygen consumption (VO2) during exhaustive exercise in age-matched normal subjects (NO), elderly patients with heart failure due to systolic dysfunction (SD), and elderly patients with heart failure with normal systolic function, presumed diastolic dysfunction (DD). Exercise capacity is severely reduced in elderly patients with diastolic heart failure and to a similar degree as in those with classic systolic heart failure. (From data in Ref. 39.)

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Figure 4 LV diastolic function assessed by invasive cardiopulmonary exercise testing in patients with heart failure and normal systolic function (open boxes) and age-matched normals (closed boxes). Pressure–volume relation was shifted upward and leftward at rest. In the patients with exercise, LV diastolic volume did not increase despite marked increase in diastolic (pulmonary wedge) pressure. Due to diastolic dysfunction, failure of the Frank-Starling mechanism resulted in severe exercise intolerance. (From Ref. 40.)

pressure and thoracic aortic wall thickness and markedly decreased aortic distensibility, which correlated closely with their severely decreased peak exercise VO2 (r = 0.8; p < 0.001) (Fig. 5) [41]. It is very likely that systolic hypertension plays an important role in the genesis of diastolic HF in the elderly. In animal models, diastolic dysfunction develops early in systemic hypertension, and LV diastolic relaxation is very sensitive to increased afterload [43–48]. Increased afterload impairs LV relaxation, leading to increased LV ﬁlling pressures, decreased stroke volume, and symptoms of dyspnea and congestion. [48] Nearly all (88%) diastolic HF patients have a history of chronic systemic hypertension [5,49]. In addition, severe systolic hypertension is usually present during acute exacerbations (pulmonary edema) [50,51]. Although the role of ischemia in diastolic HF is uncertain, it would seem likely that it is a signiﬁcant contributor in many cases. It had been hypothesized that patients found to have a normal ejection fraction following an episode of CHF may have had transiently reduced systolic function and/or ischemia at the time of the acute exacerbation. If so, then the term ‘‘diastolic heart failure’’ would be an inappropriate label for this disorder and all therapeutic eﬀorts would be aimed at therapy of ischemia and reversible systolic dysfunction. A recent study addressed this important issue by performing echocardiograms at the time of presentation in 38 consecutive patients with acute hypertensive pulmonary edema and, again, about 3 days later after resolution of pulmonary edema and hypertension [51]. The LV ejection fraction and wall motion score index at follow-up were similar to those found during the acute echocardiogram. Of those who had LV ejection fraction z50% at follow-

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Figure 5 Data and images from representative subjects from healthy young, healthy elderly, and elderly patients with diastolic heart failure. Maximal exercise oxygen consumption (VO2max), aortic distensibility at rest, and left ventricular mass:volume ratio. Patients with diastolic heart failure have severely reduced exercise tolerance (VO2max) and aortic distensibility and increased aortic wall thickness. (Adapted from Ref. 41.)

up (n = 18), all but two had LV ejection fraction z50% acutely, and in both of those cases, the LV ejection fraction was >40%, above the level that would be expected to cause acute heart failure on the basis of primary systolic dysfunction (Fig. 6). These data suggest that marked transient systolic dysfunction does not often play a primary role in patients presenting with acute HF in the presence of severe systolic hypertension who are subsequently found to have a normal ejection fraction. Furthermore, these ﬁndings indicate that the ejection fraction measured at follow-up accurately reﬂects that during an acute episode of HF. This and a related study, in which pulmonary edema recurred in about half of such patients despite coronary revascularization, support the concept that acute pulmonary edema in these patients is most likely due to an exacerbation of diastolic dysfunction caused by severe systolic hypertension rather than by ischemia [50]. Neurohormonal activation is felt to play an important, even fundamental, role in the pathophysiology of systolic HF. In a group of patients with primary diastolic HF, Clarkson et al. showed that atrial natriuretic peptide and brain natriuretic peptide were substantially

Figure 6 Left ventricular ejection fraction (LVEF) measured during acute pulmonary edema and at follow-up, 1–3 days after treatment. Nearly all patients found to have normal EF (>50%) at follow-up also had normal EF during acute pulmonary edema. (Adapted from Ref. 51.)

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Figure 7 Basal, resting venous norepinephrine levels in age matched normal subjects (NO), elderly patients with heart failure due to systolic dysfunction (SD), and elderly patients with heart failure and normal systolic function, presumed diastolic dysfunction (DD). Neuroendocrine activation in elderly patients with diastolic heart failure can be as severe as that seen in classic systolic heart failure, conﬁrming that diastolic heart failure is ‘‘real’’ heart failure and a distinct entity. (From data in Ref. 39.)

increased and there was an exaggerated response during exercise [52], a pattern similar to that described in patients with systolic HF. Furthermore, atrial natriuretic peptide levels among older frail subjects are predictive of the subsequent development of HF [53]. In a study using two diﬀerent control groups—age-matched healthy normal subjects and agematched systolic HF patients—Kitzman et al. showed that older patients with isolated diastolic HF have markedly increased norepinephrine levels, equivalent to those seen in systolic HF (Fig. 7), and had levels of atrial and brain natriuretic peptide that were increased tenfold compared to age-matched normals [39]. In the above study, diastolic HF patients were also shown to have severely reduced health-related quality of life [39]. In the same study, detailed Doppler measures of LV diastolic ﬁlling were similar between systolic HF and diastolic HF patients [39]. The diastolic HF patients had severely increased LV mass/volume ratio, reﬂecting their concentric hypertrophic remodeling [39,41]. The role of genetic predisposition in the genesis of diastolic HF in the elderly is not known. However, data from the HyperGen study have shown signiﬁcant heritability of hypertension [54], LV mass [55], and Doppler diastolic ﬁlling [56], all factors that likely play a role in diastolic HF in the elderly.

PRECIPITANTS Relatively few published data exist regarding the speciﬁc precipitants of HF in the elderly. In a series of 154 consecutive HF patients aged 75 F 8 years admitted to an Italian geriatrics

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ward, 71% had coronary artery disease, 45% hypertension, and 32% valvular heart disease [57]. Factors precipitating HF were evident in 62% of patients and included atrial ﬁbrillation (16%), lack of drug compliance (10%), renal failure (8%), fever (7%), and anemia (6%). The important contribution of atrial ﬁbrillation to the development of HF in the elderly has been observed in multiple studies and probably relates to the greater reliance of older versus younger patients on the atrial contribution to LV ﬁlling. In this elderly group, 45% of whom had normal LV systolic function, the presence of HF was associated with an average of ﬁve unrelated diseases [57]. In the EPESE community-based cohort, myocardial infarction was the precipitant of HF in 49 of 173 cases (28%) [10]. Acute elevation of blood pressure appears to be responsible for a signiﬁcant proportion of patients presenting with acute pulmonary edema [50,51]. It is diﬃcult in such patients, however, to determine whether the elevated blood pressure seen at presentation was the primary precipitant of HF or was secondary, at least in part, to the heightened sympathetic tone associated with acute pulmonary edema. That hypertension per se rather than ischemia is responsible for many such episodes is suggested by the ﬁnding that of 19 patients who underwent coronary revascularization after presenting with acute pulmonary edema, nine were rehospitalized with pulmonary edema over the next 6 months [50].

DIAGNOSIS AND CLINICAL FINDINGS Because HF is a clinical syndrome rather than a speciﬁc disease, the diagnosis is based on a constellation of ﬁndings rather than on a speciﬁc clinical feature or laboratory test. Unfortunately, this has led to a variety of diagnostic criteria for HF, none of which is universally accepted. Further complicating matters is the recent introduction of proposed deﬁnitions for diastolic versus systolic HF [58,59]. The diagnosis of HF in the elderly is particularly challenging for several reasons. First, many of the symptoms and signs of HF are similar to those of other frequent disorders among the elderly (Table 3). Second, many elderly patients may be unable to give an adequate history because of cognition or sensory impairments. Third, many older patients will consciously or unconsciously reduce their level of physical activity, thereby masking the two cardinal symptoms of exertinal dyspnea and fatigue. It is therefore useful to ask patients to detail recent changes in their activity levels and exercise tolerance. Fourth, elderly patients, including those with HF, often present with atypical, nonspeciﬁc symptoms such as weakness, fatigue, somnolence, confusion, and disorientation. Finally, the frequent occurrence of a normal LV ejection fraction in older HF patients may lead the clinician away from the correct diagnosis. While the Framingham criteria for HF [60] have frequently been cited, they have not been validated in a purely elderly population, and their applicability to clinical practice and research trials has not been rigorously tested. Rich et al. proposed simpliﬁed, practical criteria for the diagnosis of HF in elderly patients [23]. These are a history of acute pulmonary edema or the occurrence of at least two of the following with no other identiﬁable cause and with improvement following diuresis: dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema, or exertional fatigue. In a series of 154 consecutive Italian geriatic patients hospitalized with heart failure, the most common signs and symptoms were pulmonary rales (77%), orthopnea (73%), edema (62%), paroxysmal nocturnal dyspnea (56%), gallop rhythm (45%), and jugular venous distension (32%) [57]. Although statistical associations between various demographic/clinical ﬁndings and normal versus reduced LV systolic function have been found in HF populations, none is

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Table 3 Alternate Explanations for Signs/Symptoms Suggestive of CHF in Elderly Patients Dyspnea and rales chronic pulmonary disease pneumonia Pedal edema benign idiopathic edema primary venous insuﬃciency renal or hepatic disease medications Fatigue anemia hypothyroidism extreme obesity severe deconditioning Aortic or mitral stenosis/regurgitation Constrictive pericarditis Ischemic heart disease Cautions Elderly often have multiple confounding conditions Normal aging alone does not cause exertional fatigue, dyspnea

reliable enough to obviate the need for measuring LV performance. Thus, evaluation of new HF in any patient, young or old, should include an imaging test. An echocardiogram is usually the preferred initial imaging procedure because it can detect important disorders such as aortic or mitral valvular disease, hypertrophic cardiomyopathy, cardiac amyloidosis, or pericardial eﬀusion in addition to assessing LV systolic and diastolic performance. General agreement exists that a LV ejection fraction V40 to 45% represents reduced systolic function, the substrate for systolic HF. However, a deﬁnitive noninvasive measure for diastolic dysfunction is not available. Doppler LV diastolic ﬁlling indices vary with LV load and with normal aging. The patterns of ﬁlling are helpful, and the newer tissue Doppler techniques are particularly promising [61]. However, their role in the diagnosis and management of diastolic HF remains unclear. Some have believed that invasive measurements are needed to deﬁnitively conﬁrm the presence of diastolic dysfunction. However, a particularly important recent paper demonstrated that measurement of diastolic function, either invasive or noninvasive, may be unnecessary in most patients [62]. This study found that in patients with LVH and symptoms compatible with HF, nearly all had abnormal diastolic function when measured invasively [62]. The diagnosis of diastolic HF should probably be viewed as one of exclusion [39]. However, most persons who have typical heart failure symptoms and typical demographics of diastolic HF (older women with a history of hypertension) will not be found to have other explanations for their symptoms and probably have diastolic HF. Among other explanations for symptoms, obesity deserves special mention. While severe obesity per se can indeed cause exertional symptoms, large epidemiological studies show that classic systolic HF, even when patients are at ‘‘dry weight,’’ is associated with signiﬁcantly increased body weight and body mass index. Further, in longitudinal studies, obesity is a common precursor to HF. Elderly diastolic HF patients, as a group, have increased body weight compared to

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controls, but this is identical to the average weight of conﬁrmed systolic HF patients [6,17]. Thus, in patient with otherwise typical features, mild-to-moderate obesity alone should not exclude the diagnosis of diastolic HF.

TREATMENT General Considerations The treatment goals in older HF patients resemble those for any chronic disorder and include relief of symptoms, improvement in functional capacity and quality of life, prevention of acute exacerbations, and prolongation of survival. In the elderly, however, the latter goal is generally less important than preservation of independence and a satisfactory quality of life. A systematic management plan should incorporate attention to diet, physical activity, and other lifestyle factors, avoidance of aggravating conditions, and careful titration of medications and frequent follow-up. Adequate education of patient and/or caregiver and enhancement of their disease management skills can also reap major beneﬁts. The management team might involve a nurse, dietitian, pharmacist, social worker, or physical therapist, in addition to the attending physician. During the past decade, the value of multidisciplinary HF management programs has been repeatedly demonstrated to reduce HF exacerbations and rehospitalizations, reduce costs, and improve quality of life [23,63–65]. One study also suggested enhanced survival [63]. Heart failure management programs can also rectify the substantial underutilization of proven therapies like angiotensin-converting-enzyme inhibitors (ACEI) and beta-adrenergic blockers known to occur in elderly HF patients [66]. Such programs emphasize frequent contact with health-care providers to avoid acute decompensation and typically utilize periodic phone calls, frequent follow-up visits and monitoring programs, including via the internet. Adjustment of diuretics can be made by nurses over the telephone or by the patients themselves, using simple algorithms. Adjunctive strategies such as elimination of tobacco and alcohol, appropriate administration of inﬂuenza and pneumococal vaccines, minimal use of sodium-retaining medications, and use of cardiac rehabilitation should also be addressed. Common HF precipitants such as atrial ﬁbrillation, anemia, renal failure, and pulmonary infections should be aggressively treated. Diet Although it is widely recognized that indiscreet use of sodium is a common cause of HF exacerbations, few objective data exist regarding the optional sodium intake for a HF patient of any age. Moderate sodium restriction to about 2 g/day is adequate to prevent weight gain in most stable patients. More severe sodium restriction may allow a reduction in diuretic dose but is often impractical for patients to maintain. Water restriction is not usually necessary unless signiﬁcant hyponatremia is present. The age-associated reduction in glomerular ﬁltration rate seen in HF patients adds to the complexity of maintaining proper sodium balance in the elderly. Physical Activity Given that exercise intolerance is a hallmark of the HF syndrome, it seems logical that HF patients would derive a signiﬁcant beneﬁt from exercise training. Surprisingly, the poten-

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tial beneﬁts of aerobic training programs in such patients was not widely recognized until the past decade. Although several prospective trials have now demonstrated substantial increases in peak VO2, cardiac output, and other physiological parameters in patients with systolic HF, these studies included very few patients z70 years old, very few women, and no diastolic HF patients [67,68]. However, the most important limitation of existing HF training studies is that none has been adequately powered to deﬁnitively address the impact on survival. A recent relatively small trial by Belardinelli did ﬁnd a 71% reduction in HF hospitalizations and 63% lower mortality in 50 patients assigned to exercise training compared to 49 controls over 14 months of follow-up [69]. A new NHLBI-sponsored, large, multicenter, randomized trial (HF-ACTION) involving 2 years of aerobic exercise training in 3000 systolic HF patients with LV ejection fraction V35% should provide a deﬁnitive answer regarding the critical question of impact of this intervention on mortality and morbidity and will likely also provide additional valuable information regarding the elderly.

PHARMACOTHERAPY FOR SYSTOLIC HEART FAILURE Over the past two decades, numerous randomized trials have deﬁned the role of angiotensinconverting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), other vasodilators, digitalis and other inotropes, beta-adrenergic blockers, and various other drugs in patients with HF and reduced systolic function. Although many of the studies from the 1980s and early 1990s included very few elderly patients and women, more recent trials have generally been less restrictive. Thus, the strength of the data deﬁning the relative beneﬁts of these drugs in the elderly varies widely among studies. Diuretics Diuretics provide the cornerstone for prompt symptomatic relief and control of pulmonary congestion and peripheral edema in HF patients. Perhaps for this reason, they have been the subject of very few randomized HF clinical trials. Although they are needed to control ﬂuid retention in most patients, no diuretic other than spironolactone has been shown to reduce HF mortality. Furthermore, their potential for reducing renal function causing multiple electrolyte derangements and exacerbating the hyperactivity of the reninangiotensin system dictate that they be titrated to the lowest eﬀective dose, especially in the elderly. Most HF patients will require a loop diuretic to maintain euvolemia, although a thiazide may suﬃce in some patients with mild HF. Patients with more severe ﬂuid retention or concomitant renal dysfunction may require the addition of metolazone 2.5 to 10 mg/day. Because most patients have an intrinsic diuretic threshold below which diuresis will not occur, a single morning dose above this threshold is more eﬀective than multiple subthreshold doses. In patients with nocturnal congestive symptoms, a twice-daily regimen may be necessary. Systemic steroids or nonsteroidal anti-inﬂammatory drugs, commonly used in the elderly, should be discontinued or used at the lowest possible dose because of their sodium-retaining properties. Careful monitoring of ﬂuid and electrolyte balance is necessary during active diuresis, with replacement of potassium, magnesium, and chloride as necessary. Fluid restriction may be needed if hyponatremia occurs. Need for escalating

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doses of diuretics in a previously stable patient suggests medication and/or dietary noncompliance, poor drug absorption due to bowel edema, a concomitant exacerbating condition or medication, or progression of the underlying cardiac disorder. The aldosterone antagonist and mild diuretic spironolactone 25 mg daily was recently shown to reduce mortality by 27% in patients with New York Heart Association (NYHA) Class III–IV HF [70]. The mortality beneﬁt was similar in younger and older patients and was thought to be independent of its weak diuretic eﬀect [71]. Spironolactone is currently recommended for patients with NYHA Class IV HF and no hyperkalemia; the drug is relatively contraindicated in patients with major renal dysfunction or prior serum potassium z5.0 Eq/L. Painful gynecomastia occurs in up to 10% of patients during chronic therapy, but is lower in women. Clinical trials are in progress with eplerenone, an aldosterone antagonist that appears to have a lower incidence of gynecomastia. ACE Inhibitors Numerous studies across varying patient proﬁles have established ACE inhibitors as a critical component of drug therapy for systolic HF. In the landmark CONSENSUS trial, the ﬁrst study to demonstrate their beneﬁcial eﬀect on mortality, enalapril 10 to 20 mg twice daily reduced 6-month mortality from 48% to 29% in older patients with NYHA Class IV systolic HF despite diuretics and digitalis; the mortality beneﬁt and symptomatic improvement were similar in patients above and below the median age of 70 years [72]. Subsequent studies have conﬁrmed that these salutary eﬀects of ACE inhibitors on survival and quality of life are not diminished in the elderly [73]. These ﬁndings indicate that ACE inhibitors should be initiated in essentially all elderly HF patients without contraindications to their use. The primary relative contraindication is advanced renal dysfunction. ACE inhibitors are thought to be beneﬁcial in HF compared to other vasodilators because they antagonize the renin-angiotension system, whose activation is thought to be pivotal to disease progression and adverse prognosis in HF patients. Although they have minimal eﬀect on cardiac function, they inhibit progressive LV dilation, which occurs in patients with systolic HF [74,75]. This eﬀect is particularly prominent in patients with reduced systolic function after myocardial infarction [74]. Similar to other drugs in the elderly, ACE inhibitors should be initiated at low doses and increased slowly toward the doses proven eﬀective in clinical trials with careful monitoring for adverse eﬀects. The most common eﬀects limiting full dosing are hypotension and worsening renal function. To minimize the risk for hypotension, volume depletion should be corected before the ﬁrst dose is administered, especially in patients with SBP <100 mmHg, severe LV dysfunction, or hyponatremia. A mild, dry cough develops in up to 5% of patients but is not age-related and often regresses over time. Even when persistent, it can often be tolerated when patients understand the signiﬁcant survival advantage imparted by the ACE inhibitor drug [76]. Among patients who are unable to tolerate standard doses of ACE inhibitors, data from the ATLAS study suggest that doses as low as 2.5 to 5 mg daily of the long-acting ACE inhibitor lisinopril may be eﬀective [77]. Interestingly, this eﬀect was observed particularly in older individuals [77]. Of the many ACE inhibitors currently available, all except captopril allow once- or twice-daily dosing to optimize compliance. Despite claims of between-drug diﬀerences in tissue penetration or other properties of ACE inhibitors, the clinical literature suggests similar beneﬁts among ACE inhibitors used in systolic HF. Three ACE inhibitors are now

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available in generic formulations and two of them are long-acting—enalapril and lisinopril. Health-care providers should familiarize themselves with the local costs of the available ACE inhibitors to minimize the ﬁnancial burden on their older patients.

Angiotensin-Receptor Blockers Like ACE-inhibitors, agents in this newer drug class also antagonize the renin-angiotensin system. ARBs have not been deﬁnitively proven to be equivalent to ACE inhibitors in reducing morbidity and mortality in HF patients of any age. Although ELITE-1 suggested a survival advantage of the ARB losartan over the ACE inhibitor captopril in patients z65 years of age [78], the larger ELITE-2 study failed to conﬁrm this ﬁnding; annual mortality was 11.7% with losartan, and 10.4% with captopril, a statistically nonsigniﬁcant diﬀerence [79]. Given the more voluminous literature establishing the beneﬁts of ACE inhibitors and the statistically nonsigniﬁcant trend favoring them compared to ARB seen in ELITE-II, ACE inhibitors remain the preferred initial agents. An advantage of ARB over ACE inhibitors is a lower incidence of cough. However, ELITE-I demonstrated that, contrary to the primary study hypothesis, the overall incidence of renal dysfunction and other side eﬀects is not lower with ARB than with ACE inhibitors. For patients unable to tolerate an ACE inhibitor, an ARB is a suitable alternative. In most settings, generic ACE inhibitors are available at considerably lower cost to the patient than ARBs. The addition of ARBs to patients who remain symptomatic despite maximal doses of ACE inhibitors may improve symptoms and exercise tolerance [80]. This combination was associated with more favorable LV remodeling than either agent alone in the RESOLVD trial [81]. However, in VALHEFT, the combination of ACE inhibitor and ARB did not reduce the primary endpoint of all-cause mortality but eﬀected a 28% reduction in hospitalization and improved quality of life [82]. This eﬀect, however, was not seen in persons who were also taking beta-blockers. The cost of combination ARB/ACE inhibitor therapy, which is much higher than generic ACE inhibitors alone, should be taken into consideration. In VALHEFT, the small subgroup not on ACE inhibitors at baseline (mean age 67 years) experienced a 45% reduction in all-cause mortality, conﬁrming ARBs as an acceptable alternative in patients proven to be intolerant of ACE inhibitors.

Hydralazine and Isosorbide Dinitrate The combination of hydralazine 75 mg qid and isosorbide dinitrate 40 mg qid used in VHEFT-I was the ﬁrst drug regimen shown to prolong life in HF patients [83]. However, VHEFT-II established that ACE inhibition with enalapril was superior to this combination in reducing mortality [84]. Further disadvantages of this combination are its qid dosing requirement, low tolerability, and minimal experience in women and elderly patients. Hydralazine and isosorbide dinitrate may nevertheless represent an alternative for patients with contraindications or intolerance to ACE inhibitors or ARBs.

Beta Adrenergic Blockers Several large randomized trials that included patients up to 80 years of age have shown that beta-adrenergic blockers reduce all-cause mortality and hospitalizations and improve

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symptoms in systolic HF; beneﬁts are similar in older versus younger patients [85–87]. Nevertheless, relative contraindications to beta-blockade, such as conduction system disturbances, obstructive lung disease, and claudication are more prevalent among the elderly and may limit the achievement of maximal recommended doses. In all age groups, beta-blockers should be started at very low doses (carvedilol 3.125 mg twice daily, extended release metoprolol 12.5 mg daily) in clinically stable patients receiving appropriate doses of ACE inhibitors and diuretics; upward dose titrations should occur at intervals z2 weeks. Although it is not known whether it is equivalent to extended release metoprolol for mortality reduction, generic metoprolol is available in most settings at considerably lower cost than either of the above formulations.

Digoxin Despite its use in HF for more than 200 years, the deﬁnitive role of digitalis in this setting has only been clariﬁed within the past decade. The multicenter Digitalis Investigation Group study randomized nearly 8000 HF patients in sinus rhythm with LVEF V45% on ACE inhibitors and diuretics to digoxin or placebo [88]. Over 37 months of mean follow-up, digoxin had no eﬀect on mortality but reduced HF symptoms and hospitalizations. The eﬀects of digoxin were similar across age groups, including those z80 years old [89]. The drug is therefore recommended in HF patients who remain symptomatic on diuretics and ACE inhibitors. Digoxin may be particularly useful in those HF patients with atrial ﬁbrillation in whom it can help control ventricular rate. The age-associated reduction in its volume of distribution and in its renal clearance, however, result in higher serum digoxin levels in older versus younger patients given a ﬁxed digoxin dose [90]. Furthermore, serum digoxin levels >1.5 ng/dL are accompanied by increased toxicity but no greater eﬃcacy than lower doses among the elderly [91]. Thus, the maintenance digoxin dose is lower in older versus younger HF patients; 0.125 mg per day is appropriate for most older patients without signiﬁcant renal dysfunction. Serum levels of digoxin need only be obtained when toxicity is suspected. Treatment of digitalis toxicity is similar regardless of age. Other Inotropes Although several oral phosphodiesterase inhibitors, including amrinone, milrinone, and vesnarinone initially showed promise in HF therapy, their long-term use was associated with increased mortality [92,93]; thus, none are approved for clinical use. However, intravenous amrinone may be used to treat acute HF exacerbations resistant to conventional drugs. No data speciﬁc to the elderly are available for intravenous amrinone. Synthetic catecholemines such as dobutamine or dopamine may also be used to treat refractory HF symptoms. In a small study of patients in an intensive care setting, Rich and Imburgia [94] demonstrated that given infusion rates of dobutamine elicited lesser increases in cardiac output in patients >80 years old than in younger patients, consistent with the ageassociated decreased sensitivity to catecholamines that occurs in normals. These drugs are probably more likely to elicit tachyarrhythmias in the elderly. Low-dose dopamine, a renal vasodilator, improved creatinine clearance and urine output when added to intravenous bumetazide in elderly HF patients compared to bumetazide alone [95]. Intermittent intravenous infusions of inotropic drugs have been successfully used in elderly outpatients with refractory HF [96], although randomized controlled trials are lacking.

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Devices and Surgery The high morbidity and mortality associated with HF despite maximal medical therapy has led to the pursuit of additional interventions using devices and surgery in this population. Recent studies have shown that atrial-synchronized biventricular pacing can improve LV function and enhance functional capacity and quality of life in HF patients with QRS prolongation >120 ms. The MIRACLE study conﬁrmed these ﬁndings and also demonstrated a 40% reduction in death or hospitalization for worsening HF in a randomized double-blind trial of 453 such patients [97]. Although no age-speciﬁc analysis was performed, the mean age of 64 years and the absence of an upper age limit make these ﬁndings relevant to the elderly. The MADIT-II study demonstrated that prophylactic implantation of a deﬁbrillator in patients with a prior MI and ejection fraction V0.30 reduced all-cause mortality from 20% to 14% over a 20-month mean follow-up [98]. The beneﬁt in patients z70 years old was similar to that in younger individuals. Although HF was not required for study entry, approximately 75% of patients were receiving diuretics, presumably for HF. Selected older patients with HF may derive major beneﬁts from cardiac surgery. Indeed, aortic valve replacement is the treatment of choice for elderly individuals with HF secondary to calciﬁc aortic stenosis and may be accomplished with a mortality <10% in octogenarians [99,100]. Coronary revascularization may ameliorate HF symptoms in selected elderly HF patients with substantial amounts of viable but ischemic myocardium due to coronary artery disease [101]. Various surgical procedures, such as LV aneurysmectomy and partial left ventriculectomy, have been developed to excise nonfunctional myocardium, thereby reducing LV size, in patients with HF due to coronary artery disease. Although several studies have suggested improved clinical status and hemodynamics after these procedures, the lack of randomized controlled studies and the small number of elderly patients included prevent ﬁrm conclusions about their eﬃcacy in this age group. Cardiac transplantation has been successfully employed to treat end-stage HF in carefully selected patients in their seventh decade. In one such series, the 1-year actuarial survival was 84%, only 4% developed a serious infection and the incidence of rejection was 2.2 episodes per patient [102]. These results compared favorably with those in younger individuals. Nevertheless, the shortage of donors and the high likelihood of medical contraindications, such as intrinsic renal or cerebrovascular disease in this age group, markedly limit the applicability of cardiac transplantation in the elderly. A promising therapy in such end-stage older HF patients is the implantation of a permanent LV-assist device. Although used initially as a temporary bridge for patients undergoing cardiac transplantation, these devices have been used increasingly for long-term use in patients who are not transplant candidates [103]. In a recent multicenter trial of 129 patients (mean age 67 years) with endstage HF, 1-year survival was 52% in those receiving the LV-assist device versus 25% in the controls; quality of life and mobility were also improved by the assist device [104].

PHARMACOTHERAPY FOR DIASTOLIC HEART FAILURE The literature base regarding therapy of diastolic HF is scant [105]. In contrast to systolic HF, where numerous studies over the past 30 years have generated data for evidence-based treatment, there is not a single large, multicenter trial on diastolic HF [105,106]. This is incongruous with the high prevalence, substantial morbidity, and signiﬁcant mortality of diastolic HF [107,108]. A recent update to the joint ACC/AHA Guidelines for Evaluation

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and Management of Heart Failure noted the absence of published trial data to guide management of diastolic HF [106]. Given the dearth of data, therapy is empiric [105]. If one considers the remarkable paradoxes encountered on the journey to evidence-based therapy for systolic HF during the past three decades (recall early opinions regarding inotropes, vasodilators, and beta-blockers), one may anticipate potential surprises in store as we develop evidence to guide diastolic HF therapy. Advances in therapy of diastolic HF have been hindered by lack of standard case deﬁnition; absence of a readily available, reliable test that characterizes and quantitates diastolic function; and relatively poor understanding of the pathophysiology of diastolic HF [39,105]. A physician survey of practitioners caring for elderly patients conﬁrmed that, in contrast to systolic HF, there is no single pattern of diastolic HF therapy [109]. General Approach The general approaches discussed above for systolic HF are applicable to diastolic HF [106]. Diuretics should be used for initial control of congestion and edema. Subsequently, there should be a search for a primary etiology. Most such patients will be found to have hypertension as their main underlying condition [106]. A noninvasive stress test or coronary angiography may be warranted in selected patients with chest pain and/or ﬂash pulmonary edema to exclude severe coronary heart disease, since ischemia is not only a therapeutic target in its own right but also strongly impairs diastolic relaxation [106]. Occasional patients will be found to have hypertrophic cardiomyopathy [110,111] with or without dynamic obstruction, undiagnosed valvular or coronary disease, or rarely amyloid heart disease [112]. Each of these underlying etiologies has speciﬁc prognostic and therapeutic implications aside from and that supercede whatever concomitant diastolic dysfunction that is present. From the discussion above of HF pathophysiology, control of hypertension may be the most important strategy for diastolic HF. Chronic hypertension causes left ventricular hypertrophy and ﬁbrosis which impair diastolic chamber compliance. Acute hypertension signiﬁcantly impairs diastolic relaxation. Several large studies indicate that therapy of chronic, mild systolic hypertension in the elderly is a potent means of preventing the development of HF, and it is likely that a major portion of cases prevented are due to diastolic HF [113–117]. Although not speciﬁcally designed to address this issue, data available from large studies in elderly hypertensives suggest there may be diﬀerences between classes of agents for preventing HF. For instance the STOP-2 trial in elderly (aged 70–84 years) mildly favored ACE inhibitors [118]. ALLHAT reports showed that the diuretic chlorthalidone was superior to the alpha-adrenergic antagonist doxazocin [119] and suggested that the diuretic was at least equivalent to other classes, including ACE inhibitors and calcium antagonists, for prevention of CHF in older hypertensives [120]. Both chlorthalidone and hydrochlorothiazide are generic and quite inexpensive. Because loss of atrial contraction impairs LV ﬁlling, sinus rhythm should be achieved and maintained, although this can be diﬃcult in the elderly where the rate of atrial ﬁbrillation is high [106]. A more modest goal of rate control can also be beneﬁcial.

Specific Pharmacological Therapy Since there are no data available from large trials to address mortality speciﬁcally in this disorder, no ﬁrm recommendations can be given for speciﬁc agents. Several large, random-

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ized, controlled trials are currently underway in order to address this major gap. In the meantime, all therapy is currently empiric. Empirically, most patients with this disorder have fewer symptoms and repeat HF exacerbations when blood pressure is well-controlled. Digoxin In the DIG trial, which included a substantial number of elderly patients with preserved systolic function, results were similar regardless of ejection fraction, with symptomatic improvement and prevention of hospitalizations but no diﬀerence in overall mortality compared with placebo [88]. Thus, as suggested in the recently revised ACC/AHA guidelines, digoxin could play a role in adjunctive therapy to help relieve symptoms in diastolic HF [106]. ACE Inhibitors Several lines of evidence suggest that anglotensin-II antagonism, whether with ACE inhibitors or with ARBs, may be eﬀective therapy for patients with diastolic HF. First, they are the cornerstone of systolic HF therapy, reduce mortality and hospital admissions, and improve exercise tolerance and symptoms. Second, they interfere with the increased neurohormonal activation that is thought to be pivotal to the HF state, which, as discussed above, is present in patients with diastolic HF [39,52]. Third, they control hypertension and reduce left ventricular hypertrophy, reduce myocardial ﬁbrosis, and improve left ventricular relaxation and aortic distensibility [121–125]. In a group of elderly patients (mean age 80) with NYHA Class III HF and presume diastolic dysfunction (EF > 50%), Aronow et al. showed that enalapril signiﬁcantly improved functional class, exercise duration, ejection fraction, diastolic ﬁlling, and left ventricular mass [126]. In an observational study of 1402 patients, ACE inhibitor use in diastolic HF patients was associated with substantially reduced all-cause mortality (odds ratio 0.61) and HF death (odds ratio 0.55) [127]. However, another study from a large database of hospitalized elderly HF patients with relatively preserved ejection fractions suggested increased mortality in patients treated with ACE inhibitors [105,128]. The ultimate answer will, of course, come from appropriately powered randomized, controlled trials. The European trial PEP-CHF is assessing the eﬀect of the ACE inhibitor perindopril on death, HF admission, quality of life, and 6-min walk distance in elderly (age > 70 years) HF patients with a LV ejection fraction z40% [129]. ARBs In a blinded randomized, controlled, cross-over trial of 20 elderly patients with diastolic dysfunction and an exaggerated blood pressure response to exercise, the ARB losartan improved exercise capacity and quality of life and reduced exercise systolic and pulse pressure [130]. The ongoing trial CHARM is assessing the eﬀect of candesartan on death and hospital admission in HF patients with EF > 40%. The I-PRESERVE trial is assessing the eﬀect of the ARB irbesartan on all-cause mortality and cardiovascular morbidity in patients with well-deﬁned diastolic HF. Calcium Channel Antagonists Setaro examined 22 elderly men with HF and ejection fraction >45% in a randomized, double-blind, placebo-controlled cross-over trial of verapamil [131]. There was a 33% improvement in exercise time and signiﬁcant improvements in HF score and peak ﬁlling rate in the absence of a signiﬁcant diﬀerence in blood pressure and ejection fraction. Verapamil has also been shown to improve symptoms and exercise capacity in patients with hyper-

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trophic cardiomyopathy [132–135]. In animal models, dihydropyridines prevent ischemiainduced increases in LV diastolic stiﬀness [136] and improve diastolic performance in pacing-induced HF [137,138]. However, negative inotropic calcium antagonists impair early relaxation and have generally shown a tendency toward adverse outcome in patients with systolic HF [139–143]. Beta-Adrenergic Blockers Beta-adrenergic blockers substantially improve mortality in systolic HF patients, regress left ventricular hypertrophy, increase the ischemic threshold, and increase in the time for diastolic ﬁlling, all portending potential beneﬁt in diastolic HF [43,46,49,144,145]. On the other hand, Cheng et al. and others have shown that early diastolic relaxation is impaired by beta-adrenergic blockade [146,147]. The role of beta-blockers, like ACE inhibitors and calcium channel antagonists, will only be known when the results of well-designed large clinical trials are available. A signiﬁcant percentage of older patients have relative contraindications to beta-blockers.

ACKNOWLEDGMENT Supported in part by National Institute on Aging Grant #RO1 AG18915.

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23 Supraventricular Tachyarrhythmias in the Elderly Wilbert S. Aronow and Carmine Sorbera New York Medical College, Valhalla, New York, U.S.A.

ATRIAL FIBRILLATION Atrial ﬁbrillation (AF) is a cardiac rhythm that has irregular undulations of the baseline electrocardiogram (ECG) of varying amplitude, contour, and spacing known as ﬁbrillation waves, with the atrial rate between 350 and 600 beats per minute. The ﬁbrillatory waves are seen best in leads V1, II, III, and aVF. The ﬁbrillation waves may be large and coarse, or they may be ﬁne with an almost ﬂat ECG baseline. The ventricular rate in AF is irregular unless complete atrioventricular (AV) block or dissociation is present. The contour of the QRS complex in AF is normal unless there is prior bundle branch block, an intraventricular conduction defect, or aberrant ventricular conduction. If AF is associated with a slow regular ventricular response, there is complete AV block with an AV junctional escape rhythm or idioventricular escape rhythm. Myocardial infarction, degenerative changes in the conduction system, and drug toxicity such as digitalis toxicity are major causes of complete AV block. If AF is associated with a regular ventricular response between 60 to 130 beats per minute, there may be complete AV dissociation with an accelerated AV junctional rhythm caused by an acute inferior myocardial infarction, digitalis toxicity, open heart surgery, or myocarditis, usually rheumatic. Regularization of the ventricular response in AF may also occur in patients with complete AV dissociation due to ventricular tachycardia or a ventricular paced rhythm. Prevalence AF is the most common sustained cardiac arrhythmia. The prevalence of AF increases with age [1–5]. In the Framingham Study, the prevalence of chronic AF was 2% in persons aged 60 to 69 years, 5% in persons aged 70 to 79 years, and 9% in persons aged 80 to 89 years [1]. In a study of 2101 persons, mean age 81 years, the prevalence of chronic AF was 5% in persons aged 60 to 70 years, 13% in persons aged 71 to 90 years, and 22% in persons aged 91 to 103 years [2]. Chronic AF was present in 16% of 1160 men, mean age 80 years, and in 13% of 2464 women, mean age 81 years [3]. In 5201 persons aged 65 years and older in the Cardiovascular Health Study, the prevalence of AF was 6% in men and 5% in women [4]. In 1563 persons, mean age 80 years, living in the community, the prevalence of chronic AF was 559

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9% [5]. In the Cardiovascular Health Study, the incidence of AF was 19.2 per 1000 personyears [6]. AF may be paroxysmal or chronic. Episodes of paroxysmal AF may last from a few seconds to several weeks. Sixty-eight percent of persons presenting with AF of<72 duration spontaneously converted to sinus rhythm [7]. Predisposing Factors Multiple, small reentrant circuits arising in the atria, exhibiting variable wavelengths, colliding, being extinguished, and arising again usually cause AF [8]. Rapidly ﬁring foci are commonly located in or near the pulmonary veins and may also cause AF [9]. Factors responsible for onset of AF include triggers that induce the arrhythmia and the substrate that sustains it. Atrial inﬂammation or ﬁbrosis acts as a substrate for the development of AF. Triggers of AF include acute atrial stretch, accessory AV pathways, premature atrial beats or atrial tachycardia, sympathetic or parasympathetic stimulation, and ectopic foci occurring in sleeves of atrial tissue within the pulmonary veins or vena caval junctions [10]. Predisposing factors for AF include age, alcohol, aortic regurgitation and stenosis, atrial septal defect, autonomic dysfunction, cardiac or thoracic surgery, cardiomyopathies, chronic lung disease, cocaine, congenital heart disease, coronary heart disease, congestive heart failure (CHF), diabetes mellitus, drugs (especially sympathomimetics), emotional stress, excess coﬀee, hypertension, hyperthyroidism, hypoglycemia, hypokalemia, hypovolemia, hypoxia, left atrial enlargement, left ventricular (LV) dysfunction, LV hypertrophy, male gender, mitral annular calcium (MAC), mitral stenosis and regurgitation, myocardial infarction (MI), myocarditis, neoplastic disease, pericarditis, pneumonia, pulmonary embolism, rheumatic heart disease, sick sinus syndrome, smoking, systemic infection, and the Wolﬀ-Parkinson-White (WPW) syndrome. In 254 older persons with AF compared to 1445 older persons with sinus rhythm, mean age 81 years, two-dimensional and Doppler echocardiography showed that the prevalence of AF was increased 17.1 times by rheumatic mitral stenosis, 2.9 times by left atrial enlargement, 2.5 times by abnormal LV ejection fraction, 2.3 times by aortic stenosis, 2.2 times by MAC and by z1+ mitral regurgitation, 2.1 times by z1+ aortic regurgitation, and 2.0 times by LV hypertrophy [11]. The Framingham Study demonstrated that low serum thyrotropin levels were independently associated with a 3.1 times increase in the development of new AF in older patients [12]. Associated Risks In the Framingham Study, the incidence of death from cardiovascular causes was 2.7 times higher in women and 2.0 times higher in men with chronic AF than in women and men with sinus rhythm [13]. The Framingham Study also found that after adjustment for preexisting cardiovascular conditions, the odds ratio for mortality in persons with AF was 1.9 in women and 1.5 in men [14]. At 42-month follow-up of 1359 persons with heart disease, mean age 81 years, patients with chronic AF had a 2.2 times increased risk of having new coronary events than patients with sinus rhythm after controlling for other prognostic variables [15]. AF was present in 22% of 106,780 persons aged z65 years with acute MI in the Cooperative Cardiovascular Project [16]. Compared with sinus rhythm, patients with AF had a higher in-hospital mortality (25% vs. 16%), 30-day mortality (29% vs. 19%), and

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1-year mortality (48% vs. 33%) [16]. AF was an independent predictor of in-hospital mortality (odds ratio = 1.2), 30-day mortality (odds ratio = 1.2), and 1-year mortality (odds ratio = 1.3) [16]. Older patients developing AF during hospitalization had a worse prognosis than older patients presenting with AF [16]. In the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO-III) study, 906 of 13,858 patients (7%) developed AF during hospitalization [17]. After adjusting for baseline diﬀerences, AF increased the 30-day mortality (odds ratio = 1.6) and the 1-year mortality (odds ratio = 1.6) [17]. In the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptors Suppression Using Integrilin Therapy (PURSUIT) trial, AF developed in 6.4% of 9432 patients with acute coronary syndromes without ST-segment elevation [18]. After adjustment for other variables, patients with AF had a higher 30-day mortality (hazard ratio = 4.0) and 6-month mortality (hazard ratio = 3.0) than patients without AF [18]. AF is also an independent risk factor for stroke, especially in older persons [1,2]. In the Framingham Study, the relative risk of stroke in patients with nonvalvular AF compared with patients with sinus rhythm was increased 2.6 times in patients aged 60 to 69 years, increased 3.3 times in patients aged 70 to 79 years, and increased 4.5 times in patients aged 80 to 89 years [1]. Chronic AF was an independent risk factor for thromboembolic (TE) stroke with a relative risk of 3.3 in 2101 persons, mean age 81 years [2]. The 3-year incidence of TE stroke was 38% in older persons with chronic AF and 11% in older persons with sinus rhythm [2]. The 5-year incidence of TE stroke was 72% in older persons with AF and 24% in older persons with sinus rhythm [2]. At 37-month follow-up of 1476 patients who had 24-h ambulatory ECGs (AECGs), the incidence of TE stroke was 43% for 201 patients with AF (relative risk = 3.3), 17% for 493 patients with paroxysmal supraventricular tachycardia, and 18% for 782 patients with sinus rhythm [19]. In 2384 persons, mean age 81 years, AF was present in 17% of older persons with LV hypertrophy and in 8% of persons without LV hypertrophy [20]. Both AF (risk ratio = 3.2) and LV hypertrophy (risk ratio = 2.8) were independent risk factors for new TE stroke at 44-month follow-up [20]. The higher prevalence of LV hypertrophy in older patients with chronic AF contributes to the increased incidence of TE stroke in older patients with AF. Both AF (risk ratio = 3.3) and 40 to 100% extracranial carotid arterial disease (ECAD) (risk ratio = 2.5) were independent risk factors for new TE stroke at 45-month follow-up of 1846 persons, mean age 81 years [21]. Older persons with both chronic AF and 40 to 100% ECAD had a 6.9 times higher probability of developing new TE stroke than older persons with sinus rhythm and no signiﬁcant ECAD [21]. Cerebral infarctions were demonstrated in 22% of 54 autopsied patients aged z70 years with paroxysmal AF [22]. Symptomatic cerebral infarction was 2.4 times more common in older patients with paroxysmal AF than in older patients with sinus rhythm [22]. AF also causes silent cerebral infarction [23]. AF predisposes to CHF in older patients. As much as 30 to 40% of LV end-diastolic volume may be attributable to left atrial contraction in older persons. Absence of a coordinated left atrial contraction reduces late diastolic ﬁlling of the LV because of loss of the atrial kick. In addition, a fast ventricular rate in AF shortens the LV diastolic ﬁlling period, further reducing LV ﬁlling and stroke volume. A retrospective analysis of the Studies of Left Ventricular Dysfunction Prevention and Treatment Trials demonstrated that AF was an independent risk factor for all-cause mortality (relative risk = 1.3), progressive pump failure (relative risk = 1.4), and death or hospitalization for CHF (relative risk = 1.3) [24]. AF was present in 37% of 355 patients,

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mean age 80 years, with prior MI, CHF, and abnormal LV ejection fraction and in 33% of 296 patients, mean age 82 years, with prior MI, CHF, and normal LV ejection fraction [25]. In this study, AF was an independent risk factor for mortality with a risk ratio of 1.5 [25]. A fast ventricular rate associated with chronic or paroxysmal AF may cause a tachycardia-related cardiomyopathy that may be an unrecognized curable cause of CHF [26,27]. Slowing the rapid ventricular rate by radiofrequency ablation of the AV node with permanent pacing caused an improvement in LV ejection fraction in patients with medically refractory AF [28]. In a substudy of the Ablate and Pace Trial, 63 of 161 patients (39%) with AF referred for AV junction ablation and right ventricular pacing had an abnormal LV ejection fraction [29]. Forty-eight of the 63 patients had follow-up echocardiograms. Sixteen of the 48 patients (33%) had a marked improvement in LV ejection fraction to a value >45% after ventricular rate control by AV junction ablation [29]. Clinical Symptoms Patients with AF may be symptomatic or asymptomatic with their arrhythmia diagnosed by physical examination or by an ECG. Examination of a patient after a stroke may lead to the diagnosis of AF. Symptoms caused by AF may include palpitations, skips in heartbeat, exercise intolerance, fatigue on exertion, cough, chest pain, dizziness, and syncope. A rapid ventricular rate and loss of atrial contraction decrease cardiac output and may lead to angina pectoris, CHF, hypotension, acute pulmonary edema, and syncope, especially in patients with aortic stenosis, mitral stenosis, or hypertrophic cardiomyopathy. Diagnostic Tests When AF is suspected, a 12-lead ECG with a 1-min rhythm strip should be obtained to conﬁrm the diagnosis. If paroxysmal AF is suspected, a 24-h AECG should be obtained. All patients with AF should have an M-mode, two-dimensional, and Doppler echocardiogram to determine the presence and severity of the cardiac abnormalities causing AF and to identify risk factors for stroke. Appropriate tests for noncardiac causes of AF should be obtained when clinically indicated. Thyroid function tests should be obtained as AF or CHF may be the only clinical manifestations of apathetic hyperthyroidism in older patients. Treatment of Underlying Causes Management of AF should include therapy of the underlying disease (such as hyperthyroidism, pneumonia, or pulmonary embolism) when possible. Surgical candidates for mitral valve replacement should have mitral valve surgery if it is clinically indicated. If mitral valve surgery is not performed in patients with signiﬁcant mitral valve disease, elective cardioversion should not be attempted in patients with AF since early frequent relapses are common if AF converts to sinus rhythm. Precipitating factors such as CHF, infection, hypoglycemia, hypokalemia, hypovolemia, and hypoxia should be treated immediately. Alcohol, coﬀee, and drugs (especially sympathomimetics) that precipitate AF should be avoided. Paroxysmal AF associated with the tachycardia–bradycardia (sick sinus sydrome) should be treated with permanent pacing in combination with drugs to decrease a rapid ventricular rate associated with AF [30].

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Control of Very Rapid Ventricular Rate Direct-current (DC) cardioversion should be performed immediately in patients who have paroxysmal AF with a very fast ventricular rate associated with an acute MI, chest pain caused by myocardial ischemia, hypotension, severe CHF, syncope, or preexcitation syndromes. Intravenous beta-blockers [31–34], diltiazem [35], or verapamil [36] may be used to reduce immediately a very rapid ventricular rate associated with AF, except in patients with preexcitation syndromes. Propranolol should be given intravenously in a dose of 1.0 mg over a 5-min period and then administered intravenously at a rate of 0.5 mg/min to a maximum dose of 0.1 mg/kg. Esmolol administered intravenously in a dose of 0.5 mg/kg over 1 min followed by 0.05 to 0.1 mg/kg per min may also be used to decrease a very rapid ventricular rate in AF. After the very rapid ventricular rate is reduced, oral propranolol should be started with an initial dose of 10 mg given every 6 h. This dose may be increased progressively to a maximum dose of 80 mg every 6 h if necessary. Other beta-blockers can be used with appropriate doses. The initial dose of diltiazem administered intravenously to slow a very rapid ventricular rate in AF is 0.25 mg/kg given over 2 min. If this dose does not slow the very fast ventricular rate or cause adverse eﬀects, a second dose of 0.35 mg/kg administered intravenously over 2 min should be given 15 min after the ﬁrst dose. After slowing the very fast ventricular rate, oral diltiazem should be started with an initial dose of 60 mg given every 6 h. If necessary, this dose may be increased to a maximum dose of 90 mg every 6 h. The initial dose of verapamil given intravenously is 0.075 mg/kg (to a maximum dose of 5 mg). If this dose does not decrease the very rapid ventricular rate or cause adverse eﬀects, a second dose of 0.075 mg/kg (to a maximum dose of 5 mg) should be administered intravenously 10 min after the ﬁrst dose. If the second dose of intravenous verapamil does not decrease the very rapid ventricular rate or cause adverse eﬀects, a dose of 0.15 mg/kg (to a maximum dose of 10 mg) should be administered intravenously 30 min after the second dose. After slowing the very rapid ventricular rate, oral verapamil should be started with an initial dose of 80 mg every 6 to 8 h. This dose may be increased to 120 mg every 6 h over the next 2 to 3 days.

Control of Rapid Ventricular Rate Digitalis glycosides are ineﬀective in converting AF to sinus rhythm [37]. Digoxin is also ineﬀective in decreasing a rapid ventricular rate in AF if there is associated fever, hyperthyroidism, acute blood loss, hypoxia, or any condition involving increased sympathetic tone [38]. However, digoxin should be used to decrease a rapid ventricular rate in AF unassociated with increased sympathetic tone, hypertrophic cardiomyopathy, or the WPW syndrome, especially if there is LV systolic dysfunction. The usual initial dose of digoxin administered to undigitalized patients with AF is 0.5 mg orally. Depending on the clinical response, a second oral dose of 0.25 mg may be given in 6 to 8 h, and a third oral dose of 0.25 mg may be given in another 6 to 8 h to slow a rapid ventricular rate. The usual maintenance oral dose of digoxin given to patients with AF is 0.25 to 0.5 mg daily, with the dose reduced to 0.125 to 0.25 mg daily for older patients who are more susceptible to digitalis toxicity [39]. Oral beta-blockers [40], diltiazem [41], or verapamil [42] should be added to the therapeutic regimen if a rapid ventricular rate in AF occurs at rest or during exercise despite

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digoxin. These drugs act synergistically with digoxin to depress conduction through the AV junction. In a study of atenolol 50 mg daily, digoxin 0.25 mg daily, diltiazem-CD 240 mg daily, digoxin 0.25 mg plus atenolol 50 mg daily, and digoxin 0.25 mg plus diltiazem-CD 240 mg daily, digoxin and diltiazem as single drugs were least eﬀective and digoxin plus atenolol was most eﬀective in controlling the ventricular rate in AF during daily activities [43]. Amiodarone is the most eﬀective drug for reducing a rapid ventricular rate in AF [44,45]. The noncompetitive beta-receptor inhibition and calcium channel blockade are powerful AV nodal conduction depressants. However, the adverse side eﬀect proﬁle of amiodarone limits its use in the treatment of AF. Oral doses of 200 to 400 mg of amiodarone daily may be given to selected patients with symptomatic life-threatening AF refractory to other drugs. Therapeutic concentrations of digoxin do not decrease the frequency of episodes of paroxysmal AF or the duration of episodes of paroxysmal AF diagnosed by 24-h AECGS [46,47]. Digoxin has been shown to increase the duration of episodes of paroxysmal AF, a result consistent with its action in reducing the atrial refractory period [46]. Therapeutic concentrations of digoxin also do not prevent a fast ventricular rate from developing in patients with paroxysmal AF [46–48]. After a brief episode of AF, digoxin increases the shortening that occurs in atrial refactoriness and predisposes to the reinduction of AF [49]. Therefore, digoxin should be avoided in patients with sinus rhythm with a history of paroxysmal AF. Nondrug Therapies Radiofrequency catheter modiﬁcation of AV conduction should be performed in patients with symptomatic AF in whom a rapid ventricular rate cannot be decreased by drugs [50,51]. If this procedure does not control the fast ventricular rate associated with AF, complete AV block produced by radiofrequency catheter ablation followed by permanent pacemaker implantation should be performed [52]. In a randomized controlled study of 66 persons with CHF and chronic AF, AV junction ablation with implantation of a VVIR pacemaker was superior to drug treatment in controlling symptoms [53]. Long-term survival is similar for patients with AF whether they receive radiofrequency ablation of the AV node and implantation of a permanent pacemaker or drug therapy [54]. Surgical techniques have been developed for use in patients with AF in whom the ventricular rate cannot be decreased by drug treatment [55,56]. The maze procedure is a surgical dissection of the right and left atrium creating a maze through which the electrical activation is compartamentalized, preventing the formation and perpetuation of the multiple wavelets needed for maintenance of AF. This procedure is typically performed in association with mitral valve surgery or coronary artery bypass surgery (CABS). At 2- to 3-year follow-up, 74% of 39 patients and 90% of 100 patients undergoing the maze procedure remained in sinus rhythm [57,58]. Thirty-ﬁve of 43 patients (85%) with drug-refractory, lone paroxysmal AF were arrhythmia-free after maze surgery [59]. Another intraoperative approach for treating AF in patients undergoing mitral valve surgery is cryoablation limited to the posterior left atrium. Sinus rhythm was restored in 20 of 29 patients (69%) with chronic AF undergoing this procedure [60]. Ablation of pulmonary vein foci that cause AF is a developing area in the treatment of AF. However, recurrent AF develops in 40 to 60% of patients despite initial eﬃcacy with this procedure [61]. Another problem with this approach is a 3% incidence of pulmonary vein stenosis occurring after this procedure [61]. Modiﬁcation of the substrate responsible

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for AF can be accomplished in the right and/or left atrium with linear lesions. This catheter maze-ablation approach is eﬀective in a small percentage of patients [62]. The Atrioverter, an implantable deﬁbrillator connected to right atrial and right coronary sinus deﬁbrillation leads, causes restoration of sinus rhythm by low-energy shock and has an 80% eﬃcacy in terminating AF [63]. Further eﬀorts are needed to improve patient tolerability and to prevent earlier recurrence of AF after successful transvenous atrial deﬁbrillation. The implanted atrial deﬁbrillator is currently available only in combination with a ventricular deﬁbrillator. The Atrioverter may also convert atrial tachycardia to sinus rhythm using an atrial pacing overdrive algorithm before such tachycardias induce AF. Pacing Paroxysmal AF associated with the tachycardia–bradycardia (sick sinus) syndrome should be treated with a permanent pacemaker combined with drugs to slow a rapid ventricular rate associated with AF [30]. Ventricular pacing is an independent risk factor for the development of chronic AF in patients with paroxysmal AF associated with the tachycardia– bradycardia syndrome [64]. Patients with paroxysmal AF associated with the tachycardia– bradycardia syndrome and no signs of AV conduction abnormalities should be treated with atrial pacing or dual-chamber pacing rather than with ventricular pacing, because atrial pacing is associated with less AF, fewer TE complications, and a lower risk of AV block [65]. Many older patients are able to tolerate AF without the need for therapy because the ventricular rate is slow due to concomitant AV nodal disease. These patients should not be treated with drugs that depress AV conduction. A permanent pacemaker should be implanted in patients with AF who develop cerebral symptoms such as dizziness or syncope associated with ventricular pauses longer than 3 s that are not drug-induced, as documented by a 24-h AECG [66]. If patients with AF have drug-induced symptomatic bradycardia, and the causative drug cannot be discontinued, a permanent pacemaker must be implanted. Atrial pacing is eﬀective in treating vagotonic AF [67] and may be considered if treatment with a vagolytic antiarrhythmic drug such as disopyramide is ineﬀective. Atrial pacing is also eﬀective in treating patients with the sick sinus syndrome [65]. However, when bradycardia is not an indication for pacing, atrial-based pacing may not prevent episodes of AF [68]. Dual-site atrial pacing is more eﬃcacious than single-site pacing for preventing AF [69]. However, the patients in this study had a bradycardia indication for pacing and continued to need antiarrhythmic drugs [69]. Dual-site atrial pacing with continued sinus overdrive for AF in patients with bradycardia prolonged time to AF recurrence and reduced AF burden in patients with paroxysmal AF [70]. However, there was no diﬀerence in AF checklist symptom scores or overall quality-of-life scores [70]. The absence of an eﬀect on symptom control suggests that pacing should be used as adjunctive therapy with other treatment modalities for AF [70]. Biatrial pacing after CABS has also been demonstrated to reduce the incidence of AF [71]. All ECGs in patients with paced rhythm should be examined closely for underlying AF to prevent under-recognition of AF and undertreatment with anticoagulants [72]. Wolff-Parkinson-White Syndrome DC cardioversion should be performed if a rapid ventricular rate in patients with paroxysmal AF associated with the Wolﬀ-Parkinson-White (WPW) syndrome is life-

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threatening or fails to respond to drug therapy. Drug treatment for paroxysmal AF associated with the WPW syndrome includes propranolol plus procainamide, disopyramide, or quinidine [73]. Digoxin, diltiazem, and verapamil are contraindicated in patients with AF with the WPW syndrome because these drugs shorten the refractory period of the accessory AV pathway, resulting in more rapid conduction down the accessory pathway. This results in a marked increase in ventricular rate. Radiofrequency catheter ablation or surgical ablation of the accessory conduction pathway should be considered in patients with AF and rapid AV conduction over the accessory pathway [74]. In 500 patients with an accessory pathway, radiofrequency catheter ablation of the accessory pathway was successful in 93% of patients [75]. Elective Cardioversion Elective DC cardioversion has a higher success rate than does medical cardioversion in converting AF to sinus rhythm [76]. Table 1 shows favorable and unfavorable conditions for elective cardioversion of chronic AF. The American College of Cardiology (ACC)/American Heart Association (AHA)/ European Society for Cardiology (ESC) guidelines state that Class I indications for cardioversion of AF to sinus rhythm include (1) immediate DC cardioversion in patients with paroxysmal AF and a rapid ventricular rate who have ECG evidence of acute MI or symptomatic hypotension, angina, or CHF that does not respond promptly to pharmaco-

Table 1 Conditions Favorable and Unfavorable for Cardioversion of Atrial Fibrillation Favorable Conditions <1 year duration of AF No or minimal cardiomegaly Echocardiographic left atrial dimension <45 mm After treatment of a precipitating cause such as acute MI, cardiac or thoracic surgery, hyperthyroidism, pneumonia, or pericarditis After corrective valvular surgery Symptomatic AF with hemodynamic improvement and decrease in symptoms expected from sinus rhythm, especially in patients with valvular aortic stenosis or hypertrophic obstructive cardiomyopathy Unfavorable Conditions Duration of atrial ﬁbrillation >1 year Moderate-to-severe cardiomegaly Echocardiographic left atrial dimension >45 mm Digitalis toxicity (contraindicated) Slow ventricular rate (contraindicated) Sick sinus syndrome (contraindicated) Chronic obstructive lung disease Mitral valve disease Heart failure Recurrent AF despite antiarrhythmic drugs Inability to tolerate antiarrhythmic drugs

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logical measures and (2) DC or drug cardioversion in patients with chronic AF without hemodynamic instability when symptoms of AF are unacceptable [77]. Elective cardioversion of AF either by DC or by antiarrhythmic drugs should not be performed in asymptomatic elderly patients with chronic AF. Rectilinear, biphasic shocks have been found to have greater eﬃcacy and need less energy than the traditional damped sine-wave monophasic shocks [78]. Therefore, biphasic shocks to cardiovert AF should become the clinical standard. Antiarrhythmic drugs that have been used to convert AF to sinus rhythm include amiodarone, disopyramide, dofetilide, encainide, ﬂecainide, ibutilide, procainamide, propafenone, quinidine, and sotalol. None of these drugs is as successful as DC cardioversion, which has a success rate of 80 to 90% in converting AF to sinus rhythm. All of these drugs are proarrhythmic and may aggravate or cause cardiac arrhythmias. Encainide and ﬂecainide caused atrial proarrhythmic eﬀects in 6 of 60 patients (10%) [79]. The atrial proarrhythmic eﬀects included conversion of AF to atrial ﬂutter with a 1-to-1 AV conduction response and a very fast ventricular rate [79]. Flecainide has caused ventricular tachycardia (VT) and ventricular ﬁbrillation (VF) in patients with chronic AF [80]. Antiarrhythmic drugs including amiodarone, disopyramide, ﬂecainide, procainamide, propafenone, quinidine, and sotalol caused cardiac adverse eﬀects in 73 of 417 patients (18%) hospitalized for AF [81]. Class IC drugs such as encainide, ﬂecainide, and propafenone should not be used in patients with prior MI or abnormal LV ejection fraction because these drugs may cause life-threatening ventricular tachyarrhythmias in these patients [82]. Dofetilide and ibutilide are Class III antiarrhythmic drugs that have been used for the conversion of AF to sinus rhythm. Eleven of 75 patients (15%) with AF treated with intravenous dofetilide converted to sinus rhythm [83]. Torsades de pointes occurred in 3% of patients treated with intravenous dofetilide [83]. After 1 month, 22 of 190 patients (12%) with AF and CHF had sinus rhythm restored with dofetilide compared to 3 of 201 patients (1%) treated with placebo [84]. Torsades de pointes developed in 25 of 762 patients (3%) treated with dofetilide and in none of 756 patients (0%) treated with placebo [84]. Twentythree of 79 patients (29%) with AF treated with intravenous ibutilide converted to sinus rhythm [85]. Polymorphic VT developed in 4% of patients who received intravenous ibutilide in this study [85]. Baseline bradycardia with AF may predispose to ibutilideinduced polymorphic VT. DC cardioversion of AF has a higher success rate in converting AF to sinus rhythm and a lower incidence of cardiac adverse eﬀects than treatment with any antiarrhythmic drug. However, pretreatment with ibutilide has been found to facilitate transthoracic cardioversion of AF [86]. Unless transesophageal echocardiography has demonstrated no thrombus in the left atrial appendage before cardioversion [87], oral warfarin should be administered for 3 weeks before elective DC or drug conversion of patients with AF to sinus rhythm [88]. Anticoagulant therapy should also be given at the time of cardioversion and continued until sinus rhythm has been maintained for 4 weeks [88]. After DC or drug cardioversion of AF to sinus rhythm, the left atrium becomes stunned and contracts poorly for 3 to 4 weeks, predisposing to TE stroke unless the patient is maintained on oral warfarin [89,90]. The maintenance dose of oral warfarin should be titrated by serial prothrombin times so that the International Normalized Ratio (INR) is 2.0 to 3.0 [88]. In a multicenter, randomized, prospective study, 1222 patients with AF of >2 days duration were randomized to either treatment guided by the ﬁndings on transesophageal

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echocardiography or to management with conventional therapy [91]. The primary endpoint was cerebrovascular accident, transient ischemic attack, and peripheral embolism within 8 weeks. The incidence of embolic events at 8 weeks was 0.8% in the transesophageal echocardiography treatment group and 0.5% in the conventional treatment group [91]. At 8 weeks, there were also no signiﬁcant diﬀerences between the two groups in the rates of death, maintenance of sinus rhythm, or functional status [91]. However, there was a trend toward a higher rate of death from any cause in the transesophageal echocardiography treatment group (2.4%) than in the conventional treatment group (1.0%) ( p=0.06) [91]. This study showed the importance of maintaining therapeutic anticoagulation in the period after cardioversion even if there is no transesophageal echocardiographic evidence of thrombus [90,92]. The best management strategy for patients with evidence of an atrial thrombus on initial transesophageal echocardiography remains controversial [93]. In the absence of data from a randomized trial, patients probably should have follow-up transesophageal echocardiography after 1 month of warfarin therapy to document resolution of the atrial thrombus [93,94].

Use of Antiarrhythmic Drugs to Maintain Sinus Rhythm The eﬃcacy and safety of antiarrhythmic drugs after cardioversion of AF to maintain sinus rhythm has been questioned. A meta-analysis of six double-blind, placebo-controlled studies of quinidine involving 808 patients who had direct-current cardioversion of chronic AF to sinus rhythm demonstrated that 50% of patients treated with quinidine and 25% of patients treated with placebo remained in sinus rhythm at 1 year follow-up [95]. However, the mortality was signiﬁcantly higher in patients treated with quinidine (2.9%) than in patients treated with placebo (0.8%) [95]. In a study of 406 patients, mean age 82 years, with heart disease and complex ventricular arrhythmias, the incidence of adverse eﬀects causing drug cessation was 48% for quinidine and 55% for procainamide [96]. The incidence of total mortality at 2-year follow-up was insigniﬁcantly higher in patients treated with quinidine or procainamide compared with patients not receiving an antiarrhythmic drug [96]. In another study, 85 patients were randomized to quinidine and 98 patients to sotalol after DC cardioversion of AF to sinus rhythm [97]. At 6-month follow-up, 48% of quinidine-treated patients and 52% of sotalol-treated patients remained in sinus rhythm [97]. At 1-year follow-up of 100 patients with AF cardioverted to sinus rhythm, 37% of 50 patients randomized to sotalol and 30% of 50 patients randomized to propafenone remained in sinus rhythm [98]. In a study of 403 patients with at least one episode of AF in the prior 6 months, 201 patients were treated with amiodarone and 202 patients were treated with sotalol or propafenone [99]. At 16-month follow-up, AF recurred in 35% of patients treated with amiodarone and in 63% of patients treated with sotalol or propafenone [99]. Adverse eﬀects causing discontinuation of drug occurred in 18% of patients treated with amiodarone and in 11% of patients treated with sotalol or propafenone [99]. After cardioversion of 394 patients with AF to sinus rhythm, 197 patients were randomized to metoprolol CR/XL and 197 patients to placebo [100]. At 6-month follow-up, the percent of patients in sinus rhythm was signiﬁcantly higher on metoprolol CR/XL (51%) than on placebo (40%) [100]. The heart rate in patients who relapsed into AF was also signiﬁcantly lower in patients treated with metoprolol CR/XL than in patients treated with placebo [100].

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In a study of 384 patients with a history of AF or atrial ﬂutter, azimilide lengthened the median time to ﬁrst symptomatic arrhythmia recurrence from 17 days in the placebo group to 60 days in the azimilide group [101]. However, additional data on both eﬃcacy and safety of azimilide are necessary before knowing its role in clinical practice. Of the 1330 patients in the Stroke Prevention in Atrial Fibrillation (SPAF) Study, 127 persons were taking quinidine, 57 procainamide, 34 ﬂecainide, 20 encainide, 15 disopyramide, and 7 amiodarone [102]. Patients who were taking an antiarrhythmic drug had a 2.7 times higher adjusted relative risk of cardiac mortality and a 2.3 times higher adjusted relative risk of arrhythmic death compared with patients not taking an antiarrhythmic drug [102]. Patients with a history of CHF who were taking an antiarrhythmic drug had a 4.7 times increased risk of cardiac death and a 3.7 times increased risk of arrhythmic death than patients with a history of CHF not taking an antiarrhythmic drug [102]. A meta-analysis of 59 randomized, controlled trials comprising 23,229 patients that investigated the use of aprindine, disopyramide, encainide, ﬂecainide, imipramine, lidocaine, mexiletine, moricizine, phenytoin, procainamide, quinidine, and tocainide after MI also demonstrated that mortality was signiﬁcantly higher in patients receiving Class I antiarrhythmic drugs (odds ratio = 1.14) than in patients not receiving an antiarrhythmic drug [103]. None of the 59 studies showed a decrease in mortality by antiarrhythmic drugs [103]. Amiodarone is the antiarrhythmic drug with the highest success rate in maintenance of sinus rhythm after cardioversion of AF [99]. However, in the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation Study, the incidence of pulmonary toxicity was 10% at 2 years in patients receiving amiodarone in a mean dose of 158 mg daily [104]. The incidence of adverse eﬀects from amiodarone also approaches 90% after 5 years of therapy [105]. Ventricular Rate Control Because maintenance of sinus rhythm with antiarrhythmic drugs may require serial cardioversions, exposes patients to the risks of proarrhythmia, sudden cardiac death, and other adverse eﬀects, and requires the use of anticoagulants in patients in sinus rhythm who have a high risk of recurrence of AF, many cardiologists prefer the management strategy of ventricular rate control plus use of anticoagulants in patients with AF, especially in the elderly. Beta-blockers such as propranolol 10 to 30 mg given 3 to 4 times daily can be administered to control ventricular arrhythmias [106] and after conversion of AF to sinus rhythm. Should AF recur, beta-blockers have the added advantage of slowing the ventricular rate. Beta-blockers are also the most eﬀective drugs in preventing and treating AF after CABS [107]. The Pharmacological Intervention in Atrial Fibrillation trial was a randomized trial of 252 patients with AF of between 7 and 360 days duration which compared ventricular rate control (125 patients) with rhythm control (127 patients) [108]. Diltiazem was used as ﬁrstline therapy in patients randomized to ventricular rate control. Amiodarone was used as ﬁrst-line therapy in patients randomized to rhythm control. Amiodarone administration resulted in conversion of 23% of patients to sinus rhythm [108]. Symptomatic improvement was reported in a similar percentage of patients in both groups. Assessment of quality of life showed no signiﬁcant diﬀerence between the two treatment groups. The incidence of hospital admission was signiﬁcantly higher in patients treated with rhythm control (69%) than in patients treated with ventricular rate control (24%) [108]. Adverse drug eﬀects

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caused a change in drug therapy in signiﬁcantly more patients treated with rhythm control (25%) than in patients treated with ventricular rate control (14%) [108]. The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study randomized 3957 patients, mean age 70 years (39% women), with paroxysmal or chronic AF of less than 6 months duration at high risk for stroke to either maintenance of AF with ventricular rate control or to an attempt to maintain sinus rhythm with antiarrhythmic drugs after cardioversion [109]. Patients in both arms of this study were treated with warfarin. All-cause mortality at 5 years was insigniﬁcantly increased 15% in the maintenance of sinus rhythm group compared to the ventricular rate control group (24% vs. 21%; p = 0.08) [109]. TE stroke was insigniﬁcantly reduced in the ventricular rate control group (5.5% vs. 7.1%), and all-cause hospitalization was signiﬁcantly reduced in the ventricular rate control group (73% vs. 80%; p< 0.0001) [109]. In both groups, the majority of strokes occurred after warfarin was stopped or when the INR was subtherapeutic. There was no signiﬁcant diﬀerence in quality of life or functional status between the two treatment groups [109]. The Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group randomized 522 patients with persistent AF after a previous electrical cardioversion to receive treatment to aimed at ventricular rate control or rhythm control [109a]. Both groups were treated with oral anticoagulants. At 2.3-year follow-up, the composite endpoint of death from cardiovascular causes, heart failure, TE complications, bleeding, implantation of a pacemaker, and severe adverse eﬀects of drugs was 17.2% in the ventricular rate control group versus 22.6% in the rhythm control group [109a]. Risk Factors for Thromboembolic Stroke Table 2 lists risk factors for TE stroke in patients with AF [1,2,21,110–120]. In the SPAF Study involving patients, mean age 67 years, recent CHF (within 3 months), a history of hypertension, previous thromboembolism, echocardiographic left atrial enlargement, and echocardiographic LV systolic dysfunction were associated independently with the develop-

Table 2 Risk Factors for Stroke in Patients with Atrial Fibrillation Age [1,110–113] Echocardiographic left ventricular dysfunction [112,114–116] History of heart failure [111,115,117] Hypertension [110,113,115,117] Prior thromboembolic events [2,21,110–112,115–118] Women older than 75 years of age [115] Rheumatic mitral stenosis [112,113] Mitral annular calcium [109,119] Diabetes mellitus [111] History of myocardial infarction [110,111,113,120] Echocardiographic left atrial enlargement [113,114] Echocardiographic left ventricular hypertrophy [112,113] Extracranial carotid arterial disease [21] Hypercholesterolemia [112] Low-serum high-density lipoprotein cholesterol [112]

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ment of new TE events [114,117]. The incidence of new TE events was 18.6% per year if three or more risk factors were present, 6.0% per year if one or two risk factors were present, and 1.0% per year if none of these risk factors was present [114]. In the SPAF Study III involving patients mean age 72 years, patients were considered at high risk for developing TE stroke if they had either CHF or abnormal LV systolic function, prior thromboembolism, a systolic blood pressure of >160 mmHg, or the patient was a woman older than age 75 years [115]. In a study of 312 patients with chronic AF mean age 84 years, independent risk factors for the development of new TE stroke were prior stroke (risk ratio = 1.6), rheumatic mitral stenosis (risk ratio = 2.0), LVH (risk ratio = 2.8), abnormal LVEF (risk ratio = 1.8), serum total cholesterol (risk ratio = 1.01 per 1 mg/dL increase), serum high-density lipoprotein cholesterol (risk ratio = 1.04 per 1 mg/dL decrease), and age (risk ratio = 1.03 per 1 year increase) [112]. Antithrombotic Therapy Prospective, randomized trials [110,115,118,121–127] and prospective, nonrandomized observational data from patients mean age 83 years [116] and mean age 84 years [128] have documented that warfarin is eﬀective in decreasing the incidence of TE stroke in patients with nonvalvular AF. Analysis of pooled data from ﬁve randomized, placebo-controlled studies showed that warfarin signiﬁcantly decreased the incidence of new TE stroke by 68% and was signiﬁcantly more eﬀective than aspirin in decreasing the incidence of new TE stroke [111]. In the Veterans Aﬀairs Cooperative study, the incidence of new TE events was 4.3% per year in patients on placebo versus 0.9% per year in patients on warfarin in patients with no prior stroke, 9.3% per year in patients on placebo versus 6.1% per year in patients on warfarin in patients with prior stroke, and 4.8% per year in patients on placebo versus 0.9% per year in patients on warfarin in patients older than age 70 [125]. In the European Atrial Fibrillation Trial involving patients with recent transient cerebral ischemic attack or minor ischemic stroke, at 2.3-year follow-up, the incidence of new TE events was 12% per year in patients taking placebo, 10% per year in patients taking aspirin, and 4.0 per year in patients taking warfarin [118]. Nonrandomized observational data from older patients with chronic AF, mean age 83 years, found that 141 patients treated with oral warfarin to achieve an INR between 2.0 and 3.0 (mean INR was 2.4) had a 67% signiﬁcant decrease in new TE stroke compared with 209 patients treated with oral aspirin [116]. Compared with aspirin, warfarin caused a 40% signiﬁcant decrease in new TE stroke in patients with prior stroke, a 31% signiﬁcant decrease in new TE stroke in patients with no prior stroke, a 45% signiﬁcant reduction in new TE stroke in patients with abnormal LVEF, and a 36% signiﬁcant reduction in new TE stroke in patients with normal LVEF [116]. At 1.1-year follow-up in the SPAF Study III, patients with AF considered to be at high risk for developing new TE stroke who were randomized to treatment with oral warfarin to achieve an INR between 2.0 and 3.0 had a 72% signiﬁcant decrease in ischemic stroke or systemic embolism compared with patients randomized to treatment with oral aspirin 325 mg daily plus oral warfarin to achieve an INR between 1.2 and 1.5 [115]. Adjusted-dose warfarin caused an absolute decrease in ischemic stroke or systemic embolism of 6.0% per year [115]. In the Second Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation (AFASK) Study, low-dose warfarin plus aspirin was also less eﬀective in reducing stroke or systemic TE events in patients with AF (7.2% after 1 year) than was adjusted-dose warfarin to achieve an INR between 2.0 and 3.0 (2.8% after 1 year) [127].

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Analysis of pooled data from ﬁve randomized controlled studies demonstrated that the annual incidence of major hemorrhage was 1.0% for the control group, 1.0% for the aspirin group, and 1.3% for the warfarin group [111]. The incidence of major hemorrhage in patients mean age 72 years taking adjusted-dose warfarin to achieve an INR of 2.0 to 3.0 in the SPAF III Study was 2.1% [115]. In the Second Copenhagen AFASK Study, the incidence of major hemorrhage in patients mean age 73 years was 0.8% per year for patients treated with adjusted-dose warfarin to achieve an INR between 2.0 and 3.0 and 1.0% per year for patients treated with aspirin 300 mg daily [127]. The incidence of major hemorrhage in older patients with chronic AF, mean age 83 years, was 4.3% (1.4% per year) in patients treated with warfarin to maintain an INR between 2.0 and 3.0 and 2.9% (1.0% per year) in patients treated with aspirin 325 mg daily [116]. In the SPAF III Study, 892 patients mean age 67 years at low risk for developing TE stroke were treated with oral aspirin 325 mg daily [129]. The incidence of ischemic stroke or systemic embolism was 2.2% per year [129]. The incidence of ischemic stroke or systemic embolism was 3.6% per year in patients with a history of hypertension and 1.1% per year in patients with no history of hypertension [129]. On the basis of the available data, patients with chronic or paroxysmal AF at high risk for developing TE stroke or with a history of hypertension and who have no contraindications to anticoagulation therapy should be treated with long-term oral warfarin to achieve an INR between 2.0 and 3.0 [88]. Hypertension must be controlled. Whenever the patient has a prothrombin time taken, the blood pressure should also be checked. The physician prescribing warfarin should be aware of the numerous drugs that potentiate the eﬀect of warfarin causing an increased prothrombin time and risk of bleeding [130]. Patients with AF at low risk for developing TE stroke or with contraindications to treatment with long-term oral warfarin should be treated with aspirin 325 mg orally daily [131]. Patients younger than age 60 years of age in Olmstead County, Minnesota, with lone AF (no heart disease) had a low risk of TE stroke at 15-year follow-up [132]. However, at 30year follow-up in the Framingham Heart Study, the age-adjusted percentage of patients

Table 3

American College of Cardiology/American Heart Association/European

Society for Cardiology Class I Indications for Treating Patients with Atrial Fibrillation with Antithrombotic Therapy 1. 2. 3. 4. 5. 6. 7.

Aspirin 325 mg daily or no treatment to patients aged <60 years with no heart disease (lone AF). Aspirin 325 mg daily to patients aged <60 years with heart disease but no risk factors. Aspirin 325 mg daily to patients aged z60 years with no risk factors. Oral anticoagulation to maintain INR between 2.0 and 3.0 in patients aged z60 years with coronary artery disease or diabetes mellitus. Oral anticoagulation to maintain INR between 2.0 and 3.0 in patients aged z75 years, especially women. Oral anticoagulation to maintain INR between 2.0 and 3.0 in patients with heart failure, a left ventricular ejection fraction of V35%, thyrotoxicosis, or history of hypertension. Oral anticoagulation to maintain INR between 2.5 and 3.5 in patients with rheumatic mitral stenosis, prosthetic heart valves, prior thromboembolism, or persistent atrial thrombus on transesophageal echocardiography.

Source: Adapted from Ref. 77.

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with lone AF who developed a cerebrovascular event was 28% versus 7% in the control group [133]. Table 3 shows the ACC/AHA/ESC Class I indications for antithrombotic therapy in the management of patients with AF [77]. Despite data showing the eﬃcacy of oral warfarin used in a dose to achieve an INR between 2.0 and 3.0 in reducing the incidence of new TE events in patients with paroxysmal or chronic AF, only about one-third of patients with AF who should be taking warfarin receive it [134]. In an academic hospital-based geriatrics practice, only 61 of 124 patients (49%), mean age 80 years, with chronic AF at high risk for developing TE stroke and no contraindications to warfarin were being treated with warfarin therapy [5]. Elderly patients have a higher prevalence and incidence of AF than younger patients [1–6]. Elderly patients with AF are at higher risk for developing TE stroke than are younger patients with AF [1,19,110–112]. However, physicians are more reluctant to treat elderly patients with AF with warfarin therapy. Hopefully, intensive physician education will help solve this important clinical problem.

ATRIAL FLUTTER Atrial ﬂutter (AFL) may be paroxysmal or chronic. Episodes of AFL and of AF may occur in the same patient. The AFL waves are usually best seen in leads II, III, aVF, and V1. The atrial rate usually ranges from 250 to 350 beats per minute and is most commonly 300 beats per minute. There is no isoelectric interval between the AFL waves. In the absence of drug therapy, there is usually a 2:1 AV conduction response. In the general population, the incidence of AFL increases with age and ranges from 5 per 100,000 persons younger than 50 years to 587 per 100,000 persons older than 80 years [135]. At highest risk of developing AFL are the elderly, men, and patients with CHF or chronic obstructive lung disease [135]. Documented structural heart disease or a predisposing condition such as a major surgical procedure or pneumonia was present in 178 of 181 patients (98%) with AFL [135]. The acute onset of AFL with a rapid ventricular rate reduces cardiac output and may lead to angina pectoris, CHF, hypotension, acute pulmonary edema, and syncope. Chronic AFL with a rapid ventricular rate can cause a tachycardia-mediated cardiomyopathy. Patients with AFL are also at increased risk for developing new TE stroke [136,137]. Left atrial appendage stunning occurs after cardioversion in patients with AFL, although to a lesser degree than in patients with AF [138]. Management Management of AFL is similar to management of AF. DC cardioversion is the treatment of choice for converting AFL to sinus rhythm [139]. Thirty-eight percent of 78 patients with AFL treated with intravenous ibutilide converted to sinus rhythm [83]. Fifty-four percent of 16 patients with AFL treated with intravenous dofetilide converted to sinus rhythm [85]. Atrial pacing may also be used to try to convert AFL to sinus rhythm [140]. Intravenous verapamil [36], diltiazem [35], or beta-blockers [31–34] may be used to immediately slow a very rapid ventricular rate associated with AFL. Oral verapamil [42], diltiazem [41], or beta-blocker [43] should be added to the therapeutic regimen if a rapid ventricular rate associated with AFL occurs at rest or during exercise despite digoxin. Amiodarone is the most eﬀective drug for slowing a rapid ventricular rate associated with

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AFL [45]. Digoxin, verapamil, and diltiazem are contraindicated in patients with AFL associated with the WPW syndrome because these drugs shorten the refractory period of the accessory AV pathway, causing more rapid conduction down the accessory pathway. Class I antiarrhythmic drugs such as quinidine should never be used to treat patients with AFL who are not being treated with digoxin, a beta-blocker, verapamil, or diltiazem, because a 1:1 AV conduction response may develop. Drugs used to treat AFL may also be proarrhythmic [79,80]. Since patients with AFL are at increased risk for developing new TE stroke [136,137], anticoagulant therapy should be administered prior to DC cardioversion or drug cardioversion of patients of AFL to sinus rhythm using the same guidelines as for converting AF [88–92]. Patients with chronic AFL should be treated with oral warfarin, with INR maintained between 2.0 and 3.0 [88]. Radiofrequency catheter ablation of AFL is a highly successful procedure, especially when the right atrial isthmus is incorporated in the AFL circuit [141,142]. Demonstration of bi-directional isthmus block after catheter ablation predicts a high long-term success rate [142]. A second radiofrequency catheter ablation may be needed in up to one-third of patients, especially in those with right atrial enlargement [141].

PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA Paroxysmal supraventricular tachycardia (PSVT) is a regular narrow complex tachycardia with a rate usually between 140 and 220 beats per minute. A wide QRS complex occurs in the presence of bundle branch block or aberrant ventricular conduction. If aberrant ventricular conduction is present, the QRS complex is usually<140 ms and a right bundle branch block pattern is present 85% of the time. PSVT is usually caused by reentry but may be caused by abnormal automaticity or by triggered activity. AV nodal reentrant tachycardia (AVNRT) accounts for 60% of episodes of PSVT [143]. Discrete P waves are not seen on the 12-lead ECG in two-thirds of these patients. Retrograde P waves (inverted in leads II, III, and aVF) following the QRS complex occur in approximately 30% of these patients. In approximately 10% of these patients, the reentry circuit is reversed, with anterograde conduction over the fast pathway and retrograde conduction over the slow pathway [143]. This type of PSVT is referred to as uncommon AVNRT, and the RP interval is longer than the PR interval. PSVT secondary to accessory pathway conduction occurs in 30% of patients with sustained PSVT [144]. Accessory pathway conduction can be overt as in the WPW syndrome or concealed because accessory pathways are capable of either unidirectional or bidirectional conduction Paroxysmal atrial tachycardia includes those forms of PSVT that do not involve the AV node as an obligate part of the tachycardia circuit [145]. Atrial tachycardias can be reentrant, automatic, or triggered in origin [145]. The prevalence of short bursts of PSVT diagnosed by 24-h AECG in 1476 elderly persons, mean age 81 years, with heart disease was 33% [19]. At 42-month follow-up of 1359 persons, mean age 81 years, with heart disease, short bursts of PSVT were not associated with an increased incidence of new coronary events [15]. At 43-month follow-up of 1476 persons, mean age 81 years, with heart disease, short bursts of PSVT were not associated with an increased incidence of new TE stroke [19].

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Management Sustained episodes of SVT should ﬁrst be treated by increasing vagal tone by carotid sinus massage, the Valsalva maneuver, facial immersion in cold water, or administration of phenylephrine [146]. If vagal maneuvers are unsuccessful, intravenous adenosine is the drug of choice [147]. Intravenous verapamil, diltiazem, or beta-blockers may also be used. If these measures do not convert PSVT to sinus rhythm, DC cardioversion should be used. Most patients with PSVT do not require long-term therapy. If long-term treatment is required because of symptoms due to frequent episodes of PSVT, digoxin, propranolol, verapamil, or diltiazem may be administered [148]. These drugs are the initial drug of choice for AVNRT and AV reentrant SVT. For PSVT associated with the WPW syndrome, ﬂecainide or propafenone may be used if there is no associated heart disease [149]. If heart disease is present, quinidine, procainamide, or disopyramide plus a beta-blocker or verapamil should be used [149]. Radiofrequency catheter ablation should be used to treat older persons with symptomatic, drug-resistant SVT and should be considered an early treatment option [150]. Radiofrequency catheter ablation can be successfully performed in older patients with low complication rates. Resultant complete heart block for slow pathway ablation in AVNRT occurs in patients exhibiting a signiﬁcantly prolonged baseline ﬁrstdegree AV block. Cardiac perforation risk is also increased in elderly women. Accelerated Atrioventricular Junctional Rhythm Accelerated AV junctional rhythm also called nonparoxysmal AV junctional tachycardia (NPJT) is a form of SVT caused by enhanced impulse formation within the AV junction rather than by reentry [151]. This arrhythmia is usually due to recent aortic or mitral valve surgery, acute MI, or digitalis toxicity. The ventricular rate usually ranges between 70 and 130 beats per minute. Treatment of NPJT is directed toward correction of the underlying disorder. Hypokalemia, if present, should be treated with potassium. Digitalis should be stopped if digitalis toxicity is present. Beta-blockers may be given cautiously if this is warranted by clinical circumstances. Paroxysmal Atrial Tachycardia with Atrioventricular Block Digitalis toxicity causes 70% of cases of paroxysmal atrial tachycardia (PAT) with AV block. Digoxin and diuretics causing hypokalemia should be stopped in these persons. If the serum potassium is low or low-normal, potassium chloride is the treatment of choice. Intravenous propranolol will cause conversion to sinus rhythm in about 85% of patients with digitalis-induced PAT with AV block and in about 35% of patients with PAT with AV block not induced by digitalis [146]. By increasing AV block, propranolol may also be beneﬁcial in slowing a rapid ventricular rate in PAT with AV block [146]. Multifocal Atrial Tachycardia Multifocal atrial tachycardia (MAT) is usually associated with acute illness, especially in older persons with pulmonary disease. MAT is best managed by treatment of the underlying disorder. Intravenous verapamil has been reported to be eﬀective in controlling the ventricular rate in MAT, with occasional conversion to sinus rhythm [152]. However, one of the authors found that intravenous verapamil was not very eﬀective in treating MAT

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[153]. The tendency of intravenous verapamil to aggravate preexisting arterial hypoxemia also limits its use in the group of patients most likely to develop MAT [152].

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24 Ventricular Arrhythmias in the Elderly Wilbert S. Aronow and Carmine Sorbera New York Medical College, Valhalla, New York, U.S.A.

The presence of three or more consecutive ventricular premature complexes (VPCs) on an electrocardiogram is diagnosed as ventricular tachycardia (VT) [1,2]. VT is considered sustained if it lasts z30 s and nonsustained if its lasts <30 s [2]. Complex ventricular arrhythmias (VA) include VT or paired, multiform, or frequent VPCs. We consider frequent VPCs an average of z30/h on a 24-h ambulatory electrocardiogram (AECG) or z6/min on a 1-min rhythm strip of an electrocardiogram (ECG) [2,3]. Simple VA includes infrequent VPCs and no complex forms.

PREVALENCE OF COMPLEX VENTRICULAR ARRHYTHMIAS The prevalence of nonsustained VT detected by 24-h AECG was 4% in 98 older, disease-free persons in the Baltimore Longitudinal Study of Aging [1], 4% in 106 active older persons [4], 2% in 50 older persons without cardiovascular disease [5], 4% in 729 older women and 13% in 643 older men in the Cardiovascular Health Study [6], 3% in 135 older men and 2% in 297 older women without cardiovascular disease [7], 9% in 385 older men and 8% in 806 older women with hypertension, valvular disease, or cardiomyopathy [7], and 16% in 395 older men and 15% in 771 older women with coronary artery disease (CAD) [7]. The prevalence of complex VA in older persons in these studies was 50% [1], 31% [4], 20% [20%], 16% in women and 28% in men [6], 31% in older men and 30% in older women without cardiovascular disease [7], 54% in older men and 55% in older women with hypertension, valvular disease, or cardiomyopathy [7], and 69% in older men and 68% in older women with CAD [7]. In 104 older persons, mean age 82 years, without cardiovascular disease who had a 12lead electrocardiogram with a 1-min rhythm strip obtained within 24 h of a 24-h AECG, complex VA was present on the 24-h AECG in 33% of persons and on the 1-min rhythm strips in 2% of persons [3]. In this study, of 843 older persons, mean age 82 years, with cardiovascular disease, complex VA was present on the 24-h AECG in 55% of persons and on the 1-min rhythm strip in 4% of persons [3]. In older persons with cardiovascular disease, those with an abnormal left ventricular (LV) ejection fraction [8], echocardiographic LV hypertrophy [9], or silent myocardial is585

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chemia [10] have a higher prevalence of VT and of complex VA than those with normal LV ejection fraction, normal LV mass, and no myocardial ischemia.

PROGNOSIS OF VENTRICULAR ARRHYTHMIAS No Heart Disease In the Baltimore Longitudinal Study of Aging, nonsustained VT or complex VA were not associated with an increased incidence of new coronary events at 10-year follow-up in 98 older subjects with no clinical evidence of heart disease [11]. In this study also, exerciseinduced nonsustained VT was not associated with an increased incidence of new coronary events at 2-year follow-up in older persons with no clinical evidence of heart disease [12]. And at 5.6-year follow-up in this study, exercise-induced frequent or repetitive VPCs also were not associated with an increased incidence of new coronary events in older persons with no clinical evidence of heart disease [13]. Nonsustained VT or complex VA diagnosed by 24-h AECG was not associated with an increased incidence of new coronary events at 2-year follow-up in 76 older persons with no clinical evidence of heart disease [14] and were not associated with an increased incidence of primary ventricular ﬁbrillation (VF) or sudden cardiac death in 86 older persons with no clinical evidence of heart disease [15]. Complex VA diagnosed by 24-h AECG or by 12-lead ECG with 1-min rhythm strips also were not associated with an increased incidence of new coronary events at 39-month follow-up in 104 older persons with no clinical evidence of heart disease [3]. Nonsustained VT or complex VA diagnosed by 24-h AECG was not associated with an increased incidence of new coronary events at 45-month follow-up of 135 men and at 47-month follow-up of 297 women without cardiovascular disease [7]. Because nonsustained VT or complex VA is not associated with an increased incidence of new coronary events in older persons with no clinical evidence of heart disease, asymptomatic nonsustained VT or complex VA in older persons without heart disease should not be treated with antiarrhythmic drugs. Because simple VA in older persons with heart disease is not associated with an increased incidence of new coronary events [3,7,11,14,15], simple VA in older persons without heart disease should not be treated with antiarrhythmic drugs. Heart Disease Numerous studies have documented that patients with VT or with complex VA associated with heart disease are at increased risk for developing new coronary events [16–19]. Prospective studies in older persons, mean age 82 years, with heart disease also demonstrated that nonsustained VT and complex VA were signiﬁcantly associated with an increased incidence of new coronary events and with an increased incidence of primary VF or sudden cardiac death (Table 1) [3,7,11,14,15].

MEDICAL THERAPY General Measures Underlying causes of complex VA should be treated, if possible. Treatment of congestive heart failure (CHF), digitalis toxicity, hypokalemia, hypomagnesemia, hypertension, LV

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Table 1 Association of Complex Ventricular Arrhythmias and Ventricular Tachycardia with New Coronary Events in Elderly Patients with Heart Disease Mean age (years)

Cardiac status

Follow-up (months)

Incidence of new coronary events

Aronow et al. (n=843) [3] Aronow et al. (n=391) [14]

82

Heart disease

39

82

Heart disease

24

Aronow et al. (n=468) [15]

82

Heart disease

27

Aronow et al. (n=404) [10]

82

Heart disease

37

Aronow et al. (n=395 men) [7]

80

CAD

45

Aronow et al. (n=385 men) [7]

80

HT, VD, or CMP

45

Aronow et al. (n=771 women) [7]

81

CAD

47

Aronow et al. (n=806 women) [7]

81

HT, VD, or CMP

47

Increased 1.7 times by complex VA With normal LVEF, increased 2.5 times by complex VA and 3.2 times by VT; increased 7.6 times by complex VA plus abnormal LVEF and increased 6.8 times by VT plus abnormal LVEF With no LVH, SCD or VF increased 2.4 times by complex VA and 1.8 times by VT; SCD or VF increased 7.3 times by complex VA plus LVH and increased 7.1 times by VT plus LVH Increased 1.7 times by VT and 2.4 times by complex VA; increased 2.5 times by VT plus SI and 4.0 times by complex VA plus SI Increased 2.4 times by complex VA and 1.7 times by VT Increased 1.9 times by complex VA and 1.9 times by VT Increased 2.5 times by complex VA and 1.7 times by VT Increased 2.2 times by complex VA and 2.0 times by VT

Study

Abbreviations: VA = ventricular arrhythmias; VT = ventricular tachycardia; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; SCD = sudden coronary death; VF = primary ventricular ﬁbrillation; CAD = coronary artery disease; HT = hypertension; VD = valvular heart disease; CMP = cardiomyopathy; SI = silent ischemia.

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dysfunction, LV hypertrophy, myocardial ischemia by anti-ischemic drugs such as betablockers or by coronary revascularization, hypoxia, and other conditions may abolish or reduce complex VA. The older person should not smoke or drink alcohol and should avoid drugs that may cause or increase complex VA. All older persons with CAD should be treated with aspirin [20–23], beta-blockers [23– 28], and angiotensin-converting enzyme (ACE) inhibitors [28–33] unless there are contraindications to these drugs. Older persons with CAD who have elevated serum low-density lipoprotein cholesterol levels should be treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [23,34–38]. Age-related physiological changes may aﬀect absorption, distribution, metabolism, and excretion of cardiovascular drugs [39]. There are numerous physiological changes with aging that aﬀect pharmacodynamics with alterations in end-organ responsiveness to cardiovascular drugs [39]. Drug interactions between antiarrhythmic drugs and other cardiovascular drugs are common, especially in older persons [39]. There are also important drug–disease interactions that occur in older persons [39]. Class I antiarrhythmic drugs have an unacceptable proarrhythmia rate in patients with heart disease and should be avoided. Class III antiarrhythmic drugs should also be used with caution in older patients with heart disease since multiple factors may increase the incidence of proarrhythmia. Except for betablockers, all antiarrhythmic drugs may cause torsades de pointes (VT with polymorphous appearance associated with prolonged QT interval). Class I Antiarrhythmic Drugs Class I antiarrhythmic drugs are sodium channel blockers. Class Ia antiarrhythmic drugs have intermediate channel kinetics and prolong repolarization. These drugs include quinidine, procainamide, and disopyramide. Class Ib antiarrhythmic drugs have rapid channel kinetics and slightly shorten repolarization. These drugs include lidocaine, mexilitine, tocainide, and phenytoin. Class Ic drugs have slow channel kinetics and have little eﬀect on repolarization. These drugs include encainide, ﬂecainide, moricizine, propafenone, and lorcainide. None of the Class I antiarrhythmic drugs have been demonstrated in controlled, clinical trials to reduce sudden cardiac death, total cardiac death, or total mortality. The International Mexilitine and Placebo Antiarrhythmic Coronary Trial (IMPACT) was a prospective, double-blind, randomized study in survivors of myocardial infarction (MI), mean age 57 years, in whom 317 persons were randomized to mexilitine and 313 persons to placebo [40]. Complex VA was present on 24-h AECG at study entry in 31% of persons randomized to mexilitine and in 38% of persons randomized to placebo. At 1-year follow-up, mortality was 7.6% for mexilitine-treated patients versus 4.8% for placebotreated patients [40]. The Cardiac Arrhythmia Suppression Trial (CAST) I was a prospective, double-blind, randomized study in survivors of MI with asymptomatic or mildly symptomatic VA in which 730 patients were randomized to encainide or ﬂecainide and 725 patients to placebo [41]. The prevalence of nonsustained VT was 21%. Mean LV ejection fraction was 40%. Thirty-eight percent of patients were 66 to 79 years of age. Adequate suppression of VA by encainide or ﬂecainide was required before randomization. Despite adequate suppression of VA, at 10-month follow-up, encainide and ﬂecainide signiﬁcantly increased mortality from arrhythmia or cardiac arrest (relative risk = 3.6; 95% CI, 1.7 to 8.5) and signiﬁcantly increased total mortality (relative risk = 2.5; 95% CI, 1.6 to 4.5) [41]. Older age increased the

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likelihood of adverse events, including death, in patients receiving encainide and ﬂecainide [42]. CAST-II was a prospective, double-blind, randomized study in survivors of MI with asymptomatic or mildly symptomatic VA in which 581 patients were randomized to moricizine and 574 patients to placebo [43]. The prevalence of nonsustained VT was 30%. Mean LV ejection fraction was 33%. Thirty-eight percent of patients were 66 to 79 years of age. Adequate suppression of VA by moricizine was required before randomization. At 18month follow-up, the mortality from arrhythmia or cardiac arrest was 8.4% for patients treated with moricizine and 7.3% for patients treated with placebo [43]. The 2-year survival rate was 81.7% for patients treated with moricizine and 85.6% for patients treated with placebo [43]. The investigators concluded that the use of moricizine in this study was ‘‘. . .not only ineﬀective but also harmful’’ [43]. Older age increased the likelihood of adverse events, including death, in patients receiving moricizine [42]. An analysis of the CAST-I and CAST-II studies showed that older age was an independent predictor of adverse events (relative risk 1.30 per decade of age) [42]. On the basis of the CAST-I and CAST-II data, we would not use encainide, ﬂecainide, or moricizine for the treatment of VT or complex VA in older or younger patients with heart disease. Aronow et al. [44] performed a prospective study in 406 older persons, mean age 82 years, with heart disease (58% with prior MI) and asymptomatic complex VA diagnosed by 24-h AECG. The prevalence of nonsustained VT was 20%. The prevalence of an abnormal ejection fraction was 32%. The incidence of adverse eﬀects causing cessation of drug was 48% for quinidine and 55% for procainamide. Of 406 older persons, 220 were treated with quinidine (n = 213) or procainamide (n = 7) and 186 with no antiarrhythmic drug. Followup 24-h AECG in 25 persons with nonsustained VT and in 104 persons with complex VA showed that quinidine or procainamide decreased nonsustained VT more than 90% in 84% of the persons and decreased the average number of VPC/h more than 70% in 84% of the persons [44]. At 24-month follow-up, the incidences of sudden cardiac death, total cardiac death, and of total death were not signiﬁcantly diﬀerent in persons treated with quinidine, procainamide, or no antiarrhythmic drug [44]. The incidence of total mortality was 65% for persons treated with quinidine or procainamide and 63% for persons treated with no antiarrhythmic drug. Quinidine or procainamide did not decrease sudden cardiac death, total cardiac death, or total death in comparison with no antiarrhythmic drug in older patients with ischemic or nonischemic heart disease, abnormal or normal LV ejection fraction, and presence versus absence of VT [44]. Moosvi et al. [45] performed a retrospective analysis of the eﬀect of empiric antiarrhythmic therapy in 209 resuscitated out-of-hospital cardiac arrest patients, mean age 62 years, with CAD. Of the 209 patients, 48 received quinidine, 45 received procainamide, and 116 received no antiarrhythmic drug. The 2-year sudden death survival was 69% for quinidine-treated patients, 69% for procainamide-treated patients, and 89% for patients treated with no antiarrhythmic drug ( p < 0.01) [45]. The 2-year total survival was 61% for quinidine-treated patients, 57% for procainamide-treated patients, and 71% for patients treated with no antiarrhythmic drug ( p < 0.05) [45]. Hallstrom et al. [46] performed a retrospective analysis of the eﬀect of antiarrhythmic drug use in 941 patients, mean age 62 years, resuscitated from prehospital cardiac arrest attributable to VF between 1970 and 1985. Quinidine was administered to 19% of the patients, procainamide to 18% of the patients, beta-blockers to 28% of the patients, and no

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antiarrhythmic drug to 39% of the patients. There was an increased incidence of death or recurrent cardiac arrest in patients treated with quinidine or procainamide versus no antiarrhythmic drug (adjusted relative risk = 1.17; 95% CI, 0.98 to 1.41). Survival was signiﬁcantly worse for patients treated with procainamide than for patients treated with quinidine (adjusted relative risk = 1.57; 95% CI, 1.21 to 2.07) [46]. A meta-analysis of six double-blind studies comprising 808 patients with chronic atrial ﬁbrillation who underwent direct-current cardioversion to sinus rhythm showed that the mortality at 1 year was signiﬁcantly higher in patients treated with quinidine (2.9%) than in patients treated with placebo (0.8%) ( p < 0.05) [47]. Of 1330 patients in the Stroke Prevention in Atrial Fibrillation Study, 127 received quinidine, 57 procainamide, 15 disopyramide, 34 ﬂecainide, 20 encainide, and seven amiodarone [48]. The adjusted relative risk of cardiac mortality was 1.8 times higher (95% CI, 0.7 to 3.7) and the adjusted relative risk of arrhythmic death was 2.1 times higher (95% CI, 0.8 to 5.0) in patients on antiarrhythmic drugs than in patients not on antiarrhythmic drugs [48]. In patients with a history of CHF, the adjusted relative risk of cardiac death was 3.3 times higher (95% CI, 1.1 to 8.2) and the adjusted relative risk of arrhythmic death was 5.8 times higher (95% CI, 1.2 to 13.5) in patients receiving antiarrhythmic drugs than in patients not receiving antiarrhythmic drugs [48]. Morganroth and Goin [49] performed a meta-analysis of four randomized, doubleblind controlled trials lasting two to 12 weeks in which quinidine (n = 502) was compared with ﬂecainide (n = 141), mexiletine (n = 246), tocainide (n = 67), and propafenone (n = 53) in the treatment of complex VA. There was an increased risk of mortality in patients treated with quinidine compared with patients treated with the other antiarrhythmic drugs (absolute risk increase = 1.6%; 95% CI, 0% to 3.1%) [49]. Teo et al. [50] analyzed 59 randomized controlled trials comprising 23,229 patients that investigated the use of Class I antiarrhythmic drugs after MI. The Class I drugs investigated included quinidine, procainamide, disopyramide, imipramine, moricizine, lidocaine, tocainide, phenytoin, mexiletine, aprindine, encainide, and ﬂecainide. Mortality was signiﬁcantly higher in patients receiving Class I antiarrhythmic drugs than in patients receiving no antiarrhythmic drugs (odds ratio = 1.14; 95% CI, 1.01 to 1.28). None of the 59 studies demonstrated that the use of a Class I antiarrhythmic drug decreased mortality in postinfarction patients [50]. On the basis of the data from the studies discussed in this section, none of the Class I antiarrhythmic drugs should be used for the treatment of VT or complex VA in older or younger patients with heart disease.

Calcium Channel Blockers Calcium channel blockers are not useful in the treatment of complex VA. Although verapamil can terminate a left septal fascicular VT, hemodynamic collapse can occur if intravenous verapamil is administered to patients with the more common forms of reentry VT. Teo et al. [50] analyzed randomized controlled trials comprising 20,342 patients that investigated the use of calcium channel blockers after MI. Mortality was insigniﬁcantly higher in patients receiving calcium channel blockers than in patients receiving no antiarrhythmic drugs (odds ratio = 1.04; 95% CI, 0.95 to 1.14) [50]. On the basis of these data, none of the calcium channel blockers should be used in the treatment of VT or complex VA in older or younger patients with heart disease.

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Beta-Blockers Teo et al. [50] analyzed 55 randomized controlled trials comprising 53,268 patients that investigated the use of beta-blockers after MI. Mortality was signiﬁcantly reduced in patients receiving beta-blockers compared with control patients (odds ratio = 0.81; 95% CI, .75 to .87) [50]. Beta-blockers caused a greater reduction in mortality in older persons after MI than in younger persons after MI [24–27,51]. The decrease in mortality after MI in persons treated with beta-blockers was due to a reduction in both sudden cardiac death and recurrent myocardial infarction [24–27,51]. The Beta-Blocker Heart Attack Trial was a double-blind, randomized study which included 3290 patients after MI [51–53]. Thirty-three percent of the patients were 60 to 69 years of age. At 25-month follow-up, propranolol decreased sudden cardiac death by 28% in patients with complex VA and by 16% in patients without complex VA. Propranolol signiﬁcantly reduced total mortality by 34% in patients aged 60 to 69 years ( p = 0.01) and insigniﬁcantly reduced total mortality by 19% in patients aged 30 to 59 years (Table 2) [51– 53]. Beta-blockers reduce complex VA including VT [53–55]. Beta-blockers also increase VF threshold in animal models and have been found to decrease VF in patients with acute myocardial infarction [56]. A randomized, double-blind, placebo-controlled study of propranolol in high-risk survivors of acute MI at 12 Norwegian hospitals showed a 52% Table 2 Effect of Beta-Blockers on Mortality in Patients with Heart Disease and Complex Ventricular Arrhythmias Study Hallstrom et al. [46]

Beta Blocker Heart Attack Trial [51–53]

Norwegian Propranolol Study [56] Aronow et al. [60]

Cardiac Arrhythmia Suppression Trial [65]

Results At 108-month follow-up, the adjusted relative risk of death or recurrent cardiac arrest on beta-blockers versus no antiarrhythmic drug was 0.62. At 25-month follow-up, propranolol decreased sudden cardiac death by 28% in persons with complex VA and by 16% in persons without VA; propranolol signiﬁcantly reduced total mortality by 34% in persons aged 60–69 years. High-risk survivors of acute myocardial infarction treated with propranolol for 1 year had a 52% signiﬁcant reduction in sudden cardiac death. At 29-month follow-up, compared with no antiarrhythmic drug, propranolol caused a 47% signiﬁcant decrease in sudden cardiac death, a 37% signiﬁcant reduction in total cardiac death, and a 20% borderline signiﬁcant reduction in total death. Persons on beta-blockers had a signiﬁcant reduction in all-cause mortality of 43% at 30 days, of 46% at 1 year, and of 33% at 2 years and a signiﬁcant reduction in arrhythmic death or cardiac arrest of 66% at 30 days, of 53% at 1 year, and of 36% at 2 years; beta-blockers were an independent factor for reduced arrhythmic death or cardiac arrest by 40% and for reduced all-cause mortality by 33%.

Abbreviations: VA = ventricular arrhythmias.

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signiﬁcant reduction in sudden cardiac death in patients treated with propranolol for 1 year ( p = 0.038) (Table 2) [56]. Beta-blockers reduce myocardial oxygen demand and decrease myocardial ischemia, which may reduce the likelihood of VF. Stone et al. [57] showed by 48-h AECG in 50 patients with stable angina pectoris that propranolol, but not diltiazem or nifedipine, caused a signiﬁcant reduction in the mean number of episodes of myocardial ischemia and in the mean duration of myocardial ischemia compared with placebo. Beta-blockers also decrease sympathetic tone, increase vagal tone, and stabilize cardiac membrane potentials which reduces the likelihood of VF. In addition, beta-blockers are antithrombotic [58] and may prevent atherosclerotic plaque rupture [59]. In the retrospective study by Hallstrom et al. [46] in 941 patients, mean age 62 years, resuscitated from prehospital cardiac arrest attributed to VF, beta-blockers were administered to 28% of the patients and no antiarrhythmic drug to 39% of the patients. At 108month follow-up, patients treated with beta-blockers had a signiﬁcant decreased incidence of death or recurrent cardiac arrest compared to patients treated with no antiarrhythmic drug (adjusted relative risk = 0.62; 95% CI, 0.50 to 0.77) (Table 2) [46]. Aronow et al. [60] performed a prospective study in 245 older persons, mean age 81 years, with heart disease (64% with prior MI and 36% with hypertensive heart disease), complex VA, and no sustained VT diagnosed by 24-h AECG, and a LV ejection fraction z40%. Nonsustained VT occurred in 32% of patients. Silent myocardial ischemia occurred in 33% of patients. Of the 245 patients, 123 were randomized to propranolol and 122 to no antiarrhythmic drug. Follow-up was 29 months. Propranolol was discontinued because of adverse eﬀects in 14 of 123 patients (11%). Follow-up 24-h AECG was obtained at a median of 6 months in 91% of patients treated with propranolol and in 89% of patients treated with no antiarrhythmic drug [60]. Propranolol was signiﬁcantly more eﬀective than no antiarrhythmic drug in reducing VT > 90% (71% versus 25% of patients) ( p < 0.001) and in decreasing the average number of VPC/h >70% (71% versus 25% of patients) ( p < 0.001) (60). The prevalence of silent myocardial ischemia on the follow-up 24-h AECG was insigniﬁcantly higher on no antiarrhythmic drug. However, silent ischemia was signiﬁcantly abolished by propranolol, with 37% of patients with silent ischemia on their baseline 24-h AECG having no silent ischemia on their follow-up 24-h AECG ( p < 0.001) [60]. Multivariate Cox regression analyses showed that propranolol caused a 47% signiﬁcant reduction in sudden cardiac death ( p = 0.01), a 37% signiﬁcant decrease in total cardiac death ( p = 0.003), and a 20% insigniﬁcant decrease in total death ( p = 0.057) (Table 2) [60]. Univariate Cox regression analysis showed that among patients taking propranolol, suppression of complex VA caused a 33% insigniﬁcant reduction in sudden cardiac death, a 27% insigniﬁcant decrease in total cardiac death, and a 30% insigniﬁcant reduction in total death [61]. Among patients taking propranolol, abolition of silent myocardial ischemia caused a 70% signiﬁcant decrease in sudden cardiac death (95% CI, 0.12 to 0.75), a 70% signiﬁcant reduction in total cardiac death (95% CI, 0.14 to 0.56), and a 69% signiﬁcant decrease in total death (95% CI, 0.18 to 0.53) [61]. There was also a circadian distribution of sudden cardiac death or fatal MI with the peak incidence occurring from 6 AM to 12 PM (peak hour was 8 AM and a secondary peak occurred around 7 PM) in patients treated with no antiarrhythmic drug [62] Propranolol abolished this circadian distribution of sudden cardiac death or fatal MI [62]. In this study, propranolol also markedly reduced the circadian variation of complex VA [63] and abolished the circadian variation of myocardial ischemia [64].

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In a retrospective analysis of the data from the CAST study, Kennedy et al. [65] found that 30% of patients with a LV ejection fraction V40% were receiving beta-blockers. Forty percent of the patients were between 66 and 79 years of age. Patients on beta-blockers had a signiﬁcant decrease in all-cause mortality of 43% at 30 days ( p = 0.03), of 46% at 1 year ( p = 0.001), and of 33% at 2 years ( p < 0.001) (Table 2) [65]. Patients receiving beta-blockers had a signiﬁcant reduction in arrhythmic death or cardiac arrest of 66% at 30 days ( p = 0.002), of 53% at 1 year ( p = 0.001), and of 36% at 2 years ( p = 0.001) [65]. Multivariate analysis showed that beta-blockers were an independent factor for decreasing arrhythmic death or cardiac arrest by 40% (95% CI, 0.36 to 0.99), for reducing all-cause mortality by 33% ( p = 0.05), and for decreasing occurrence of new or worsened CHF by 32% (95% CI, 0.49 to 0.94) (Table 2) [65].

Angiotensin-Converting Enzyme Inhibitors ACE inhibitors have been demonstrated to cause a signiﬁcant reduction in complex VA in patients with CHF in some studies [66,67] but not in other studies [68,69]. ACE inhibitors have also been shown to reduce sudden cardiac death in some studies of patients with CHF [32,70]. ACE inhibitors should be administered to reduce total mortality in older and younger patients with CHF [30,32,70,71], an anterior MI (31), an MI with a LV ejection fraction V40% [28,29,32], and in all patients with atherosclerotic cardiovascular disease [23,33]. ACE inhibitors should be used to treat patients with CHF with abnormal LV ejection fraction [30,32,70,71] or with normal LV ejection fraction [72,73]. On the basis of the available data, ACE inhibitors should be used in treating older or younger patients with VT or complex VA associated with CHF, an anterior MI, an MI with LV systolic dysfunction, or atherosclerotic cardiovascular disease if there are no contraindications to the use of ACE inhibitors. Beta-blockers should be used in addition to ACE inhibitors in treating these patients.

Class III Antiarrhythmic Drugs Class III antiarrhythmic drugs are potassium channel blockers that prolong repolarization manifested by an increase in QT interval on the electrocardiogram. These drugs suppress VA by increasing the refractory period. However, prolonging cardiac repolarization and refractory period can trigger after-depolarizations and resultant torsades de pointes. In the Survival With Oral d-Sotalol (SWORD) Trial, 3121 survivors of MI, mean age 60 years, with a LV ejection fraction V40% were randomized to d-sotalol, a pure potassium channel blocker with no beta blocking activity, or to double-blind placebo (Table 3) [74]. At 148-day follow-up, mortality was 5.0% in patients treated with d-sotalol versus 3.1% in patients treated with placebo (relative risk = 1.65; 95% CI, 1.15 to 2.36) (Table 3) [74]. Presumed arrhythmic deaths accounted for the increased mortality (relative risk = 1.77; 95% CI, 1.15 to 2.74) [74]. On the basis of these data, d-sotalol should not be used for the treatment of VT or complex VA in older or younger patients with heart disease. Studies comparing the eﬀect of d,l-sotalol, a Class III antiarrhythmic drug with betablocking activity, versus placebo or beta-blockers in patients with VT or complex VA have not been performed. In a study of 1486 patients with prior MI, compared with placebo, d,lsotalol did not signiﬁcantly reduce mortality in patients followed for 1 year (Table 3) [75].

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Table 3 Effect of Class III Antiarrhythmic Drugs on Mortality in Patients with Heart Disease and Complex Ventricular Arrhythmias Study Waldo et al. [74] Julian et al. [75] Singh et al. [80]

Canadian Amiodarone Myocardial Infarction Arrhythmia Trial [81] European Myocardial Infarct Amiodarone Trial [83]

Results At 148-day follow-up, mortality was 5.0% for d-sotalol versus 3.1% for placebo (relative risk = 1.65; 95% CI, 1.15 to 2.36). At 1-year follow-up, compared with placebo, d,l-sotalol caused an insigniﬁcant reduction in mortality. Compared with placebo, amiodarone signiﬁcantly suppressed VT and complex VA ( p < 0.001); 2-year survival was not signiﬁcantly diﬀerent for amiodarone (69.4%) versus placebo (70.8%). Amiodarone was very eﬀective in suppressing VT and complex VA; at 1.8-year follow-up, compared with placebo, amiodarone caused an 18% insigniﬁcant reduction in mortality. At 21-month follow-up, mortality was similar for amiodarone (13.9%) versus placebo (13.7%).

Abbreviations: VA = ventricular arrhythmias.

In the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) study, 74% of 486 patients were z60 years of age [76]. In this study, Holter monitor–guided therapy signiﬁcantly predicted antiarrhythmic drug eﬃcacy more often than did the electrophysiological study in patients with sustained VT or survivors of cardiac arrest (77% vs. 45% of patients). However, there was no signiﬁcant diﬀerence in the success of drug therapy selected by the two methods in preventing recurrences of ventricular tachyarrhythmias. In the ESVEM study, d,l-sotalol was more eﬀective than the other six antiarrhythmic drugs (imipramine, mexiletine, pirmenol, procainamide, propafenone, and quinidine) used in reducing recurrence of arrhythmia, death from arrhythmia, death from cardiac causes, and death from any cause [77]. However, seven of 10 episodes of torsade de pointes during this study occurred in patients receiving d,l-sotalol [77]. In 481 patients with VT, d,l-sotalol caused torsades de pointes (12 patients) or an increase in VT episodes (11 patients) in 23 patients (4.9%) [78]. Women had a signiﬁcantly higher risk for drug-induced VF. On the basis of the available data, the use of beta-blockers is recommended over the use of d,l-sotalol in treating older or younger patients with VT or complex VA associated with heart disease. Amiodarone is very eﬀective in suppressing VT and complex VA associated with heart disease [79–81]. Unfortunately, the incidence of adverse eﬀects from amiodarone approaches 90% after 5 years of therapy [82]. In the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation study, the incidence of pulmonary toxicity was 10% at 2 years in patients receiving an amiodarone dose of 158 mg daily [79]. Amiodarone can also cause cardiac adverse eﬀects, gastrointestinal adverse eﬀects including hepatitis, hyperthyroidism, hypothyroidism, and neurological, dermatological, and ophthalmological adverse eﬀects. A double-blind study randomized 674 patients with CHF and complex VA to amiodarone or placebo (Table 3) [80]. Compared with placebo, amiodarone signiﬁcantly reduced

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the number of episodes of VT ( p < 0.001) and the frequency of complex VA ( p < 0.001). Twenty-seven percent of patients discontinued amiodarone in this study. At 2-year followup, survival was not signiﬁcantly diﬀerent in patients treated with amiodarone (69.4%) or placebo (70.8%) (Table 3) [80]. The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) randomized 1202 survivors of MI with nonsustained VT or complex VA to amiodarone or placebo (Table 3) [81]. Amiodarone was very eﬀective in suppressing VT and complex VA in this study (Table 3) [81]. Early permanent discontinuation of amiodarone for reasons other than adverse events occurred in 36% of patients taking this drug [81]. At 1.8-year follow-up, amiodarone caused an 18% insigniﬁcant reduction in mortality (Table 3) [81]. The European Myocardial Infarction Amiodarone Trial (EMIAT) randomized 1486 survivors of MI with a LV ejection fraction V40% to amiodarone or placebo (Table 3) [83]. Early permanent discontinuation of amiodarone occurred in 38.5% of patients taking this drug. At 21-month follow-up, mortality was similar in patients treated with amiodarone (13.9%) or with placebo (13.7%) (Table 3) [83]. Since amiodarone has not been found to reduce mortality in older or younger patients with VT or complex VA associated with MI or CHF and has a very high incidence of toxicity, beta-blockers should be used rather than amiodarone in treating these patients. There are also data suggesting that patients receiving amiodarone plus beta-blockers in the CAMIAT and EMIAT trials had a better survival than patients receiving amiodarone alone [84].

INVASIVE INTERVENTION If patients have life-threatening recurrent VT or VF resistant to antiarrhythmic drugs, invasive intervention should be performed. Patients with critical coronary artery stenosis and severe myocardial ischemia should undergo coronary artery bypass graft surgery to reduce mortality [85]. In the Coronary Artery Bypass Graft (CABG) Patch Trial, there was no evidence of improved survival among patients with CAD, LV ejection fraction <36%, and an abnormal signal-averaged electrocardiogram undergoing complete coronary revascularization in whom an automatic implantable cardioverter-deﬁbrillator (AICD) was implanted prophylactically at the time of elective coronary artery bypass graft surgery [86]. Surgical ablation of the arrhythmogenic focus in patients with life-threatening ventricular tachyarrhythmias can be curative. This therapy includes aneurysectomy or infarctectomy and endocardial resection with or without adjunctive cryoablation based on activation mapping in the operating room [87–89]. However, the perioperative mortality rate is high. Endoaneurysmorrhaphy with a pericardial patch combined with mappingguided subendocardial resection frequently cures recurrent VT with a low operative mortality and improvement of LV systolic function [90]. Radiofrequency catheter ablation of VT has also been beneﬁcial in the therapy of selected patients with arrhythmogenic foci of monomorphic VT [91,92]. Catheter ablation has been very eﬀectively used to treat patients with right ventricular outﬂow tract VT and LV fascicular VT. Automatic Implantable Cardioverter-Defibrillator However, the AICD has been widely accepted as the most eﬀective treatment for patients with life-threatening VT or VF. Tresch et al. [88,89] showed in retrospective studies that the

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AICD was very eﬀective in treating life-threatening VT in older as well as in younger patients. The Multicenter Automatic Deﬁbrillator Implantation Trial (MADIT) randomized 196 patients, mean age 63 years, with a prior MI, a LV ejection fraction V35%, a documented episode of asymptomatic nonsustained VT, and inducible nonsuppressible ventricular tachyarrhythmia on electrophysiological study to receive an AICD or conventional medical therapy (Table 4) [93]. Amiodarone was given to 74% of patients receiving conventional medical therapy versus 2% of patients receiving an AICD. Beta-blockers were given to 8% of patients receiving conventional medical therapy versus 26% of patients receiving an AICD. At 27-month follow-up, patients receiving an AICD had a 54% signiﬁcant reduction in mortality (95% CI, 0.26 to 0.82) [93].

Table 4 Effect of the Automatic Implantable Cardioverter-Defibrillator on Mortality in Patients with Ventricular Tachyarrhythmias Study Multicenter Automatic Deﬁbrillator Implantation Trial [93] Antiarrhythmics versus Implantable Deﬁbrillators Trial [94]

Canadian Implantable Deﬁbrillator Study [95] Cardiac Arrest Study Hamburg [96]

Cardiac Arrest Study Hamburg [97]

Multicenter Unsustained Tachycardia Trial [98]

Multicenter Automatic Deﬁbrillator Implantation Trial II [99]

Results At 27-month follow-up, the AICD caused a 54% signiﬁcant reduction in mortality (95% CI, 0.260.82). 1-year survival was 89.3% for AICD versus 82.3% for drug therapy (95% CI, 39 F 20% decrease in mortality); 2-year survival was 81.6% for AICD versus 74.7% for drug therapy (95% CI, 27 F 21% decrease in mortality); 3-year survival was 75.4% for AICD versus 64.1% for drug therapy (95% CI, 31 F 21% decrease in mortality). Mortality was 10.2% per year for amiodarone and 8.3% per year for an AICD (risk reduction = 20%; p = 0.142). Propafenone was discontinued at 11 months because mortality from sudden death and cardiac arrest recurrence was 23% for propafenone versus 0% for an AICD ( p < 0.05). 2-year mortality was 12.6% for an AICD versus 19.6% for amiodarone or metoprolol (37% reduction in mortality; p = 0.047). Compared with electrophysiologically guided antiarrhythmic drug therapy, the 5-year total mortality was reduced 20% by an AICD (95% CI, 0.641.01), and the 5-year risk of cardiac arrest or death from an arrhythmia was reduced 76% by an AICD (95% CI, 0.130.45). At 20-month follow-up, the AICD caused a 31% signiﬁcant reduction in mortality (95% CI, 0.510.93).

Abbreviations: AICD = automatic implantable cardioverter-deﬁbrillator.

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In the Antiarrhythmics Versus Implantable Deﬁbrillators (AVID) Trial, 1016 patients, mean age 65 years, were randomized to an AICD or Class III antiarrhythmic drug therapy (Table 4) [94]. Forty-ﬁve percent of the patients had been resuscitated from nearfatal VF. The other 55% of the patients had sustained VT with syncope or sustained VT with a LV ejection fraction V40% and symptoms suggesting severe hemodynamic compromise due to the arrhythmia (near-syncope, CHF, and angina pectoris). Amiodarone was administered to 96% of patients randomized to medical therapy and to 2% of patients who had the AICD. Sotalol was administered to 3% of patients randomized to medical therapy and to 0.2% of patients who had the AICD. Beta-blockers were administered to 17% of patients randomized to medical therapy and to 42% of patients who had the AICD. The 1-year survival was 89.3% for patients who had the AICD versus 82.3% for patients treated with drug therapy (95% CI, 39 F 20% decrease in mortality) (Table 4) [94]. The 2-year survival was 81.6% for patients who had the AICD versus 74.7% for patients treated with drug therapy (95% CI, 27 F 21% reduction in mortality) (Table 4) [94]. The 3-year survival was 75.4% for patients who had the AICD versus 64.1% for patients treated with drug therapy (95% CI, 31 F 21% decrease in mortality) (Table 4) [94]. The Canadian Implantable Deﬁbrillator Study (CIDS) randomized 659 patients with VF, cardiac arrest, or hypotensive VT to an AICD or amiodarone therapy (Table 4) [95]. Cardiac arrhythmic mortality was 4.5% per year in patients treated with amiodarone versus 3% per year in patients treated with an AICD (risk reduction = 33%; p = 0.047). Total mortality was 10.2% per year in patients treated with amiodarone versus 8.3% per year in patients treated with an AICD (risk reduction = 20%; p = 0.142) (Table 4) [95]. The Cardiac Arrest Study Hamburg (CASH) randomized 230 patients surviving sudden cardiac death due to documented VT and/or VF to propafenone, metoprolol, amiodarone, or an AICD (Table 4) [96]. Propafenone was stopped after 11 months because mortality from sudden death and cardiac arrest recurrence was 23% in patients randomized to propafenone versus 0% in patients randomized to an AICD ( p < 0.05) (Table 4) [96]. The 2-year mortality was 12.6% for 99 patients randomized to an AICD versus 19.6% for 189 patients randomized to amiodarone or metoprolol (37% reduction; p = 0.047) (Table 4) [97]. The Multicenter Unsustained Tachycardia Trial randomized 704 patients with inducible, sustained ventricular tachyarrhythmias to three treatment groups (Table 4) [98]. Compared with electrophysiologically guided antiarrhythmic drug therapy, the 5-year total mortality was reduced 20% by an AICD (95% CI, 0.64-1.01), and the 5-year risk of cardiac arrest or death from an arrhythmia was reduced 76% by an AICD (95% CI, 0.13-0.45) (Table 4) [98]. Neither the total mortality incidence or rate of cardiac arrest or death from arrhythmia was lower in patients randomized to electrophysiologically guided therapy and treated with antiarrhythmic drugs than in patients randomized to no antiarrhythmic treatment [98]. MADIT-II randomized 1232 patients, mean age 64 years, with a prior MI and a LV ejection fraction of V30% to an AICD or to conventional medical therapy (Table 4) [99]. Beta-blockers were given to 70% of AICD patients versus 70% of conventional medical therapy patients. ACE inhibitors were given to 68% of AICD patients versus 72% of conventional medical therapy patients. Statins were given to 67% of AICD patients versus 64% of conventional medical therapy patients. Amiodarone was given to 13% of AICD patients versus 10% of conventional medical therapy patients. At 20-month follow-up, compared with conventional medical therapy, the AICD reduced all-cause mortality from 19.8% to 14.2%, p = 0.016 (hazard ratio = 0.69; 95% CI, 0.51–0.93) (Table 4) [99]. The

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eﬀect of AICD therapy in improving survival was similar in patients stratiﬁed according to age, sex, LV ejection fraction, New York Heart Association class, and QRS interval [99]. After AICD implantation, 35 patients were randomized to treatment with metoprolol and 35 patients to treatment with d,l-sotalol [100]. VT recurrence was 17% at 1 year and 20% at 2 years for patients treated with metoprolol versus 43% at 1 year and 49% at 2 years for patients treated with d,l-sotalol ( p = 0.016). At 26-month follow-up, survival was 91% for patients treated with metoprolol plus an AICD versus 83% for patients treated with d,lsotalol plus an AICD ( p = 0.287) [100]. These data favor using a beta-blocker in patients with an AICD requiring antiarrhythmic drug therapy. The American College of Cardiology/American Heart Association guidelines recommend that Class I indications for therapy with an AICD are (1) cardiac arrest due to VF or VT not due to a transient or a reversible cause; (2) spontaneous sustained VT in association with structural heart disease; (3) syncope of undetermined origin with clinically relevant, hemodynamically signiﬁcant sustained VT or VF induced at electrophysiological study when drug therapy is ineﬀective, not tolerated, or not preferred; (4) nonsustained VT with CAD, prior myocardial infarction, LV dysfunction, and inducible VF or sustained VT at electrophysiological study that is not suppressed by a Class I antiarrhythmic drug and (5) spontaneous sustained VT in patients who do not have structural heart disease that is not amenable to other treatments [101]. We concur with these recommendations. An AICD may also be eﬀective in preventing sudden death in patients with hypertrophic cardiomyopathy at high risk for sudden death [102] and in patients at high risk for sudden death because of a long QT interval or the Brugada syndrome [103]. An AICD may be useful in preventing sudden death in patients with syncope and ventricular tachyarrhythmias associated with poor LV ejection fraction, regardless of the result of the electrophysiological study [104]. In addition, an AICD may be useful in survivors of VT or VF as a bridge to cardiac transplantation [105].

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25 Bradyarrhythmias and Cardiac Pacemakers in the Elderly Anthony D. Mercando Columbia University College of Physicians and Surgeons, New York, and Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, U.S.A.

DIAGNOSIS While bradycardia is used to describe any slow heart rhythm, usually under 60 bpm, it is always caused by speciﬁc abnormalities in cardiac impulse formation or conduction. Mean heart rates decline with age, but the prevalence and signiﬁcance of bradyarrhythmias in the elderly remain controversial [1–6]. Degenerative disease in the sinus node can lead to pathological sinus bradycardia, sinus arrest, or sinus exit block. Sick sinus syndrome is a condition that includes one or several abnormalities in sinus node or atrioventricular (AV) node function. AV block and block in the His-Purkinje system can occur as a result of ischemic heart disease or various degenerative processes. Baroreceptor and autonomic abnormalities can produce symptomatic sinus slowing or AV node block. Bradyarrhythmias are in the diﬀerential diagnosis of syncope and presyncope in the elderly. The identiﬁcation of bradycardia as a cause of syncope is crucial because pacemaker therapy usually relieves the problem.

History Bradycardia should be suspected in patients who present with symptoms of syncope, presyncope, episodes of light-headedness, or palpitations. Patients should be questioned about the relationship of these symptoms to time of day, activity, and position, since the causes of bradycardias are usually intermittent or precipitated by speciﬁc events. Often there are associated symptoms, such as dyspnea or chest pain, that can give a clue to the etiology of an arrhythmia. The patient should be asked to tap out any associated palpitations to help in diﬀerentiating rapid from slow and regular from irregular rhythms. If symptoms are associated with activity or rapid palpitations, a bradycardia is unlikely to be an isolated cause of the patient’s complaints. However, tachycardias can end with a prolonged pause, which could produce syncope or presyncope. History of associated illness, such as thyroid disease, and use of sedative drugs or medications that can produce bradycardia (such as 607

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beta-blockers, digoxin, or calcium channel blockers) should be elicited [7]. Family members should be instructed to take the patient’s pulse during episodes and to comment on the regularity and rate of the pulse. Physical Examination During an arrhythmia, pulse rate, rhythm, and blood pressure abnormalities may be detected. In addition, AV dissociation and variability of systolic blood pressure from beat to beat may give clues to the types of arrhythmia. The changes associated with AV dissociation may be seen as abnormalities in the venous pulse, such as intermittent high-volume A waves. Electrocardiography The ﬁndings obtained during history and physical examination may be nonspeciﬁc, and the diagnosis of symptomatic bradyarrhythmias rests with demonstration of the abnormality by electrocardiography (possibly with carotid sinus massage) and electrophysiological testing. Because of the intermittent nature of sinus node and conduction system abnormalities, a single 12-lead electrocardiogram (ECG) or a longer ECG rhythm strip is usually inadequate to make a diagnosis. Twenty-four-hour ambulatory (Holter) recordings should be obtained early in the evaluation of the patient. Careful evaluation of the rate and relationship of P waves and QRS complexes should be made. All pauses greater than 1.5 s on Holter monitoring should be examined to identify the mechanism of the event. In all cases, symptoms should be correlated with ECG abnormalities, and the patient should be instructed to keep a detailed diary of symptoms during the time of the Holter recording. Pauses of greater than 2 to 3 s may occur in normal individuals. If the event does not produce symptoms and is due to sinus node dysfunction, Mobitz Type I AV block, or excess vagal tone, a pacemaker is not usually indicated. Lack of heart rate increase with exercise may be pathological and could result in presyncope. In many individuals, 24 or 48 h of Holter monitoring may be inadequate to identify symptomatic bradycardias. In these cases, a patient-activated event recorder or continuous memory loop recorder may be useful. Event recorders store several seconds or minutes of ECG data when an event button is activated. The stored tracing can be sent to a central location via telephone after the patient has recovered from the event. If episodes produce immediate syncope and do not allow the patient suﬃcient time to activate an event recorder, a memory loop recorder is more appropriate. These devices are more cumbersome, since they remain on the patient for prolonged periods of time (up to 1 month or more), but for recording and correlating rare symptoms their use may be necessitated. Until recently, loop recoders required manual activation after an event took place. A new looping device that auto-triggers on slow, rapid, or irregular rhythms is now available for clinical use. In extreme cases, an implantable loop recorder that lasts up to 14 months (Medtronic RevealR, Medtronic Corporation, Minneapolis, MN, U.S.A.) can provide diagnostic rhythm tracings with or without patient activation. Provocative Testing When the preceding techniques fail to provide a diagnosis, exercise testing, carotid sinus massage, or pharmacological testing can be employed. All such tests are generally insensitive and nonspeciﬁc, so they must be used in concert with other diagnostic tests. Failure of the

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sinus node rate to increase with exercise has been reported in sick sinus syndrome [8,9]. An abnormally long pause during carotid sinus massage (greater than 3 s) may indicate hypersensitive carotid sinus reﬂex, but this may occur in asymptomatic elderly patients [10]. Determination of intrinsic heart rate following autonomic blockade with propranolol and atropine may identify sinus node function that falls outside population-determined norms. Since all these tests fail to correlate abnormalities with symptoms, however, their usefulness is limited.

Electrophysiological Testing The technique of electrophysiological testing can be useful in the diagnosis and management of a wide variety of atrial and ventricular arrhythmias [11]. Pacing wires are inserted via a subclavian and/or femoral vein, with electrodes in the high right atrium and the right ventricular apex, and via the right femoral vein across the tricuspid valve, with electrodes in the region of the Bundle of His (Fig. 1). Recordings are made from these sites and from others (e.g., the coronary sinus) as necessary. By analyzing conduction times, sites of block can be deﬁned; by pacing the atrium and ventricle, the integrity of the conduction system can be studied and arrhythmias can be reproduced.

Figure 1 Surface electrocardiograms and intracardiac electrograms recorded during an electrophysiological study. Arrows show location of electrodes in the heart. I, II, V1—standard surface ECG leads; HRA—high right atrium; HBE—His bundle electrogram; RVA—right ventricular apex; CS— coronary sinus; PA interval—time from ﬁrst atrial depolarization to lower atrial depolarization; AH interval—time from lower atrial depolarization to His bundle depolarization; HV interval—time from His bundle depolarization to ﬁrst ventricular depolarization. The PR interval is approximately equal to PA + AH + HV intervals.

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Sinus node function is usually evaluated during electrophysiological testing using sinus node recovery time and sinoatrial conduction time. The sinus node recovery time examines the ability of the sinus node to recommence ﬁring after overdrive suppression with atrial pacing. A normal value in most laboratories is less than 1500 ms. The measurement can be corrected for baseline sinus rate, in which case normal values range from 350 to 550 ms, depending upon the laboratory. Sinoatrial conduction time is an indirect measurement of the time it takes for an impulse to travel into and then exit from the sinus node. The sensitivity of these techniques, even when combined, is only about 64%, with a speciﬁcity of about 88% [12]. Atrial conduction, AV node function, and His-Purkinje system function are assessed by measuring intracardiac conduction intervals and by atrial pacing. An electrophysiological study can be useful in identifying the site of atrioventricular block and in assessing the competence of the His-Purkinje system at rest and during pacing. An electrophysiological study should be performed in patients with suspected sinus node disease or AV block who are symptomatic with syncope or presyncope and in whom the relationship between symptoms and a bradyarrhythmia has not been established. Patients who have symptoms documented to be due to bradyarrhythmias or patients with degrees of heart block that require permanent pacing (see section on indications for cardiac pacing) do not require an electrophysiological study. When the site of AV block cannot be determined by electrocardiography or Holter monitoring and diﬀerentiation of the site would help in the decision to implant a pacemaker, a His bundle study should be performed. This may be necessary in patients with ﬁxed 2:1 AV block and bundle branch block or in patients with Mobitz type II block with a normal QRS in whom block in the Bundle of His is suspected. The use of electrophysiological testing to diagnose patients with syncope of undetermined origin is discussed in Chapter xx.

NORMAL CARDIAC CONDUCTION SYSTEM The understanding of bradyarrhythmias and their management is enhanced by a knowledge of the normal cardiac conduction system (Fig. 2). Normal cardiac activation originates in a group of cells in the high right atrium, known as the sinus node. The node is composed of nodal cells, which are the source of normal impulse formation, transitional cells, which may form the pathway for impulse conduction to the atrium, and working atrial myocardial cells, which extend into the node from surrounding atrial tissue. The sinus node receives innervation from postganglionic adrenergic and cholinergic nerve endings. Vagal stimulation slows sinus node discharge and prolongs conduction times within the node through release of acetylcholine, which hyperpolarizes the cell membrane producing an increase in the time for the cell to reach ﬁring threshold. Adrenergic stimulation of beta-1 receptors increases sinus rate by increasing the slope of diastolic depolarization. From the sinus node, the normal cardiac impulse travels through atrial tissue and possibly through internodal and interatrial pathways, although this latter point is controversial [13,14]. Conduction from right to left atrium appears to travel preferentially over a band of muscle ﬁbers known as Bachmann’s bundle. The signal eventually reaches the AV node, located in the lower part of the right atrium near the septal leaﬂet of the tricuspid valve, anterior to the ostium of the coronary sinus. The AV node conducts the impulse from the atrium to the Bundle of His. In normal hearts, the remainder of the interface between atria and ventricles is electrically insulated. In patients

Bradyarrhythmias and Cardiac Pacemakers

Figure 2

611

Components of the cardiac conduction system (see text).

with Wolﬀ–Parkinson–White syndrome, this insulator and the AV node are short-circuited via a bypass tract known as a Kent bundle. AV nodal tissue exhibits a characteristic known as decremental conduction: the more rapidly impulses stimulate and attempt to pass through the AV node, the more slowly the node will conduct, even to the point of intermittent block. Like the sinus node, the AV node is richly innervated by cholinergic and adrenergic nerve endings. Vagal stimulation increases AV node conduction time and can produce block. Sympathetic stimulation shortens AV node conduction time and refractory periods. From the AV node, the cardiac impulse travels to the Bundle of His, the ﬁrst part of the specialized ventricular conduction system. From the Bundle of His, the impulse travels through the bundle branches and eventually to terminal Purkinje ﬁbers. These ﬁbers form interweaving branches on the endocardial surface of both ventricles and allow rapid transmission of the impulse to the entire ventricular myocardium in a period of 60 to 100 ms. Without the specialized ventricular conduction system, as in bundle branch block, muscle conduction of the cardiac impulse requires longer periods of time, typically on the order of 120 to 160 ms. This results in a prolonged QRS duration on the surface ECG. The anatomy of the bundle branches is variable between individuals, although the most common conﬁguration is that of a main right bundle branch and a left bundle branch that bifurcates into an anterior and a posterior fascicle. Bradyarrhythmias can result from abnormalities in impulse formation in the sinus node or impulse conduction in the sinus node, atrial myocardium, AV node, Bundle of His, or bundle branches. Total or subtotal destruction of the sinus node or transitional zone tissue may be found in patients with sick sinus syndrome. Inﬂammatory and degenerative changes can also be seen in some cases. AV nodal block may be due to inﬁltration of the node by ﬁbrosis or calciﬁcation from adjacent structures (Lev’s disease), like that in calciﬁc aortic

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stenosis. The ventricular conduction system can be aﬀected by degeneratiion caused by chronic ischemic heart disease or by a sclerotic degenerative process (Lenegre’s disease) [15].

SINUS NODE DYSFUNCTION Sinus Bradycardia Sinus bradycardia is deﬁned as a sinus node rhythm with a rate of less than 60 bpm. The arrhythmia may result from excessive vagal tone or diminished sympathetic tone, medications, such as beta-blockers, digoxin, or calcium channel blockers, or because of sick sinus syndrome and its associated anatomical abnormalities. Well-trained athletes can exhibit sinus bradycardia, but this is a less common cause in the elderly population. Sinus bradycardia can also occur during sleep, with manipulation of the eye during surgery, or secondary to hypothyroidism, hypothermia, intracranial tumors, meningitis, or increased intracranial pressure. Excessive vagal tone, as is seen during intense vomiting, can also produce symptomatic sinus bradycardia. Besides beta-blockers and calcium channel blockers, lithium and clonidine have been reported to cause sinus bradycardia. Beta-blocker eye drops may be absorbed and produce sinus slowing or AV node block [16,17]. The ECG during sinus bradycardia shows normal-appearing P-waves before each QRS complex and occurring at a rate less than 60 bpm. Normal-appearing P-waves imply that the impulse originates in the sinus node. There can be coexisting AV block, which can further lower the ventricular rate. Treatment of sinus bradycardia is usually not necessary unless the patient is symptomatic during the periods of slow rhythm. In the acute setting, such as following a myocardial infarction, symptomatic patients can be treated with 0.5 mg intravenous (IV) atropine, repeated every 5 min up to 2 mg. If atropine fails, an external transthoracic pacemaker or a temporary transvenous pacemaker should be employed. If temporary pacing is not available, consider cautious use of IV dopamine (5–20 Ag/kg/min) or IV epinephrine (2– 10 Ag/min). Isoproterenol is no longer recommended because it can increase myocardial oxygen demand and is proarrhythmic even at low doses. If the patient exhibits chronic symptomatic sinus bradycardia not attributable to medications, permanent pacing is the treatment of choice. Sinus Arrest Sinus arrest occurs because of an abnormality in impulse formation caused by medications or any of the disease processes mentioned previously. Bradycardia occurs if lower pacemakers such as the AV node fail to produce an appropriate escape rhythm. On the ECG, P-waves are identiﬁed before each QRS and are normal in conﬁguration, as they are in sinus bradycardia. The tracing shows a pause in the sinus rhythm, with a P–P interval that is not equal to a multiple of the patient’s basic P–P interval (Fig. 3). Treatment for asymptomatic sinus arrest is usually not required. For symptomatic patients, treatment is similar to that outlined for sinus bradycardia. Sinoatrial Exit Block Sinoatrial exit block represents an abnormality in impulse conduction from the sinus node to surrounding atrial tissue. It can be caused by medications, including type IA antiar-

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Figure 3 Sinus arrest. The escape beat is from the AV node, and the peaked T-wave following this beat implies that a P-wave is buried in the T-wave.

rhythmic drugs such as quinidine and procainamide. The arrhythmia can also be caused by the other sinus node abnormalities described earlier. On the ECG, there is a pause in the sinus rhythm, which is equal to a multiple of the underlying P–P interval. The treatment for patients with symptomatic sinoatrial exit block is similar to that for sinus bradycardia. For asymptomatic patients, no treatment is required and the block may be transient, resolving after any oﬀending medications are discontinued. Sick Sinus Syndrome Sick sinus syndrome includes a number of abnormalities of the sinus node, atrial myocardium, and AV node. It is often considered synonymous with the bradycardia–tachycardia syndrome, which consists of paroxysmal regular or irregular atrial tachycardias alternating with episodes of bradyarrhythmias, but bradycardia–tachycardia is only one manifestation of sick sinus syndrome. Also included in the deﬁnition are persistent sinus bradycardia not caused by medications, episodes of sinus-arrest or sinus exit block, abnormalities of sinus node and atrial functionin conjunction with AV conduction abnormalities (such as atrial ﬁbrillation with slow ventricular response), or any combination of these conditions (Fig. 4). The etiology of sick sinus syndrome is probably multifactorial, varying from patient to patient. There may be inﬂammatory or degenerative changes in the sinus node and perinodal tissues. Autonomic abnormalities are also common [18,19].

Figure 4 Long sinus pause after spontaneous conversion of atrial ﬁbrillation to sinus rhythm in a patient with sick sinus syndrome. Prolonged recovery of the sinus node is characteristic of this condition and can also produce long pauses following electrical cardioversion.

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Treatment of sick sinus syndrome can be problematic, since medications used to suppress or slow chronic or paroxysmal atrial tachycardias may exacerbate the associated bradycardias. Digoxin, in particular, can cause profound bradyarrhythmias in these patients. Often ventricular or atrioventricular pacing must be used with drug therapy to treat patients with the bradycardia–tachycardia syndrome. Although prophylactic pacing is not indicated, patients who require digoxin, betablockers, calcium channel blockers, or antiarrhythmic medications should be monitored after these medications are started. If long ventricular pauses occur or if patients become symptomatic, they should receive permanent pacing.

CAROTID SINUS HYPERSENSITIVITY Hypersensitive carotid sinus syndrome is deﬁned as ventricular asystole greater than 3 s during carotid sinus stimulation, although the deﬁnition is arbitrary. Studies have shown conﬂicting results regarding the signiﬁcance of the 3-s pause during carotid sinus massage [20–22]. Hypersensitive carotid sinus response can be found in elderly patients complaining of syncope or presyncope, but many of these patients have multiple causes for their symptoms. The cause of hypersensitive carotid sinus syndrome is not known but may involve an abnormal baroreceptor set point, excessive release of acetylcholine, inadequate cholinesterase to metabolize the acetylcholine, or abnormal central autonomic response. Carotid sinus hypersensitivity may manifest clinically following carotid stimulation from head turning or from tight collars. On the ECG during carotid sinus stimulation, either sinus arrest or sinus exit block is found. Although AV node block can occur, it is infrequent because the sinus slowing usually masks its manifestation. Atropine can blunt the cardioinhibitory eﬀects of carotid sinus hypersensitivity, but long-term treatment requires ventricular pacing. Medications, such as beta-blockers, calcium channel blockers, digitalis, and clonidine, should be avoided in patients who do not have an implanted ventricular pacemaker.

ATRIOVENTRICULAR BLOCK Atrioventricular block is a nonphysiological delay in conduction or a lack of conduction of the electrical impulse from atria to ventricles. Block can result from abnormal conduction in any part of the electrical system of the heart. Blocks that occur during a period of time in which the AV conduction system should be refractory (e.g., an atrial premature contraction that occurs early after a normally conducted beat) must be excluded. The causes of block have been discussed previously and include ischemic heart disease, degenerative and inﬁltrative diseases, drug toxicities, and excess vagal activity. Atrioventricular block can be paroxysmal or ﬁxed. A patient can exhibit diﬀerent degrees of AV block at diﬀerent times and under diﬀerent pathophysiological conditions. Electrocardiographic criteria are used to deﬁne degrees of block. First-degree AV block refers to a delay in AV conduction without nonconduction. On the ECG, normal sinus P-waves are followed by QRS complexes, but with a P–R interval that is prolonged at greater than 0.20 s. Occasionally, the P–R interval can be as long as 1 s. P–R interval prolongation can be due to slowed conduction in the atrium (prolonged P–A interval), in the AV

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Figure 5 Second-degree AV block, type I (Wenckebach). Note the prolongation of the P–R interval before the blocked P-wave.

node (prolonged A–H interval), or in the His–Purkinje system (prolonged H–V interval) (see Fig. 1). The presence of a narrow QRS usually indicates disease in the AV node, but ﬁrstdegree AV block with a widened QRS morphology does not localize disease to the AV node or the His-Purkinje system [23]. Second-degee AV block is manifested by intermittent lack of conduction from atria to ventricles. Mobitz type I second-degree AV block (also called Wenckebach block) is usually, but not always, due to disease in the AV node and produces a gradual prolongation of P–R intervals in successive beats until a P-wave is completely blocked for one beat (Fig. 5). Mobitz type II second-degree block, which usually involves disease below the AV node in the His–Purkinje system, produces intermittent block in AV conduction without prior prolongation of the P–R interval (Fig. 6). Type I block is usually considered benign, since AV node disease is the usual site of block and the prognosis is good. There is less tendency for the process to progress to complete heart block and frank syncope. Type I block can occur with inferior wall myocardial infarction and tends to be transient. Patients are generally asymptomatic and temporary or permanent pacing is not required. Type II block occurs more commonly after anterior wall myocardial infarction and usually indicates a large area of myocardial damage. Type II block also leads to complete heart block more frequently than type I and consequently produces more symptoms. Temporary and permanent pacing are usually indicated for type II block because of this propensity to advance to complete heart block. Following anterior wall myocardial infarction, mortality remains high despite permanent pacing, because of the association with extensive myocardial damage. There is a special case of second-degree block in which every other P-wave is blocked. This is known as 2:1 block. Since two successive P–R intervals cannot be examined, it is not possible to further classify the rhythm as type I (Wenckebach) or type II second-degree block. When the QRS interval is narrow, the block is usually in the AV node. When the QRS interval is wide, the block can be in either the AV node or the His–Purkinje system. In such

Figure 6 Second-degree AV block, type II. Note that the P–R intervals are not prolonged before the blocked P-wave.

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Figure 7 Third-degree (complete) AV block, with narrow complex escape rhythm (AV nodal escape). Note the blocked P-waves, A–V dissociation, and regular ventricular response (from the escape rhythm).

cases, it is necessary to examine long rhythm strips or 24-h Holter recordings in an attempt to ﬁnd evidence for Wenckebach or non-Wenckebach conduction. The term ‘‘high-grade AV block’’ is used by many cardiologists but is not uniformly deﬁned. Usually the term refers to a situation in which multiple consecutive P-waves are blocked. Typically, the P–R interval does not change in conducted beats, so this rhythm resembles type II second-degree AV block. In third-degree or complete AV block there is a total lack of conduction and communication between atria and ventricles. The atrial rhythm does not aﬀect the ventricular rhythm, which is produced by an escape focus in the AV node (junctional escape rhythm) or, more commonly, in the ventricle (idioventricular escape rhythm). The ECG during complete heart block usually exhibits three features: (1) nonconducted P-waves; (2) atrioventricular dissociation (atrial and ventricular rhythms are independent); and (3) a regular ventricular response produced by the escape rhythm (Fig. 7). An algorithm can be constructed to aid in the correct identiﬁcation of the degree of heart block based on the surface electrocardiogram (Fig. 8). By answering several simple

Figure 8 Algorithm for the ECG diagnosis of AV block (see text).

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yes–no questions, an accurate diagnosis can be established. One must ﬁrst determine whether there are blocked P-waves. If there are none and the P–R interval is greater than 0.20 s, the patient has ﬁrst-degree AV block. If there are blocked P-waves, then the P–R intervals must be examined. The algorithm does not require that an assessment be made of whether a particular P-wave is causing a QRS; simply identify a QRS, ﬁnd the P-wave that precedes that QRS, and deﬁne that as a P–R interval. If the intervals are not variable, then the special case of second-degree block with 2:1 conduction must be excluded. If 2:1 conduction is present, it is not possible to further categorize the block as Mobitz type I or Mobitz type II, and the diagnosis of second-degree AV block, 2:1 is made. If the patient has constant P–R intervals and is not in 2:1 block, then the diagnosis of second-degree AV block, Mobitz type II, is made. If the P–R intervals are changing and the ventricular rhythm is not regular, then the diagnosis of second-degree AV block, Mobitz type I, is present. If the ventricular response is regular, then the criteria for third-degree (complete) AV block have been met. Electrophysiological testing can be used to identify the site of the atrioventricular block. In the nonmedicated state, the patient’s rhythm is recorded and the P–A, A–H, and H–V intervals are determined (Fig. 1). Lack of a His bundle depolarization following a blocked P-wave signiﬁes that the AV node is the site of the block. Presence of the His bundle signal following a blocked P-wave indicates that the impulse has traveled through the AV node, has stimulated the Bundle of His, and has blocked below that point. Block below the Bundle of His generally requires permanent pacing. First-degree block alone does not require treatment, except in patients with left ventricular dysfunction in whom a shorter AV interval results in hemodynamic improvement. Second-degree block, Mobitz type I, in an asymptomatic patient does not require treatment. Symptomatic Mobitz I can be treated acutely with temporary pacing and eventually with permanent pacing. A permanent pacemaker should be used only after possible causative medications have been discontinued. Permanent pacing is indicated in patients with symptomatic and asymptomatic Mobitz type II block and probably in Mobitz II block acquired during an acute myocardial infarction. Even with permanent pacing, however, the mortality rate in this group of patients with anterior wall myocardial infarction remains high. Acquired third-degree block requires permanent pacing, since the patient is dependent upon an escape rhythm that may be unreliable. If the patient exhibits symptoms with complete heart block, a temporary pacemaker should be inserted while the patient waits for deﬁnitive therapy with a permanent pacemaker.

PACEMAKER THERAPY FOR BRADYCARDIAS Indications Guidelines for permanent pacemaker implantation have been developed by a joint committee of the American Heart Association, the American College of Cardiology, and the North American Society of Pacing and Electrophysiology [24], and the Health Care Financing Administration has published guidelines for reimbursement for pacemaker implantation. In general, permanent pacing is indicated to treat symptomatic bradyarrhythmias. If a causative drug can be identiﬁed and stopped, this should be done. Pacing should be undertaken only if the symptomatic arrhythmia persists. When symptoms cannot be temporally related to a bradyarrhythmia, controversies regarding indications for implantation exist.

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Class I indications are those in which a permanent pacemaker is generally considered acceptable and necessary if the cause is not transient. These include third-degree and advanced second-degree AV block: with symptoms (such as syncope, seizures, congestive heart failure, dizziness, or limited exercise tolerance) due to bradycardia; with asystole >3 s or an escape rate less than 40 bpm; after catheter ablation of the AV node; after cardiac surgery; or secondary to certain neuromuscular diseases. Also included are type II seconddegree AV block, intermittent third-degree AV block, alternating bundle branch block, certain second- or third-degree AV blocks following acute myocardial infarction, symptomatic bradycardia resulting from required long-term drug treatment without acceptable alternative drugs, bradycardia that leads to potentially life-threatening ventricular arrhythmias, sinus node dysfunction with documented symptomatic bradycardia or chronotropic incompetence, and recurrent syncope caused by carotid sinus hypersensitivity. Class II indications include those in which there is some divergence of opinion. Class IIa indications are those in which evidence or opinion are in favor of usefulness, while Class IIb indications are less well established. The Class IIa indications for pacing include asymptomatic third-degree AV block with average ventricular rates of 40 bpm or faster; asymptomatic type II AV block with a narrow QRS; asymptomatic type I second-degree AV block localized in or below the Bundle of His; ﬁrst- or second-degree AV block with signs or symptoms suggestive of pacemaker syndrome (e.g., dizziness, near syncope, confusion, heart failure, hypotension, fatigue, weakness, lethargy, lightheadedness, pulsations in the neck, palpitations); syncope not demonstrated to be due to AV block when other causes have been excluded; syncope with sinus node abnormalities discovered at electrophysiological studies; syncope in a patient with hypersensitive carotid sinus response (>3 s of asystole); and neurally mediated syncope with bradycardia found on tilt-table testing. Class IIb indications include marked ﬁrst-degree AV block in patients with congestive heart failure in whom a shorter AV interval results in hemodynamic improvement; persistent second- or third-degree AV block following myocardial infarction; and minimally symptomatic patients with chronic heart rates of less than 40 bpm while awake. Class 3 conditions are those in which pacing is not routinely indicated and scientiﬁc evidence cannot support its use. Such situations include asymptomatic ﬁrst-degree or type I second-degree AV block; transient AV block that is expected to resolve; asymptomatic fascicular block; transient AV or fascicular block following myocardial infarction; sinus node dysfunction in asymptomatic patients; hypersensitive carotid sinus sensitivity in the absence of symptoms or in the presence of vague symptoms; and situational vasovagal syncope where avoidance behavior is possible and eﬀective. Modes of Cardiac Pacing and Cardiac Pacemaker Codes The earliest cardiac pacemakers were simple devices that paced the ventricle or atrium and lacked the ability to sense the patient’s underlying heart rhythm. As the technology advanced, the ability to sense the patient’s native heart beat was added, as was dual-chamber pacing. In the 1980s, multiprogrammability became common, allowing adjustments in many pacemaker parameters using an external programming device. Newer pacemakers have the ability to record certain details of pacemaker operation and electrograms during arrhythmic events. Most modern pacemakers can modulate their pacing rates independent of sinus node activity by using physiological sensors (such as activity, acceleration, body temperature, and minute ventilation). Some newer pacemakers incorporate dual sensors. Pacemakers with

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two or more ventricular leads are being implanted to treat congestive heart failure, even in the absence of bradyarrhythmias. A pacemaker code system was developed by committees of the Intersociety Commission for Heart Disease Resources, the North American Society of Pacing and Electrophysiology (NASPE), and the British Pacing and Electrophysiology Group (BPEG) (Table 1) [25]. The code consists of at least three and up to ﬁve positions: the ﬁrst identiﬁes the chamber(s) paced; the second identiﬁes the chamber(s) sensed; the third indicates the response of the pacemaker to a sensed event; the fourth indicates presence or absence of sensor rate modulation; and the ﬁfth indicates the presence of multisite pacing (i.e., two leads in the atria or ventricles). Pacemakers with no sensing capabilities are identiﬁed as VOO or AOO. A ventricular demand pacemaker is designated VVI and, with rate modulation, VVIR (or VVIRO). The same pacemaker used in the atrium is designated AAI or AAIR. A pacemaker that senses atrial activity but only paces the ventricle following an atrial sensed event is designated VAT, or VDD with accompanying ventricular sensing (AV synchronous pacemaker). Such a pacemaker is useful in treating patients with complete heart block in whom sinus node activity is normal and can be used to modulate the ventricular pacing rate. A single pacing lead that provides atrial sensing (but not pacing) and ventricular sensing and pacing (VDD mode) is available from several manufacturers, and reduces some of the cost and complexity of a two-lead system. Such pacemakers are not appropriate for patients with slow atrial rhythms since they cannot pace in the atrium. A pacemaker that paces both chambers but senses only the ventricle is designated DVI and is useful in patients with symptomatic sinus bradycardia in whom AV synchrony is desired (AV sequential pacemaker). A pacemaker that combines both dual-chamber pacing with dual-chamber sensing is designated DDD and is capable of tracking atrial activity and providing AV synchrony under all conditions. This is the most common dual-chamber mode used in modern pacemakers. Rate modulation in DDD pacing (DDDR) is useful in patients with an inadequate sinus node response to exercise. An interesting mode is DDI pacing, during which the pacemaker paces and senses both chambers but does not deliver a ventricular stimulation following a sensed atrial event. This mode (and DDIR) is useful for patients with frequent atrial arrhythmias in whom one wishes to maintain AV pacing when the patient is not in an atrial arrhythmia. DDDRV mode indicates DDD pacing, with rate response, in a patient with two or more leads in one or both ventricles (e.g., for congestive heart failure).

Table 1

Pacemaker Codes

Position I Chamber(s) paced O A V D

= None = Atrium = Ventricle = Dual (A + V) S = Single (A or V)

II Chamber(s) sensed O A V D

= None = Atrium = Ventricle = Dual (A + V) S = Single (A or V)

III Response to sensed event O T I D

= None = Triggered = Inhibited = Dual (T + I)

IV Rate modulation

V Multisite pacing

O = None R = Rate modulation

O A V D

= None = Atrium = Ventricle = Dual (A + V)

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Dual-chamber pacing was once considered inappropriate for patients with frequent atrial tachyarrhythmias, in particular paroxysmal atrial ﬁbrillation, because sensing of an atrial tachyarrhythmia would result in unwanted rapid ventricular pacing. However, newer pacemakers have the capability to switch modes from DDD to VVI, VVIR, DDI, or DDIR during paroxysmal atrial tachycardias [26,27], thereby avoiding undesirable tracking of the arrhythmia. Consequently, the only absolute contraindication to dual-chamber pacing is chronic, continuous atrial ﬁbrillation. There are diﬀering opinions regarding the relative beneﬁts of dual-chamber over single-chamber pacing in the elderly population. Patients with sinus node dysfunction, but not those with atrioventricular block, seem to have an improved quality of life with dual-rather than single-chamber pacing [28,29]. Programming rate-modulated parameters should involve the use of rate response tailoring, such as through some form of exercise testing, to achieve an optimum rate response prescription. Rate-modulated devices typically allow the physician to determine a threshold level for rate increase and a slope of heart-rate increase in response to the sensed physiological parameter. Pacemaker Follow-up Although modern pacemakers and leads are extremely reliable, periodic evaluation of the pacemaker–lead–patient system is required. Initial thresholds for stimulation of the heart may change with time or with partial or complete dislodgement of the implanted leads. Follow-up is also required to predict impending battery depletion to allow for elective replacement of the pulse generator. Pacemakers are usually followed via some combination of trans-telephone monitoring and periodic patient visits. Medicare guidelines for pacemaker follow-up frequency, originally issued in 1984, are based upon the demonstrated longevity of the particular pacemaker model being tested (Table 2). Most modern pacemakers meet the speciﬁcations for Guideline II. There is no mandate that these recommendations be followed, but they provide a framework for establishing a follow-up schedule individualized to each patient. Patient symptoms or concerns may dictate additional ad hoc monitoring. During a trans-telephone-monitoring session, rhythm strips in the free-running mode and with magnet application are transmitted back to the receiving station at the physician’s oﬃce or commercial monitoring service. This testing allows for analysis of pacemaker sensing, capture, and battery integrity, but usually does not give information about sensitivity or output thresholds. In-oﬃce testing involves a pacemaker interrogation and stimulation threshold testing. Most current pacemakers will report certain abnormalities, such as detected tachyarrhythmias, evidence of lead malfunction, and occurrences of mode switching (e.g., from DDD to VVI mode during paroxysmal atrial ﬁbrillation). The followup also involves reassuring patients and answering questions that they or family members may have regarding the pacemaker. Future of Cardiac Pacing The future promises devices with more sophisticated (but more ’’user-friendly‘‘) programming capabilities, more reliable and more physiological metabolic rate sensors, and more capacity for providing useful telemetric information from the patient. Great strides are being made in the application of devices to the treatment of atrial and ventricular tachyarrhythmias using antitachycardia pacing, low-energy cardioversion, and high-energy deﬁbrillation. At present, an implanted pacemaker is a permanent contraindication to the

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Trans-Telephone Pacemaker Follow-Up Schedules

Pacemaker type

Months after implantation

Scheduled trans-telephone contacts

Guideline I: Pacemakers that do not meet longevity data requirements of guideline II or pacemakers without suﬃcient longevity data. Single-chamber 1. Every 2 weeks 2.–36 Every 8 weeks >36. Every 4 weeks Dual-chamber 1. Every 2 weeks 2.–6 Every 4 weeks 7.–36 Every 8 weeks >36. Every 4 weeks Guideline II: Pacemakers with demonstrated longevity greater than 90% at 5 years, and whose output voltage decreases <50% over 3 months and whose magnet rate decreases <20% or 5 pulses per minute over that period. Single-chamber

Dual-chamber

1. 2.–48 >48. 1. 2.–30 31.–48 >48.

Every Every Every Every Every Every Every

2 weeks 12 weeks 4 weeks 2 weeks 12 weeks 8 weeks 4 weeks

use of magnetic resonance imaging (MRI), since all pacemakers and leads contain ferromagnetic components. In the future, it may be possible to develop pacemakers and leads that are totally non-ferromagnetic, thus allowing patients to undergo MRI studies.

CONCLUSIONS Bradycardias and the sick sinus syndrome, symptomatic and asymptomatic, are common in elderly individuals. Treating patients for such arrhythmias involves careful history taking, physical examination, and diagnostic testing. Correlating symptoms with abnormalities of the rhythm can be challenging and, in some cases, impossible. However, such a correlation is important to allow proper therapy by medications and implanted devices. There is debate about the use of pacemakers for certain indications, but the demonstration of bradycardiainduced symptoms usually makes the decision straightforward.

REFERENCES 1. 2. 3.

Agruss NS, Rosen KY, Adolph RJ, Fowler NO. Signiﬁcance of chronic sinus bradycardia in elderly people. Circulation 1972; 46:924–930. Camm AJ, Evans KE, Ward DE, Martin A. The rhythm of the heart in active elderly subjects. Am Heart J 1980; 99:598–603. Fleg JL, Kennedy HL. Cardiac arrhythmias in a healthy elderly population: detection by 24-hour ambulatory electrocardiography. Chest 1982; 81:302–307.

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Mercando Kostis JB, Moreyra AK, Amendo MT, DiPietro J, Cosgrove N, Kuo PT. The eﬀect of age on heart rate in subjects free of heart disease. Studies by ambulatory electrocardiography and maximal exercise stress testing. Circulation 1982; 65:141–145. Frishman WH, Heiman M, Karpenos A, Ooi WL, Mitzner A, Goldkorn R, Greenberg S. Twenty-four-hour ambulatory electrocardiography in elderly subjects: prevalence of various arrhythmias and prognostic implications (report from the Bronx Longitudinal Aging Study). Am Heart J 1996; 132(2 Pt 1):297–302. Rathore SS, Gersh BJ, Berger PB, Weinfurt KP, Oetgen WJ, Schulman KA, Solomon AJ. Acute myocardial infarction complicated by heart block in the elderly: prevalence and outcomes. Am Heart J 2001; 141(1):47–54. Sagie A, Strasberg B, Kusnieck J, Sclarovsky S. Symptomatic bradycardia induced by the combination of oral diltiazem and beta-blockers. Clin Cardiol 1991; 14:314–316. Holden W, McAnulty JH, Rahimtoola SH. Characterization of heart rate response to exercise in the sick sinus syndrome. Br Heart J 1978; 40:923–930. Crook B, Jennison C, van der Kemp P, Nijhof P. The chronotropic response of the sinus node to exercise: a new method of analysis and a study of pacemaker patients. Eur Heart J 1995; 16:993– 998. Peretz DI, Abdulla A. Management of cardioinhibitory hypersensitive carotid sinus syncope with permanent cardiac pacing: a seventeen year prospective study. Can J Cardiol 1985; 1:86– 91. Fisher JD. The role of electrophysiologic testing in the diagnosis and treatment of patients with known and suspected bradycardias and tachycardias. Prog Cardiovasc Dis 1981; 24:25–90. Zipes D, Jackman W, Dimarco J, Myerburg R, Gillette P, Rahimtoola S. Guidelines for clinical intracardiac electrophysiologic and catheter ablation procedures: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on clinical intracardiac electrophysiologic and catheter ablation procedures). J Am Coll Cardiol 1995; 26:555–573. James TN, Sherf L, Schiant RC, Silverman ME. Anatomy of the conduction system of the heart. In: Hurst JW, ed. The Heart. 5th ed. New York: McGraw-Hill, 1982:46–56. Anderson RH, Becker AK. Gross anatomy and microscopy of the conducting system. In: Mandel WJ, ed. Cardiac Arrhythmias, Their Mechanisms, Diagnosis and Management. Philadelphia: J. B. Lippincott, 1980. Lev M. Anatomic basis for atrioventricular block. Am J Med 1964; 37:742. VanBuskirk EM. Adverse reactions from timolol administration. Ophthalmology 1980; 87:447– 450. Stewart WC, Nussbaum LL, Weiss H, Netland PA, Cohen JS. Eﬃcacy of carteolol hydrochloride 1% vs timolol maleate 0.5% in patients with increased intraocular pressure. Nocturnal Investigation of Glaucoma Hemodynamics Trial Study Group. Am J Ophthalmol 1997; 124:498–505. Kang PS, Gomes JA, Kelen G, El-Sherif E. Role of autonomic regulatory mechanism in sinoatrial conduction and sinus node automaticity in sick sinus syndrome. Circulation 1981; 64:832–838. Gomes JA, Kang PS, El-Sherif N. Eﬀects of digitalis on the human sick sinus node after pharmacologic autonomic blockade. Am J Cardiol 1981; 48:783–788. Hilgard J, Ezri MD, Denes P. Signiﬁcance of ventricular pauses of three seconds or more detected on twenty-four hour Holter recordings. Am J Cardiol 1985; 55:1005–1008. Ector H, Rolies L, DeGeest H. Dynamic electrocardiography and ventricular pauses of three seconds and more: Etiology and therapeutic implications. PACE 1983; 6:548–551. Volkman H, Schnerch B, Kuhnert H. Diagnostic value of carotid sinus hypersensitivity. PACE 1990; 13:2065–2070. Sokoloﬀ NM. Bradyarrhythmias: AV conduction disturbances. Geriatrics 1985; 40:83–86. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, Winters SL. ACC/AHA/NASPE 2002 guideline

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update for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee on Pacemaker Implantation). 2002. Available at: www. acc.org/ clinical/guidelines/pacemaker/pacemaker.pdf. Bernstein AD, Daubert J-C, Fletcher RD, Hayes DL, Lu¨deritz B, Reynolds DW, Schoenfeld MH, Sutton R. The revised NASPE/BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. PACE 2002; 25:260–264. Ellenbogen KA, Barold SS, Wood MA, Mond HG. Failure of automatic mode switching: recognition and management. PACE 1997; 20(2 Pt 1):268–275. Lamas GA, McNeil B, Normand SL, Pashos CL. Permanent pacemaker selection and subsequent survival in elderly Medicare pacemaker recipients. Circulation 1995; 91:1063–1069. Lamas GA, Orav EJ, Stambler BS, Ellenbogen KA, Sgarbossa EB, Huang SK, Marinchak RA, Estes NA, III, Mitchell GF, Lieberman EH, Mangione CM, Goldman L. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dualchamber pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med 1998; 338:1097– 1104. Lamas GA, Lee KL, Sweeney MO, Silverman R, Leon A, Yee R, Marinchak RA, Flaker G, Schron E, Orav EJ, Hellkamp AS, Greer S, McAnulty J, Ellenbogen K, Ehlert F, Freedman RA, Estes NA III, Greenspon A, Goldman Lfor the Mode Selection Trial in Sinus-Node Dysfunction. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med 2002; 346:1854–1862.

26 Cerebrovascular Disease in the Elderly Patient Jesse Weinberger The Mount Sinai School of Medicine, New York, New York, U.S.A.

INTRODUCTION Stroke is primarily a disease of the elderly. The incidence of stroke under age 65 is less than 2/ 1000/year, but rises to 4.6/1000/year for men and 3.8/1000/year for women ages 65 to 74, and to 9.4/1000/year for men and 7.4/1000/year for women ages 75 to 84 [1]. Stroke is the third leading cause of death in the United States and is the leading cause of neurological disability. It is often felt to be a fate worse than death by elderly patients. Stroke is caused by disruption of the circulation of blood to the brain, and can be ischemic, due to occlusion of an artery, or hemorrhagic, due to rupture of an artery. Ischemia accounts for 80 to 85% of stroke while hemorrhage accounts for 15 to 20% [2,3]. Ischemic stroke is caused primarily by atherosclerotic disease of large extracranial and intracranial vessels, occlusion of intracranial vessels by emboli from a cardiac source, and small vessel intracranial occlusive disease secondary to hypertension and diabetes (Figs. 1,2). Hemorrhage can be intraparenchymal in the brain itself, mainly from hypertension, or subarachnoid from rupture of an aneurysm arising from the vessels of the Circle of Willis. The major risk factor for cerebrovascular disease in studies of patients matched for other cardiovascular risk factors is hypertension [4]. Diabetes [5] and cigarette smoking also play a signiﬁcant role [6], while elevation of serum lipids is less consequential for cerebrovascular disease than for coronary artery disease [7]. Control of these risk factors at a young age has contributed to an impressive reduction in the incidence of stroke in recent years, but addressing these risk factors in the elderly patient still plays an important role [1]. Cardiogenic embolization, particularly from nonvalvular atrial ﬁbrillation, assumes greater importance as an etiology for stroke in the elderly patient and strategies have currently been developed to reduce the incidence of stroke in these patients [8]. While prevention of stroke is the principal goal in the treatment of patients with cerebrovascular disease, medical therapy for the elderly stroke patient can enhance outcome. New treatment modalities to restore cerebral circulation with thrombolytic therapy have changed the outlook on treatment of stroke and therapeutic trials are under way to determine if neuroprotective agents can diminish the extent of irreversible brain damage in acute stroke. 625

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Figure 1 The anatomy of the cerebral circulation is diagrammed demonstrating the potential etiologies of ischemic stroke: cardioembolic, carotid atherothrombotic, intracranial atherosclerosis and small vessel intracranial vascular disease. (From Ref. 2.)

Figure 2 The incidence of the various etiologies of ischemic stroke. (From Ref. 2.)

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ANATOMY AND PHYSIOLOGY OF THE CEREBRAL CIRCULATION The brain is supplied by an extensive interconnected network of arterial circulation. Each cerebral hemisphere receives blood ﬂow from the ipsilateral internal carotid artery, which branches into the middle cerebral artery over the lateral surface of the brain and the anterior cerebral artery over the medial surface of the brain. The brainstem and cerebellum receive blood ﬂow from the vertebral and basilar arteries, which terminate in the posterior cerebral arteries that feed the posterior portions of the cerebral hemisphere, including the occipital and posterior parietal lobes and the thalamus. Connections exist between the two carotid arteries through the anterior communicating artery and between the basilar artery and the two carotid arteries through the posterior communicating arteries. These collateral channels form a complete circuit of arterial supply known as the Circle of Willis. Collateral circulation can also be provided by the external carotid artery, which branches from the internal carotid artery at the bifurcation of the cervical common carotid. The external carotid artery can connect to the internal carotid circulation distally through the ophthalmic artery and through anastomoses between the meningeal branches of the external carotid artery and the surface branches of the cerebral arteries. Because of this collateral circulation, the brain can tolerate complete occlusion of a carotid artery without injury or symptoms, and there are case reports of patients with bilateral carotid artery occlusion and unilateral vertebral artery occlusion whose only symptoms are nonspeciﬁc dizziness [9]. Another protective mechansim for circulation to the brain is autoregulation. Blood ﬂow is maintained constantly at an average of 50 to 70 mL/100 g/min in the gray matter containing neuronal cell bodies and 10 to 20 mL/100 g/min in the white matter containing the neuronal axons at ranges of mean arterial blood pressure from 60 to 160 mmHg without ﬂuctuations due to changes in pressure [10]. Blood ﬂow does ﬂuctuate with the blood pCO2, increasing or decreasing 4% per 1 torr of pCO2. This insures that there will be increased blood supply to metabolically active regions of brain that are producing large amounts of carbon dioxide so that suﬃcient oxygen can be delivered.

PATHOPHYSIOLOGY OF ISCHEMIC STROKE Ischemic stroke is caused by thrombotic or embolic occlusion of arteries supplying the brain. Atherosclerotic disease at the cervical carotid artery bifurcation accounts for about 20% of ischemic stroke [1,2]. Because of the extensive collateral circulation of blood to the brain, it is unusual for ischemic stroke to occur on a hemodynamic basis because of occlusive disease in the carotid or vertebrobasilar arteries unless the channels through the Circle of Willis are incomplete. Therefore, the primary mechanism for stroke due to occlusive disease at the carotid artery bifurcation is embolization of thrombus or atherosclerotic debris from plaque at the bifurcation, which occludes an intracerebral artery [11]. With complete occlusion of the internal carotid artery (Fig. 3), a thrombus can propagate distally in the artery and obstruct collateral channels, causing infarction of a large portion of the cerebral hemisphere. Infarction can sometimes occur on a hemodynamic basis because of hypoperfusion in watershed areas that are supplied by the distal territories of two arterial trees, such as the parietal lobe, which receives terminal branches from both the middle and posterior cerebral arteries. Watershed infarcts can also sometimes occur when there is hypoperfusion due to cardiac arrhythmia, syncope, or cardiac arrest [12].

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Figure 3 Internal carotid artery occlusion. Magnetic resonance angiography of the extracranial circulation performed using a 2-D time-of-flight sequence. This four-vessel view shows flow in the left internal carotid artery (curved arrow) and in the vertebral arteries (arrowheads) but no flow in the right internal carotid artery.

Cardiogenic emboli to intracranial arteries accounts for 20 to 30% of ischemic strokes [1,2] (Fig. 4). The largest sources of these emboli are thrombi from the left atrium in patients with atrial ﬁbrillation, particularly in patients over age 75 with a marked preponderance in women over age 80 [8]. Valvular heart disease, thrombus from akinetic ventricular wall with myocardial infarction or cardiomyopathy, or right-to-left shunts through a patent foramen ovale or atrial septal defect also contribute to cardioembolic stroke [1,2,13]. Artery-to-artery

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Figure 4 Middle cerebral artery occlusion. Computerized axial tomography at the level of the frontal horns of the lateral ventricles demonstrates a well-defined wedge-shaped area of low attenuation involving both gray and white matter of the left frontal lobe. There is mass effect demonstrated by shift of the midline to the right. This is consistent with a subacute (3- to 5-day old) infarct in the middle cerebral artery territory secondary to suggesting middle cerebral artery occlusion.

emboli can also arise from atheromatous plaque at the arch of the aorta and may account for up to 4% of strokes [14,15]. Atherosclerotic occlusive disease of the large intracranial arteries is an unusual cause of stroke in white patients, but is more common in African American and Asian patients [11]. Intracranial thrombosis of small penetrating arteries supplying the deep structures of the brain, such as the internal capsule and basal ganglia, account for about 25 to 50% of ischemic strokes [1,2]. These vessels are endarteries that do not have collateral ﬂow to the regions they supply. Thrombosis usually occurs because of proliferative thickening of the walls of these arteries due to ﬁbrinoid necrosis or lipohyalinization caused by diabetes and hypertension [16]. When these arteries occlude, they produce small holes in the deep white matter, often referred to as lacunes [16] (Fig. 5). While the lesions may be small in size, if they

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Figure 5 Multiple lacular infarcts. Axial T2 weighted magnetic resonance imaging sequence demonstrates multiple rounded areas of high signal intensity within the basal ganglia and thalamus (arrowheads). There is also an old infarct in the right frontal region (hollow arrow).

are located in signiﬁcant white matter tracts such as the internal capsule, which carries the main motor and sensory ﬁbers from the cerebral hemispheres, a devastating neurological deﬁcit such as complete paralysis of the contralateral arm and leg can result. Unusual causes of stroke, such as vasculitis, hypercoaguable state from anticardiolipin antibody or protein C and protein S deﬁciency, arterial dissection, and hematological abnormalities such as sickle-cell disease occur mainly in younger patients and are less likely to occur in the elderly [17–21]. Even with the advent of noninvasive imaging techniques to identify the nature and causes of ischemic stroke, in 5 to 10% of strokes the etiology cannot be identiﬁed and these are classiﬁed as cryptogenic strokes [1,2]. Intracerebral hemorrhage usually involves rupture of a microaneurysm formed on the deep penetrating arteries and arterioles caused by hypertension—Charcot-Bouchard aneurysms [22]. These hypertensive hemorrhages occur mainly in the deep structures of the brain in the region of the basal ganglia and external capsule (Fig. 6). In the elderly, more superﬁcial

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Figure 6 Hypertensive hemorrhage. Axial CT scan at the level of the third ventricle shows acute hypertensive hemorrhage in the left side of the thalamus (arrow), which has broken through into the third ventricle with blood seen layering in the occipital horns of the lateral ventricles (curved arrows).

hemorrhages into the lobes of the brain, lobar hemorrhages, become more frequent. Many of these lobar hemorrhages are still due to hypertension or can be hemorrhagic transformation of an embolic infarct [23]. Another common cause of lobar hemorrhage in the elderly is amyloid angiopathy (Fig. 7), which can occur with or without coincident senile dementia of the Alzheimer’s type [24]. Subarachnoid hemorrhage can also occur in the elderly, but a demonstrable berry aneurysm is less frequent than in younger patients [25]. There are reports of newly diagnosed arteriovenous malformations in elderly patients [26], but these are also a less common source of bleeding in the elderly than in younger patients.

DIAGNOSIS OF STROKE The symptoms and signs occurring with a stroke are determined by the anatomical location of the lesion. Most strokes involve the cerebral hemispheres, with contralateral hemiparesis or sensory loss, loss of vision in the contralateral visual ﬁeld, and behavioral and speech disturbances. Strokes involving the brainstem present with ipsilateral deﬁcits of cranial nerve function such as abnormality of eye movements and a contralateral hemiparesis.

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Figure 7 Amyloid angiopathy. Axial gradient echo sequence MRI shows an acute lobar hemorrhage in the posterior left frontal region with numerous areas of previous hemorrhage (arrows). The appearance of multiple areas of prior hemorrhage is not specific, but in an elderly patients is suggestive of cerebral amyloid angiopathy.

Dizziness is a common symptom in the elderly, but dizziness alone is rarely an indication of stroke unless it is accompanied by other signs of dysfunction in the region of the vestibular nuclei in the lateral medulla. Loss of sensation on the ipsilateral face and contralateral body, ipsilateral Horner’s syndrome, and loss of gag reﬂex and diﬃculty swallowing from involvement of the nucleus ambiguous supplying the vagus nerves are signs of lateral medullary infarction, known as Wallenberg’s syndrome. Ataxia is found with strokes in the cerebellum as well as the brainstem. It is important to establish the etiology of the stroke because treatment regimens vary with diﬀerent subtypes of stroke. The clincial history and physcial examination and

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laboratory analysis are obtained to identify risk factors that potentially could have caused the stroke. The neurological examination is helpful in determining if there is an extensive lesion caused by occlusion of a large vessel or a major hemorrhage by determining if there is alteration in the level of consciousness along with the focal deﬁcits involved. Lacunar strokes from occlusion of small vessels can also be diagnosed if the typical syndromes of pure motor stroke, pure sensory stroke, dysarthria, clumsy hand syndrome, or ataxic hemiparesis are present in an alert patient [16]. The neck is auscultated with the stethoscope to detect a vascular bruit that could signify atherosclerosis at the carotid artery bifurcation as the cause of atheroembolic stroke.

Figure 8 Diffusion weighted MRI. A diffusion weighted MRI sequence demontrates an acute infarct in the region of a previous middle cerebral artery territory infarction (dark arrow) as well as an acute watershed type infarct in the right parietal region (curved arrow).

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The blood pressure is taken to determine if there is hypertension and the blood glucose is measured to determine if diabetes is present. An electrocardiogram is essential to document if arrhythmias such as atrial ﬁbrillation are present, which could predispose to cardioembolic stroke. Computerized axial tomography (CAT scan) of the brain is usually performed initially to diﬀerentiate between hemorrhagic and ischemic stroke. Signs of infarction often are not visualized on CAT scan within the ﬁrst 4 to 12 h after ischemic stroke and the CAT scan may have to be repeated after 48 h to determine the location of the stroke. This is important in order to help diﬀerentiate whether the stroke was atherothrombotic or cardioembolic. Thrombotic strokes more frequently occur in the deep structures of the brain. Cardioembolic strokes usually occur by occluding major branches of the internal carotid artery such as the middle cerebral artery [27], producing an infarct in the discrete territory of the artery involved or occluding distal branches resulting in cortical infarctions (Fig. 4). Magnetic resonance imaging (MRI) is more sensitive than CAT scan for detecting early signs of infarction in the ﬁrst 4 to 12 h, particularly when the technique of diﬀusion MRI is employed (Fig. 8) [28]. The presence of a small, deep, lacunar infarct in a patient with diabetes and/or hypertension usually indicates that the stroke was caused by small-vessel occlusive disease. A cortical infarct in a patient with a known cardiogenic source such as atrial ﬁbrillation usually is suﬃcient to diagnose a cardioembolic stroke. Carotid duplex ultrasonography is usually performed in all patients with ischemic stroke to determine whether atherosclerotic disease at the carotid artery bifurcation is the cause since carotid occlusive disease can produce both superﬁcial or deep cerebral infarction [29]. Magnetic resonance angiography (MRA) can also be performed (Fig. 3) [30]. Transcranial Doppler can identify occlusive disease of large intracranial arteries [31]. Transthoracic echocardiography is employed to rule out a cardiogenic source for stroke. If the suspicion is high that the patient had a cardioembolic stroke and no obvious source is identiﬁed, transesophageal echocardiography (TEE) is indicated. TEE is necessary to rule out thrombus in the atrium, right–left shunts in the heart such as patent foramen ovale or atrial septal defect, and plaque in the arch of the aorta [32–34].

THERAPY OF ISCHEMIC STROKE The management of ischemic stroke is summarized in Table 1. Prevention of Ischemic Stroke At the present time, therapy is limited once an ischemic stroke has already occurred. The major goal for the management of cerebrovascular disease is prevention of stroke. Recent developments indicate that most strokes can be prevented, even when treatment is begun when the patient is already elderly, although early intervention is certainly preferable. Control of Risk Factors The modalities for prevention of occlusive cerebrovascular disease are similar to the strategies for prevention of coronary artery disease. Primary prevention is instituted in patients with the primary risk factors for cerebrovascular disease: hypertension, diabetes,

Cerebrovascular Disease Table 1

635

Management of Stroke

Stroke subtype Ischemic 1. Lacunar 2. Cardioembolic

3. Large vessel

Hermorrhagic 1. Intracranial 2. Subarachnoid

Etiology

Therapy

Hypertension Diabetes Atrial ﬁbrillation Cardiac valve thrombi Cardiac valve replacement Occult (PFO, ASD) Atherosclerotic

Control of hypertension and diabetes aspirin, ticlopidine, tPA heparin, warfarin, aspirin, tPA

Hypertension Amyloid angiopathy Aneurysm Arteriovenous malformation

Extracranial—aspirin, ticlopidine, tPA, carotid endarterectomy Intracranial—aspirin, warfarin, tPA Control of hypertension steroids?, ventriculostomy?, removal? Control of hypertension Nimodipine, malformation epsilonaminocaproic acid?, aneurysm clipping, coils.

Note: Question marks indicate controversial therapy.

atrial ﬁbrillation, smoking, and elevated cholesterol. Secondary prevention is applied to patients who have had warning signs of occlusive cerebrovascular disease: auscultation of a cervical carotid artery bruit, transient ischemic attack lasting up to 24 h (TIA), transient monocular blindness (amaurosis fugax), reversible ischemic neurological deﬁcits lasting over 24 h (RIND), or mild stroke from which the patient is not signiﬁcantly disabled. Hypertension is the most signiﬁcant risk factor for stroke. While prevention of stroke is more eﬀective when treatment is started when the patient is young, it is also beneﬁcial to treat hypertension in the elderly [35]. Treatment of isolated systolic hypertension to a pressure below 160 mmHg with a thiazide diuretic and additional atenolol 25 mg as necessary [36], or with the calcium channel blocker nitrendipine signiﬁcantly reduces the risk of stroke in the elderly [37]. However, caution must be applied when treating elderly patients, since aggressive lowering of diastolic blood pressure below 65 mmHg may actually increase the risk of stroke. The risk of stroke is also increased with elevated diastolic blood pressure and the lowest risk for stroke for elderly patients is in the range of 140/80 mmHg [38]. In coronary disease, some antihypertensive agents have been shown to have a greater protective eﬀect than others, but in prevention of stroke all agents appear to be equally eﬀective as long as there is an equivalent reduction in blood pressure [39]. Diabetes causes proliferation of the walls of small arteries in the deep structures of the brain that can lead to thrombosis [40]. Strict control of blood sugar can prevent similar vascular changes observed in the retina [41] and probably does so in the brain as well, although it has never been deﬁnitively documented that strict control of blood sugar prevents ischemic stroke. Control of blood sugar may lessen the severity when a stroke occurs because hyperglycemia at the time of a stroke increases the extent of infarction from an equivalent vascular occlusion [42]. The angiotensin-converting-enzyme inhibitor ramipril has been used primarily to reduce the complications of diabetic nephropathy. Treatment with ramipril 10 mg per day reduced the risk of stroke by 33% for diabetic patients over age

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55 with at least one other risk factor for cardiovascular disease [43]. Ramipril also reduces the relative risk of stroke by 0.68 in patients with evidence of vascular disease or diabetes plus one other cardiovascular risk factor who have no reduction in cardiac ejection fraction or heart failure. Serum lipids are not as signiﬁcant a risk factor for stroke as they are for coronary heart disease, but reduction in serum cholesterol with the HMG coreductase inhibitors simvistatin and pravastatin for prevention of myocardial infarction also reduce the incidence of stroke in coronary patients by 33% [44,45]. High dietary content of the antioxidants beta-carotene and vitamin E also have been shown to reduce the incidence of stroke, probably by prevention of propagation of atherosclerosis [46,47]. Maintenance aspirin therapy has been shown to be eﬀective in prevention of myocardial infarction in asymptomatic elderly patients [48] and low-dose aspirin is commonly taken by the elderly on a daily basis. No deﬁnite similar reduction in the incidence of stroke in the well elderly patient has been documented with chronic maintenance aspirin therapy [49]. Cigarette smoking is a signiﬁcant risk factor for stroke. Cessation of smoking reduces the risk of stroke to a level similar to nonsmokers after 3 years of abstinence. Elderly patients should still be encouraged to stop smoking.

Management of Patients with Transient Ischemic Attack Platelet Antiaggregant Therapy Transient ischemic attacks (TIA) are a warning sign of impending stroke. About 25 to 33% of patients with TIA go on to have a completed stroke [50]. The incidence of stroke can be reduced by 50% in male patients with TIA treated with the platelet antiaggregant aspirin 650 mg twice a day, but may not be eﬀective in women [51]. Subsequent studies have demonstrated that lower doses of aspirin ranging from 30 to 325 mg signiﬁcantly reduce the risk of stroke in both men and women [52–55], but that higher doses may be more eﬀective than lower doses [56]. The platelet antiaggregant ticlopidine (Ticlid), was developed for patients who could not tolerate the gastrointestinal side eﬀects of aspirin. Ticlopidine is actually a stronger platelet antiaggregant than aspirin. It blocks the ADP receptor, which is close to the ﬁnal common pathway for platelet aggregation [57], while aspirin inhibits thromboxane synthesis by cyclooxygenase [58]. In a trial comparing aspirin 650 mg twice a day to ticlopidine 250 mg twice a day in TIA patients, ticlopidine conferred a 48% risk reduction of stroke after 1 year and 25% risk reduction after 5 years compared to therapy with aspirin 650 mg twice a day [59]. Subgroup analysis revealed that ticlopidine had an advantage over aspirin in women, African Americans, and in prevention of lacunar-type stroke from small-vessel disease [60]. However, ticlopidine was associated with the signiﬁcant hematological complications of leukopenia in 2% of patients [59] and thrombotic thrombocytopenic purpura in 1 out of every 8000 patients [60]. Clopidegrel (Plavix) inhibits platelet aggregation by the same mechanism as ticlopidine, binding to the platelet ADP receptor, but does not have the hematological side-eﬀect proﬁle of ticlopidine [61]. Clopidegrel 75 mg a day has been shown to decrease the number of ischemic vascular events of all kinds by 8.7% compared to aspirin 325 mg a day in patients with atherosclerotic vascular disease including heart attack, peripheral vascular disease, and stroke [61]. The addition of aspirin 75 to 325 mg a day to clopidegrel produced a further

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reduction in vascular events of 20% [62]. Clopidegrel has now virtually replaced ticlopidine for treatment of patients with TIA who cannot tolerate aspirin or who have recurrent vascular events while on aspirin therapy. However, clopidegrel has never been evaluated directly for prevention of stroke in TIA patients. Ticlopidine 250 mg twice daily can still be used if the blood count and liver proﬁle is followed every 2 weeks for the ﬁrst 3 months to rule out complications of neutropenia, thrombocytopenic purpura, and hepatitis. Dipyridamole prevents platelet aggregation by inhibiting the enzyme phosphodiesterase [63]. Immediate-release dipyridamole has not been shown to be eﬀective alone in preventing stroke in TIA patients [64] and does not appear to have an additive protective eﬀect in combination with aspirin compared to aspirin alone [65]. A time-released preparation of dipyridamole 200 mg twice a day reduced the risk of stroke in TIA patients by 18% compared to placebo, the same reduction as treatment with 50 mg of aspirin [66]. The combination of aspirin 25 mg twice a day with this time-released preparation of the platelet antiaggregant Persantine (Aggrenox) 200 mg reduced the rate of stroke by 37% compared to placebo [66]. However, the eﬃcacy of this drug has not been compared to a higher dosage of aspirin. Aggrenox has a low side-eﬀect proﬁle. Gastrointestinal symptoms are reduced with a low dose of aspirin. The only adverse reaction has been headache, which can be minimized by starting the drug once a day and increasing the dose to twice a day after 1 week. Therefore, Aggrenox appears to be a safe and eﬀective drug for prevention of stroke in elderly TIA patients. Carotid Artery Disease Occlusive atherosclerotic disease at the carotid artery bifurcation is found in 50% of patients with TIA. In patients with TIA and less than 40% stenosis, carotid endarterectomy has been shown to be of no beneﬁt compared to aspirin therapy 650 mg twice a day for prevention of stroke. A ﬁnal resolution has not yet been determined for patients with 40 to 69% stenosis. For patients with 70% or greater stenosis of the internal carotid artery at the bifurcation ipsilateral to a TIA, surgical therapy has been shown to provide a 20% reduction in the incidence of subsequent stroke compared to medical therapy with aspirin in a center where the risk of the procedure itself is 2% or less [67]. Patients presenting with TIA are initially screened with ultrasonographic examination of the carotid bifurcation employing duplex sonography. The bifurcation is imaged with Bmode sonography to visualize atheroslcerotic plaque [68]. The degree of stenosis is determined by Doppler sonography, which measures the velocity of the red cells ﬂowing through the artery by the change in frequency shift of the ultrasound as it reﬂects back from the red cells as they go by [69]. The velocity is increased as the lumen diameter narrows. Identiﬁcation of stenosis greater than 70% can be obtained with about 95% accuracy compared to angiography [69]. If a stenosis of 70% or greater is established by duplex sonography, or if the results of the testing are not defnitive, magnetic resonance angiography is performed to document the degree of stenosis [30]. Magnetic resonance angiography also has an accuracy of 95% compared to angiography [30]. When the results of the two studies agree, the accuracy is 99% [30]. Performing these two noninvasive studies can avoid the risk of angiography, which can be as high as a 1% incidence of stroke, myocardial infarction, or death in patients with cerebrovascular disease [70]. When the two studies do not agree, angiography is usually performed to determine if there is a greater than 70% stenosis or to be certain that there is not an inoperable complete occlusion of the internal carotid. For patients that cannot have

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an MRA, CT angiography can be performed. This procedure also has a 90% accuracy compared to catheter angiography, but requires injection of a large volume of contrast dye so that it may not be possible to perform on patients with congestive heart failure or renal disease. Once the imaging procedures have documented a greater than 70% stenosis, the patient is usually treated with carotid endarterectomy, unless there are outweighing medical contraindications to performing the surgery. For elderly patients who are not surgical candidates, stenting of carotid stenosis can be performed. The risk of stroke during the procedure is similar to that of carotid endarterectomy, but the systemic complications are reduced [71]. The long-term eﬃcacy of carotid stent has not yet been established. The management of asymptomatic carotid artery stenosis remains controversial. The Asymptomatic Carotid Atherosclerosis Study (ACAS) documented a signiﬁcant beneﬁt of carotid endarterectomy compared to medical therapy with aspirin 650 mg bid in patients with greater than 60% stenosis of the internal carotid artery [72]. However, the diﬀerence was small, with a 10% risk of stroke in the medical group compared to a 5% risk of stroke in the surgical group over a 5-year follow-up period. Furthermore, the results did not diverge until the ﬁfth year of follow-up. This has implications for elderly patients because an immediate risk of complication of carotid surgery may outweigh a risk of stroke 5 years in the future if the life expectancy of the patient is diminished by other illnesses. Several studies have indicated that acute proliferation of plaque with hemorrhagic changes and plaque growth are implicated in the etiology of thromboembolic events causing stroke from the carotid bifurcation [73–75]. Since the overall incidence of stroke is low in asymptomatic patients, endarterectomy after the initial identiﬁcation of asymptomatic carotid stenosis is usually reserved for patients with a very high-grade lesion or a plaque with large amounts of heterogeneous lucencies suggestive of recent thrombus [74,75]. The remaining patients can be followed with sequential duplex Doppler examinations every 6 months and endarterectomy performed if a progressive stenosis is identiﬁed [75,76] or if the patient becomes symptomatic with a TIA. Prevention of Cardioembolic Stroke The major risk factor for cardioembolic stroke in the elderly is nonvalvular atrial ﬁbrillation [8]. Patients under 70 years of age with atrial ﬁbrillation but no other associated heart disease can be managed with aspirin to eﬀectively prevent stroke [77–80]. In elderly patients over 70, all clinical trials for stroke prevention in patients with atrial ﬁbrillation have shown that aspirin is ineﬀective in preventing embolic stroke due to atrial ﬁbrillation and anticoagulation with warfarin had a signiﬁcant protective eﬀect [77,78,81–83]. In the Stroke Prevention in Atrial Fibrillation Trial (SPAF), the risk of hemorrhagic stroke and other hemorrhagic complications in the elderly over age 75 equaled the risk reduction of cardioembolic stroke induced by warfarin compared to aspirin [77]. The degree of anticoagulation in the SPAF trial as measured by the INR was higher than in the other trials of warfarin to prevent stroke in atrial ﬁbrillation, in which a signiﬁcant reduction in the number of ischemic strokes and poor outcomes was demonstrated [81–83]. Therefore, the current recommendation is to treat elderly patients over 75 who have atrial ﬁbrillation with warfarin for stroke prophylaxis, keeping the INR between 2.0 and 2.9, with a target of 2.5. Cardioversion of patients with atrial ﬁbrillation has been employed as a strategy to prevent cerebral emboli. However, these patients may still require anticoagulation. In the AFFIRM Trial, 3500 patients with atrial ﬁbrillation, mean age 70, were randomized to

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treatment with rate control plus warfarin or maintenance of sinus rhythm plus warfarin. The incidence of stroke was 5.7% in the rate-control group compared to 7.3% in the sinus rhythm group. While this diﬀerence was not signiﬁcant, 78% of the strokes occurred if warfarin was discontinued or the INR was below 2.0, indicating a continuing need for anticoagulation in these patients in order to prevent stroke [84]. Patients with mechanical cardiac valve replacements are generally treated with warfarin for prevention of embolic stroke with the INR maintained from 3.0 to 3.5 [85]. Anticoagulation with warfarin has also been beneﬁcial in preventing stroke during the ﬁrst 3 months after myocardial infarction [86], although aspirin is usually used for long-term prophylaxis. Atherosclerotic plaque in the ascending aorta and aortic arch has also been implicated as a potential source of cardioembolic stroke [34]. When these plaques are identiﬁed as an incidental ﬁnding with transesophageal echocardiography performed for cardiac disease, stroke prophylaxis should be instituted, although it has not been documented whether aspirin therapy is suﬃcient or anticoagulation with warfarin is necessary. Recently, a technique has been developed to image aortic arch plaque with transcutaneous duplex ultrasound so that patients undergoing carotid duplex sonography can be examined for aortic arch plaque as well [87]. Multi-Infarct Dementia Elderly patients being evaluated for dementia are often found to have small infarcts or ischemic changes on images of the brain with MRI and CAT scan (Fig. 5) [88]. Hypertensive patients have small lacunar infarcts in the deep structures, which may not be causing any focal neurological deﬁcits such as hemiparesis but may cause or contribute to cognitive decline. Patients with atrial ﬁbrillation or other cardioembolic sources of stroke may have silent infarcts that cause cognitive deﬁcits without focal signs. Patients with a history of stroke and mild focal neurological deﬁcits may still have cognitive disturbances. When ischemia is identiﬁed as a contributor to the dementia, identiﬁcation of stroke risk factors and vascular pathology is made and appropriate antithrombotic therapy is instituted.

TREATMENT OF ACUTE ISCHEMIC STROKE There are four objectives in the treatment of the acute stroke patient: (1) diagnosis and prevention of medical complications that could be life threatening; (2) prevention of progression of the current stroke; (3) prevention of recurrent stroke; and (4) reversal of the symptoms of the current stroke. Medical Complications The major medical complications associated with stroke are myocardial infarction, pulmonary emboli, aspiration pneumonia, and airway obstruction or reduction in level of consciousness that compromises respiration. Electrocardiogram is imperative to rule out a concurrent mycoardial infarction and, if there is any suggestive history, serial enzymes are obtained. Stroke units with monitored beds are useful in detecting and preventing complications of arrhythmia that could occur with concomitant myocardial infarction or as the result of the stroke itself. While echocardiographic changes of ST-segment depression,

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U-waves, and ventricular ﬁbrillation are more common with hemorrhagic strokes, they can occur with large infarctions severe enough to produce release of catecholamines that can injure the endocarium [89]. Patients who are immobilized from their strokes are treated with low-dose subcutaneous heparin 5000 U bid to prevent thrombophlebitis. If there is a substantial risk of bleeding, pressurized air boots can be used instead of low-dose anticoagulation. If there is airway obstruction or obtundation interfering with respiration, prophylactic endotracheal intubation is sometimes initiated. Observation of the oxygen saturation with a pulse oximeter may be suﬃcient to determine when a patient is becoming hypoxic and intubation is necessary. Patients are generally not fed when there is any obtundation or diﬃculty swallowing, usually for a period lasting 48 h after acute onset of the stroke. However, if there is prolonged inability to swallow, a nasogastric tube or percutaneous gastric tube must be inserted to maintain nutrition for better recovery of the stroke patient. Prevention of Progression Prevention of progression of stroke is attained by careful monitoring of the patient. The blood pressure must be maintained at a suﬃcient level to insure perfusion of the ischemic penumbra, the region of brain around the core area of infarction that is ischemic but not irreversibly damaged. Most stroke patients have an elevation of the blood pressure for the ﬁrst 48 h, a response to the ischemic event, which resolves without treatment [90]. If the blood pressure rises to a critical level over 200/120, moderate reduction with intravenous labetalol is employed to bring the pressure to the 180/100 range. Drastic reduction in blood pressure with agents such as nitroprusside can cause severe worsening of the stroke. Progression of stroke can occur in both large-vessel occlusive disease and in lacunar or small-vessel occlusive disease. Administration of aspirin near onset of ischemic stroke has been shown to improve outcome [91]. Acute intravenous anticoagulation with heparin or the low-molecular-weight heparanoid Orgaron has not been eﬀective in improving outcome in controlled clinical trials [92,93], although subcutaneous administration of low-molecularweight heparin has shown a small, but signiﬁcant, beneﬁcial outcome for stroke patients in one trial [94]. Therefore, it is generally not necessary to anticoagulate all stroke patients acutely, while aspirin therapy should be instituted as soon as possible. Patients with large-vessel occlusive disease who show signs of evolving stroke may beneﬁt from anticoagulation with heparin [95,96], particularly when there is brainstem infarction [97]. However, the evolution of infarction must be in the extent of focal neurological ﬁndings, such as a worsening of limb weakness or new cranial nerve deﬁcits. Decline in the level of consciousness of the patient without new focal deﬁcits is common, particularly in patients with middle cerebral artery occlusion from cardioembolic stroke who develop cerebral edema associated with reperfusion. In this instance, anticoagulation can be associated with adverse outcome due to hemorrhagic transformation of the infarction and anticoagulation should not be administered. Anticoagulation should be employed judicously in elderly patients over 80 who have a higher risk of hemorrhagic complications. With mass lesions of the brain, corticosteroid medications such as Decadron and osmotic diuretics such as Mannitol are useful in reducing the amount of vasogenic edema surrounding the lesion. Acute administration of corticosteroids to all stroke patients has been shown to be of no beneﬁt and may actually be deleterious to the patient’s outcome [98]. In patients with reperfusion, vasogenic edema can develop, which responds to corticosteroids and osmotic agents [99]. These agents can have adverse consequences for stroke

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patients because the hyperglycemia associated with corticosteroids may cause exacerbation of infarction [42] and the dehydration associated with osmotic diuretics may cause reduced perfusion in the ischemic zone. When the patient is in danger of brain herniation, Decadron 10 mg IV acutely and 4 mg q6h can be administered for several days until the edema abates and the patient becomes less obtunded. Mannitol 1000 g IV over 1 h can be administered when herniation is imminent, particularly in cases of hyperperfusion with infarction following carotid endarterectomy [100]. In extreme cases, hemicraniectomy of the skull on the aﬀected side has been recommended to acutely relieve intracranial pressure and prevent herniation, but this has been associated with long-term complications [101]. In some instances, brainstem stroke that is likely to progress can be diagnosed clinically when a pontine infarct is located rostral to the facial nerve nucleus, with ipsilateral face, arm, and leg weakness [102]. This lesion usually involves the ventral anterior pons, where the pyramidal tracts carrying motor ﬁbers from each cerebral hemisphere are located contiguously. Spread of infarction to both sides of the brainstem in this location can result in the locked-in state, where there is quadraparesis and inability to speak, but the patient remains fully conscious. This type of stroke is often associated with basilar artery occlusion and identiﬁcation and early heparinization of these types of patients may be beneﬁcial in preventing worsening of the stroke. Carotid and transcranial ultrasound studies can be performed on acute stroke patients to identify large-vessel occlusive disease in the carotid or vertebrobasilar circulation because these patients may beneﬁt from early anticoagulation with low-molecular-heparin, although this has not been deﬁnitively established [103]. Prevention of Recurrent Stroke Prevention of recurrent stroke is particularly important in patients with a cardioembolic source of stroke such as atrial ﬁbrillation or cardiac valve replacement. These patients can have repeat embolization of clot from the heart [104]. Cardioembolic stroke almost always causes red infarction, with petechial hemorrhage or hemorrhagic transformation of the infarct when reperfusion occurs with retraction of the embolic clot. Reperfusion usually occurs between 24 to 48 h after the acute event. Early anticoagulation with heparin can lead to increased size of the hemorrhagic transformation with associated worsening of the neurological condition as well as coma and death from brain herniation. This is particularly applicable to elderly patients, as the risk of major hemorrhagic transformation increases with age [105,106]. In several studies, it has been determined that the risk of reemoblization in patients with atrial ﬁbrillation is about 2%, while the risk of major hemorrhagic transformation resulting in clinical deterioration is about 8% in the ﬁrst 48 h after stroke [104–106]. Early anticoagulation of stroke patients with atrial ﬁbrillation with heparin or the low-molecularweight heparinoid Orgaron showed no beneﬁt compared to placebo [93,107]. Therefore, in patients with atrial ﬁbrillation, anticoagulation is usually held for the ﬁrst 48 h, a CAT scan of the brain is repeated, and anticoagulation is initiated if the infarct is not very large and there is no hemorrhagic transformation. In patients who do have large infarction or hemorrhagic transformation, it is usually safe to anticoagulate from 96 h to 1 week following the actue stroke [108]. A small area of infarction on the initial CAT scan does not indicate that it is safe to anticoagulate acutely because the full extent of the lesion may not be detected until up to 48 h after the initial event. MRI, particularly with the diﬀusion-weighted-imaging technique, is more sensitive in identifying the full extent of early infarction, and when the region of ischemic brain on these studies is small, early anticoagulation can be instituted.

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Early anticoagulation is also necessary in patients with prosthetic cardiac valves who break through with stroke because the risk of early reemoblization is greater, particularly when noninfectious vegetations are seen on the prosthesis with echocardiography. However, bacterial endocarditis must be ruled out in these instances prior to anticoagulation because mycotic aneurysms can form from infected emboli and can cause hemorrhage when the patient is anticoagulated [109]. Long-term anticoagulation with warfarin can be started at the same time as acute anticoagulation with heparin to shorten the length of hospital stay. A loading dose of 10 mg per day for 2 days is started and subsequent doses are titrated to the prothrombin time, unless the patient has demonstrated sensitivity to warfarin. As in patients with progressive stroke, anticoagulation should be performed judiciously in elderly patients over 80 because of a higher risk of hemorrhagic complications. The International Stroke Trial demonstrated a beneﬁcial eﬀect of aspirin 300 mg orally given at the time of onset of ischemic stroke when outcome was analyzed after 3 months. A 1% reduction in poor outcomes was obtained, primarily from prevention of recurrent stroke. Subcutaneous heparin administration up to 12,500 units bid had a similar reduction in poor outcome from ischemic strokes, but this reduction was equaled by adverse hemorrhagic events associated with anticoagulation [110]. Reversal of Stroke Symptoms Administration of the thrombolysin tissue plasminogen activator (tPA) intravenously at a dosage of 0.9 mg/kg over 1 h with 10% given by bolus within 3 h after the onset of stroke increases the number of patients with a good outcome from stroke after 3 months. As measured by functional scales, 31% of treated patients had improved outcome compared to 21% of placebo patients [111]. There is an immediate improvement in 14% of the stroke patients administered tPA acutely, but there is a 3.6% rate of cerebral hemorrhage causing death so that the overall diﬀerence within the ﬁrst 24 h between control and treated patients was not signiﬁcant. However, after 3 months, the overall mortality rate is equal in treated and untreated patients. To avoid hemorrhagic complications, the prothrombin time and partial thromboplastin time should not be elevated and the platelet count should not be reduced. The patient should not have a history of recent surgery or any other illness that could result in signiﬁcant systemic bleeding. An unexplained anemia could indicate an occult source of bleeding and is also a contraindication for adminstration of tPA. Administration of intravenous tPA to patients more than 3 h after ischemic stroke or to patients who have early changes of infarction on CAT scan of the brain by the time they are ready for treatment leads to an unacceptable degree of hemorrhagic complications and should be avoided [112]. Administration of streptokinase had a very high rate of hemorrhagic complications and is not employed in the treatment of acute ischemic stroke [113]. TPA or pro-urokinase can also be administered by intra-arterial catheterization directly to the occluded vessel under angiographic control. A randomized trial of 9 mg intra-arterial pro-UK followed by heparin infusion was performed in 180 patients with middle cerebral artery occlusion treated within 6 h after stroke. A favorable outcome occurred in 40% of 121 patients treated with pro-UK and 27% of 59 patients treated only with heparin [114]. The improvement in outcome was signiﬁcant ( p = 0.04). Recanalization was also signiﬁcantly improved to 66% in the treated group compared to 19% in the heparin group. However, the risk of symptomatic intracranial hemorrhage was 10% in the treated group compared to 2% in the heparin group. Intrarterial thrombolytic therapy may be more

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valuable in vertebrobasilar occlusive disease when there are progressive symptoms and the expected outcome is so grave that it outweighs the risk of hemorrhagic complications [115]. pro-UK is no longer available and randomized studies with tPA have not been completed. Therefore, thrombolytic therapy given by the intra-arterial route must still be employed judiciously, particularly in elderly patients who are more at risk for hemorrhage. Another strategy that is under development for the treatment of acute ischemic stroke is the use of neuroprotective agents. Ischemia induces release of excitotoxic neurotransmit-

Figure 9 The ischemic cascade induced by release of the excitatory amino acids, glutamate, and aspartate which stimulate the NMDA and AMPA receptors is diagrammed. Experimental therapeutic strategies include inhibition of release of the excitatory neurotransmitters (lamotrigine, riluzole), inhibition of sodium influx from stimulation of the AMPA receptor (APV, NBQX), and inhibition of calcium influx from stimulation of the NMDA receptor (aptigenel, dextrorphan, memantine, selfatel, polyamines). (From Ref. 105.)

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ters, particularly glutamic acid. In the setting of ischemia, glutamate causes neuronal death by stimulation of the N-methyl-d-aspartate receptor (NMDA), which induces lethal amounts of calcium to enter the neuron. In experimental animal models, administration of NMDA receptor antagonists protects neurons in the border zone of the infarct from irreversible ischemic necrosis, reducing the infarct volume and improving functional recovery (Fig. 9) [116]. Several NMDA receptor antagonists have been examined in controlled treatment trials of ischemic stroke, but so far no signiﬁcant improvement in outcome of stroke patients with these agents has been documented [117]. Future studies may include reperfusion of the ischemic zone by administration of thrombolytic agents followed by administration of neuroprotective agents to prevent ischemic neuronal death. The relative success of immediate treatment of stroke with tPA within 3 h after onset has altered the attitude about the management of stroke. Stroke now has to be considered an emergency just like heart attack and is currently referred to as a brain attack. Early recognition of stroke and emergency transport to a hospital facility capable of acute management of stroke patients has become imperative.

MANAGEMENT OF HEMORRHAGIC STROKE Intracranial Hemorrhage There are two types of hemorrhagic stroke, intracranial and subarachnoid. Intracranial hemorrhage usually commences with severe headache and progressive focal deﬁcit, often leading to obtundation. Most intracranial hemorrhage is due to hypertension and involves the deep structures of the brain around the basal ganglia and internal capsue (Fig. 6) [22]. Hemorrhage into a superﬁcial lobe in the brain is more common in elderly patients than younger patients, in part due to amyloid angiopathy of the cerebral arteries (Fig. 7) [24]. Medical therapy of hemorrhage consists primarily of reduction in blood pressure in hypertensive patients and supportive care. Endotracheal intubation may be necessary for airway protection and for impending brain herniation with respiratory failure. Hyperventilation may be helpful to reduce increased intracranial pressure. The osmotic diuretic Mannitol can be administered intravenously at a dosage of 100 g to reduce cerebral edema acutely in cases of impending herniation. There is no evidence that steroid medications are of any beneﬁt in improving the outcome of patients with intracranial hemorrhage [118], but they are still commonly employed for the individual case where reduction of cerebral edema may be helpful. Decadron 10 mg IV acutely followed by 4 mg every 6 h is often used. Care must be taken to control blood sugar and prevent gastrointestinal hemorrhage when administering steroid medications. Surgical management of intracranial hemorrhage is employed in certain instances. Shunting of ﬂuid and removal of blood from the ventricular system can reduce intracranial pressure and prevent hydrocephalus. Deep hemorrhages are usually not beneﬁted by surgical intervention, but occasionally improvement can be obtained with removal of lobar hemorrhage [119,120]. The one instance in which surgical management is generally utilized is cerebellar hemorrhage, where drainage of the hematoma can be performed without inordinate risk to prevent compression of the brainstem and death. Cerebellar hemorrhage usually presents initially with dizziness and loss of balance along with headache, progression of focal ataxic symptoms, and often somnolence and coma. Early recognition of this condition can improve the outcome with surgery considerably [119].

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Subarachnoid Hemorrhage The major intracranial vessels are located in the subarachnoid space between the pia mater and dura mater covering the brain. Aneurysms form primarily at branch points from the vessels of the Circle of Willis at the base of the brain. Rupture of these aneurysms produces severe headache, photophobia, and stiﬀ neck. The patient may become somnolent or lapse into coma. A third nerve paralysis with ptosis, pupillary dilation, and ophthalmoplegia can result when a hematoma forms on the oculomotor nerve running just below the posterior communicating artery. Focal neurological disturbances such as hemiparesis can also result acutely. Patients with mild-to-moderate deﬁcits have a better prognosis than patients with focal neurological deﬁcit or stupor. CAT scan of the brain can visualize subarachnoid hemorrhage in most cases, but sometimes lumbar puncture is necessary when the CAT scan is negative and there is a high clinical suspicion of subarachnoid hemorrhage. The aneurysm is identiﬁed by cerebral angiography. The optimum care for subarachnoid hemorrhage is prevention of rebleeding by clipping the aneurysm within the ﬁrst 24 h in patients with mild-to-moderate deﬁcits. Surgical management after 24 h is dangerous because of increased ischemic complications because of vasospasm. If surgery cannot be performed within the ﬁrst 24 h, it is usually deferred for up to 14 days [121]. The ischemic consequences of spasm can be reduced by administration of the calcium channel blocker Nimodipine 60 mg p.o. every 6 h [122,123]. In some instances, the antiﬁbrinolysin epsilon amino caproic acid is administered to prevent rebleeding when surgical therapy cannot be performed immediately, but is associated with an increase in ischemic complications [124]. Spasm can be detected by measurement of increased ﬂow velocities with transcranial Doppler, which can be employed to monitor patients for the onset of spasm after subarachnoid hemorrhage. When spasm occurs postoperatively, the blood pressure can be elevated to increase cerebral perfusion. Angioplasty can also be performed to dilate vessels when spasm is severe and is causing hemiparesis or stupor [125]. When an elderly patient is at high risk for aneurysm surgery, endovascular placement of coils under radiological guidance can be employed to thrombose the aneurysm [126]. Arteriovenous malformations of the brain, in which arteries feed directly into the venous system without going through a capillary bed, can also be a cause of subarachnoid hemorrhage. Surgical extirpation can be performed to eliminate the source of the bleeding, but often the AVM can recur or too much brain parenchyma is at risk for resection to be feasible [127]. Emoblization of colloidal particles or enodvascular insertion of coils can be employed to thrombose the arteriovenous malformation. It is unusual to be able to eliminate the arteriovenous malformation by these methods, but the size can be reduced so that it becomes amenable to surgical removal. Radiosurgery with gamma knife technology can also be performed to eliminate or reduce the volume of the arteriovenous malformation [128].

CONCLUSION New developments in the understanding of the pathophysiology of stroke and imaging technology for identifying the cause of stroke have dramatically changed the management of cerebrovascular disease. While the main focus remains prevention, new treatments with

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thrombolysis have changed the concept of stroke from a hopeless condition to a treatable disease. Further developments with neuroprotective agents hold the promise for further advancements in the treatment of stroke. The treatment of stroke as an acute emergency, a brain attack, has introduced a new era in the management of stroke which can markedly alter the course of the disease in the elderly.

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27 Evaluation of Syncope in the Elderly Patient Scott Hummel and Mathew S. Maurer Columbia University, College of Physicians & Surgeons, New York, New York, U.S.A.

INTRODUCTION Syncope is deﬁned as a sudden transient loss of consciousness and postural tone with relatively rapid and spontaneous recovery. Transient cerebral hypoperfusion is the underlying pathophysiological event that results in syncope. The elderly are particularly vulnerable due to age-associated physiological changes in heart rate and blood pressure regulation, comorbid medical conditions such as hypertension and atherosclerosis, and the concurrent use of medications that aﬀect blood pressure regulation. Syncope is not in and of itself a disease; it is a symptom with am underlying pathophysiology. The assignment of an etiology can have profound eﬀects on the prognosis and treatment of individual patients, but may be diﬃcult to accomplish in practice. The diﬀerential diagnosis of syncope is extensive and spans a spectrum from common benign problems to severe, complex, and often life-threatening disorders. Another diﬃculty in evaluating elderly patients with syncope is the presence of multiple possible contributing factors. Patients over the age of 65 have an average of 3.5 chronic medical comorbidities and use three times as many medications as younger patients. An analysis of elderly institutionalized adults with syncope suggested that 81% had two or more comorbid conditions that could have been implicated [1], and 25% of elderly referred to an integrated ‘‘syncope clinic’’ for diagnosis were found to have two or more attributable conditions [2]. Given the complexity of the diﬀerential diagnosis in the aged and the increased morbidity and mortality detailed below, it is not surprising that syncope often produces as much anxiety and frustration for medical professionals as for elderly patients and their families.

EPIDEMIOLOGY Large-scale population studies indicate that the incidence of syncope increases with age, rising most sharply after age 70. In the Framingham cohort, syncope was reported at 11.1 events per 1000 person-years in persons age 70 to 79; in patients older than 80, the incidence 653

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of syncope was 16.9 to 19.5 events per 1000 person-years [3]. The prevalence of syncope in very elderly (mean age 87 years) institutionalized patients is 23% over 10 years; the yearly incidence is estimated to be at least 6% in this group with a 30% recurrence rate [1]. Eighty percent of emergency room patients evaluated for syncope are over age 65, and syncope accounts for 1 to 6% of all hospital admissions and 3% of all emergency room visits [4].

IMPACT OF SYNCOPE The consequence of syncope for the aging population are wide ranging, both on an individual and societal basis. An early large-scale prospective study by Kapoor et al. of relatively young (mean age 57 years) persons with syncope estimated a 5-year mortality of 34% [5]. Several years later, the same group demonstrated a 27% 2-year mortality rate in elderly patients presenting with syncope [6]. The falls associated with syncope can produce devastating injuries in the elderly. Five to 30% of falls in the community result in injury; approximately 5% of these are fractures and 1% are hip fractures. One in 40 communitydwelling elders who fall will be hospitalized. Only about half of these hospitalized patients will be alive 1 year after the fall [7]. Unintentional injury is the sixth leading cause of death, and falls account for 70% of the accidental mortality among people over 65 years of age. Even if no injury results, the fear of falling can be debilitating; elderly patients who fall often restrict their activities and show a higher incidence of depression and dependence in activities of daily living than their peers [8]. Overall perception of health is proportional to the number of syncopal events in those with frequent recurrences [9], and such patients have impairment in their quality of life similar to those suﬀering from rheumatoid arthritis [10].

ETIOLOGIES AND THE IMPORTANCE OF RISK STRATIFICATION The causes of syncope are traditionally broken down into several major etiological categories. We have found the following pathophysiological classiﬁcation helpful: (1) primary cardiac arrhythmia (bradycardia or tachycardia); (2) structural cardiovascular disorder; (3) neurally mediated reﬂex disorders of blood pressure control; (4) orthostatic/ dysautonomic disorders of blood pressure control; and (5) primary neurological or psychiatric diagnoses (Table 1). In a majority of the published studies, the term ‘‘cardiovascular syncope’’ is used to refer to the combined diagnoses of structural cardiovascular disorder and primary cardiac arrhythmia, and will be used so here. The goals of diagnosing and treating patients with syncope are to reduce mortality and morbidity. In that vein, risk stratiﬁcation for causes associated with excess mortality should be performed in all patients, and etiological diagnosis should be made to prevent morbidity associated with syncope recurrence by treating the underlying causes. Unfortunately, the evaluation of syncope is often nondirected and costly and frequently leads to great variability in practice and unsatisfying diagnostic conclusions. Two recent examinations of current diagnostic strategies used in hospitalized elderly patients with syncope identiﬁed several relevant issues. Simple, inexpensive, and nonharmful evaluations are vastly underutilized; for example, postural vital signs were recorded in only 27% of one sample. Potentially high-yield provocative tests such as tilt table testing (TTT) and electrophysiological study (EPS) are infrequently used, while at least one low-

Neurally mediated Simple faint Carotid sinus hypersensitivity Neuralgias Situational micturition cough swallow defecation laugh postexercise

Primary Arrhythmic

Tachyarrhythmias Ventricular Torsades de pointes Supraventricular Atrial ﬁbrillation/ﬂutter Bradyarrhythmias Sick sinus syndrome AV nodal block Sinus bradycardia Pacemaker malfunctions Pacemaker-mediated tachycardia Pacemaker syndrome

Table 1 Differential Diagnosis of the Causes of Syncope

Hypovolemia Medication-related Postprandial Shy-Drager syndrome Parkinson’s disease Spinal cord disease Diabetic neuropathy Other peripheral neuropathies

Dysautonomia/orthostatic hypotension Aortic dissection Atrial myxoma Pulmonary embolus Pulmonary hypertension Subclavian steal Hypertrophic cardiomyopathy Aortic stenosis Mitral stenosis Pump failure Myocardial ischemia Pericardial disease/ tamponade

Structural cardiovascular

Vertebrobasilar TIA Stroke Migraine Seizure Narcolepsy Panic attacks Anxiety disorder

Neurological/psychiatric

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yield neurological study, such as carotid Doppler ultrasonography and head computed tomography (CT) scan is obtained in nearly half of admissions. After an average length of stay of 3 to 5 days, 42 to 49% of cases remain undiagnosed [11,12]. These results may be contrasted with the ﬁndings from trials investigating a standardized approach to syncope diagnosis in emergency room patients that indicate diagnostic eﬃciency of 76 to 83% [13,14]. A logical approach to diagnosis of syncope in the elderly patient begins with an understanding of the diﬀerential diagnosis and epidemiology (Table 2), although the true distribution of syncope etiology is diﬃcult to determine because of diﬀerences between populations studied and wide variance in strategies for evaluation. While many studies have examined the etiology of syncope in a variety of clincal settings, few speciﬁcally focus on patients older than 65 years of age or stratify their data by age range. Studies often include patients without true syncope, such as seizures or metabolic derangements. Many trials were performed prior to the common usage of testing modalities such as EPS and TTT and, consequently, the percentage of patients with an ‘‘unknown’’ etiology following evaluation is great in early studies. Nonetheless, some conclusions can be drawn from the available data. A large percentage of patients have orthostatic/dysautonomic or neurally mediated disorders of blood pressure control. Primary arrhythmias are fairly common, and structural cardiovascular disorders and primary neurological syncope are comparatively rare. Data from cohort and prospective trials have revealed that syncope patients can be stratiﬁed into groups with high and low risks of death based on etiology. In a prospective study of 204 primarily hospitalized patients evaluated for syncope and followed for 1 year, the overall mortality rate was 30% and rate of sudden death 24% in patients with a cardiovascular cause as compared to 12% and 4%, respectively, in patients with a noncardiovascular etiology [5]. In the Framingham cohort, patients with isolated syncope (i.e., syncope in the absence of prior or concurrent neurological, coronary, or other cardiovascular disease stigmata) did not suﬀer from excess all-cause or cardiovascular (including sudden death) mortality [15]. Similarly, a recent examination of a community-based sample from the Framingham cohort (average age 66 years) indicates that the excess mortality in patients with syncope is attributable almost entirely to those with a cardiovascular etiology (adjusted hazard ratio for mortality of 2.01, 95% CI 1.48–2.73), while subjects with neurally mediated, medication-related, or orthostatic/dysautonomic syncope (45% of the sample) did not show increased mortality (adjusted hazard ratio of 1.08; 95% CI 0.88–1.34) [3]. A prospective multivariate analysis comparing 940 relatively young (mean age 52.5 years) patients with similar cardiovascular disease severity on a symptom scale, with and without syncope, suggested that mortality was related to underlying cardiac disease severity much more strongly than to the incidence of a syncopal event itself [16]. Initial Workup The initial diagnostic workup should consist of history, physical examination, and 12-lead electrocardiography (ECG). Studies across a wide range of subjects indicate that the history and physical exam alone can directly make a diagnosis in 20 to 50% of patients with syncope, and can suggest possible etiologies in many more. The ECG makes a deﬁnitive diagnosis in only a few patients, but is helpful in identifying patients likely to have underlying structural heart disease [17]. Laboratory tests are rarely deﬁnitive and probably can be limited to those patients in whom a particular disorder (anemia, hypoglycemia, severe dehydration) is suspected as a contributing factor.

67 210 65 1516 195 822

1986 [6]

1993 [2]

1999 [12]

1999 [14]

2002 [3]

N

1985 [1]

Date [Ref.]

66

63

73

78

71

87

Mean age

Community

ED

Nursing home ED, inpatients Syncope clinic In-patients

Clinical setting

6 (3%)

67 (4%)

0 (0%)

14 (7%)

10 (15%)

Structural cardiovascular

78 (10%) (reported together in this trial)

35 (18%)

217 (14%)

14 (21%)

54 (26%)

3 (4%)

Primary arrhythmia

174 (21%)

69 (35%)

193 (13%)

37 (56%)

25 (12%)

11 (16%)

Neurally mediated

Abbreviations: ED = Emergency department. a Percentages add up to more than 100% because some subjects were found to have multiple causes of syncope.

Lipsitz et al. (retrospective) Kapoor et al. (prospective) McIntosh et al. (prospective)a Getchell et al. (prospective) Ammirati et al. (prospective) Soteriades et al. (prospective)

Study design (investigators)

Table 2 Epidemiology of Syncope in the Elderly Patient

133 (16%)

12 (6%)

254 (17%)

21 (32%)

25 (12%)

15 (22%)

Orthostatic— dysautonomic, drug-related

74 (9%)

38 (20%)

69 (5%)

12 (18%)

10 (5%)

7 (10%)

Primary neurological psychiatric

363 (44%)

35 (18%)

716 (47%)

10 (15%)

83 (40%)

21 (31%)

Unknown, other unspeciﬁed

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History In evaluating patients, it is essential to diﬀerentiate syncope from other entities. Conditions such as vertigo, substance intoxication, and hypoglycemia which do not result in a transient loss of consciousness with spontaneous recovery, are not syncope. Arrhythmic events requiring electrical or chemical cardioversion are part of a spectrum including syncope and sudden cardiac death; in these cases the diagnosis is usually not in question and the evaluation strategy to follow is clear. Seizures are another common cause of unexplained loss of consciousness, but also do not constitute true syncope. Distinguishing between syncope and seizure is a common diagnostic problem, but can usually be accomplished from the history. It should be noted that many patients with syncope have myoclonic jerks that can be mistaken for seizure activity by witnesses. In a study of 94 consecutive patients who had transient loss of consciousness, the best discriminatory ﬁnding was orientation immediately after the event according to the eyewitness. Nausea and sweating before the event were useful to exclude a seizure but, contrary to common clinical teaching, incontinence and trauma were not discriminatory ﬁndings [18]. Another study found that lateral tongue biting had a sensitivity of 24% and a speciﬁcity of 99% for the diagnosis of generalized tonic–clonic seizures [19]. A recent standardized evaluation of 671 patients with loss of consciousness added head turning and unresponsiveness during unconsciousness as predictive of seizures, while dizziness or diaphoresis prior to the event or loss of consciousness after prolonged sitting or standing were suggestive of syncope [20]. In addition, patients with seizures often have a history of prior seizures or other neurological symptoms or ﬁndings on neurological exam that suggest the diagnosis. Distinguishing syncope and falls can be diﬃcult. The traditional view considers these entities as two separate syndromes, often with separate etiologies, but there is considerable clincal overlap in the elderly. Discriminating between syncope and falls relies upon accurate accounts from patients and/or witnesses of the event. Many elderly patients have retrograde amnesia regarding the event; one study demonstrated that 32% of cognitively normal older adults could not remember falling 3 months afterward [21]. Other trials have shown that 21 to 32% of subjects with witnessed syncope during carotid sinus massage have amnesia for the loss of consciousness [22,23]. A witnessed account is unavailable in many cases of falls brought to medical attention. Recent research has shown that falls not resulting from an obvious cause, such as impaired gait or balance with a resulting slip or trip, often have an attributable cardiovascular cause (particularly bradycardia or neurally mediated blood pressure control disorders) [23]. Thus, in the elderly, syncope and unexplained falls are often indistinguishable clinical manifestations of the same pathophysiological process, and for this reason we treat any unexplained fall in an elderly adult as syncope. Once it has been established that the patient has had syncope, the primary history taking should focus on precipitating factors, prodromal symptoms, and symptoms following the event. Chronology of recurrence, if applicable, can aid in evaluation. Parallel history attained from a reliable witness is often invaluable. Historical factors associated with particular etiologies of syncope are detailed in Table 3. Particular attention should also be paid to the use of vasodilating, antiarrhythmic, or negatively chronotropic medications. Nausea, warmth, diaphoresis, and lightheadedness are typical prodromal factors associated with neurally mediated syncope, but elderly patients commonly experience syncope without a prodrome. Residual symptoms are uncommon in patients with arrhythmia-induced syncope, while those with neurally medi-

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Table 3 Historical Factors Associated with Various Etiologies of Syncope Historical feature Nausea, diaphoresis, warmth, long prodrome, total duration of episodes greater than 4 years During or after micturition, defecation, coughing, laughing, swallowing With neck pressure (tight collar, shaving, head turning) Postepisode confusion, lateral tongue biting, head turning during episode Diplopia, ataxia, vertigo, dysarthria With arm exercise Upon assuming upright posture During or after exertion While supine History of myocardial infarction or congestive heart failure

Associated diagnosis Neurally mediated syndrome

Neurally mediated situational syncope Carotid sinus hypersensitivity Seizure Neurological (transient ischemic attack, migraine, stroke) or subclavian steal Subclavian steal Orthostatic hypotension Aortic stenosis, myocardial ischemia, vasodepressor response to exercise Arrhythmia Arrhythmia

ated disorders of blood pressure control may describe moderate-to-severe fatigue afterward [24]. An extensive evaluation of cardiovascular symptoms (i.e., angina, dyspnea, edema, and exercise tolerance) should be obtained in all patients. In patients with suspected or known structural heart disease, the most speciﬁc historical elements for cardiovascular syncope are syncope while supine or during exertion, blurred vision, and duration of symptoms less than 4 years. In patients without suspected heart disease, palpitations are the only predictor of a cardiovascular etiology [25]. Physical Examination A detailed physical examination should be performed in all patients with syncope. Hydration status and orthostatic changes in vital signs should be assessed. A careful cardiovascular examination should be performed with attention to signiﬁcant cardiac murmurs and their alteration with body position and various maneuvers, evidence of left ventricular enlargement, and delayed or diminished carotid upstrokes. The extremities should be examined for diminished or absent peripheral arterial pulsations and bruits. A meticulous neurological exam with attention to the presence of nystagmus, aniscoria, facial asymmetry, plegia, ataxia, and dysmetria should be performed in all patients with syncope. Neurological ﬁndings that are focal, especially if recent in onset, suggest central nervous system pathology. Electrocardiography The ECG is most commonly normal following a syncopal episode. Deﬁnitive diagnoses on initial ECG include Mobitz II second- or third-degree atrioventricular (AV) block, alter-

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nating left and right bundle branch block, ventricular tachycardia (VT), pacemaker malfunction, paroxysmal supraventricular tachycardia (PSVT), sinus bradycardia, sinoatrial block, or pauses, if associated with symptoms. Such ﬁndings are rare (less than 5%) because arrhythmias resulting in syncope are often self-limited, but other electrocardiographic rhythm and conduction abnormalities can guide further evaluation. For example, ﬁrst-degree or Mobitz type I second-degree AV nodal block, sinus bradycardia, and bundle branch blocks may suggest a bradycardia event, while evidence of prior myocardial infarction or left ventricular hypertrophy raises the possibility of ventricular tachycardia. Results of the Initial Evaluation The simple initial evaluation described above is very eﬀective in separating patients at risk for a cardiovascular etiology for syncope (and therefore increased mortality). A large, prospectively followed cohort of emergency room patients presenting with syncope demonstrated that the four factors independently predicting increased risk of death in the following year are age greater than 45, history of congestive heart failure, history of ventricular arrhythmias, and abnormal electrocardiogram at presentation [26]. In another population, only 4 of 146 patients not suspected to have structural heart disease following history, physical, and ECG were found to have had cardiovascular syncope after extensive evaluation [25]. Patients with evidence of structural heart disease by history, physical examination, or ECG should be admitted to the hospital for further evaluation. Diagnostic testing in this group should be aimed at evaluating for the type of underlying heart disease as well as identifying whether a spontaneous arrhythmia is the cause of syncope. The Role of Echocardiography in Initial Evaluation Echocardiography can directly diagnose severe valvular abnormalities, ventricular hypertrophy with outﬂow obstruction, severe pulmonary hypertension, and atrial myxoma or thrombus, but such ﬁndings are rare in the absence of a suggestive initial evaluation. An echocardiogram may be beneﬁcial in conﬁrming or excluding structural heart disease, but may not be required in all patients. In one study of 650 consecutive syncope patients (average age 60, with 44% older than 75 years), echocardiography was mainly useful in conﬁrming suspected severe aortic stenosis and in risk-stratifying patients with known cardiac disease by ejection fraction. Echocardiography was normal or nonrelevant in all patients without cardiac disease by history, physical, or ECG in this study group [27]. The role of routine echocardiography in the evaluation of all patients with unknown syncope remains to be fully deﬁned, but it seems reasonable to defer echocardiography in patients without suggestion of structural heart disease from history, physical examination, or ECG. Etiological Categories and Diagnostic Testing The remainder of this chapter will focus on the separate etiological categories of syncope as described above. A general description and salient pathophysiological information will be presented for each, followed by an examination of speciﬁc testing strategies and their eﬃcacy. The frequency of use of typical diagnostic tests at our medical center and the estimated diagnostic eﬃcacy of each from the literature are detailed in Table 4. These data highlight the discrepancy between the tests that are likely to yield deﬁnitive diagnoses, based on the published literature, and the current practice patterns that focus on low-yield nonprovocative testing.

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Table 4 Diagnostic Utility of Commonly Used Tests in Elderly Patients with Syncope Test History and physical exam Electrocardiograma Telemetry monitoring Echocardiograma CT scan of headb Holter monitoring Carotid Dopplerb EEGb Electrophysiological study Tilt-table test Carotid sinus massage

Frequency of ordering

Diagnostic yield from literature

100% 100% 81% 55% 40% 30% 19% 13% 10% 6% 5%

20–50% 2–11% 2–15% 5–10% 1% 2–15% 1% 1% 15–25% 30–60% 14–68%

Data from a series of consecutive patients (mean age 68, with 65% over age 65) admitted to Columbia Presbyterian Medical Center over a 2-year period (1995–1996) [81]. Representative data on diagnostic yield as evaluated from published literature (see text for details). a While ECG and echocardiography have low direct diagnostic yield, they are important in the identiﬁcation of structural cardiac disease and risk stratiﬁcation in patients with syncope. b In the absence of suggestive history and physical examination.

Structural Cardiovascular Disorders Most of the etiologies in this category (such as subclavian steal syndrome, pulmonary embolism, and aortic dissection) can be directly diagnosed or at least strongly suggested by the initial evaluation. A careful history and physical examination can guide speciﬁc conﬁrmatory testing such as echocardiography, ventilation-perfusion or computed tomography (CT) imaging, and angiography. The full diagnostic workup of these disorders is beyond the scope of this chapter and will not be discussed further here. The most common etiology in this category among the elderly is aortic stenosis; myocardial ischemia resulting in cardiac pump failure or arrhythmia is a rare primary cause of syncope. Aortic Stenosis Calciﬁc or degenerative aortic stenosis (AS) is the most common valvular lesion in the elderly. Risk factors include advancing age, congenital bicuspid valve, smoking, and hypertension; the estimated prevalence of critical aortic stenosis approaches 6% by 86 years of age [28]. Syncope occurs in up to 42% of patients with severe valvular AS, commonly with exercise [29]. When patients with AS experience syncope not linked to exertion, the symptom is usually unrelated to the valve disease [30]. Dehydration or the use of vasodilating drugs may predispose individuals with AS to decreased cardiac output and syncope. Other rare causes of syncope in AS include ventricular tachyarrhythmias, paroxysmal AV block, and atrial ﬁbrillation with loss of ‘‘atrial kick.’’ In AS, syncope has prognostic signiﬁcance, with an average survival of 2 to 3 years in aﬀected patients after its onset in the absence of valve replacement. Physical ﬁndings in severe AS may include decreased amplitude and delay of the carotid pulse, paradoxical splitting of S2, and a very

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late-peaking systolic murmur heard best at the right upper sternal border (occasionally at the apex in the elderly), as well as manifestations of pulmonary hypertension and congestive heart failure, if present [31]. The diagnosis of critical AS is usually suggested by history and physical examination and may be conﬁrmed with transthoracic echocardiography or leftsided cardiac catheterization. Myocardial Ischemia Although one report suggests that syncope as a presenting manifestation of myocardial infarction (MI) may increase in incidence with age, particularly in the oldest old (>80 years) [32], in a large observational series of hospitalized syncope patients (average age 73, with prevalence of known coronary artery disease 34%), syncope was caused by myocardial ischemia in only 1% [11]. In another group of elderly patients, 77% had serial measurement of cardiac enzymes following admission for syncope; only 1 out of 80 patients ‘‘ruled in’’ for MI, and this patient presented with unstable angina and syncope in the setting of chest pain [33]. The diagnostic utility of ‘‘ruling out’’ active ischemia with serial cardiac enzyme testing in all elderly patients admitted with syncope is low in the absence of ECG changes or symptoms of myocardial ischemia. Cardiac stress testing in syncope diagnosis has not been prospectively studied, but is unlikely to add to the diagnostic evaluation unless patients present with anginal features or exertional syncope. Even among patients who have syncope during exertion, severe aortic stenosis or a vasodepressor response to exercise are probably more common causes than myocardial ischemia. Primary Arrhythmic Syncope Tachyarrhythmias Ventricular tachyarrhythmias are a relatively infrequent, but life-threatening, etiology of syncope in the elderly. The increased prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and coronary artery disease in the elderly increases the likelihood of decreased left ventricular function from myocardial infarction or cardiomyopathy in this cohort. Elderly patients also more commonly have left ventricular hypertrophy and aortic stenosis, two conditions that predispose to ventricular dysrhythmias. The use of QTinterval-prolonging medication or drugs that predispose to hypokalemia or hypomagnesemia places elderly patients at risk for torsades de pointes. Supraventricular tachyarrhythmias are a rare cause of syncope, but may be more likely to result in cerebral hypoperfusion in elderly patients with dehydration, on venodilating agents, or with diastolic dysfunction where reliance on cardiac preload is high. These arrhythmias should always be correlated with symptoms prior to assuming that they are the cause of syncope. Bradyarrhythmias Bradycardia is a much more common etiology of syncope in the elderly than in the young. While bradycardia has traditionally been grouped with ventricular tachyarrhythmias and structural cardiovascular disorders under the heading of ‘‘cardiovascular syncope’’ in epidemiological studies, the excess mortality in patients with bradycardia is likely small in comparison. Two types of precipitants exist: intrinsic disease of the myocardial conduction system, and extrinsic reﬂex bradycardia secondary to autonomic inﬂuences. Intrinsic conduction system disease leads to two main types of conduction disturbance: sick sinus syndrome (SSS) and AV nodal blockade. The SSS is intermittent failure of

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sinus node output, resulting in cardiac standstill until the sinus node recovers or a subsidiary pacemaker takes over. Inappropriate sinus bradycardia not caused by medications and tachycardia–bradycardia syndrome are also often included in the description of this disorder. Risk factors for the development of SSS include age, structural heart disease (including inﬁltrative cardiomyopathies), and cardiac surgery. The SSS is an indication for permanent cardiac pacing [34], but survival in the elderly is related to underlying cardiac structural disease and not to the presence of SSS itself [35]. High-grade AV block is another common cause of syncope in th elderly and indication for pacemaker placement [34] in the absence of contributing medications. Mortality in the oldest old (>80 years of age) is increased regardless of the presence of structural heart disease; in those aged 65 to 79 the picture is less clear, but syncope has been identiﬁed as an independent contributor to mortality [36]. Extrinsic bradycardia is mediated by alterations in autonomic tone and is seen in neurally mediated syncope such as carotid sinus hypersensitivity and the common ‘‘vasovagal faint.’’ It is important to identify those with extrinsic bradycardia, as patients with a signiﬁcant vasodepressor component of a neurally mediated syndrome (see below) may not beneﬁt from standard pacemaker placement. Short-Term Electrocardiographic Monitoring Short-term continuous ECG monitoring, such as telemetry or Holter monitor, is often utilized in an attempt to diagnose syncope etiology. However, patients with arrhythmiarelated syncope may go weeks, months, or even years between recurrent events. Another central problem in attributing syncope to arrhythmias is that the vast majority of detected arrhythmias in patients with syncope are brief and result in no symptoms [37–40]. Particularly in the case of bradycardia, abnormal rhythms on monitoring should be correlated with presyncope or syncope prior to initiating pacemaker therapy. In one recent series of 649 syncope inpatients, telemetry monitoring was used in 100% of admissions. Abnormalities were found in only 7% of patients, with only 1% being diagnostic of syncope etiology [12,41]. Outpatient Holter monitoring is similarly ineﬀective, with an incidence of symptom-correlated arrhythmias of approximately 4% in selected patients and less in unselected subjects [40]. Thus, the eﬃcacy of short-term ECG monitoring in diagnosing or ruling out arrhythmic causes of syncope is questionable, although the presence of frequent ventricular ectopy or nonsustained VT can be used to identify patients at higher risk for malignant arrhythmias and guide further testing [39]. Long-Term Electrocardiographic Monitoring In patients with multiple episodes of syncope separated by relatively long time intervals, longer-term ECG monitoring is useful. Patient-activated external intermittent loop recorders may capture the rhythm during syncope after the patient has regained consciousness, since several minutes of retrograde ECG recording can be obtained. External event monitors are superior to Holter monitoring in the capture of arrhythmias during syncope and in suggesting alternate diagnoses when syncope occurs in the absence of documented arrhythmia [42,43]. Compliance with external event monitors for longer than 1 month is problematic, however, as patients must wear ﬁxed electrodes during the entire monitoring interval. Additionally, as event monitors record only a 5-min intervals of data, elderly patients or their caregivers must be able to activate recording shortly after syncope. A promising development in the diagnosis of arrhythmic syncope is the implantable loop recorder (ILR), which is placed in a subcutaneous pouch (similar to a pacemaker) using

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local anesthesia and has a battery life of 18 to 24 months. In one series of 64 patients, syncope was correlated with ECG evidence of arrhythmia in 27% [44]. An excellent diagnostic yield has been suggested even in patients with recurrent syncope of unknown etiology after extensive testing. A small study of patients with negative workup including ambulatory ECG, TTT, and EPS demonstrated that 46% had symptom-correlated arrhythmias captured by ILR during a 2-year follow-up period; most of these events were bradycardic in origin. Only 14% of patients had recurrence of symptoms during the ﬁrst month, illustrating the limitation of external monitoring [45]. Up-front costs of implantation are high, and the procedure carries a small risk of complication. However, cost-beneﬁt analyses suggest that the increased diagnostic yield from ILR in the long run may lead to decreased overall expenditure in syncope diagnosis [46]. A recent randomized assessment of ILR versus a ‘‘conventional’’ diagnostic strategy, including EPS and TTT, in elderly patients with syncope showed signiﬁcantly improved (52% vs. 20%) diagnostic accuracy in the ILR group. However, patients with left ventricular ejection fraction (EF) less than 35% and patients with clinical symptoms suggesting neurally mediated syncope were excluded from the study group, biasing the results in favor of ILR [47]. Electrophysiological Study EPS involves the placement of several catheters into the right atrium and ventricle of the heart via central venous cannulation. Intracardiac ECG can be obtained and electrical stimuli can be delivered through the catheters to precipitate and record arrhythmic events. Patients with critical aortic stenosis, severe hypertrophic obstructive cardiomyopathy, unstable angina, decompensated CHF, or left main or severe three-vessel coronary artery disease should be excluded from EPS. An EPS carries the standard risks of infection and bleeding from any invasive procedure; more serious complications, such as pulmonary embolus, pneumothorax, and cardiac perforation leading to pericardial tamponade, are rare, but are more likely in the elderly. The use of EPS is gradually increasing among elderly subjects with syncope, and its diagnostic yield may be one of the highest among available testing strategies in appropriately selected patient populations. One study of 75 elderly patients with recurrent syncope referred for EPS found that 68% had abnormalities that could have produced syncope, including sinus node dysfunction (55%); abnormal His–bundle conduction (39%); and inducible ventricular tachycardia (14%) [48]. Despite this potential, EPS was performed in only 2% of 1516 elderly adults hospitalized for syncope in one observational study [11]. A diagnostic study is deﬁned by the following: (1) inducible sustained monomorphic VT; (2) paroxysmal SVT with symptomatic hypotension; (3) suﬃcient His-Purkinje conduction delay; and/or (4) sinus node dysfunction as delineated by sinus node recovery time greater than 3 s. Induced atrial ﬁbrillation, SVT without hypotension, polymorphic VT, and VF are generally regarded as nonspeciﬁc ﬁndings. Even ‘‘diagnostic’’ ﬁndings on EPS must be interpreted with caution, as concerns exist regarding the sensitivity, speciﬁcity, and clinical consequences of a positive study; routine evaluation with EPS in patients with suspected bradycardia is not recommended because of its low sensitivity. The advent of eﬀective therapy for malignant ventricular tachyarrhythmias via automatic implantable cardioverter-deﬁbrillator (AICD) has profoundly changed the importance of risk stratiﬁcation for life-threatening VT. Any discussion of EPS to diagnose VT-induced syncope is by nature tied to this life-saving therapy. Several trials have shown a decrease in overall mortality by following AICD implantation in survivors of cardiac

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arrest with severely decreased left ventricular EF [49–51]. The data supporting the use of EPS for the diagnosis of VT in syncope comes from the observation of high-risk patients following AICD implantation. In a trial in which 178 patients with syncope and inducible monomorphic VT on EPS and 568 patients with documented clinical sustained VT or VF who were followed prospectively after AICD implantation, the actuarial probability of appropriate AICD therapy in both groups was 49% at 1 year and clinical outcomes did not diﬀer. Recurrent syncope in this trial was associated with VT or VF in 85 to 90% of episodes [52]. Little data exist, but newer AICDs capable of antitachycardia pacing and earlier termination of VT events may lead to fewer episodes of clinical syncope in these patients [53]. The diagnostic yield of EPS in patients with unexplained syncope is much greater in patients with preexisting heart disease [54] (i.e., previous MI, ejection fraction <0.40, and/ or an abnormal rest ECG (especially bundle branch block) [55]. Such patients should be strongly considered for EPS following even their ﬁrst episode of syncope, unless an alternative diagnosis is clear from initial evaluation. Electrophysiological testing is unlikely to demonstrate a potential cause of syncope in patients who have no structural heart disease, a left ventricular ejection fraction >0.40, no ventricular ectopic activity during cardiac monitoring, and a normal ECG. The absence of all these variables in a patient with multiple syncopal episodes predicts with a high degree of certainty (greater than 99%) that the EPS will be negative and the risk of sudden death low [55]. It should also be noted that while syncope in patients with nonischemic dilated cardiomyopathy is a predictor of sudden death [56], the sensitivity and speciﬁcity of EPS in this population are insuﬃcient to make it useful in the prediction of ventricular tachyarrhythmias [57,58]. Patients with negative EPS and ischemic heart disease have an excellent long-term prognosis with respect to mortality. In two trials of patients with nondiagnostic or negative EPS after syncope, the incidence of sudden death was 2% after follow-up of 2 to 3 years. Syncope recurrence in these patients, however, was still common at approximately 20%. Most of these episodes were found to be noncardiac in origin; those with cardiovascular etiologies were most often found to have bradycardia missed by EPS [59,60]. While EPS is a high-yield diagnostic test in the elderly patient with structural heart disease, the decision to undergo EPS should be made on a case-by-case basis. Patients with poor functional capacity, severe cognitive impairment or comorbidities likely to result in death within a relatively short period of time are probably not appropriate candidates. Patients who do not wish deﬁnitive therapy such as permanent pacemaker or AICD implantation may have an unacceptable risk–beneﬁt ratio with EPS as well. Noninvasive Assessment of Risk for Ventricular Tachycardia Noninvasive strategies for the prediction of ventricular tachyarrhythmias are attractive in the elderly population, particularly in patients reluctant to undergo EPS. Two techniques currently in use are the signal-averaged ECG (SAECG) and T-wave alternans (TWA) testing. However, data supporting the eﬃcacy of either test in the evaluation of syncope are limited, and these tools cannot be applied to a signiﬁcant portion of elderly patients with other than normal sinus rhythm. The SAECG averages multiple QRS complexes in the attempt to identify ‘‘late potentials,’’ delayed electrical conduction through diseased areas of myocardium. It is more diﬃcult to interpret in patients with bundle branch block or intraventricular conduction delay, as the lengthened overall depolarization time obscures low-amplitude late potentials.

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The test has not been studied prospectively in outcomes related to syncope, but has been evaluated with respect to predicting the results of EPS. In patients with unexplained syncope, the combination of prior MI and abnormal SAECG had a positive predictive value of 60% for inducible VT at EPS, but the real utility of a SAECG may be to exclude patients at high risk for ventricular tachycardia [61]. The TWA analyzes microvolt changes in the T-wave (repolarization) portion of the ECG on an every-other-beat basis, and is usually performed during exercise to increase sensitivity. The test cannot be interpreted in atrial ﬁbrillation or with frequent premature cardiac beats. Patients with microvolt T-wave alternans, particularly in the setting of prior MI or dilated cardiomyopathy, show higher incidence of ventricular arrhythmias. A large prospective trial of patients undergoing EPS (41% with syncope) suggested the relative risk of malignant ventricular arrhythmia (average follow-up 297 days) in patients with positive TWA was 10.9 as compared with 7.1 for inducible VT on EPS and 4.5 for SAECG [62]. However, no trials using TWA speciﬁcally to examine patients with syncope have been published. Furthermore, many elderly patients may be unable to exercise to a suﬃcient heart rate and pharmacologically assisted TWA testing has not been well studied to date. Orthostatic Hypotension and Dysautonomic Disorders of Blood Pressure Control Orthostatic hypotension (OH) is an important cause of syncope in the elderly. Following the assumption of a standing position, gravity induces pooling of blood in the lower extremities. Blood pressure is normally maintained in this setting of decreased circulatory volume by vasoconstriction and increased heart rate. Numerous age-related changes in cardiovascular structure and function, including impaired baroreﬂex function, diastolic dysfunction, a higher prevalence of disorders that directly or indirectly impair autonomic function, the common use of vasoactive medications, and an impairment in salt and water balance, all contribute to an increase in the incidence and prevalence of OH in the elderly. All elderly patients with syncope should have measurement of orthostatic vital signs. Which parameter (systolic, diastolic, or mean blood pressure) is the best measure of orthostasis, how long patients should stand before blood pressure is measured, and what deﬁnes a signiﬁcant change in blood pressure have not been well studied. The most commonly accepted deﬁnition is a decline in systolic blood pressure of >20 mmHg or >10 mmHg in diastolic blood pressure upon standing. In the vast majority of patients with OH, the drop in blood pressure is detected within 2 min of assuming upright posture [63]. However, in certain patients, there is a delayed orthostatic intolerance and blood pressure progressively falls over 15 to 45 min. This response is termed a dysautonomic response to upright posture and can be observed during TTT. Orthostatic hypotension is a common ﬁnding in the elderly and is frequently not associated with symptoms [64]. In one prospective study of 223 patients with syncope, OH was detected in 69 patients (31%), but was common in patients for whom other probable causes of syncope were assigned following evaluation [63]. Syncope should not be attributed to orthostatic changes alone unless orthostatic symptoms are present or systolic blood pressure declines to less than 90 mmHg upon postural change [65]. Decreased intravascular volume and adverse eﬀects of drugs are the most common causes of symptomatic OH in the elderly [64]. The status of the patient’s hydration preceding the syncopal event should be assessed as well as their daily intake of salt and alcohol. The

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medications most commonly contributing to orthostasis in the elderly are nitrates, diuretics, antihypertensives, anti-Parkinsonian drugs, antidepressants, and antipsychotics. Certain situational factors may predispose elderly patients to orthostasis, notably the redistribution of circulatory volume to the splanchnic circulation following a meal. An evaluation of 47 community-dwelling elders and 3 patients admitted for syncope evaluation indicated that symptomatic hypotension during TTT occurred earlier and increased in incidence from 12 to 22% in the postprandial state [66]. Orthostatic hypotension may also be an important manifestation of autonomic dysfunction resulting from a wide variety of diseases and drugs. The Shy-Drager syndrome is associated with autonomic failure and involvement of the corticospinal, extrapyramidal, and cerebellar tracts, including a Parkinson-like syndrome. Parkinson’s disease itself can be associated with autonomic dysfunction. Lesions of the spinal cord caused by cervical trauma and other disorders, such as transverse myelitis, syringomyelia, and various tumors, may result in severe OH. Orthostatic hypotension may also be a manifestation of peripheral neuropathy that involves sympathetic ﬁbers. This may be associated with such diseases as diabetes mellitus, amyloidosis, porphyria, chronic alcoholism, and pernicious anemia. Neurally Mediated Disorders of Blood Pressure Control This collection of disorders involves a neural reﬂex mediated by the nucleus tractus solitarius, an area in the brainstem that regulates blood pressure. The receptors for the aﬀerent limb of the reﬂex are contained in several possible locations; examples include the left ventricle (vasovagal syncope), carotid sinus body (carotid sinus hypersensitivity), pharynx, or trachea (cough syncope), and the bladder (postmicturition syncope). In susceptible individuals, stimulation of the reﬂex results in withdrawal of sympathetic vasomotor tone and vasodilatation with resultant syncope. When accompanied by bradycardia, the term ‘‘vasovagal’’ is used while the term ‘‘vasodepressor’’ is employed for reﬂex reactions that are not accompanied by signiﬁcant bradycardia. Vasovagal Syncope The ‘‘simple faint’’ has traditionally been considered a disease of the young patient. Early studies of elderly institutionalized and community-dwelling patients indicated that syncope was neurally mediated in only 1 to 5% of cases [1,6]. At the time, neurally mediated syncope was diagnosed with the classical features of a precipitating event followed by nausea, pallor, and sweating. The elderly more commonly have syncope without a prodrome or with retrograde amnesia for the event, making diagnosis by history alone problematic. The more frequent use of TTT has suggested that neurally mediated syncope is much more common in the elderly than previously believed, and likely constitutes a signiﬁcant fraction of those previously carrying an ‘‘unknown’’ diagnosis. Carotid Sinus Hypersensitivity Carotid sinus hypersensitivity (CSH) has recently been described as a relatively underappreciated cause of unexplained falls and syncope in the elderly, with a prevalence in elderly adults presenting to the emergency department with unexplained falls of 34% in one trial [67]. Attacks may be precipitated by factors that exert pressure on the carotid sinus (tight collars, shaving, sudden turning), a history of which is obtained in one-quarter of patients with this syndrome. Syncope from CSH occurs predominantly in men, 70% of whom are

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over the age of 50; the majority of patients have coronary artery disease or hypertension. Other predisposing factors include cervical pathology such as enlarged lymph nodes, scars resulting from surgery to the neck, carotid body tumors, parotid, thyroid, and head and neck tumors. Carotid sinus hypersensitivity can manifest as bradycardia or vasodilatation and is classiﬁed according to its predominant hemodynamic manifestation. Cardioinhibitory CSH is deﬁned as sinus pauses greater than 3 s, while vasodepressor CSH is denoted as a fall in systolic blood pressure greater than 50 mmHg; if both mechanisms are noted, the disorder is termed mixed-type CSH. The diagnosis is made with carotid sinus massage (CSM), which some investigators consider positive only if symptoms are also reproduced during the examination [68]. Tilt-Table Testing In TTT, patients are secured to a motorized table with a footboard and brought quickly to an upright position at an angle of 60j to 80j while undergoing ECG and beat-to-beat blood pressure monitoring. Various protocols have been evaluated for the provocation of neurally mediated syncope through TTT, either in the drug-free state or with various pharmacological agents (nitroglycerin, isoproterenol, adenosine). In general, sensitivity of TTT increases with the use of pharmacological agents, longer duration of TTT, and a greater angle of head uptilt. However, with the addition of pharmacological agents, the speciﬁcity declines [69,70]. In patients with negative EPS, rates of hypotension on upright TTT (without pharmacological provocation) of 27 to 67% are reported as compared to approximately 10% in controls without syncope [71–74]. A retrospective evaluation of TTT in 352 subjects with unexplained syncope (including 133 patients >65 years of age and 43 patients >80 years of age) showed an age-related decline in positive TTT. However, a surprisingly high proportion of elderly patients with unexplained syncope had a positive TTT (37% of patients aged 65 and older, and 23% of patients aged 80 and older) [75]. These data demonstrate that a large proportion of elderly patients may have neurally mediated syncope that may be diﬃcult to diagnose based on clinical grounds alone. Upright TTT can conﬁrm the diagnosis in these patients and can help reassure patients that they have an excellent long-term prognosis in regard to mortality. Carotid Sinus Massage Many physicians have been hesitant to perform CSM because of the theoretical risk of stroke. However, after exluding patients with clinical history of stroke or TIA and/or audible carotid artery bruits, the risk of neurological complications was 0.17 to 0.45% in two studies on the safety of the maneuver [68,76]. Patients with history of VF or VT should be excluded, as ventricular dysrhythmias during CSM have been reported, albeit rarely, in this setting. Carotid sinus massage should be performed on one side at a time by applying gentle digital pressure for 5 to 10 s at the bifurcation of the carotid artery, below the angle of the jaw at the level of the cricothyroid cartilage. The procedure was initially performed only in the supine position, but CSM in the upright position (usually performed during a TTT session) increases sensitivity [77]. The distinction between cardioinhibitory and vasodepressor types is important so the test should be performed with continuous beat-to-beat blood pressure monitoring in addition to continuous ECG if possible. Dual-chamber pacing has been shown to prevent falls in patients with cardioinhibitory CSH [67], but the beneﬁts in mixedtype and vasodepressor forms of CSH are less clear.

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Primary Neurological Syncope As previously noted, primary neurological causes of syncope are relatively rare. Despite this ﬁnding, examination of current clinical practice indicates that speciﬁc neurological testing is performed in approximately half of syncope evaluations [12,41]. Seizures and Electroencephalography In patients with a clinical history compatible with a seizure or in whom the diagnosis is suspected after initial evaluation, EEGs may be beneﬁcial in conﬁrming the diagnosis. However, EEG should not be performed routinely in the evaluation of patients with syncope. In one study of 99 patients referred for EEG because of syncope, near-syncope, or related complaints, 15 had abnormal ﬁndings, but in only one patient was the ﬁnal diagnosis or treatment of the syncope aﬀected by the EEG. In addition, almost all patients with abnormal EEGs had clinical histories compatible with seizures or focal neurological ﬁndings on examination [78]. Strokes, Transient Ischemic Attacks, and Specific Testing In the elderly, cerebrovascular atherosclerosis and impaired cerebrovascular autoregulation secondary to hypertension can contribute to cerebral hypoperfusion in a variety of circumstances. However, syncope is generally not a primary manifestation of cerebrovascular disease unless disease of the posterior circulation is present. When secondary to vertebrobasilar disease, syncope is almost always accompanied by other neurological symptoms traced to ischemia in the same territory, such as vertigo and ataxia [79,80]. The common practice of cerebrovascular imaging via ultrasonography or other methods has not been extensively studied, but in the absence of suggestive history probably contributes little to diagnosis [81]. Brain imaging in the evaluation of syncope yields helpful information only in the setting of a suggestive history or abnormal ﬁndings on neurological examination. A review of 195 patients estimated the diagnostic yield of head CT at 4%; in all of these patients, a witnessed seizure or focal neurological examination was present [17]. In the setting of syncope and suspected trauma, head CT may be indicated to exclude a subdural hematoma. Suggested Diagnostic Algorithm Determining the underlying cause and risk stratiﬁcation for subjects with syncope relies on the performance of a complete history, physical examination (including orthostatic vital signs), and ECG. Approximate one-third of patients have a clear diagnosis evident at presentation. Another third of patients have a particular etiology highly suggested after initial evaluation, and directed testing can be performed in this group to conﬁrm the suspected diagnoses. Primary neurological causes of syncope are rare and speciﬁc neurological tests rarely are deﬁnitive in the absence of a suggestive history and physical examination. A suggested strategy for the diagnosis of syncope in the elderly patient is detailed below and in Figure 1. In the remaining patients with unexplained syncope after initial evaluation, cardiac testing, speciﬁcally with consideration of EPS, should be performed in patients with structural heart disease. For patients with recurrent unexplained syncope without structural heart or cardiac conduction system disease (or patients with structural heart disease and

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Figure 1 Suggested diagnostic algorithm for elderly patients with syncope. (Adapted from Ref. 82.)

negative cardiac testing), TTT to evaluate for orthostatic hypotension and neurally mediated causes is appropriate. This should be performed prior to long-term ECG monitoring in order to identify the signiﬁcant percent of subjects with neurally mediated syncope and resultant bradycardia who do not require pacing. If the etiology of syncope is still undetermined following directed cardiac and autonomic testing, long-term ECG monitoring should be employed. The ILR has excellent potential to obtain a diagnosis in these patients even if external monitoring is negative, particularly if episodes are separated by long time intervals.

CONCLUSIONS Syncope is common in the elderly and is associated with signiﬁcant morbidity and mortality. It is a symptom, not a disease, and has a complex diﬀerential diagnosis ranging from benign to malignant causes; elderly patients commonly have multiple possible contributing factors. The assignment of the underlying etiology can be greatly facilitated through an understanding of syncope epidemiology and the utility of relevant diagnostic tests. Identifying patients with underlying structural heart disease is important for risk stratiﬁcation. For

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patients with unexplained syncope, provocative tests (electrophysiological study, tilt-table test, and carotid sinus massage) are more likely to yield a deﬁnitive diagnosis than observational testing strategies.

ACKNOWLEDGMENTS Supported by the Society of Geriatric Cardiology and the National Institutes of Health. Dr. Hummel was supported by the Society of Geriatric Cardiology’s Merck Award. Dr. Maurer was supported by the National Institute on Aging, Bethesda, Maryland (K23AG00966A).

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28 Anticoagulation in the Elderly Jonathan L. Halperin The Zena and Michael Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, New York, U.S.A.

PHARMACOLOGY OF COUMARIN ANTICOAGULANT DRUGS The coumarin derivative warfarin acts as an anticoagulant by inhibiting formation of the vitamin K–dependent coagulation factors II, VII, IX, and X and interfering with carboxylation of the coagulation-regulating proteins C and S. The anticoagulant and antithrombotic eﬀects of warfarin can be distinguished; reduction of prothrombin and factor X are more important for the antithrombotic eﬀect than reduction of factors VII and IX. Whereas the anticoagulant eﬀect develops in 2 days, the antithrombotic eﬀect requires 6 days of treatment [1]. The relationship between dose and response is inﬂuenced by genetics, environment [2,3], drugs, diet, and various diseases. Variability also results from laboratory inaccuracy, patient noncompliance, and miscommunication between patients and physicians. Other drugs may inﬂuence the pharmacokinetics of warfarin, reducing gastrointestinal absorption, disrupting metabolic clearance, or inducing hepatic enzymatic activity [4]. Long-term warfarin therapy is sensitive to ﬂuctuating levels of dietary vitamin K [5,6], derived predominantly from the phylloquinone content of plant material [6]. Resistance to warfarin occurs in patients consuming green vegetables or vitamin K–containing supplements, while decreased dietary vitamin K1 intake in malabsorption states and in patients treated with antibiotics and intravenous ﬂuids without vitamin K supplementation potentiates the eﬀect of warfarin. Hepatic dysfunction potentiates the response to warfarin through impaired synthesis of coagulation factors. Hypermetabolic states associated with fever or hyperthyroidism increase responsiveness to warfarin, probably through catabolism of coagulation factors [7,8]. Drugs may inhibit synthesis or increase clearance of coagulation factors or interfere with other pathways of hemostasis. Aspirin [9] and nonsteroidal anti-inﬂammatory drugs [10] increase the risk of warfarinassociated bleeding by inhibiting platelet aggregation. These drugs can also cause gastric erosions and thereby increase the risk of upper gastrointestinal bleeding. The risk of clinically important bleeding is heightened by high doses of aspirin during high-intensity warfarin therapy (INR 3.0–4.5) [9,11]. In patients with prosthetic heart valves [12] and in asymptomatic individuals at high risk for coronary artery disease [13], low doses of aspirin (75 to 100 mg daily) were also associated with increased rates of minor bleeding when combined with moderate and low-intensity warfarin anticoagulation. 677

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DOSE ADJUSTMENT AND MONITORING OF ANTICOAGULATION INTENSITY The prothrombin time (PT) is the most common test used to monitor oral anticoagulant therapy [14]. The PT responds to reduction of three of the four vitamin K–dependent procoagulant clotting factors (II, VII, and X) at a rate proportionate to their respective halflives. Thus, during the ﬁrst few days of warfarin therapy, the PT reﬂects mainly reduction of factor VII, which has a half-life of approximately 6 h, while reduction of factors X and II subsequently contributes. The assay is performed on citrated plasma by adding calcium and thromboplastin (a phospholipid-protein extract containing both the tissue factor and phospholipid necessary to promote activation of factor X by factor VII) [15]. Because of the variability of thromboplastin responsiveness to warfarin, PT monitoring of warfarin treatment is imprecise when expressed as a ratio of the PT value of the patient’s plasma over that of normal control plasma. Adoption of the INR standard increases the safety of monitoring oral anticoagulant therapy. The INR is calculated as follows: INR ¼ ðpatient PT=mean normal PTÞISI or log INR ¼ ISIðlog observed PT ratioÞ; where ISI denotes the International Sensitivity Index of the thromboplastin used to perform the PT measurement. The ISI reﬂects the responsiveness of a given thromboplastin to reduction of the vitamin K–dependent coagulation factors compared to the primary international standard; the more responsive the reagent, the lower the ISI value [15]. As warfarin therapy is initiated, the INR should be checked daily until it reaches the therapeutic range and is sustained in this range for 2 consecutive days, then 2 or 3 times weekly for 1 to 2 weeks, and then less often, depending upon the stability of the results. Once the INR becomes stable, the frequency of testing can be reduced to intervals as long as 4 weeks. Dose adjustments require more frequent monitoring. The safety and eﬀectiveness of warfarin therapy depends critically on maintaining the INR within the therapeutic range. On-treatment analysis of the primary prevention trials in atrial ﬁbrillation found that a disproportionate number of thromboembolic and bleeding events occurred when the PT ratio was outside the therapeutic range [16], and subgroup analyses of other cohort studies have also shown an increased risk of bleeding when the INR exceeds the therapeutic range [17–20]and increased risk of thromboembolism when the INR falls below 2.0 [21,22]. One of the challenges inherent in warfarin therapy, however, is the diﬃculty maintaining anticoagulation intensity within such a narrow range. In the primary prevention trials in atrial ﬁbrillation, for example, despite management of a carefully selected patient population by dedicated staﬀ following rigid research protocols, INR values fell within the target range for 42 to 83% of net exposure (Fig. 1). Point-of-care (POC) PT measurements oﬀer the potential to simplify oral anticoagulation management in both the physician’s oﬃce and in the patient’s home. Over a 6month period, among 325 newly treated elderly patients randomized to either conventional treatment by personal physicians based on venous sampling or adjustment of dosage by a central investigator based on INR results from patient self-testing at home, the rate of hemorrhage was 12% in the usual care group compared to 6% in the self-testing group [23].

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Figure 1 The challenge of maintaining warfarin anticoagulation intensity within the target therapeutic range was demonstrated in trials involving patients with nonvalvular atrial ﬁbrillation. Despite more favorable conditions than those generally encountered in clinical practice, approximate INR values fell within the targeted range only about half the time. (AFASAK [81], BAATAF [88], SPAF [102], CAFA [103], SPINAF [104], EAFT [77])

Coupled with self-testing, self-management using POC instruments oﬀers independence and freedom of travel to selected patients. When compared with the outcomes of highquality anticoagulation clinic management, there was little diﬀerence between groups in time spent within therapeutic range, but patient self-management was associated with less deviation from the target INR. Several computer programs have been developed to guide warfarin dosing based on querying physicians [24], Bayesian forecasting [25], and mathematical equations [26]. In the INR range of 2.0 to 3.0, computerized dosage programs were comparable to dosing by experienced clinic staﬀ, but the computerized approach achieved signiﬁcantly better control at the higher intensity range of INR 3.0 to 4.5 [27]. Computer-guided warfarin dose adjustment may also be superior to manual dose regulation by inexperienced personnel.

MANAGEMENT OF PATIENTS WITH HIGH INR VALUES Even though the risk of bleeding increases, the daily absolute risk of bleeding is still low when the INR exceeds 4 to 5. The ﬁrst step when this occurs is to stop warfarin; the second is to administer vitamin K1; the third and most rapidly eﬀective measure is to infuse fresh plasma or prothrombin concentrate. Since no randomized trials have compared these strategies using clinical endpoints, the choice is based on clinical judgment. The INR falls over several days once warfarin is interrupted, reaching the normal range in 4 to 5 days when INR is between 2.0 and 3.0. In contrast, the INR declines substantially within 24 h after oral administration of vitamin K1, 1 to 2.5 mg [28], more rapidy than simply withholding warfarin [29], making oral vitamin K1 the treatment of choice unless more rapid reversal of anticoagulation is required, in which case vitamin K1 can be administered by slow intravenous infusion [30].

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BLEEDING DURING ORAL ANTICOAGULANT THERAPY Factors other than the intensity of anticoagulation that contribute to bleeding are the underlying clinical disorder [31,32] and concomitant administration of aspirin, nonsteroidal anti-inﬂammatory drugs, or other drugs that impair platelet function, produce gastric erosions, or impair synthesis of clotting factors. Bleeding that occurs at INR <3.0 is frequently associated with trauma or an underlying lesion in the gastrointestinal or urinary tract [31]. The risk of major bleeding is also related to age over 65 years, a history of stroke or gastrointestinal bleeding, and comorbid conditions such as renal insuﬃciency or anemia [31,33], and these factors are additive [34]. Even after controlling for anticoagulation intensity, the elderly are more prone to bleeding (Fig. 2) [16,35]. Long-term management of patients who have developed bleeding during warfarin anticoagulation yet require thromboembolic prophylaxis (e.g., those with mechanical heart valves or high-risk patients with atrial ﬁbrillation) presents a diﬃcult therapeutic challenge. When bleeding occurs at an INR above the therapeutic range, warfarin can be resumed once bleeding has stopped and its cause has been corrected. When the risk of bleeding is persistent, targeting a lower INR seems sensible [21].

MANAGEMENT OF ANTICOAGULATION IN PATIENTS UNDERGOING SURGICAL PROCEDURES The management of patients treated with warfarin who require interruption of anticoagulation for surgery or other invasive procedures involves a choice between several approaches, depending on the risk of thromboembolism [36]. In most patients, warfarin is stopped 4 to 5 days preoperatively, allowing the INR to return to
Figure 2 Cumulative rates of major bleeding in the Italian Study of Complications of Anticoagulant Therapy (ISCOAT). The cumulative incidence of major bleeding in patients over 75 years of age (10.8%; 95% CI, 1.8 to 19.8) was signiﬁcantly higher than in younger patients (2.8%; 95% CI, 0.3 to 5.3; p = 0.006). Major primary bleeding unrelated to organic lesions occurred signiﬁcantly more often in patients >75 years old (cumulative incidence 9.6%; 95% CI 0.8 to 18.4) than in younger patients (1.2%; 95% CI, 0 to 3.0; p = 0.0003) [105].

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tional anticoagulant therapy can be given preoperatively with either heparin or lowmolecular-weight heparin to limit the period of time that the patient remains unprotected and anticoagulant therapy can be recommenced postoperatively once it is deemed safe to restart treatment.

NONHEMORRHAGIC ADVERSE EFFECTS OF WARFARIN Other than hemorrhage, the most important side eﬀect of warfarin is skin necrosis. This uncommon complication is usually observed on the third to eighth day of therapy [37,38] and is caused by extensive thrombosis of venules and capillaries within subcutaneous fat. The pathogenesis of this striking complication is uncertain. An association between warfarin-induced skin necrosis and protein C deﬁciency [39–41] and, less commonly, protein S deﬁciency [42] has been reported, but warfarin-induced skin necrosis also occurs in patients without these deﬁciencies. Patients with coumarin-induced skin necrosis who require further anticoagulant therapy are problematic. Warfarin can be restarted at a low dose (e.g., 2 mg daily) while therapeutic doses of heparin are administered concurrently, and gradually increase warfarin over several weeks to avoid an abrupt fall in protein C levels before reduction in levels of coagulation factors occurs [40,41].

CLINICAL APPLICATIONS OF ORAL ANTICOAGULANT THERAPY Oral anticoagulants are eﬀective for primary and secondary prevention of venous thromboembolism, for prevention of systemic embolism in patients with prosthetic heart valves or atrial ﬁbrillation, for prevention of acute myocardial infarction in patients with peripheral arterial disease and in those otherwise at high risk, and for prevention of stroke, recurrent infarction, or death in patients with acute myocardial infarction [13]. Although eﬀectiveness has not been proven by a randomized trial, oral anticoagulants are also indicated for prevention of systemic embolism in high-risk patients with mitral stenosis and in patients with presumed systemic embolism, either crytogenic or in association with patent foramen ovale. For most of these indications, a moderate anticoagulant intensity (INR 2.0 to 3.0) is appropriate. Although anticoagulants are sometimes used for secondary prevention of cerebral ischemia of presumed arterial origin when antiplatelet agents have failed, the SPIRIT study found high-intensity oral anticoagulation (INR 3.0 to 4.5) dangerous in such cases [19]. The trial was stopped at the ﬁrst interim analysis of 1316 patients with a mean follow-up of 14 months because there were 53 major bleeding complications during anticoagulant therapy (27 intracranial, 17 fatal) versus 6 on aspirin (3 intracranial, 1 fatal). The authors concluded that oral anticoagulants are not safe when adjusted to a targeted INR range of 3.0 to 4.5 in patients who have experienced cerebral ischemia of presumed arterial origin. In a second study (the WARSS trial), 2206 patients with noncardioembolic ischemic stroke were randomly assigned to receive either low-intensity warfarin (INR 1.4 to 2.8) or aspirin (325 mg/day). The primary endpoint of death or recurrent ischemic stroke in patients assigned to warfarin (17.8%) and those assigned to aspirin (16.0%) were not signiﬁcantly diﬀerent, nor were rates of major bleeding (2.2% and 1.5% in the warfarin and aspirin groups, respectively) [20].

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PREVENTION AND TREATMENT OF VENOUS THROMBOEMBOLISM Oral anticoagulants when given at a dose suﬃcient to maintain INR between 2.0 and 3.0 are eﬀective for prevention of venous thrombosis after hip surgery [43,44] and major gynecological surgery [45,46]. The risk of clinically important bleeding at this intensity is modest. A very low ﬁxed dose of warfarin (1 mg daily) was eﬀective in one small study involving patients undergoing gynecological surgery [46] and in a larger study in which subclavian vein thrombosis was prevented in patients with malignancy and indwelling venous catheters [47]. In contrast, four randomized trials found this dose of warfarin ineﬀective for preventing postoperative venous thrombosis in patients undergoing major orthopedic surgery [48–51]. In general, when warfarin is used to prevent venous thromboembolism, the targeted INR should be 2.0 to 3.0. The optimum duration of oral anticoagulant therapy is inﬂuenced by the competing risks of bleeding and recurrent venous thromboembolism. The risk of major bleeding during oral anticoagulant therapy is about 3% per year with an annual case fatality rate of about 0.6%. On the other hand, the case fatality rate from recurrent venous thromboembolism is about 5 to 7%, the rate being higher in patients with pulmonary embolism. Therefore, at an annual recurrence rate of 12%, the risk of death from recurrent thromboembolism is balanced by the risk of death from anticoagulant-related bleeding. The risk of recurrent thromboembolism when anticoagulant therapy is discontinued depends upon whether thrombosis is unprovoked (idiopathic) or secondary to a reversible cause; a longer course of therapy is warranted when thrombosis is idiopathic or associated with a continuing risk factor [52]. The reported risk of recurrence in patients with idiopathic proximal vein thrombosis has been reported to be between 10 and 27% when anticoagulants are discontinued after 3 months. Extending therapy beyond 6 months appears to reduce the risk of recurrence to 5 to 7% during the year after treatment is discontinued. In general, patients should be treated with anticoagulants for a minimum of 3 months. Treatment should also be longer in patients with proximal vein thrombosis and in those with recurrent thrombosis. Laboratory evidence of thrombophilia may also warrant a longer duration of anticoagulant therapy. Oral anticoagulant therapy is indicated for 6 to 12 weeks in those with symptomatic calf vein thrombosis, for at least 3 months in patients with proximal deep vein thrombosis [53,54], and for at least 6 months in those in whom a reversible cause cannot be eliminated and in those with recurrent thrombosis [55–57]. Indeﬁnite anticoagulant therapy should be considered in patients with more than one episode of idiopathic proximal vein thrombosis, thrombosis complicating malignancy, or idiopathic venous thrombosis and homozygous factor V Leiden genotype, the antiphospholipid antibody syndrome, or deﬁciencies of antithrombin-III, protein C, or protein S [58–60].

PREVENTION OF CORONARY EVENTS The Thrombosis Prevention Trial evaluated warfarin (target INR 1.3 to 1.8), aspirin (75 mg/ day), both, or neither in 5499 men aged 45 to 69 years at risk of a ﬁrst myocardial infarction [13]. The primary outcome was acute myocardial ischemia, deﬁned as coronary death or nonfatal myocardial infarction. The annual incidence of coronary events was 1.4% per year in the placebo group, while the combination of warfarin and aspirin reduced the relative risk by 34% ( p = 0.006). Given separately, neither warfarin nor aspirin produced a signiﬁcant

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reduction in acute ischemic events, and the eﬃcacy of the two drugs was similar (relative risk reductions 22% and 23% with warfarin and aspirin, respectively). The combined treatment was associated with a small but signiﬁcant increase in hemorrhagic stroke. These results suggest that, in the primary prevention setting, low-intensity warfarin anticoagulation targeting an INR of 1.3 to 1.8 is eﬀective for prevention of acute ischemic events (particularly fatal events) and that the combination of low-intensity warfarin plus aspirin is more eﬀective than either agent alone at the price of a small increase in bleeding.

ACUTE MYOCARDIAL INFARCTION Initial evidence supporting anticoagulation in patients with acute myocardial infarction (AMI) dates to the 1960s and l970s, when warfarin given in moderate intensity (approximate corresponding INR 1.5 to 2.5) was found eﬀective for prevention of stroke and pulmonary embolism [61–65]. Eﬀectiveness of oral anticoagulants in the long-term management of patients with AMI was supported by a meta-analysis of seven randomized trials published between 1964 and 1980, which showed that oral anticoagulants reduced the combined endpoints of mortality and nonfatal reinfarction by approximately 20% during treatment periods between 1 and 6 years [64–66]. In the Sixty-Plus Re-infarction Study of patients over age 60 years treated with oral anticoagulants for at least 6 months, lower rates of reinfarction and stroke were observed in patients randomized to continue anticoagulant therapy than in those from whom anticoagulation was withdrawn [67]. As a treatment interruption trial in a select age group, the generalizability of these ﬁndings was limited, but ithe Warfarin Re-infarction Study (WARIS) with no age restriction found a 50% reduction in the combined outcomes of recurrent infarction, stroke, and mortality [68]. The Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Trial [17], which also had no age restriction, reported z50% reduction in reinfarction and a 40% reduction in stroke among survivors of myocardial infarction. In each of these studies, high-intensity warfarin regimens were employed (INR 2.7 to 4.5 in the Sixty-Plus Study and 2.8 to 4.8 in the WARIS and ASPECT studies), and the incidence of bleeding was increased with anticoagulants. A conservative approach to anticoagulation in patients with acute myocardial infarction is to give heparin initially with thrombolytic therapy or when there is an increased risk of systemic or pulmonary embolism (anterior Q-waves, severe LV dysfunction, CHF, previous systemic or pulmonary embolism or echocardiographic evidence of mural thrombus), followed by warfarin (INR 2.0 to 3.0) for up to 3 months, and by aspirin thereafter. For patients with atrial ﬁbrillation, warfarin (INR 2.0 to 3.0) should be continued indeﬁnitely. A small dose of aspirin (80 to 100 mg/day) may be given concurrently with warfarin (INR 2.0 to 3.0), but the combination increases the risk of bleeding and should be restricted to situations in which either therapy alone has failed or there is unusually high thromboembolic risk.

PROSTHETIC HEART VALVES Guidelines developed by the European Society of Cardiology [69] call for anticoagulant intensity proportionate to the thromboembolic risk associated with speciﬁc types of

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prosthetic heart valves. For patients with ﬁrst-generation prostheses, INR 3.0 to 4.5 was recommended, an INR 3.0 to 3.5 was considered sensible for second-generation valves in the mitral position, while INR 2.5 to 3.0 was deemed suﬃcient for second-generation valves in the aortic position. The American College of Chest Physicians guidelines of 2001 recommend INR 2.5 to 3.5 for most patients with mechanical prosthetic valves, and 2.0 to 3.0 for those with bioprosthetic valves and low-risk patients with bileaﬂet mechanical valves (such as the St. Jude MedicalR device) in the aortic position [70]. Similar guidelines have been promulgated conjointly by the American College of Cardiology and the American Heart Association [71]. In contrast, some European investigators have recommended a higher upper limit for the therapeutic range (INR 4.8 to 5.0) [18,72].

ATRIAL FIBRILLATION Atrial ﬁbrillation (AF) is the most common sustained cardiac arrhythmia, and there is a strong correlation between increasing age and the prevalence of AF, which rises to 5.9% among people older than 65 years of age. Seventy percent of patients with AF are between 65 and 85 years old, and it is estimated that nearly one-third of all cases of AF occur in people older than 80 [73]. Application of age-speciﬁc estimates of the prevalence of AF to U.S. census data yield a projection that, in the year 2050, 5.6 million adults in the United States will be diagnosed with AF [74]. AF is a potent risk factor both for ischemic stroke and for mortality. Impaired atrial emptying associated with AF leads to stasis and increases the risk of thrombus formation, particularly in the left-atrial appendage (LAA). The surface of the newly formed thrombus is itself highly thrombogenic, creating a local hypercoagulable state and promoting its continued development. Exposure to the dynamic circulatory forces within the cardiac chambers promotes embolization of cardiogenic thrombi and subsequent ischemic events, including stroke and peripheral arterial occlusion. In addition to this mechanism, patients with AF commonly have other cardiovascular disease states, such as hypertension and atherosclerosis, which raise the risk of cerebrovascular ischemic events. According to the National Heart, Lung, and Blood Institute’s Framingham study, 15% of all strokes are associated with nonvalvular AF (AF unrelated to rheumatic mitral valve disease or a prosthetic heart valve) [75]. The importance of AF as a potent independent risk factor for stroke is borne out by this and other epidemiological studies. A combined analysis of ﬁve primary prevention trials found stroke rate over 8% per year in patients with AF older than 75 years of age with one clinical risk factor, and 12% per year at any age in patients with a history of thromboembolism [76,77]. Three-year stroke rates in elderly nursing home patients not anticoagulated are in excess of 50% [78]. Multiple well-designed trials have established that appropriate prevention strategies can dramatically decrease the risk of cardioembolic stroke associated with AF. Aspirin is associated with a relative risk reduction (RRR) of approximately 21%; adjusteddose warfarin (INR 2.0 to 3.0) has demonstrated RRR of approximately 68% [79]. Comparing the two prophylactic modalities reveals that adjusted-dose warfarin is considerably more eﬀective than aspirin (RRR, 36% [CI, 14% to 52%]) [80]; underuse of warfarin in patients with AF, however, is a serious problem that impedes eﬀective prevention of stroke. In recent decades, several randomized trials have demonstrated the eﬃcacy of adjusted-dose warfarin for the prevention of ischemic stroke in patients with AF with

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RRR between 47 and 86% versus placebo. The AFASAK-1 trial showed a statistically signiﬁcant 48% RRR in the warfarin treatment group (approximate INR 2.8 to 4.2) compared with aspirin (75 mg daily) for prevention of stroke and systemic embolism [79,81]. The adjusted-dose warfarin (target INR 2.5 to 4.0) arm of the European Atrial Fibrillation Trial (EAFT), which enrolled patients with AF who had recently suﬀered a minor ischemic stroke (deﬁned as grade 3 or less on the modiﬁed Rankin functional scale), had RRR of 40% (95% CI, 0.41 to 0.87; p = 0.008) compared with aspirin (300 mg daily). The risk reduction for the composite endpoint was driven by a statistically signiﬁcant RRR of 62% for all strokes (95% CI, 0.23 to 0.64; p < 0.001) [77]. According to the available data, oral anticoagulation with warfarin (INR 2.0 to 3.0) is more eﬀective in prevention of primary and secondary stroke than aspirin. The SPAF-II study distinguished patients on the basis of age less than or greater than 75 at entry and randomized them to aspirin versus adjusted-dose warfarin. Over a mean of 3 years, the rate of primary events was 1.9% per year on aspirin versus 1.3% per year on warfarin (RRR = 33%; p = 0.2) among the AF patients <75 years old (absolute rate reduction 0.7% per year; 95% CI, 0.4 to 1.7) [82]. Among patients >75 years old, the rate of primary events (mean follow-up 2 years) was 4.8% per year on aspirin versus 3.6% per year on warfarin (RRR = 27%; p = 0.4; absolute event reduction 1.2% per year 95% CI, 1.7 to 4.1). A high rate of intracranial hemorrhage during anticoagulation in those >75 years old (1.8% per yr) oﬀset the reduction in ischemic stroke (Fig. 3). The SPAF-II trials demonstrated only small beneﬁts of warfarin over aspirin for unselected AF patients (number needed-to-treat >200 for reduction of ischemic and hemorrhagic stroke) and drew attention to the importance of stroke risk stratiﬁcation to identify AF patients who beneﬁt substantially from anticoagulation. In the SPAF-III trial, adjusted-dose warfarin (INR 2.0 to 3.0) was much more eﬀective than the combination of ﬁxed, low-dose warfarin (initial INR 1.2 to 1.5) and aspirin (325 mg daily) in patients with AF and additional risk factors for stroke (1.9% versus 7.9%; 95% CI, 3.4 to 8.6; p < 0.0001) without an increase in hemorrhagic complications [22]. The

Figure 3 Rates of disabling stroke in the Stroke Prevention in Atrial Fibrillation (SPAF)-II study. The upper portions of each bar indicate hemorrhagic strokes, while the lower portions represent ischemic strokes. Event rates were higher among elderly patients than younger ones, and the risk of disabling brain hemorrhage on warfarin (mean INR 2.6) outweighed the net gain from reduction of ischemic events, compared to treatment with aspirin, 325 mg daily [82]. Bleeding rates in elderly patients with AF were higher in the SPAF-II study than in other trials, and anticoagulation is currently recommended for most older patients with AF.

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AFASAK-2 study was similarly designed to evaluate the eﬀectiveness of ﬁxed minidose warfarin and aspirin, alone or in combination, for prevention of stroke in patients with AF, but it was stopped prematurely based on the results of SPAF-III [83]. There is a clear reduction in the risk of stroke or systemic embolization associated with the use of adjusted-dose warfarin in patients with AF. A pooled analysis found that adjusted-dose warfarin reduces the risk of stroke by about two-thirds versus control [79,80]. The magnitude of the beneﬁt associated with adjusted-dose warfarin was fairly consistent among the ﬁve trials despite variations in design and the intensity of anticoagulation. Current treatment guidelines recommend a target INR of 2.5 (range 2.0 to 3.0) for patients with nonvalvular (nonrheumatic) AF who have risk factors for thromboembolism [79,84]. Compared with aspirin, adjusted-dose warfarin reduces the overall risk of stroke by 36% (CI, 14 to 52%) and ischemic stroke by 46% (CI, 27 to 60%) [80]. The discrepancy is driven largely by the results of the SPAF-II trial (mean INR 2.6) in an patient cohort older than enrolled in many other studies [85]. The risk of intracranial bleeding among patients receiving adjusted-dose warfarin was substantially increased in this study among patients older than 75 years of age. Exclusion of SPAF-II data from the meta-analysis revealed a 49% reduction in the risk of all stroke for adjusted-dose warfarin compared with aspirin (95% CI 26 to 65%) [80]. Despite the well-documented eﬃcacy of warfarin for prevention of stroke, fewer than 40% of patients with AF who are eligible for adjusted-dose warfarin therapy receive warfarin [86]. Concern regarding hemorrhagic complications, especially intracranial bleeding, is thought to inﬂuence the use of anticoagulation therapy in prevention of stroke. A recent meta-analysis of randomized trials of anticoagulant/antiplatelet prevention of stroke in patients with AF reported only a 0.2% absolute annual increase in major extracranial bleeding among patients receiving warfarin compared with those receiving aspirin, but a 2.1fold increase in intracranial bleeding [80]. The use of aspirin was not associated with signiﬁcantly increased rates of major bleeding compared with placebo. Although it is apparent that adjusted-dose warfarin carries the risk of hemorrhagic complications, the stroke-prevention beneﬁt seen in patients with AF justiﬁes the use of this therapy, particularly for secondary prevention. For most patients, therefore, the risk of bleeding does not oﬀset the beneﬁt of therapy. The magnitude of the absolute reduction in stroke achieved through prophylactic therapy in patients with AF varies based upon the inherent risk for stroke [80]. For example, in patients at relatively low risk receiving doseadjusted warfarin as primary prevention, six strokes may be prevented at the cost of three major extracranial bleeds per 1000 patients treated per year, whereas in patients with a high risk of stroke receiving dose-adjusted warfarin, 36 strokes may be prevented per 1000 patients per year treated at the same cost of bleeding. As a result, risk-stratiﬁcation algorithms have been developed to assist clinicians considering the beneﬁts and bleeding risks of therapy. Deciding which course of antithrombotic therapy is appropriate for a particular patient ultimately depends on the risks of stroke and major hemorrhage, adequacy of monitoring, and patient preference. In balancing the risks of warfarin against its beneﬁts, many physicians conclude that the risk of hemorrhage outweighs the protective eﬀect of prophylaxis with warfarin. Other patient-, physician-, and technology-related impediments to stroke prophylaxis with warfarin have been described [87]. The narrow therapeutic margin of warfarin and interactions with countless other medications and with foods and alcohol contribute to

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considerable underuse of oral anticoagulant therapy in patients with AF who stand to beneﬁt. According to a 1996 national ambulatory care survey, only 33% of patients with AF in whom warfarin was indicated were taking it [86], whereas aspirin was used by 20% of patients not using warfarin. A multiple logistic regression analysis found that patients with AF and a history of stroke were more likely to receive warfarin, and those seeing cardiologists or internists had a higher rate of warfarin use than those under the care of family or general practitioners. Patients older than 80 years were less likely to receive warfarin (odds ratio, 0.60; 95% CI 0.37 to 0.98) than younger patients [86]. Of 312 persons with AF, average age 84 years, who resided in a chronic care facility, rates of stroke over 3 years in those not anticoagulated were 56% in those with no prior history of thromboembolism and 81% in those with prior thromboembolism [78]. Patients 65 years or older with AF and a history of ischemic stroke are at an exceptionally high risk of recurrent thrombotic events (>10% per year), yet a study of such cases among Medicare recipients found warfarin used suboptimally [88,89]. Brass and colleagues found that only 53% of stroke survivors were prescribed warfarin on discharge, and aspirin was prescribed in only 38% of those not receiving warfarin, indicating that a substantial percentage of stroke survivors did not receive any medication at all for secondary prevention [89]. There was a slight, but statistically signiﬁcant, increase in use of warfarin among patients who had no contraindications to anticoagulation but no increase among patients with additional risk factors for ischemic stroke, which supports the hypothesis that fear of hemorrhage plays a large role in the selection of patients for anticoagulant therapy.

ANTICOAGULATION IN ELDERLY PATIENTS WITH ATRIAL FIBRILLATION Concern over hemorrhagic complications, especially catastrophic intracranial bleeding, inﬂuences the use of anticoagulation therapy for prevention of stroke, particularly among patients z80 years old. Older patients with AF are at an increased risk of both ischemic stroke and bleeding. In one study in an academic, hospital-based geriatrics practice, 90% of patients at mean age of 80 years with electrocardiographically documented AF were categorized at high risk for stroke and had no contraindications to warfarin [90]. Only 49% of these patients were receiving adjusted-dose warfarin; 36% were taking aspirin; and the remaining 15% received no prophylaxis. Similar ﬁndings were reported in the Cardiovascular Health Study, in which only 37% of these high-risk patients with AF were receiving adjusted-dose warfarin, whereas 47% received aspirin [91]. To assist clinicians in balancing the risks and beneﬁts of anticoagulation in elderly patients based on age and weighted risks of hemorrhage and thromboembolism rather than clinical judgment, Eckman and coworkers proposed a decision-analysis tool [92]. Patient-speciﬁc risk ratios are plotted on a decision grid leading to three possible outcomes: anticoagulate; do not anticoagulate; and neither decision will have a signiﬁcant impact on risk. Currently available antithrombotic regimens for prevention of stroke in patients with AF are saddled with limitations. Warfarin is much more eﬀective than aspirin for prevention of stroke, but is used by less than 40% of patients with AF for whom it is indicated, mainly

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because of the real and perceived risks of hemorrhage as well as the inconvenience and expense imposed by the need for frequent monitoring. An eﬀective, safe oral anticoagulant exhibiting a predictable linear dose response would preclude the routine laboratory monitoring necessary with warfarin. An agent with minimal side eﬀects or food–medication interactions is desirable for patients with AF who are typically more than 65 years old and taking nearly ﬁve other medications for various medical conditions. Rapid onset of therapeutic eﬀect and easy reversibility would constitute signiﬁcant additional advantages over warfarin, which takes several days to become fully eﬀective when started and a similarly delayed oﬀset of anticoagulant eﬀect when discontinued. The oral agent ximelagatran—a prodrug of the direct thrombin inhibitor, melagatran—exhibits rapid absorption and biotransformation to the active form. Melagatran is primarily excreted renally. The linear dose–response relationships and wide therapeutic windows observed with both ximelagatran and melagatran obviate the need for routine anticoagulation monitoring [93–96]. Drug interaction studies involving cytochrome-P450 enzymes and food interaction studies are ongoing with ximelagatran, but no interactions have been reported to date. The drug is currently under investigation for the prevention and treatment of venous thromboembolism and for prevention of ischemic stroke in patients with AF. The eﬃcacy and safety of ximelagatran for prevention of stroke in patients with AF is being evaluated in the Stroke Prevention Using Oral Thrombin Inhibition in Atrial Fibrillation (SPORTIF) clinical trials. SPORTIF-II was a randomized, parallel group, dose-ﬁnding, phase 2 trial involving patients with nonvalvular AF and at least one additional risk factor for stroke (median age 70 years). The primary outcome was the number of adverse events (thromboembolism or stroke). A total of 257 patients were randomized to treatment in one of four groups; three groups (n = 187) received ximelagatran 20, 40, or 60 mg twice daily, and the fourth was treated with adjusted-dose warfarin (INR 2.0 to 3.0). Over 3 months, two of the 67 patients in the warfarin group (3%) experienced TIA. In the ximelagatran groups, one of 187 patients had a TIA (0.5%), and one developed ischemic stroke (0.5%); both events occurred in the 60-mg arm. Major bleeding occurred in only one patient who was receiving warfarin. Minor bleeding rates were low and similar among all the groups. Ximelagatran was well tolerated and did not require routine anticoagulation monitoring or dose adjustment. SPORTIF-IV is an open-label extension of SPORTIF-II in which patients originally randomized to ximelagatran continued this agent in a ﬁxed dose of 36 mg twice daily, and the others continued warfarin to prevent stroke and systemic embolism. Two phase 3 trials—SPORTIF-III (in 25 nations, open label) and SPORTIF-V (in North America, double blind)—are each randomizing more than 3000 patients with AF to treatment with adjusted-dose warfarin or ximelagatran, 36 mg twice daily. As an emerging therapeutic modality, oral direct thrombin inhibitors may have a substantial impact on the management of patients with AF in the future.

OTHER INDICATIONS FOR ORAL ANTICOAGULANT THERAPY Other widely accepted indications for oral anticoagulant therapy have not been evaluated in properly designed clinical trials. Among these are atrial ﬁbrillation associated with valvular heart disease and mitral stenosis in the presence of sinus rhythm. Long-term oral

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anticoagulation (INR 2.0 to 3.0) is also indicated in patients who have sustained one or more episodes of systemic thromboembolism. Anticoagulants are not presently indicated in patients with ischemic cerebrovascular disease [20,97]. Reduced left ventricular systolic function is associated with both stroke and mortality even in the absence of documented atrial ﬁbrillation [98]. Warfarin is used frequently in patients with dilated cardiomyopathy, although no randomized trials have conﬁrmed the beneﬁt of anticoagulation [99]. Longterm anticoagulant therapy is also indicated in patients with ischemic stroke of unknown origin who have a combination of a patent foramen ovale and atrial septal aneurysm, since these patients have an increased risk of recurrent stroke despite treatment with aspirin [100,101].

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42. Grimaudo V, Gueissaz F, Hauert J, Sarraj A, Kruithof EK, Bachmann F. Necrosis of skin induced by coumarin in a patient deﬁcient in protein S. BMJ 1989; 298:233–234. 43. Francis CW, Marder VJ, Evarts CM, et al. Two-step warfarin therapy: prevention of postoperative venous thrombosis without excessive bleeding. JAMA 1983; 249:374–378. 44. Powers PJ, Gent M, Jay RM, et al. A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip. Arch Intern Med 1989; 149:771–774. 45. Taberner DA, Poller L, Burslem RW, et al. Oral anticoagulants controlled by the British comparative thromboplastin versus low-dose heparin in prophylaxis of deep vein thrombosis. BMJ 1978; 1:272–274. 46. Poller L, McKernan A, Thomson JM, et al. Fixed minidose warfarin: A new approach to prophylaxis against venous thrombosis after major surgery. BMJ 1987; 295:1309–1312. 47. Bern MM, Lokich JJ, Wallach SR, et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. Ann Intern Med 1990; 112:423–428. 48. Poller L, MacCallum PK, Thomson JM, et al. Reduction of factor VII coagulant activity (VIIC), a risk ractor for ischaemic heart disease, by ﬁxed dose warfarin: A double blind crossover study. Br Heart J 1990; 63:231–233. 49. Dale C, Gallus AS, Wycherley A, et al. Prevention of venous thrombosis with minidose warfarin after joint replacement. BMJ 1991; 303:224. 50. Fordyce MJF, Baker AS, Staddon GE. Eﬃcacy of ﬁxed minidose warfarin prophylaxis in total hip replacement. BMJ 1991; 303:219–220. 51. Poller L, Thomson JM, MacCallum PK, et al. Minidose warfarin and failure to prevent deep vein thrombosis after joint replacement surgery despite inhibiting the postoperative riise in plasminogen activator inhibitor activity. Clin Appl Thromb Hemostas 1995; 1:267– 273. 52. Hirsh J. The optimal duration of anticoagulant therapy for venous thrombosis. N Engl J Med 1995; 332:1710–1711. 53. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979; 302:855–858. 54. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306:189–194. 55. Lagerstedt CI, Fagher BO, Albrechtsson U, et al. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985; 2:515–521. 56. Schulman S, Rhedin A, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a ﬁrst episode of venous thromboembolism. N Engl J Med 1995; 332:1661–1665. 57. Schulman S, Granqvist S, Holmstrom M, et al. the Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336:393–398. 58. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998; 104:332–338. 59. Simioni P, Prandoni P, Zanon E, et al. Deep venous thrombosis and lupus anticoagulant: A case-control study. Thromb Haemost 1996; 76:187–189. 60. Rance A, Emmerich J, Fiessinger JN. Anticardiolipin antibodies and recurrent thromboem bolism. Thromb Haemost 1997; 77:221–222. 61. Veterans Administration Cooperative Study Group. Anticoagulants in acute myocardial infarction: Results of a cooperative clinical trial. JAMA 1973; 225:724–729. 62. Drapkin A, Merskey C. Anticoagulant therapy after acute myocardial infarction. JAMA 1972; 222:541–548. 63. Medical Research Council Group. Assessment of short-term anticoagulant administration after cardiac infarction: report of the Working Party on Anticoagulant Therapy in Coronary Thrombosis. BMJ 1969; 1:335–342.

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29 Acute Pulmonary Embolism in the Elderly Paul D. Stein and Fadi Kayali St. Joseph Mercy Oakland, Pontiac, Michigan, U.S.A.

The frequency of acute pulmonary embolism (PE) increases sharply with age [1–6]. In a general hospital, PE was diagnosed in 0.39% of hospital admissions of patients 70 years of age or older [7].

PREDISPOSING FACTORS IN ELDERLY PATIENTS Age itself appears to be an important predisposing factor, although the illnesses associated with age, in fact, may be the true predisposing factors. Among patients z70 years old, 67% were immobilized before the pulmonary embolism, and surgery preceded the pulmonary embolism in 44% [8]. Malignancy was more frequent among patients z70 years than among younger patients, occurring in 26% [8].

SYNDROMES OF PULMONARY EMBOLISM IN ELDERLY PATIENTS The usual syndromes of pulmonary embolism are (1) pulmonary hemorrhage or infarction syndrome characterized by pleuritic pain or hemoptysis; (2) isolated dyspnea, unaccompanied by hemoptysis, pleuritic pain, or circulatory collapse; and (3) circulatory collapse. The syndrome of pulmonary hemorrhage or pulmonary infarction is the most common syndrome of acute PE among patients in whom a diagnosis is made antemortem [9,10]. These syndromes were observed with comparable frequency among elderly patients and younger patients [8]. However, 11% of patients z70 years of age, in contrast to younger patients, did not show these syndromes [8]. Pulmonary embolism in these patients was suspected on the basis of unexpected radiographic abnormalities, which may have been accompanied by tachypnea or a history of thrombophlebitis. Unexplained radiographic abnormalities in elderly patients may be an important clue to the diagnosis of pulmonary embolism [8,11]. 695

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Table 1 Symptoms of Acute Pulmonary Embolism in the Elderly z70 years (n = 72) (%) Dyspnea Pleuritic pain Cough Leg swelling Leg pain Palpitation Wheezing Angina-like pain Hemoptysis

78 51 35 35 31 13 10 10 8

SYMPTOMS OF PE IN ELDERLY PATIENTS In considering all elderly patients, including those who may have had prior cardiopulmonary disease, dyspnea, and pleuritic pain were the most frequent symptoms (Table 1). Dyspnea occurred in 78% of elderly patients with PE and pleuritic pain occurred in 51% [8]. Hemoptysis occurred less frequently among patients z70 years than among younger patients [8]. Other symptoms occurred with comparable frequency among all age groups. Among elderly patients with the pulmonary hemorrhage/infarction syndrome who did not have prior cardiopulmonary disease, pleuritic pain was more frequent than hemoptysis (88% versus 12%) [12].

SIGNS OF PE IN ELDERLY PATIENTS Among all patients z70 years of age, regardless of prior cardiopulmonary disease, tachypnea (respiratory rate z20/min) was the most frequent sign of PE. Tachypnea Table 2 Signs of Acute Pulmonary Embolism According to Age z70 years (n = 72) (%) Tachypnea (z20/min) Rales Tachycardia (>100/min) Increased P2 Deep venous thrombosis Diaphoresis Wheezes Temperature >38.5 jC Third heart sound Pleural friction rub Homans’ sign Cyanosis P2= component of second heart sound.

74 65 29 15 15 8 8 7 7 6 4 3

Acute Pulmonary Embolism Table 3

697

Combinations of Signs and Symptoms in Elderly Patients (%)

Dyspnea or tachypnea Dyspnea or tachypnea Dyspnea or tachypnea Dyspnea or tachypnea Dyspnea or tachypnea Dyspnea or tachypnea Dyspnea or tachypnea abnormality

or or or or or or

hemoptysis pleuritic pain signs of deep venous thrombosis pleuritic pain or signs of deep venous thrombosis radiographic atelectasis or parenchymal abnormality pleuritic pain or radiographic atelectasis or parenchymal

92 92 92 94 94 100 100

The addition of hemoptysis did not improve the sensitivity of the combination for the detection of pulmonary embolism. Tachypnea = respiratory rate z20/min.

occurred in 74% and tachycardia (heart rate > 100/min) occurred in 29% of elderly patients with PE [8] (Table 2). All signs occurred with a comparable frequency among all age groups.

COMBINATIONS OF SYMPTOMS AND SIGNS IN ELDERLY PATIENTS Dyspnea or tachypnea or pleuritic pain occurred in 94% of all elderly patients, including those with prior cardiopulmonary disease. Dyspnea or tachypnea or radiographic evidence of atelectasis or a parenchymal abnormality occurred in 100% [8] (Table 3).

THE ELECTROCARDIOGRAM IN ELDERLY PATIENTS WITH PE Among all elderly patients, some of whom had prior cardiopulmonary disease, nonspeciﬁc ST-segment or T-wave changes were the most frequent electrocardiographic abnormalities [8]. Either or both occurred in 56% of patients z70 years old [8] (Table 4). With the

Table 4 Electrocardiographic Findings in Elderly Patients with Acute Pulmonary Embolism (n = 57) z70 Years (%) Normal ST segment or T-wave changes Left axis deviation Left ventricular hypertrophy Acute myocardial infarction pattern Low-voltage QRS Complete right boundle branch block Right ventricular hypertrophy Right axis deviation Right atrial enlargement Incomplete right bundle branch block

21 56 18 12 12 9 7 4 2 2 2

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exception of left anterior hemiblock (left axis deviation) among patients z70 years of age, other electrocardiographic abnormalities occurred in 12% or fewer elderly patients. No diﬀerence in the frequency of any electrocardiographic abnormalities occurred among diﬀerent age groups [8]. Among elderly patients with the pulmonary hemorrhage/infarction syndrome, and no prior cardiopulmonary disease, the electrocardiogram was normal in 62% [12]. If abnormal, the most frequent abnormalities were nonspeciﬁc ST-segment or T-wave changes (38%).

BLOOD GASES IN ELDERLY PATIENTS WITH PE The partial pressure of oxygen in arterial blood (PaO2) was lower among elderly patients with PE than among younger patients [8]. The PaO2 among elderly patients with PE, some of whom had prior cardiopulmonary disease, was 61 F 12 mmHg (mean F standard deviation). The alveolar–arterial oxygen diﬀerence (gradient) among elderly patients with PE was 47 F 14 mmHg, which was higher than among younger patients. The alveolar–arterial oxygen diﬀerence in normal adults increases with age [13–16]. Elderly patients with the pulmonary hemorrhage/infarction syndrome who had no prior cardiopulmonary disease had a higher pulmonary artery mean pressure (25 F 9 mmHg) and lower PaO2 (64 F 10 mmHg) than patients less than 40 years of age [12].

CHEST RADIOGRAPH AMONG ELDERLY PATIENTS WITH PE The chest radiograph was normal in 4% of all elderly patients with PE, including those with prior cardiopulmonary disease [8]. Atelectasis or pulmonary parenchymal abnormalities were the most frequent radiographic abnormalities (Table 5). All radiographic abnormalities occurred with a comparable frequency among all age groups.

Table 5 Chest Radiograph in Acute Pulmonary Embolism Among Elderly Patients (n = 72) (%) Normal Atelectasis or pulmonary parenchymal abnormality Pleural eﬀusion Pleural-based opacity Prominent central pulmonary artery Elevated diaphragm Cardiomegaly Decreased pulmonary vascularity Pulmonary edema Westermark’s sign

4 71 57 42 29 28 22 19 13 7

Westermark’s sign = prominent central pulmonary artery and decreased pulmonary vascularity.

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699

Among elderly patients with PE and no prior cardiopulmonary disease who had the pulmonary hemorrhage/infarction syndrome, the chest radiograph showed atelectasis or a pulmonary parenchymal abnormality in 82% [12]. The central pulmonary artery appeared dilated in 29%. A normal chest radiograph was uncommon in elderly patients with the pulmonary hemorrhage/infarction syndrome, occurring in 6% [12].

CLINICAL ASSESSMENT IN ELDERLY PATIENTS When physicians were 80 to 100% conﬁdent that pulmonary embolism was present in elderly patients on the basis of clinical judgment and simple laboratory tests, they were correct in 90% in a small sample of patients (9 of 10 patients) [8]. When they believed that there was less than 20% likelihood of pulmonary embolism, they correctly excluded the diagnosis in 81% of patients. In most elderly patients, physicians were uncertain of the diagnosis, believing that there was a 20 to 79% chance of pulmonary embolism. The accuracy of clinical assessment was comparable among patients in all age groups [8].

VENTILATION/PERFUSION LUNG SCANS IN ELDERLY PATIENTS The utility of ventilation/perfusion lung scans among patients z70 years old was comparable with that in younger patients [8]. Among patients z70 years of age with ventilation/ perfusion lung scans indicating a high probability of pulmonary embolism, 94% had pulmonary embolism (Table 6). The positive predictive value of all probabilities of ventilation/perfusion lung scans using original PIOPED criteria [17] were comparable in all age groups [8]. The sensitivity of ventilation/perfusion scans interpreted as a high probability of pulmonary embolism among patients z70 years of age was 47% [8]. The sensitivity did not diﬀer signiﬁcantly among age groups. The speciﬁcity of ventilation/perfusion scans interpreted as a high probability of pulmonary embolism among patients z70 years of age was 99%. The speciﬁcity was similar among all age groups [8]. Elderly patients with no prior cardiopulmonary disease who had the pulmonary hemorrhage/infarction syndrome tended to show more mismatched perfusion defects than patients under age 40, regardless of whether the defects were large or moderate in size [12]. In patients with no prior cardiopulmonary disease, a high positive predictive value can be achieved with fewer mismatched perfusion defects than are required for a high-

Table 6 Ventilation-Perfusion Scans in Elderly Patients with Acute Pulmonary Embolism (PE) z70 Years

High Intermediate Low Near normal/normal

Number of patients

%

34/36 27/100 10/71 1/8

94 27 14 13

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probability interpretation in patients with prior cardiopulmonary disease [18,19]. Stratiﬁcation according to the presence or absence of prior cardiopulmonary disease was particularly useful for the evaluation of V/Q lung scans in patients z70 years, although only 23% of elderly patients had no prior cardiopulmonary disease. Among patients z70 years who had no prior cardiopulmonary disease, z2 mismatched large- or moderate-size perfusion defects showed a sensitivity of 74%, a speciﬁcity of 100%, and a positive predictive value of 100% [20].

COMPLICATIONS OF PULMONARY ANGIOGRAPHY AMONG ELDERLY PATIENTS Major complications of pulmonary angiography occurred in 1.0% of 200 patients z70 years [8]. Renal failure, either major or minor, was the most frequent complication of angiography among elderly patients. It occurred in 3% of patients z70 years of age [8]. ‘‘Minor’’ complications of renal failure were important complications, although dialysis was not required. Patients with these complications showed either an elevation of the serum creatinine from previously normal levels to z2.1 mg/100 mL (range 2.1 to 3.5 mg/100 mL) or an increase in a previously abnormal serum creatinine level z2 mg/100 mL. Minor complications of prior angiography included urticaria, pulmonary edema requiring only diuretics, nausea and vomiting, arrhythmias that were not life threatening, hematomas, interstitial staining with contrast material, and narcotic overdose [8]. Minor complications occurred in 7.0% of patients z70 years old.

CONTRAST-ENHANCED SPIRAL COMPUTED TOMOGRAPHY Contrast-enhanced spiral computed tomography (CT) can be particularly useful in elderly patients because it is noninvasive, although the risk of renal toxicity from contrast material remains [8]. Even though contrast-enhanced spiral CT is used throughout the United States, it has not yet been fully evaluated [21]. Individual small case series showed sensitivities that ranged from 50 to 93% in studies that used 5-mm CT sections [22–27]. In the central pulmonary arteries using CT with 5-mm sections, average sensitivity and speciﬁcity were higher, both 94% [22,23,28–30], but in subsegmentaal pulmonary arteries, sensitivity was dismal (13%) [22,23]. With a collimation of 3 mm, better results were reported; the sensitivity was 87% and speciﬁcity 95% [31]. More recent collaborative trials failed to clarify the validity of spiral CT. The European Collaborative Trials (ESTIPEP and ANTELOPE) showed sensitivities that ranged from 60 to 95%, depending on whether the images were read centrally or locally (local readers did better) [32–34]. It is speculated that the results will be better with newer multidetector scanners that are faster and reduce motion artifact.

GADOLINIUM-ENHANCED MAGNETIC RESONANCE ANGIOGRAPHY Magnetic resonance angiography (MRA) of the pulmonary vasculature has been hampered by a multitude of factors such as respiratory and cardiac motion artifacts, saturation problems, poor signal-to-noise ratio, long acquisition times, and limited spatial resolution

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[35]. Intravenous gadolinium, a paramagnetic agent, gives additional enhancement of the blood signal. The most appealing approach to the application of gadolinium-enhanced MRA is its potential use for showing intraluminal ﬁlling defects. The intraluminal ﬁlling defect is considered the characteristic that is diagnostic of PE [17,21]. Data on the use of gadoliniumenhanced MRA for the diagnosis of acute PE are sparse. Gadolinium-enhanced MRA for the diagnosis of acute PE had a sensitivity that ranged from 77% to 100% and speciﬁcity that ranged from 95% to 98% [36–38]. With the present state of the art, it is likely that MRA would be most useful in patients with a strong suspicion of PE, in whom results of less expensive tests are equivocal and radiographic contrast material or ionizing radiation are contraindicated.

STRATEGIES OF DIAGNOSIS Serial noninvasive leg tests accompanied by ventilation/perfusion lung scans may permit a diagnosis without the need for pulmonary angiography [39]. Although elderly patients have been shown to tolerate pulmonary angiography, it is sensible to avoid the procedure if possible. The risk of fatal PE has been shown to be small if serial noninvasive leg tests show no deep venous thrombosis [40,41]. Conversely, if deep venous thrombosis is present, the treatment with anticoagulants is the same as with PE [42]. Unfortunately, many insurance programs will not pay for serial noninvasive leg tests, and often patients cannot arrange for serial tests. Alternative diagnostic strategies have been introduced for the exclusion of PE. If the clinical assessment for PE was low probability and the D-dimer was also low, PE was excluded in 99.8% [43]. If the clinical assessment was low, the ventilation/perfusion lung scan was nondiagnostic, and a single leg test was negative, PE was excluded in 98% [43].

ANTICOAGULANT THERAPY Recommendations for prophylaxis and antithrombotic therapy for PE were made in the Sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy [42–44]. The recommendations for treatment are shown in Table 7. Several studies found that the frequency of bleeding during warfarin therapy is higher in older patients, although this was not observed by some [45]. In one study, the relative risk for major bleeding was 3.2 for patients aged 65 or older [46]. The risk of major hemorrhagic complications among patients of all ages with thromboembolic disease, treated with ‘‘less intense’’ warfarin, International Normalized Ratio (INR) = 2.0 to 3.0, based on pooled data, was 1.7% [47]. Older patients also have a higher risk of bleeding from heparin than younger patients [48,49]. The frequency of major hemorrhagic complications from heparin among patients of all ages treated for thromboembolic disease, was 4.9%, based on pooled data [47]. The frequency of major bleeding from heparin in high-risk patients (surgery within previous 14 days, history of peptic ulcer disease, gastrointestinal or genitourinary tract bleeding, or platelet count <150 109/L) was 10.8% [50]. Among patients at low risk for bleeding, the frequency of major bleeding with heparin was 1.1%.

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Table 7 American College of Chest Physicians Recommendations for Treatment of Acute Pulmonary Embolism 1.

Patients with deep venous thrombosis or PE should be treated acutely with low-molecularweight (LMW) heparin, unfractionated I.V. heparin, or adjusted-dose subcutaneous heparin. 2. When unfractionated heparin is used, the dose should be suﬃcient to prolong the APTT to a range that corresponds to a plasma heparin level of 0.2 to 0.4 IU/mL by protamine sulfate or 0.3 to 0.6 IU/mL by an amidolytic anti-Xa assay 3. LMW heparin treatment may result in slightly less recurrent venous thromboembolism (VTE) and may oﬀer a survival beneﬁt in patients with cancer. LMW heparin is recommended over unfractionated heparin. Initial Anticoagulation with Heparin 1. Treatment with heparin or LMW heparin should be continued for at least 5 days and oral anticoagulation should be overlapped with heparin or LMW heparin for at least 4 to 5 days. 2. For massive PE or severe iliofemoral thrombosis, a longer period of heparin therapy of approximately 10 days is recommended. 3. Oral anticoagulant therapy should be continued for at least 3 months to prolong the prothrombin time to a target INR of 2.5 (range 2.0 to 3.0). 4. Patients with reversible or time-limited risk factors should be treated for at least 3 months. 5. Patients with a ﬁrst episode of idiopathic VTE should be treated for at least 6 months. 6. For patients with recurrent idiopathic VTE or a continuing risk factor such as cancer, antithrombin deﬁciency, or anticardiolipin antibody syndrome, treatment for 12 months or longer is recommended. Duration of therapy continues to be individualized in patients with deﬁciency of proteins C or S, multiple thrombophilic conditions, homocystinemia, and homozygous factor V Leiden. 7. Symptomatic isolated calf vein thrombosis should be treated with anticoagulation for at least 6 to 12 weeks. Thrombolytic Therapy In general, patients with hemodynamically unstable PE or massive iliofemoral thrombosis, who are at low risk for bleeding are the most appropriate candidates. Inferior Vena Caval Procedures An inferior vena caval ﬁlter is recommended when there is a contraindication or complication of anticoagulant therapy in an individual with or at high risk for proximal vein thrombosis or PE. An inferior vena caval ﬁlter is also recommended for recurrent thromboembolism that occurs despite adequate anticoagulation, for chronic recurrent embolism with pulmonary hypertension, and with the concurrent performance of surgical pulmonary embolectomy or pulmonary thromboendarterectomy. Source: Adapted from Ref. 42.

THROMBOLYTIC THERAPY Intracranial bleeding appears to be more common in elderly patients following thrombolytic therapy, based on experience following myocardial infarction [51]. The average reported risk of major bleeding in patients of all ages who were administered tPA for acute PE was 14.7% [52]. Among those pulmonary angiograms, major bleeding at the site of insertion of the catheter was 7.0% [52]. There has been considerable concern about whether thrombolytic agents are indicated in patients with right ventricular dysfunction from acute PE who are not in shock [53]. Among stable patients with baseline right ventricular hypokinesis, the mortality was 0% among 18 patients randomized to rtPA compared with 11% among 18 patients randomized

Acute Pulmonary Embolism

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to heparin [53]. With these small numbers, there was no statistically signiﬁcant diﬀerence in the death rate. However, the frequency of recurrent PE was greater in the group treated only with heparin. In a retrospective investigation of 64 patients with right ventricular dysfunction who received thrombolytic therapy, compared with 64 who received heparin alone, the mortality was comparable in both groups and the rate of recurrent PE was the same in both groups [54]. Konstantinides and associates reported the clinical course of stable patients with submassive acute PE who were treated either with rtPA plus heparin or heparin alone [55]. Right ventricular dysfunction was present in 31% of patients in both treatment arms. Mortality was comparable in both groups. ‘‘Rescue thrombolysis’’ was required in 23% of the patients in the heparin arm [55]. The most appropriate indication for thrombolytic therapy in patients with PE is massive PE complicated by hypotension in the absence of contraindications to thrombolytic therapy [42].

CONCLUSION In conclusion, the signs and symptoms known to occur among younger patients also occurred in elderly patients, although occasional exceptions were observed. Even among elderly patients, typical signs and symptoms occurred with suﬃcient frequency to suggest the possibility of pulmonary embolism in the diﬀerential diagnosis. In the absence of these signs and symptoms, unexplained radiographic abnormalities were important diagnostic clues. When the diagnosis of pulmonary embolism is uncertain, pulmonary angiography can be performed safely in elderly patients, although renal failure can be a problem among elderly patients. Serial noninvasive leg tests in combination with ventilation/perfusion lung scans may eliminate the need for pulmonary angiography in many elderly patients. Other approaches for the exclusion of PE, such as a low D-dimer in combination with a lowprobability clinical assessment or low clinical assessment in combination with a nondiagnostic ventilation/perfusion lung scan and negative single leg test appear to be useful. The role of contrast-enhanced spiral CT is not yet established, but it is frequently used and multidetector scanners may improve its sensitivity and speciﬁcity. Gadolinium-enhanced MRA may oﬀer an opportunity for diagnostic imaging in those in whom radiographic contrast material is contraindicated.

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30 Peripheral Vascular Disease in the Elderly Roy M. Fujitani, Ganesha B. Perera, and Samuel E. Wilson University of California–Irvine Medical Center, Orange, California, U.S.A.

Ian L. Gordon Veterans Administration Medical Center, Long Beach, California, U.S.A.

INTRODUCTION Peripheral vascular disease has continued to be the major cause of morbidity and mortality in the geriatric population. The elderly population in the age group over 75 has been the fastest growing segment of our society, increasing 24% over the last decade. This segment of the U.S. population grew from 14.7 to 18.3 million between 1995 and 2005 [1]. Since atherosclerosis is a systemic disease, aﬀecting potentially all organs, it can exhibit symptoms in a variety of ways. Carotid bifurcation disease contributes to stroke through sudden occlusion and/or cerebral embolization. Lower extremity arterial occlusive disease results in signiﬁcant disability due to intermittent claudication, advancing to limb-threatening conditions of rest pain, ischemic ulceration, and gangrene. Aortic aneurysms are particularly life-threatening conditions, most commonly diagnosed in octogenarians, with an estimated incidence of 6% in men over 80 years of age. Other common clinical signs and symptoms in the elderly, including hypertension, renal insuﬃciency, and abdominal pain, may be due to renovascular and mesenteric ischemia resulting from arterial luminal stenoses. Additionally, venous disease and venous stasis ulceration can be a signiﬁcant problem in the elderly. Management of each of these conditions in the geriatric population requires thorough knowledge of the natural history of these peripheral vascular disease processes. This is especially important in the older patient, because common comorbid conditions such as coronary artery disease, pulmonary disease, diabetes mellitus, and renal insuﬃciency can increase the risks associated with any necessary invasive diagnostic tests and operative procedures. This chapter will examine these common considerations related to the manifestion and diagnosis of various vascular problems, and then focus on the current management of the most common peripheral vascular ailments found in the geriatric patient. 707

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GENERAL CONCEPTS The aging process causes subtle changes to occur in the wall of peripheral arteries, independent of atherosclerosis. The shape and orientation of the endothelial cells becomes less homogeneous, predisposing them to increased turbulence at the critical blood–endothelial cell interface [2,3]. The ﬂexibility of the peripheral vascular bed is altered as the calcium and lipid content of the subendothelial layer increases while, at the same time, the elasticity of the underlying muscular media is compromised by fractured cross-linking of elastin and other supportive protein moieties. As a result, this leads to increased ‘‘stiﬀness’’ of the arterial vasculature, making it less well suited to the reactive enlargement of the media and adventitia, which is the most important compensation to eccentric plaque deposition [4]. Cigarette smoking, hypertension, hypercholesterolemia, diabetes mellitus, obesity, sedentary lifestyle, and hereditary factors are known risk factors for the development and acceleration of atherosclerosis. The ﬁrst four factors are of greatest importance and appear to be cumulative in their eﬀect. Therefore, the greater number of risk factors a patient has, the more likely it is that they develop atherosclerosis. Modiﬁcation of these risk factors may inﬂuence the progression of the atherosclerotic disease process. Adequate control of hypertension has the beneﬁcial eﬀects of reducing cardiac work and microvascular injury, especially the kidneys. Management of hyperlipidemia, especially low-density lipoproteins (LDL), has been shown to reduce the progression of coronary artery atherosclerotic plaque formation [5]. Exercise has the beneﬁt of reducing heart rate and increasing high-density lipoprotein (HDL) levels [6,7]. Cessation of tobacco use has also been associated with decreasing the progression of coronary and peripheral arterial atherosclerosis. In one study [8], 11% of claudicants who continued smoking required amputation within 5 years, with no amputations in those who stopped or never smoked. Similarly, patency in lower extremity bypass grafts is worse in smokers than nonsmokers [9]. In addition, the rigid control of serum glucose in diabetics appears to diminish the entire spectrum of associated secondary peripheral vascular complications. Diabetics have at least a ﬁvefold increased risk of critical ischemia from peripheral vascular disease compared to nondiabetics. Ulcers and gangrene will occur in 10% of elderly diabetics. In one series, 6.8% of diabetics underwent lower extremity amputations compared to 0.6% of nondiabetics over a 5-year period [10,11]. Approximately 20% of diabetics with claudication progress to amputation within 5 years, compared to about 3% of nondiabetics [12,13]. Furthermore, diabetics who smoke have markedly worse prognosis for limb loss compared to nonsmokers. Unfortunately, it is not unusual for geriatric patients to present with advanced symptoms of peripheral vascular disease, often related to delays in obtaining a proper diagnosis. For instance, symptoms of intermittent claudication may be easily rationalized or attributed to other musculoskeletal causes such as arthritis, so that the ﬁrst recognized manifestation of lower extremity athero-occlusive disease is advanced limb-threatening ischemia. Vertigo, dizziness or other intermittent neurological symptoms may likewise be attributed to other reasons without adequate evaluation of extracranial arterial lesions or proximal arterial–arterial embolic sources. The incidence of abdominal aortic aneurysm is highest in the geriatric population, yet it is not unusual for these patients to present with rupture of these lesions due to an overly conservative approach to the elective surgical repair. These scenarios emphasize the great importance of very careful history taking and vigilant physical examination during regular oﬃce visits in these elderly patients.

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Figure 1 Prevalence of PAD in men and women. (From Ref. 14 with permission.)

Prevalence of peripheral arterial disease (PAD) varies with age and sex. Figure 1 demonstrates the age-dependent prevalence of PAD in the United States. In another study analyzing the prevalence of PAD in Scotland, men have a higher prevalence than women, but the gap narrows with advancing age. Scotsmen under 50 years have a less than 1% prevalence, compared to men older than 60, who have a ﬁvefold increased prevalence [14]. Similar relations between age, sex, and PAD prevalence have been found in other countries, although diﬀerent absolute prevalences are reported. The low end of the spectrum is found in Danish men aged 40 to 59 who have a 0.4% prevalence compared to with 14% prevalence reported in American men and women over the age of 65 [15,16]. At the other extreme, Italians 80 years and older have a reported prevalence of 30% [17]. Another important element that inﬂuences the natural history of PAD is the response of the arterial wall to iatrogenic trauma from therapeutic manipulation such as surgery or balloon angioplasty. The response of the injured arterial wall is to elaborate a myointimal hyperplastic reaction. Smooth muscle cells, partially under the inﬂuence of platelet-derived growth factors elaborated at the site of injury, migrate from the media into the intima and transform into unique myointimal cells, which proliferate and lay down ﬁbrous tissue. The resulting lesion is histologically distinct from atherosclerotic plaque, but has many of the same consequences including gradual reduction in blood ﬂow that may promote arterial thrombosis [18,19]. The development of myointimal hyperplasia remains the Achilles heel of vascular therapy.

DIAGNOSTIC STUDIES FOR PERIPHERAL VASCULAR DISEASE The ready availability of noninvasive vascular tests should prompt primary care physicians to consider early evaluation in elderly patients presenting with even subtle changes in symptoms of physical ﬁndings suggestive of peripheral vascular disease. These studies can quantify the extent of disease and localize lesions in many areas prone to atherosclerotic disease without the risks of more invasive procedural studies such as arteriography. In this fashion, signiﬁcant disease may be more aggressively pursued while noncritical lesions

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may be reassessed over time, thereby sparing both patients and physicians anxiety over missed pathology. Noninvasive ultrasound tests are used to assess lower extremity blood ﬂow using three main methods: determination of ankle blood pressures, characterization of velocity waveforms, and duplex ultrasound. Doppler ultrasound-based studies oﬀer the most commonly utilized noninvasive examinations for a host of peripheral vascular disease processes. One common test is to measure ankle and brachial artery systolic pressures using a Doppler stethoscope and blood pressure cuﬀs. This allows calculation of an ankle–brachial index (ABI), which is normally 0.9–1.2. An ABI below 0.9 suggests arterial occlusive disease. The lower the ABI, the more severe the restriction of blood ﬂow and the more serious the ischemia. ABIs of 0.6 to 0.9 usually correlate with mild-to-moderate claudication; values between 0.4 to 0.6 often accompany severe claudication; between 0.25 to 0.4 rest pain and tissue loss are often found; An ABI below 0.25 predicts a higher likelihood of limb loss. In addition to the ratio, the actual systolic pressure at the ankle has signiﬁcance, with pressures below 50 mmHg marking critical ischemia. Occasionally patients with calciﬁed arteries from diabetes or renal failure have relatively noncompressible arteries leading to ﬁctitiously elevated ABI values above 1.2. In addition to measuring pressure in nonpalpable arteries, Doppler ultrasound methods allow characterization of the ﬂow-versus-time velocity waveform. The normal waveform at the level of the common femoral artery is triphasic, with distal arteries having either biphasic or triphasic ﬂow. The ﬁnding of biphasic ﬂow at the groin or monophasic ﬂow more distally is good evidence of arterial obstruction even when ABI measurements are falsely elevated due to calciﬁcation [20]. Duplex ultrasound combines Doppler frequency measurements with two-dimensional images of blood vessels. Duplex ultrasound allows sophisticated hemodynamic analyses based on velocity power spectra, velocity waveforms, and ratios of systolic and diastolic ﬂows. The severity of ﬂow restriction induced by a stenosis can thus be accurately assessed and disturbed ﬂow reliably detected [21]. Duplex ultrasonography oﬀers the most comprehensive noninvasive examination of a host of vascular lesions. This modality is especially useful in screening patients for extracranial carotid and vertebral disease, mesenteric arterial disease, renovascular stenoses, abdominal aortoiliac lesions, and infrainguinal arterial disease. Other important noninvasive diagnostic methods include measurements of skin perfusion with laser Doppler techniques, determination of skin oxygen tension (tcPO2), and assessment of walking distance on a low-speed treadmill. The vascular laboratory is particularly good in documenting hemodynamic responses to interventions aimed at improving the circulation. After arterial reconstruction, increased ABIs or improvements in blood velocity waveforms reliably indicate improved blood ﬂow. Bypass grafts are easily assessed via ultrasound for patency and the presence of signiﬁcant stenosis using duplex ultrasound. The information provided by ultrasound regarding blood ﬂow and vessel patency or occlusion allows critical management decisions to be taken, without depending on arteriography. Percutaneous transcatheter contrast arteriography remains the conventional diagnostic test for a wide range of peripheral vascular problems. Commonly, noninvasive tests are performed initially as a screening study to identify speciﬁc lesions; arteriography is reserved for validating the ﬁndings to plan deﬁnitive intervention, whether an endovascular transcatheter-based treatment or open surgery. However, as noninvasive studies such as duplex ultrasonography become more sophisticated and accurate, they themselves are

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sometimes adequate to serve as the deﬁnitive diagnostic study. Furthermore, invasive studies such as arteriography should be reserved for only those individuals in whom a decision has been made that some form of deﬁnitive therapy is warranted. This approach is prudent because regardless of the indication or peripheral vascular region of interest, contrast arteriography is associated with morbidity and mortality. These adverse reactions may be categorized as being local, systemic, or neurological. Local complications, ranging in incidence from 5 to 15%, include hemorrhage, hematoma formation, arterial thrombosis, distal embolization, and pseudoaneurysm formation at the puncture site. Systemic complications include allergic reactions to the radiological ionic contrast agents as well as renal and cardiovascular manifestations. Most series report a less than 2% incidence of serious allergic reactions; however, the incidence of anaphylactic reactions may be as high as 20% in patients with a history of contrast allergy [20]. Allergic reactions may range from minor sequelae such as nausea, vomiting, hives, and chills, to major life-threatening reactions such as bronchospasm, hypotension, laryngospasm, and pulmonary edema. The ionic contrast agents may also have a deleterious eﬀect on renal function especially in patients with preexisting kidney insuﬃciency. One series reported that nonazotemic patients experienced a 2% incidence of acute renal failure following all types of contrast arteriography, while patients with chronic azotemia suﬀered a 33% incidence [21]. Finally, since these studies utilize percutaneous transluminal techniques, they may cause arterial–arterial embolization to the brain, causing strokes, especially when performing cerebrovascular examinations. Alternative imaging techniques include magnetic resonance arteriography (MRA) and computerized tomographic arteriography (CTA). They both have the advantage over conventional percutaneous transcatheter arteriography in that there is no risk of stroke or local arterial injury. Moreover, since MRA does not require infusion of contrast agents, it avoids these inherent potential systemic reactions. Although these imaging modalities have recently become widely available, rigorous correlation between MRA, CTA, and actual arterial pathology has yet to be validated. In our early experience with CTA, there appears to be excellent correlation between actual degree of arterial stenoses with the operative ﬁndings, especially in extracranial carotid bifurcation disease. When it becomes apparent that surgical intervention is warranted, critical attention should be directed toward the preoperative evaluation of cardiac, renal, and pulmonary function to minimize any perioperative morbidity and mortality. While the magnitude of the proposed intervention appropriately inﬂuences the extent of the preoperative evaluation, cardiac risk assessment must be rigorous, presuming the systemic nature of the atherosclerotic disease process. This is especially important in the diabetic patient who is more prone to have ‘‘silent’’ cardiac disease. Cardiac complications are the major cause of mortality in all types of peripheral vascular interventions. Furthermore, the symptoms of cardiac disease may be masked in elderly patients due to restrictions in daily activities as a result of claudication or musculoskeletal disorders. The utility of exercise or pharmacologically induced stress echocardiograms or radionuclide scans may uncover areas of myocardium with reversible ischemia, prompting more deﬁnitive diagnostic studies such as coronary arteriography. Formal pulmonary function tests and evaluation of renal clearance, in addition to simple measures of BUN and serum creatinine, oﬀer helpful prognostic indicators. A forced expiratory capacity of <1.0 L and a creatinine clearance of <40 mL/min both indicate an increased incidence of perioperative complications, especially for major abdominal procedures. Such preoperative evaluations can signiﬁcantly alter the operative approach to a particular peripheral vascular problem, allowing the surgeon to choose between alternative procedures. For example, for an individual patient, the most

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durable anatomical solution for advanced aortoiliac occlusive disease (aortofemoral bypass) may be a less valid choice than other less stressful procedures (extraanatomical axillobifemoral bypass or percutaneous transluminal angioplasty F stenting). A vigilant, comprehensive approach by knowledgeable physicians and surgeons to the geriatric patient with advanced peripheral vascular disease assures the best potential outcome for this highrisk group.

SPECIFIC CLINICAL PRESENTATIONS OF PERIPHERAL VASCULAR DISEASE Extracranial Carotid Disease Carotid endarterectomy (CEA) is commonly performed for prophylaxis against stroke in patients with hemodynamically signiﬁcant atherosclerotic stenosis of the internal carotid artery. The prevalence of this procedure in the US peaked at 103,000 cases in 1984, but decreased in the late 1980s to 70,000 cases in 1989 [22,23]. The number of patients undergoing CEA had once again begun to rise in the 1990s after long-standing controversy regarding its eﬀectiveness was settled by several large-scale clinical trials. These studies include the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the European Carotid Surgery Trial (ECST), the Veterans Administration Cooperative Studies 309 and 167 (VA 309, VA 167), and the Asymptomatic Carotid Atherosclerosis Study (ACAS) [24–28]. Although these trials conﬁrmed the eﬃcacy of CEA for both symptomatic and asymptomatic patients with severe carotid stenosis, the procedure must be performed with acceptable perioperative morbidity and mortality to assure patient beneﬁt. The combined mortality and stroke morbidity in the ECST study was 7.5% compared with 5.6% in VA 309 [25,26]. In asymptomatic disease, mortality and morbidity are lowest, as demonstrated by ACAS with a total of 2.3% [28]. The prospect of any perioperative mortality suggests that special consideration be taken with the geriatric patient. In managing the older patient with symptomatic or asymptomatic carotid stenosis, the referring physician and surgeon must be certain that the carotid lesion warrants an operation. In addition, the patient’s associated risk status must be good enough to recommend operation for an asymptomatic stenosis. Elderly patients are at highest risk for suﬀering stroke. Among those over age 65, the annual death rate from stroke is 394 per 100,000 [1]. Since the elderly population is the fastest growing segment of our society, CEA could potentially provide great beneﬁt for a large number of people. However, because the older patient is already at greater risk for perioperative mortality and morbidity, one must be quite discriminating in choosing the elderly patient who is ﬁt enough to undergo carotid endarterectomy. If this is kept in mind and enough precautions are taken in patient selection, one may achieve acceptably low rates comparable to the 4.3% and 2.3% in the VA 167 (mean age 64.1) and ACAS (mean age 67) [27,28]. The speciﬁc indications for CEA in the geriatric patient should generally follow those for the population at large. CEA has been shown to be beneﬁcial in minimizing subsequent ipsilateral stroke in symptomatic patients with internal carotid stenosis with diameter reduction of z70% (Fig. 2). Speciﬁc symptoms include focal hemispheric symptoms (i.e., transient ischemic attack (TIA)), reversible ischemic neurological deﬁcit (RIND); small completed stroke; stroke in evolution or amaurosis fugax. Nonhemispheric symptoms, such as dizziness, vertigo, or headache, should be assessed with caution. For patients with hemi-

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Figure 2 Arteriogram demonstrating severe atherosclerotic stenosis of the endocranial carotid artery bifurcation.

spheric symptoms, the beneﬁts of surgery are clear. Subsequent stroke rates for surgically versus medically treated patients were found to be 7.7% versus 19.4% at 11.9 months for stenosis >50% (VA 309); 10.3% versus 16.8% at 36 months for stenosis >70% (ECST); and 9% versus 26% at 24 months for stenosis >70% (NASCET) [24–26]. For the patient with signiﬁcant carotid stenosis without symptoms, selection must be somewhat more restricted. After several other studies failed to conclusively prove the beneﬁts of surgery, ACAS established that, for asymptomatic patients with stenosis >60%, surgery reduces the risk of ipsilateral stroke provided that operative morbidity and mortality be held to <3% [28]. For the elderly patient, the diﬀerence in indications for carotid endarterectomy must be tempered by the increased operative risk. Older patients who have been shown to have higher operative risk for coronary artery bypass and peripheral vascular reconstruction tend to have signiﬁcant concomitant morbidity [29–31]. The incidence of diabetes mellitus, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and hypertension all increase with advancing age [32–33]. Moreover, history of prior myocardial infarction (MI), especially if within the previous 6 months, is associated with higher operative risk. This is not uncommon, with 10% of men and 5% of women over 65 years having such a history [33]. Among patients undergoing CEA, angina, CHF, COPD,

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hypertension, and MI within the past 6 months were all correlated with increased incidence of postoperative MI [34]. This, along with postoperative stroke, is responsible for the majority of post-CEA morbidity. In two studies, advanced age (>70 years) in itself was correlated with an increased incidence of postoperative MI for a wide variety of major surgical procedure [34,35]. The beneﬁt of surgery for the elderly patient with asymptomatic carotid stenosis having signiﬁcant concomitant disease imparts a major judgmental challenge to surgical decision making. Perioperative morbidity and mortality should be kept to <3% when the indication for operation is asymptomatic disease. However, signiﬁcant medical comorbidities may increase the risk of postoperative MI, stroke, or death to 7% [34]. As with all age groups, the decision to operate is further made diﬃcult by the prevalence of cerebrovascular disease of noncarotid etiology, such as lacunar infarct or vertebrobasilar disease. Lacunar infarct has been shown not to be due to carotid embolization but rather to intracerebral small-vessel vasculopathy [36]. The presence of vertebrobasilar disease can result in such symptoms as dysarthria, dysphagia, diplopia, nystagmus, visual ﬁeld defects, hoarseness, ataxia, and syncope [37]. Presence of a combination of these symptoms may not be due to carotid disease, and distinguishing the two etiologies can be confusing. Nonhemispheric symptoms such as vertigo, lightheadedness, and blurry vision are presumably due to generalized hypoperfusion rather than embolus. Preoperative evaluation of the elderly patient found to be a candidate for CEA must be performed vigilantly. Accurate assessment of surgical risk due to concomitant disease and assurance that symptoms are caused by extracranial carotid bifurcation stenosis or plaque are important. While a conservative approach is warranted, the life expectancy of older patients should not be underestimated. These geriatric patients stand to gain extension of productive years provided their surgical risk is acceptably low. As of 1990, the remaining life expectancy was 10.9 years at age 75 and 8.3 years at age 80 [1]. In fact, the ﬁt patient at age 80 may have a longer life expectancy than a patient 20 years younger who has risk factors such as heavy tobacco use or diabetes mellitus. Fourteen studies of carotid endarterectomy in the elderly are summarized in Table 1 [30,38–50]. The age cutoﬀ for deﬁning the ‘‘elderly patient’’ varied in each of the studies (70,75, or 80 years old). In those studies that included series of younger patients below the arbitrary age cutoﬀ, none demonstrated a statistically signiﬁcant diﬀerence between younger and older patients in either mortality or incidence of postoperative stroke. Other studies [51,52] have also corroborated these numerical results. However, when the individual studies are grouped and evaluated by the age cutoﬀ (>70 year old; >75 year old; >80 year old, respectively), there is a statistically signiﬁcant ( p <0.05) increase in both morbidity alone as well as combined mortality and morbidity for the >75-year-old group (Table 2). No increase in risk for the elderly was found when 70 or 80 years was used as the cutoﬀ. Interestingly, there was a statistically signiﬁcant increased morbidity and combined morbidity and mortality for younger patients with a cutoﬀ of 70 years. It should be noted that in two of the studies, each progressively older age bracket had a correspondingly higher operative morbidity, mortality, and combined morbidity [46,50]. The failure of individual studies to ﬁnd a diﬀerence in mortality and morbidity rates between younger and older patients can be attributed to various factors. Several studies report results from referral centers with uniform surgical technique and limited patient selection by a small number of surgeons with great familiarity in performing CEA. An additional factor is the operation itself; patients undergoing CEA have relatively little postoperative pain and therefore less respiratory impairment and pulmonary complication [42].

1985 1985 1986 1986 1988 1988 1989

1990 1990 1991

1991 1992 1994 1996

Courbier Plecha Ouriel Rosenthal Schultz Loftus Fisher

Schroe Pinkerton Meyer

Roques Treiman Coyle Perler

75 75 75 80 80 70 65 70 75 80 70 75 70 75 80 75 80 80 75 992 124

483 560

5220 393 1008

Cases (young) 76 782 77 90 116 53 2089 1356 685 212 222 125 749 265 56 81 183 79 63

Cases (old)

26 (2.6) 2 (1.6)

20 (4.1) 2 (0.4)

94 (1.8) 12 (3.1) 20 (2.0)

Morbidity (young)

7 0 23 10 3 2 3 0 3

2 17 3 4 1 1 35

(3.2) (0) (3.1) (3.8) (5.4) (2.5) (1.6) (0) (4.8)

(2.6) (2.2) (3.9) (4.4) (0.9) (1.9) (1.7)

Morbidity (old)

Note: Morbidity indicates postoperative ipsilateral stroke. Percentages are showin in parentheses. Young and Old refer to patients below and above the particular age cutoﬀ for each study.

Year

Author

Age cutoﬀ

16 (1.6) 2 (1.6)

8 (1.7) 5 (0.9)

77 (1.5) 2 (0.5) 6 (0.6)

Mortality (young) 1 (1.3) 18 (2.3) 0 (0) 2 (2.2) 2 (1.7) 0 (0) 52 (2.5) 44 (3.2) 25 (3.6) 10 (4.7) 3 (1.4) 1 (0.8) 10 (1.3) 4 (1.5) 0 (0) 3 (3.7) 3 (1.6) 1 (1.3) 1 (1.6)

Mortality (old)

42 (4.2) 4 (3.2)

28 (5.8) 7 (1.3)

171 (3.3) 14 (3.6) 26 (2.6)

Combined M+M (young)

Table 1 Summary of Carotid Endarterectomy Morbidity and Mortality Rates in Young Versus Old Patients

10 1 33 14 3 5 6 1 4

3 35 3 6 3 1 87

(4.5) (0.8) (4.4) (5.3) (5.4) (6.2) (3.3) (1.3) (6.3)

(3.9) (4.5) (3.9) (6.7) (2.6) (1.9) (4.2)

Combined M+M (old)

No No

No No

No No No

Statistically signiﬁcant diﬀerence?

Peripheral Vascular Disease 715

1 5 7 6

Cutoﬀ

>65 >70 >75 >80 790 6297 2412

Total no. of young patients 2089 1368 1469 543

Total no. of old patients 52 (6.6) 110 (1.7) 82 (3.4)

Morbidity (young) 35 44 37 12

(1.7) (3.2) (2.5) (2.2)

Morbidity (old) 16 (2) 86 (1.4) 34 (1.4)

Mortality (young)

52 25 28 8

(2.5) (1.8) (1.9) (1.5)

Mortality (old)

68 (8.6) 196 (3.1) 116 (4.8)

Combined M+M (young)

87 69 65 20

(4.2) (5) (4.4) (3.6)

Combined M+M (old)

Note: Number of compiled studies totals to >16 because several studies listed results by more than one age cutoﬀ. Pairs of italicized ﬁgures indicate statistically signiﬁcant diﬀerence ( p < .05).

No. of studies compiled

Table 2 Carotid Endarterectomy Morbidity and Mortality: Studies Grouped by Age Cutoff

716 Fujitani et al.

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Generally, individual reports chronologically show a signiﬁcant decrease in mortality and morbidity rates over the years in which the studies were conducted. However, the overall morbidity and mortality has changed very little over time (Table 3). Age >65 years was once considered a high-risk threshold for performing CEA. Over the last three decades, the age limit for CEA has been extended to progressively older groups. Literature review suggests that age itself should not be the sole discriminating factor in weighing the value of CEA for clear-cut symptoms or high-grade asymptomatic stenosis. Recently, a statewide analysis of 9918 Maryland patients concluded that CEA, even among the very elderly, is a safe procedure, although the length of stay may be longer due to the concomitant medical illness [53]. There has been recent interest in endovascular stenting of carotid artery lesions in lieu of standard operative CEA. This new development is still unproven and careful prospective studies are currently in progress. Recommendations for carotid stenting will depend upon the outcomes of these randomized trials and are forthcoming. It is clear that elderly patients may beneﬁt from CEA when performed for the proper indications. However, careful assessment of their associated comorbidities is most important to assure optimal long-term beneﬁt from surgical intervention. If these caveats are respected, prevention of ischemic or embolic stroke can greatly enhance the quality of life for the geriatric patient. Vertebrobasilar Insufficiency The most common symptoms of vertebrobasilar insuﬃciency include nausea, vertigo, ipsilateral facial numbness, ipsilateral Horner’s syndrome, and limb ataxia. While these ischemic conditions may be very mild and often transient, there can be progression to actual posterior fossa infarction, which can be lethal due to extensive edema and midbrain compression. Although microembolization can contribute to posterior cerebral and cerebellar ischemic compromise, occlusive disease of the vertebral arteries or the basilar artery is the most common cause of this process. Thrombosis may occur in the basilar artery proper or the basilar branch vessels that penetrate into the brain stem. Subclavian steal syndrome is a classic vertebrobasilar symptom complex associated with proximal subclavian or innominate artery stenosis. Since the vertebral arteries originate from the subclavian arteries, they can function as collaterals to the upper extremities. With a proximal stenosis, ﬂow is reversed in the vertebral artery following ipsilateral arm exertion, decreasing blood ﬂow and perfusion pressure through the basilar arterial system. This results in posterior cerebral and cerebellar ischemic symptoms. This is exacerbated in the presence of associated carotid occlusive disease. The left subclavian artery is more commonly involved, occurring in 65% of cases. The diagnosis of subclavian steal syndrome

Table 3

Carotid Endarterectomy Morbidity and Mortality by Year of Study Publication

Five-year period

Number of studies compiled

Total cases

Morbidity

Mortality

Morbidity + Mortality

1986–1990 1991–1995 1996–

7 4 1

5216 2084 187

105 (2) 54 (2.6) 5 (2.7)

81 (1.6) 33 (1.6) 3 (1.6)

186 (3.6) 87 (4.2) 8 (4.3)

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Fujitani et al.

is supported by complaints of intermittent vertigo, light-headedness, nausea, diplopia, and vomiting exacerbated by arm exercise. Findings of a supraclavicular bruit and a signiﬁcant (>40 mmHg) blood pressure discrepancy between arms on physical examination should prompt further evaluation. The diﬀerential diagnosis in geriatric patients includes inner ear disorders and chronic subdural hematomas that may occur even after fairly trivial trauma. Symptomatic patients with vertebrobasilar occlusive disease should be considered for elective operative intervention. Procedures to treat this condition include proximal vertebral artery endarterectomy, carotid-subclavian bypass, or vertebral artery transposition to restore adequate antegrade vertebral ﬂow [54]. Abdominal Aortic Aneurysms The natural history of aortic aneurysms is that of progressive enlargement, usually without accompanying symptoms. Left undetected and untreated, it may lead to eventual rupture, often resulting in death. Early detection with appropriate screening of high-risk patients and elective operative repair of these aneurysms are the key to optimal management of this common vascular disease. Unlike some other atherosclerotic-related disease processes, the incidence of abdominal aortic aneurysms (AAAs) is increasing [55]. This is due, in part, to increased utilization of diagnostic tests that detect smaller asymptomatic aneurysms, but it also reﬂects the aging of the population. The incidence of aneurysms increases dramatically after the age of 55 years in men and after 70 years in women [56]. As a consequence of this chronologically staggered presentation, aneurysmal disease of the aorta has a substantial male predominance by a ratio of about 3:1. It is estimated that 3 to 7% of men over age 70 have an AAA and approximately 100,000 abdominal aortic aneurysms will be diagnosed in the United States this year [57]. Approximately 15,000 deaths are attributable to AAAs every year in spite of continued eﬀorts at early detection. The risk of rupture is clearly related to size, although the correlation is not perfect. That is, when considering a large group of patients, aneurysms greater than 6 cm in diameter are more likely to rupture (about 30% in 3 years) than smaller aneurysms (about 10% in 3 years). It has been well documented, however, that aneurysms as small as 4 cm do rupture [58]. More importantly, documenting stability in size over time does not necessarily predict a continued benign course [59,60]. The prognosis for a ruptured abdominal aortic aneurysm is very poor. As many as one-half of patients with ruptured AAAs die before operative management can be rendered. Although great progress has been made in surgical technique, anesthesia, and postoperative care, the operative mortality rate for patients with ruptured aneurysms reaching the operating room still remains around 50% in most series [61–63]. Conversely, over the past three decades there has been a progressive improvement in the perioperative mortality rate associated with elective aortic abdominal aneurysmorrhaphy [64]. Mortality rates of 1 or 2% are commonly reported in the literature, although the average national mortality rate is probably closer to 5% [65–66]. It is therefore clear that if the mortality rate attributable to abdominal aortic aneurysms is to be reduced, the disease must be recognized in its asymptomatic state and treated before rupture occurs. Diagnosis depends on careful physical examination and high index of suspicion for the geriatric patient. In nonobese patients, deep palpation of the abdomen between the xiphoid and umbilicus can usually outline the abdominal aorta and provide an estimate of its size. This gross measurement tends to overstate the actual diameter of the aneurysm by 1 to 2 cm. In a very thin patient, even the normal abdominal pulsation may be mistaken for an

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aneurysm. Conversely, large aneurysms may be missed in obese patients due to diﬃculty in manual palpation. During examination, attention should also be directed to the peripheral vasculature including the femoral, popliteal, dorsal pedal, and posterior tibial pulses. Ischemic changes in the foot (‘‘blue-toe syndrome’’) or diminished pulses may suggest distal atheroembolism from the aneurysm. Furthermore, concomitant peripheral aneurysms of the femoral and popliteal arteries may be found in 5 to 8% of patients with AAAs. Ultrasound imaging is an accurate method of diagnosing an abdominal aortic aneurysm. This simple, noninvasive procedure can be tolerated by virtually all patients and is the best screening test for the disease. The biplanar cross-sectional visualization of the aorta allows for determinations of the size and extent of the aneurysm, as well as the detection of intraluminal thrombus and associated iliac aneurysms. Ultrasound determination of AAA diameter is readily reproducible and allows longitudinal assessments of changes in aneurysm size. This is especially useful when following a patient with a ‘‘small’’ (<5 cm) AAA. Computed tomography (CT) oﬀers the most accurate assessment of AAA size. (Figure 3).This modality is highly predictive of size and provides precise localization of the extent of the aneurysm and valuable accessory information such as the presence of renal cysts or ectopic or horseshoe kidneys. CT scans are superior to ultrasound imaging in the identiﬁcation of those critical venous abnormalities, including retroaortic left renal veins or a left-sided vena cava, which can inﬂuence the operative approach. Although drawbacks include the increased expense over ultrasonography and exposure to contrast, the very detailed depiction of the abdominal aorta, retroperitoneum, and adjacent organs make this modality the preferred noninvasive method of preoperative evaluation. Modern helical CT scans allow for three-dimensional reconstruction of the aneurysms and adjacent organs allowing for complete visualization of the involved aorta (Fig. 3). Aortography is a more invasive procedure, but is only selectively used for preoperative evaluation once the diagnosis of an AAA is made. Aortography determines critical associated arterial anatomy, such as the number and location of the renal arteries, the

Figure 3

CT scan demonstrates infrarenal abdominal aortic aneurysm.

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Fujitani et al.

patency of the celiac axis, superior and inferior mesenteric arteries, and the condition of the iliac and distal runoﬀ arteries. It should be kept in mind, that arteriography deﬁnes only that portion of the lumen not ﬁlled with clot and should not, by itself, be used to determine the diameter of the aneurysm. The majority of abdominal aortic aneurysms are asymptomatic. When symptoms do occur, they are related to compression of surrounding structures, arterial embolization, or rupture. Pain is usually described as an intermittent ache in the abdomen or back, although discomfort in the ﬂank or scrotum may also be noted. In fact, abdominal aortic aneurysms can mimic virtually all intra-abdominal conditions. Since the pain of expansion cannot be reliably distinguished from retroperitoneal rupture, the acute onset of back pain in a patient with a known aneurysm is an indication for urgent operation. Most clinicians agree that an infrarenal aortic aneurysm greater than 5 cm in diameter is an indication for surgery in good-risk patients [67]. With elective mortality of aneurysm resection as low as 2%, patients can be returned to a normal life expectancy for age-matched controls with comparable cardiac disease. Severe pulmonary disease, ischemic heart disease, and renal dysfunction increase operative risk [68]. Age per se is not a signiﬁcant risk factor for perioperative mortality. Furthermore, the functional status of geriatric patients undergoing aneurysm repair rapidly returns to normal; most report resumption of full activities within 8 weeks of operation [69–71]. The consequences of a conservative, nonoperative approach to AAAs in geriatric patients was well documented in a classic report from the Cleveland Clinic reviewing 152 patients 75 years of age or older [72]. Of the 69 patients who did not have surgery, 37% eventually died of ruptured aneurysms. During the same interval, the perioperative mortality of those patients undergoing elective repair was not diﬀerent from that experienced by younger patients (14% vs. 9%). Another series from Toronto documented an admirable 3% operative mortality in 34 patients 80 years of age or older [73]. A ruptured aneurysm requires immediate operation to avoid the prohibitive mortality associated with delay in diagnosis and therapy. For this reason, any patient presenting with signs or symptoms consistent with a ruptured aneurysm (classic triad of abdominal pain, presence of a pulsatile abdominal mass, and hypotension) should be emergently transported to the operating room. Minimal, if any, diagnostic studies are indicated. With such an aggressive approach the mortality of ruptured aneurysm has been lowered to less than 25% in some centers, especially when the surgical procedure is begun prior to anuria and massive blood loss. Unusual presentations of aneurysmal disease include inﬂammatory aneurysms, mycotic (infected) aneurysms, and aortocaval and aortoenteric ﬁstulae. Inﬂammatory aneurysms are characterized by a dense desmoplastic soft-tissue reaction around the aorta. These lesions cause abdominal and back pains, which often suggest the diagnosis of impending rupture. In some cases, patients present with ureteral or duodenal obstruction due to the retroperitoneal reaction. Mycotic aneurysms are rare and are seen most commonly in patients with subacute bacterial endocarditis and histories of intravenous drug abuse. In our experience, they may also occur in debilitated patients receiving long-term steroid treatment. If the infection is acute, a severe systemic response is evident. Daily intermittent fevers, impressive leukocytosis, and cachexia complete the septic presentation. On occasion, however, infections are more indolent and may show only a mild leukocytosis or increased erythrocyte sedimentation rate (ESR). Preoperative diagnosis is crucial since direct arterial reconstruction in the infected ﬁeld is contraindicated and complex extra-anatomical approaches must be devised. A mycotic aneurysm should be suspected if the arteriographic image is inconsistent with the typical aortic aneurysm. In particular, irregular nonathero-

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sclerotic supraceliac aneurysms or saccular aortic aneurysms at any location have a high incidence of complicating infection. Aortocaval ﬁstulae occur when the right lateral wall of an aortic aneurysm erodes into the infrarenal vena cava. While this is a most unusual presentation (probably less than 2% of all ruptured aneurysms), it must be suspected when a patient presents with the classic triad of a pulsatile abdominal mass, continuous midabdominal bruit, and sudden onset of congestive heart failure. Surgical treatment involves routine aneurysmorrhaphy with closure of the caval defect from within the aneurysm. Primary aortoenteric ﬁstulae follow the erosion of an aortic aneurysm into the third or fourth portion of the duodenum. Aneurysms may also perforate into the sigmoid colon or small bowel. More commonly, infected anastomotic pseudoaneurysms from previously inserted aortic prosthetic grafts may also form aortoenteric ﬁstulae. Oddly, exsanguinating hemorrhage rarely occurs early in the course. Rather, patients present with multiple episodes of limited upper gastrointestinal bleeding, aptly called ‘‘sentinel hemorrhages.’’ Hence, the diagnosis should be suspected in any patient with a known aneurysm or previous aortic graft replacement with signs of gastrointestinal blood loss. Endoscopy is most useful in excluding the more common causes for bleeding such as peptic ulcer disease or gastritis. While arteriography (especially lateral views) may demonstrate extravasation or pseudoaneurysm formation, studies are often normal in patients who are not actively bleeding. The treatment of AAAs with endovascular stent-graft prostheses has proven to be eﬃcacious as an alternative to major ‘‘open’’ abdominal surgery. Endovascular repair of an aortic aneurysm allows for exclusion of the aneurysm using a composite stent-graft inserted inside the aorta from a remote site, usually via the femoral or iliac artery percutaneously or through small groin incision(s) (Figure 4). This technology has evolved signiﬁcantly over the 12 years since Dr. Juan Parodi performed the ﬁrst successful endoluminal exclusion of an AAA in Argentina using a customized tube graft [74]. Since that time a number of endoluminal devices have been developed commercially with four devices being approved by the FDA for clinical use at the time of this publication. The number of AAAs treated by endovascular means has also increased as experience with these devices has been acquired. Unfortunately, the long-term durability of these procedures is not yet clearly deﬁned. The major advantage of the endovascular method is the avoidance of a major abdominal operation and its inherent risks, especially in those with signiﬁcant comorbidities. Patient selection is a critical factor in that patients must have favorable vascular anatomy that will support an endovascular prosthesis. Other short-term advantages that have been demonstrated with endovascular exclusion are decreased hospital length of stay, decreased ICU stay, decreased intraoperative blood loss, and decreased early morbidity [75]. The major disadvantage is the unique risk of endoleaks (incomplete sealing of aneurysm sac by endograft) requiring repeated reinterventions [76,77]. These uncertainties also require a higher level of repeat surveillance studies (usually serial CT scans) to determine continued eﬃcacy of the endoluminal repair. Other known complications are stent/graft migration and material failure such as wireform fractures and graft separation [77]. In a retrospective review comparing open versus endovascular repair, Carpenter et al. found that if total hospital days were compared, including all future hospital admissions secondary to endovascular related complications, there was no signiﬁcant diﬀerence for mean length of stay [78]. In addition, these readmissions frequently necessitated further invasive interventions to maintain proper function of the endovascular prosthesis [78]. Other reported complications have been limb thrombosis, perforations, and graft rupture [79,80]. A recent meta-analysis found that endovascular graft implantation itself was an independent risk

722

Fujitani et al.

Figure 4 a) Infrarenal abdominal aortic aneurysm (AAA) prior to endograft deployment. b) Aortogram demonstrating exclusion of AAA following deployment of aortic endograft.

factor for perioperative complications [81]. However, using data from the Eurostar database, Laheij et al. also demonstrated that specialist teams with a high level of endovascular experience had signiﬁcantly lower mortality rates and fewer adverse events leading to secondary interventions [82]. Additionally, the ongoing lifetime surveillance of these endografts may entail signiﬁcant added cost. Datillo et al. in a 7-year retrospective review at their institution concluded that in their experience endovascular repair was not as durable as standard open repair [83]. Prospective controlled trials are continuing to determine the durability of these devices in comparison to open repair. However, when taking all these factors in consideration, endovascular techniques will play an important part of the surgical armamentarium in the elderly patient with multiple comorbidities and can impart signiﬁcant improvement in quality of life. Thoracoabdominal Aortic Aneurysms The incidence of thoracoabdominal aneurysms is lower than that of infrarenal AAAs, but the potential for rupture is similar [84]. The best assessments of the natural history of these lesions estimate a 50% rupture rate over 5 years for isolated thoracic or thoracoabdominal aneurysms greater than 7 cm [85]. Unfortunately, surgical therapy of these lesions is associated with a much higher mortality than the treatment of infrarenal AAAs. The incidence of perioperative morbidity, including paraplegia, is also signiﬁcant [86].

Peripheral Vascular Disease

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Thoracoabdominal aneurysms are usually asymptomatic and are found incidentally. Most often, the ﬁndings of widening of the mediastinum or an abnormal vascular density behind the heart on routine chest x-ray are the ﬁrst indication of the presence of a thoracoabdominal aneurysm. When symptoms occur, patients complain of nonspeciﬁc upper abdominal or chest discomfort or more severe chest pains secondary to direct compression of the intercostal nerves. When rupture does occur, the symptoms relate directly to the site and rate of bleeding. Rupture within the chest is often accompanied by exsanguinating hemorrhage because of the large potential space. On occasion, however, patients may leak slowly over days or weeks and complain of chest pain associated with left pleural eﬀusion. Even though thoracic aneurysms are almost always initially discovered by chest x-ray, CT scan is needed to properly deﬁne the proximal and distal extent of the aneurysm. It is also helpful in making some assessment regarding the condition of the aortic wall. Aortography remains an essential study in the preoperative evaluation of patients with thoracic and thoracoabdominal aneurysms. The mesenteric circulation and the distal extent of the aneurysm are best evaluated by conventional arteriography. Furthermore, it is sometimes possible to identify the dominant spinal blood supply from either proximal intercostal vessels or the dominant radicular artery (the artery of Adamkiewicz). The latter vessel usually arises on the left side of the aorta and can originate from the eighth thoracic to the fourth lumbar vessel [87]. Surgical treatments of these thoracoabdominal aneurysms are extensive procedures requiring detailed evaluation of perioperative risk factors, especially pulmonary, cardiac, and renal function. Whenever possible, operation should be carried out by a team of surgeons and anesthesiologists experienced in the most current measures for spinal cord and myocardial protection [88,89]. Even in the most experienced centers, 30-day mortality is high, particularly in patients over 75 years or age (10 to 20%). Nonetheless, once symptoms are evident, the risk of rupture and death mandates consideration of urgent repair. New developments in transluminally placed endografts are being evaluated to provide an alternative method of treatment, especially for aneurysms limited to the thoracic aorta [90]. At the current time, application of this technology, even in carefully selected patients, is still unproven with regard to its long-term eﬃcacy. Specialized centers are actively providing careful, prospective evaluation of these endovascular devices and techniques. Mesenteric Ischemia The elderly patient is especially prone to the development of acute mesenteric ischemia but the diagnosis is often seriously delayed because concomitant medical problems can complicate accurate assessment of the symptom presentation. Geriatric patients with underlying cardiac disease, including valvular heart disease, congestive heart failure, cardiac arrhythmias, and recent myocardial infarction are more prone to present with acute mesenteric ischemia [91]. These conditions often lead to arterial–arterial macroembolization leading to sudden occlusion of mesenteric arteries. Additionally, these serious comorbidities also decrease the likelihood of successful treatment. Alternatively, patients with chronic mesenteric ischemic syndromes due to advanced atherosclerotic involvement of mesenteric arteries may progress to sudden thrombosis leading to acute ischemic symptoms. Classically, the presentation of acute mesenteric ischemia is abdominal pain out of proportion to physical ﬁndings. The pain is usually located in the midabdominal aorta, described as steady and severe. The patient typically is found writhing in bed in distress, being unable to ﬁnd a comfortable position. Yet, typically, the physical ﬁndings are

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paradoxically quite benign early in the clinical presentation. If peritoneal signs are elicited, it is likely that intestinal infarction has already occurred. As noted by Boley et al. [92], mortality from a mesenteric event is directly related to the state of the bowel at the time of the diagnosis. The occurrence of bowel infarction greatly increases mortality and morbidity; in some series, infarction is associated with greater than 80% mortality. This fact underscores the importance of prompt diagnosis and treatment of acute ischemia with expeditious arterial reconstructions in chronic ischemic syndromes before acute ischemia supervenes. Macroembolization from a proximal source is one of the most frequently encountered causes of acute ischemia, accounting for about one-third of all mesenteric vascular catastrophes [92]. As noted earlier in this chapter, most emboli occur in association with cardiac arrhythmias (especially atrial tachyarrhythmias) or myocardial infarctions. The superior mesenteric artery (SMA) is the most common site of visceral arterial occlusions due to its orientation to the abdominal aorta. Acute thrombosis of an already compromised vessel lumen occurs in another onethird of cases. Such preexisting atherosclerotic lesions are often associated with prodromal symptoms. In fact, over 50% of patients who die due to acute SMA thrombosis have a history of postprandial abdominal pain and weight loss [92]. Intestinal angina typically occurs 15 to 60 min after meals and is more closely correlated with the volume of food consumed rather than any speciﬁc type of food. In situ thrombosis typically occurs at the origin of the superior mesenteric artery resulting in gut infarction from the proximal jejunum to the midtransverse colon. Nonocclusive mesenteric ischemia makes up most of the remaining cases of mesenteric ischemia. It most commonly involves the viscera supplied by the superior mesenteric artery. The mechanisms leading to visceral ischemia are often multifactorial. Patients typically have moderate-to-severe mesenteric atherosclerosis with marginal cardiac reserve. The administration of vasoactive agents, especially digitalis preparations, further exacerbates the process [93]. The onset is often predated by an acute decrease in cardiac function with reductions in mesenteric perfusion pressure. Paradoxical splanchnic vasonconstriction then ensues with microvascular collapse, formation of microthrombi, and capillary sludging. Venous thrombosis, a relatively uncommon cause of mesenteric vascular compromise, may begin peripherally in the small veins of the mesenteric arcade or centrally in the major trunks of the portal system [94]. Substantial splanchnic ﬂuid sequestration and hemorrhagic intestinal infarction accompany venous occlusion. Although mesenteric venous thrombosis may also present with constant, diﬀuse abdominal pain, symptoms may be intermittent at ﬁrst. About half of these patients complain of distention and nausea with low-grade fever. Many patients developing mesenteric venous thrombosis have a history of associated deep venous thrombosis of the extremities or hypercoagulable states. The clinician’s single greatest tool for the successful diagnosis of an acute mesenteric vascular event is a high index of suspicion in patients with multiple risk factors. Although many laboratory abnormalities occur with mesenteric ischemia and infarction, most are nonspeciﬁc and thus not diagnostic. These include hemoconcentration, leukocytosis with a signiﬁcant ‘‘left shift,’’ metabolic acidosis, hyperamylasemia, and hyperphosphatemia. Abdominal roentgenograms are useful in excluding other causes of abdominal pain such as mechanical small-bowel obstruction or perforation of a hollow viscus. As many as 70% of patients with mesenteric ischemia show at least one of the following signs on abdominal radiographs: ileus, ascites, small-bowel dilation, thickening of valvulae conniventes, and separation of the small-bowel loops. On occasion, a ‘‘gas-less’’ abdomen is seen due to excessive ﬂuid accumulation within the lumen.

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Barium studies are actually contraindicated but, if performed, may show evidence of small-bowel dilation and focal mucosal hemorrhage (‘‘thumbprinting’’). The considerable disadvantage of intraluminial contrast studies is the potential for interference with arteriography, which is the essential diagnostic study. The problems with all diagnostic tests except arteriography are the lack of speciﬁcity and reliability. Successful arteriography mandates prior hemodynamic stabilization of the patient since hypotension alone may cause signiﬁcant splanchnic vasoconstriction and preclude an adequate study. Infusion of any vasoactive drugs with splanchnic vasoconstrictive properties should be terminated. Both anterior/posterior (AP) and lateral views of the aorta are required (Figure 5). The anterior/posterior view best demonstrates collateral vessels, while lateral aortography better visualizes the origins of major visceral arteries that overlie the aorta in the AP plane. Arteriographic signs can generally diﬀerentiate embolic from thrombotic occlusions [95]. As noted earlier, emboli to the SMA usually lodge just proximal or distal to the origin of the middle colic artery and may be associated with minimal preexisting atherosclerotic changes. Thrombotic occlusions of preexistent stenotic lesions, on the other hand, occur more commonly at the SMA origin and are associated with both generalized atherosclerosis of the aorta and the presence of extensive collaterals. Mesenteric venous thrombosis is

Figure 5 a) Lateral aortic arteriogram of patient presenting with advanced chronic mesenteric ischemic symptoms. Note complete occlusion of both celiac axis and superior mesenteric artery (SMA) at origins. b) Large Arc of Rioian providing collateral ﬂow to visceral organs from inferior mesenteric artery to celiac and SMA mesenteric beds.

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characterized by general slowing of arterial blood ﬂow in conjunction with nonopaciﬁcation of the corresponding mesenteric or portal veins. Nonocclusive ischemia characteristically shows narrowing and irregularity of major branches of the SMA. Nonocclusive mesenteric ischemia may be primarily treated with intra-arterial infusion of a vasodilator such as papaverine into the superior mesenteric artery [96]. Papaverine should be administered continuously, infusing at a rate of 30 to 60 mg/h for at least 24 to 48 h. Surgery may be avoided in these patients with nonocclusive ischemia if the diagnosis is clear on arteriography and abdominal signs and symptoms totally resolve with papaverine infusion. In contrast, all patients with suspected embolic or thrombotic occlusions should undergo urgent exploratory celiotomy. Intravenous ﬂuid resuscitation, infusion of continuous anticoagulation with heparin, and administration of broad-spectrum antibiotics are indicated prior to surgery. Usually, an embolus can be directly extracted from the superior mesenteric artery through a transverse arteriotomy made at the base of the mesentery. If adequate inﬂow is obtained following the passage of an embolectomy catheter, no additional arterial reconstruction may be required. If thrombosis of an atherosclerotic lesion is suspected, or if extraction of the embolic material is not possible or incomplete, some form of aortomesenteric bypass should be considered. The operative approach to venous thrombectomy involves resection of infarcted bowel. Venous thrombectomy can be considered in the larger, more proximal veins, although the likelihood of recurrent thrombosis is relatively high. Chronic mesenteric ischemia is most frequently associated with atherosclerotic occlusions or stenoses [97]. Due to the abundant collateral network, multiple vessel involvement is usually required before classic postprandial symptoms occur. The presentation of chronic ischemia depends on the region of the gut aﬀected. The most common syndromes involve the midgut (jejunum, ileum, and right colon) and reﬂect vascular insuﬃciency of the distribution of the SMA due to atherosclerosis or midaortic developmental abnormalities. Since consumption of a meal predictably induces severe incapacitating pain, eating is dramatically curtailed with patients developing ‘‘food fear,’’ which invariably results in loss of weight. The weight loss is usually substantial and may exceed 25% of body mass. Ischemia of the foregut (stomach and liver) is much less common and may be irregular in its symptomatology. Patients frequently complain of nonspeciﬁc symptoms such as bloating and early satiety. The more classic symptoms of postprandial abdominal pain and weight loss are often absent. Finally, ischemias of the hindgut (left colon and rectum) rarely present with postprandial pain or weight loss. These patients may present with hemoccult-positive diarrhea and chronic strictures due to mucosal ischemia. These syndromes reﬂect insuﬃciency of the inferior mesenteric artery (IMA) and collateral pelvic circulation through the hypogastric (internal iliac) arteries, usually due to advanced athero-occlusive disease. Colonic ischemia frequently follows vascular reconstructions of the infrarenal aorta, which may inadvertently compromise collateral blood ﬂow through the internal iliac arteries. The deﬁnitive diagnosis of chronic intestinal ischemia is based on (1) symptoms consistent with the visceral arterial occlusive disease; (2) exclusion of other gastrointestinal pathology; and (3) arteriographic demonstration of appropriate occlusive lesions and development of collaterals. Selective arterial catheterizations are usually required along with oblique or lateral views to adequately image the origins of the three main visceral vessels. Vascular reconstruction for chronic foregut and midgut ischemia can be accomplished by endarterectomy or aortomesenteric bypass. Antegrade bypasses from the supra-

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celiac aorta to the celiac axis and superior mesenteric artery are currently our preferred method for visceral revascularization [98]. Renovascular Arterial Disease Although renovascular disease is a relatively rare cause of hypertension (1 to 5% of adult hypertensives), it is the most amenable to surgical correction [99]. Renovascular disease in the elderly is caused primarily by atherosclerotic narrowing of the renal arteries and may result in both progressive hypertension and diminished renal function. Recently, it has become apparent that clinically important ischemic nephropathy may occur without hypertension. The high probability of success in our ability to correct these functional alterations reinforces the need for the early diagnosis of renovascular disease, regardless of age. However, such an aggressive approach is controversial even today. Many clinicians feel elderly patients have such a high incidence of end-organ damage from atherosclerosis (especially coronary and cerebrovascular disease) that their response to surgical or other interventions would be poor and associated with untoward risk. Furthermore, there has been limited recognition of the availability of modern noninvasive screening tests to diagnose remediable renal artery lesions. The exact prevalence of renovascular hypertension is diﬃcult to determine. The incidence reported in any particular series is dependent o the age, sex, and race of the study population. Furthermore, it depends on the speciﬁc deﬁnition of hypertension being employed. Clinical features that increase the likelihood of a renovascular cause of hypertension in elderly patients include new onset of hypertension, rapid progression of previously stable hypertension, and hypertension associated with renal functional impairment. The presence of atherosclerotic disease in other vascular distributions increases the probability of associated renovascular disease. Hypertension resistant to standard threedrug treatment regimens (diuretics, beta-blockade, and converting enzyme inhibitors) has been associated with a 30% prevalence of renovascular disease, while the coexistence of accelerated hypertension with renal failure predicts a 45% likelihood of renovascular disease [100]. While the diagnosis may be suggested by detection of an abdominal or ﬂank systolic– diastolic bruit, this ﬁnding is quite nonspeciﬁc. Most importantly, absence of a bruit should not deter a more deﬁnitive evaluation in a patient with positive demographics. Traditional noninvasive screening methods for renovascular hypertension have included plasma renin measurements, intravenous pyelography, radioisotope renography, and split renal function tests. All of these have been disappointing as screening tests due to high false-negative rates [101,102]. In addition, these tests are not able to reliably address the critical issues in management—that is, which arterial lesions are functionally signiﬁcant and which patients would beneﬁt from renal revascularization. The reﬁnement of two noninvasive modalities, captopril renography and duplex scanning, have helped resolve these issues. Captopril renography is based on the principle that suppression of the reninangiotensin system in the presence of a hemodynamically signiﬁcant renal artery stenosis will result in a decrease in glomerular ﬁltration rate (GFR) in the aﬀected kidney. Theoretically, angiotensin inhibition decreases the resting vasomotor tone of the eﬀerent arteriole, thereby reducing eﬀective glomerular ﬁltration pressure across the basement membrane. The clinical applicability of this eﬀect was originally noted by Majd et al. [102], who observed that the diagnostic accuracy and sensitivity of renography with either technetium (Tc) 99m-diethylenetriamine pentaacetic acid (DTPA) uptake (measuring renal

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plasma ﬂow and excretory function) was enhanced by captopril administration. In a selected patient population, Setaro et al. [103] reported 91% sensitivity and 94% speciﬁcity in the diagnosis of renal arterial stenosis as compared with angiography. Furthermore, they also noted that the detection of captopril-induced scintigraphic abnormalities predicted cure or improvement of blood pressure control in 83% of patients who underwent revascularization. Unfortunately, other studies have reported lower sensitivities and speciﬁcities, and large prospective series are lacking [104,105]. A major limitation of this test is the requirement that antihypertensive medications be withdrawn for up to 2 weeks before testing. A further limitation is that interpretation of results is more diﬃcult in bilateral disease since the response of one kidney cannot be compared with that of the other. Renal duplex scanning has evolved into the principal noninvasive screening test for both the presence of renal arterial disease as well as its hemodynamic signiﬁcance [106]. This modality combines B-mode ultrasound imaging with pulsed Doppler ultrasound determinations of blood ﬂow velocity [107,108]. The ratio of renal artery peak systolic velocity to aortic peak systolic velocity (RAR) has been utilized to deﬁne hemodynamically signiﬁcant lesions. By retrospectively comparing renal artery duplex scanning and arteriography, Kohler et al. [107] correlated RAR of >3.5 with the presence of renal artery stenoses of >60% diameter reduction. This study reported an overall sensitivity of 91% and speciﬁcity of 95%. Others have conﬁrmed similar results [109]. The B-mode imaging also allows anatomical deﬁnition of the stenoses, especially whether the disease is localized to the oriﬁce or the more distal vessel. Duplex scanning is particularly useful in postprocedural follow-up of lesions treated by surgical revascularization or angioplasty. Recurrent stenoses or thromboses can be identiﬁed with an accuracy of 93% when compared to arteriography [110]. Arteriography, however, is still the accepted standard for diagnosis of anatomical renovascular disease. Multiplanar views of the renal vessels, including anteroposterior and oblique views, are routinely obtained (Figure 6). Newer digital subtraction techniques allow the utilization of smaller volumes of dye, lessening the chance for contract-mediated renal dysfunction following the necessary pararenal or selective injections. Traditionally, the measurement of renal vein renin levels has been employed as an adjunct to arteriography to help identify functionally signiﬁcant renal arterial stenoses [111].

Figure 6 Arteriogram demonstrating severe oriﬁcial renal artery stenosis.

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Such values can be expressed as renal vein renin ratios, which compare one kidney to the other (ratios of >1.5 are considered diagnostic), or renal/systemic renin indices, which quantify the contribution of each kidney to the total systemic renin level. Renal vein ratios are obviously less accurate in bilateral disease. In contrast, renal/systemic indices assess bilateral disease more precisely and have been a more reliable predictor of the response to revascularization [112]. The most favorable situation is unilateral disease in which renin secretion is suppressed in the contralateral kidney. A more aggressive approach in the treatment of renovascular disease has resulted from three recent distinct developments: (1) increased recognition of ischemic nephropathy as an important consequence of renovascular disease separate from hypertension; (2) widespread acceptance of percutaneous renal angioplasty; and (3) improved results of revascularization in elderly patients. In recent reports, substantial improvements in renal function have been noted even in patients over 65 years of age with signiﬁcant and progressive azotemia (serum creatinine >4 mg%) [113]. Currently accepted indications for renal revascularization include the presence of a hemodynamically signiﬁcant renal artery stenosis (>60% diameter) in patients with refractory hypertension or hypertension associated with renal functional impairment. Percutaneous renal angioplasty is an attractive option in high-risk elderly patients whose medical risks would otherwise prohibit operative revascularization [114]. However, it is optimally performed in midsegment renal artery stenoses and is not as well suited for treatment of the most prevalent oriﬁcial lesions. In appropriately selected stenoses, shortterm patency rates with angioplasty are approximately 90% [115]. The utility of balloonexpandable and self-expanding stents have broadened the number of renal artery lesions amenable to these catheter-based endovascular procedures. Operative options include endarterectomy and aortorenal or hepatorenal bypasses. Endarterectomy through a transaortic route is most useful in bilateral oriﬁcial disease but requires suprarenal aortic exposure and clamping with resultant higher cardiac risk. Aortorenal bypass from a relatively disease-free area of the infrarenal aorta has been the most widely used technique in the past, although extra-anatomical hepatorenal and splenorenal bypasses are commonly employed. The latter procedures avoid manipulation of the often-diseased aorta and obviate any need for aortic occlusion. Regardless of the origin of these bypass grafts, long-term patency is excellent, approaching 95% over 5 years if autogenous vein is used. In one recent series of 35 patients over 60 years of age, improvement or cure of hypertension was reported in 91% of patients and improvement in renal function in 37% [116]. Overall morbidity and mortality in this group (5.4% mortality, 23% perioperative morbidity) appeared to be related to generalized atherosclerosis and accompanying risk factors rather than age per se. The argument for aggressive treatment of renovascular disease in the geriatric patient population is further supported by the experience of the physicians at the Cleveland Clinic, who compared medical to surgical management in 50 patients over 3 years [117]. While this was not a randomized study, they noted better control of hypertension (90% improvement in the surgical group versus 66% improvement in the medical group) as well as improvement or stabilization of renal function in those treated surgically (91% surgical versus 50% medical group). Acute Arterial Thrombosis Sudden arterial thrombosis may result from (1) in situ thrombosis of preexisting atheroocclusive disease; (2) arterial–arterial embolization; (3) thrombosis of an aneurysm; and (4)

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vascular trauma. Obtaining a careful medical history can be very helpful in eliciting the underlying etiology. Patients with in situ thrombosis often describe a history of preexisting claudication or rest pain that has recently worsened. In contrast, arterial embolization, vascular trauma, and aneurysm thromboses usually are not associated with any previous vascular symptoms. When the occlusion is very sudden and is not associated with prior development of collateral arteries, the symptoms tend to be much more severe. Classically, the presentation of acute limb-threatening ischemia includes the six ‘‘Ps.’’ These include pallor, pain, paresthesias, paralysis, pulselessness, and poikilothermia (change in skin temperature). The level of coolness of the extremity is usually limited to the portion of the limb well beyond the occlusion. For example, with an acute femoral artery occlusion, the level of ischemia may not extend above the knee due to recruitment of collateral ﬂow to the thigh. On the other hand, internal organs, especially the intestines, kidneys, and brain are especially prone to early loss of function and infarction with sudden arterial occlusion due to the end-artery nature of their blood supply. With acute occlusions resulting from vascular graft thrombosis or emboli to native vessels, ﬂow through collaterals may sometimes be inadequate to preserve limb viability. The heart is the most common source of emboli, which also originate from plaques and aneurysms in the thoracic and abdominal aorta. Bilateral extremity involvement is common when the origin is proximal; unilateral involvement is the rule with embolism from the iliac or more distal vessels. Atherosclerosis is not the only cause of thombosis. Trauma, collagen vascular disorders, myeloproliferative diseases, and dysproteinemias are other causes for sudden arterial thrombosis. Acute arterial occlusion, regardless of the end organ, requires prompt recognition and treatment. The long nerves of the lower extremity are sensitive to ischemia and weakness, paralysis, or paresthesias, which indicate the presence of acute limb threat requiring urgent intervention correlating well with the degree of neurological impairment. Without timely revascularization, initial numbness may be rapidly followed by ischemic muscle necrosis and skin infarction. Irrevocable tissue loss may occur within 6 h. Often, however, even when rest pain is present, collateral ﬂow is suﬃcient to preserve the limb while diagnostic studies are obtained prior to operative intervention. Complete paralysis, muscle rigidity, and thrombosis of cutaneous vessels are markers of a high probability of limb loss even with successful revascularization. Delays can result in severe muscle ischemia and amputation. Patients with a sudden onset of acute limb threat often have embolized clots from a cardiac or peripheral source into the infrainguinal arteries. In many instances, the thrombosis of a previously patent bypass graft creates an identical clinical picture. Surgical management entails operative exposure of one or more of the vessels occluded, fashioning an incision (arteriotomy) into the artery, and extraction of the oﬀending thrombus via the arteriotomy. Embolectomy catheters speciﬁcally designed for these procedures are passed via the arteriotomy into the proximal and distal arterial segments. A tip-mounted balloon is inﬂated and traps the thrombus, leading to its extraction as the catheter is gently dragged out of the artery. Repeated passes of the thrombectomy catheter will usually result in satisfactory removal of clot and restoration of blood ﬂow. Adjunctive therapy in patients requiring urgent thrombectomy includes the use of systemic heparin (75 to 100 U/kg bolus, followed by a continuous infusion). Diagnostic angiography before surgery is helpful in planning the operation, and intraoperative contrast angiography can be used to position thrombectomy catheters over guidewires and to conﬁrm the restoration of blood ﬂow. Arteriography is especially helpful in cases of sudden thrombosis of preexisting disease. However, arteriography is not essential in the diagnosis

Peripheral Vascular Disease

731

and treatment of obvious embolic occlusions, especially if thrombolysis is not an option due to advanced ischemia or other contraindications. Thrombolytic drugs may be administered as part of the operation to dissolve clots that are either incompletely removed by embolectomy catheters or lodged in tibial or pedal vessels beyond their reach. The combination of ﬂuoroscopic guidance of embolectomy catheters and the use of intraoperative thrombolytic drugs both improves the overall success of operative interventions and allows distal thrombi to be adequately managed via femoral and popliteal incisions [118,119]. The use of proximal incisions is an advantage because they avoid arteriotomies of more distal vessels with the risk of intimal hyperplasia and late thrombosis. An additional concern is that incisions below the knee may compromise subsequent amputation stump healing if revascularization is unsuccessful. The overall immediate success rate with surgical thrombectomy and embolectomy for limb salvage in the face of acute occlusion is good, on the order of 70 to 90%. Patient mortality after embolic episodes, however, is strikingly high; compared to elective bypass, the reported mortality ranges from 4 to 39%, with an average rate of about 20% in recent series [120]. Some of the factors responsible for the high mortality are the metabolic disturbances that accompany acute arterial occlusion of the lower extremity including hyperkalemia, acidosis, and renal failure secondary to rhabdomyolysis. Some of these disturbances are a consequence of cellular necrosis due to ischemia and may be exacerbated by the reperfusion injury that often attends successful revascularization after severe ischemia. Delay in operative treatment of limb-threatening ischemia correlates with poor outcomes. In one series, treatment instituted within 12 h of symptom onset led to a limb salvage rate of 93% and 12% mortality. After 12 h, limb salvage fell to 78% and mortality increased to 31% [121]. Another factor in the high mortality associated with embolism is the concomitant presence of severe cardiac disease and the frequency of other comorbid conditions. Increased mortality is associated with advanced age; in one series, those younger than 70 years old were found to have 7% mortality compared to 22% for those older than age 70 [120]. Many elderly patients may have already undergone previous vascular reconstructions, which are susceptible to failure. Occluded bypass grafts may be treated by thrombectomy using techniques similar to those employed with primary thromboembolism or pharmacological thrombolysis. Both techniques are used to restore antegrade ﬂow, and the results are good if attendant technical defects restricting ﬂow (most commonly stricture of the distal anastomosis or stenosis in the native artery just beyond) are also corrected. After initial treatment of embolic occlusions, long-term postoperative anticoagulation must be strongly considered. Without anticoagulation, emboli may recur in about one-third of patients within 30 days. With the use of heparin and warfarin postoperatively, the recurrence rate decreases to less than 10%. Unfortunately, even with the best treatment, the mortality rate for acute arterial occlusion remains relatively high. This can be attributed to the often advanced age of these patients suﬀering from either in situ thrombosis or embolization together with the severity of associated myocardial disease. The most common cause of death in these patients is myocardial infarction and pulmonary embolization.

LOWER EXTREMITY ATHERO-OCCLUSIVE DISEASE Moderate peripheral arterial disease (PAD) may induce pain or weakness with walking, which resolves rapidly with rest. This symptom complex is known as intermittent claudi-

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cation. Lower extremity blood ﬂow at rest is approximately 500 mL/min but can increase tenfold to 5 L/min with maximum exercise stress. Resting skeletal muscle perfusion is 2 mL/ 100 g/min but rises to 70 mL/100 g/min with maximum exercise—a 35-fold increase. As muscle tends to be more sensitive to the imbalance between blood ﬂow requirements and what the diseased arterial system can deliver, most patients experience symptoms in muscle groups, with the calf being the most common site involved, but buttock, hip, foot, thigh, or even the inferior back muscles can be aﬀected. As the imbalance between the demand and actual perfusion is transient, claudication is considered a functional impairment. When ﬂow cannot meet the needs of resting tissue metabolism, evidenced by pain at rest or tissue loss, the lower extremity ischemia is considered critical. Rest pain from critical ischemia is usually experienced in the toes or foot. Patients may dangle their legs from bed or stand to relieve symptoms. Without intervention, rest pain may progress to ulceration or gangrene. Chronic arterial insuﬃciency ulcers tend to be bland and lack intense inﬂammation or infection. They commonly develop at the ankle, heel, or leg. Mummiﬁed, dry, black toes or devitalized soft tissue covered by a crust represents gangrene from ischemic infarction. With time, suppuration often develops, and ‘‘dry’’ changes to ‘‘wet’’ gangrene. Recent epidemiology studies indicate that only one-half of patients with documented PAD (ABI <0.9) are symptomatic. To some degree, this is due to the common ﬁnding that elderly PAD subjects are often more limited by other diseases (e.g., arthritis or emphysema), such that they never walk far or fast enough to induce muscle ischemic symptoms. Many who do experience intermittent claudication consider it a normal consequence of aging and fail to mention the problem to medical professionals. In addition, for many PAD patients suﬃcient collateral arterial channels develop such that total occlusions are surprisingly well tolerated. The symptomatic cohort is split 4 to 1 between functional and critical ischemia. Overall, the frequency of PAD rises with increasing age, involving about 25% of the U.S. population over 75 years of age. As is the case with coronary artery disease, women show a decreased incidence compared to men the same age, but the gap between genders narrows with advancing age. Only a small minority of PAD patients ever experience limb loss. Over 5 years, claudicants have about a 25% crude mortality rate (three times higher than subjects the same age without PAD), with a marked increased risk for myocardial infarction and stroke. In contrast, over 5 years they have only about a 10% risk of requiring amputation or arterial reconstruction. Smokers and diabetics and those with low ankle pressures are more prone to progress from functional to critical ischemia [122,123]. Isolated aortoiliac involvement is a favorable pattern, with better outcomes than when the infrainguinal vessels are aﬀected [124]. Infrainguinal disease is found in 65% of PAD patients over 40 compared to only 25% of younger patients [125]. With increasing age, the frequency of multisegmental arterial occlusion is higher, and the location of the diseased segments is more likely to be distal [126]. Multisegmental involvement is also associated with decreased survival and increased risk for coronary disease. When matched to patients with identical risks factors except for PAD, claudicants have a three- to sixfold higher risk for cardiovascular mortality [127]. Patients with diabetes mellitus have an increased risk for PAD and limb loss. Wound healing in diabetics may be impaired from enhanced susceptibility to infection, microangiopathy, and polyneuropathy, as well as arterial insuﬃciency. Sensory neuropathy may prevent ischemic symptoms from being experienced or recognized, leading to unfortunate delays in proper diagnosis or therapy. Motor and autonomic neuropathy may lead to deformity and enhanced skin susceptibility to injury. Neuropathic ulcers, which typically

Peripheral Vascular Disease

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develop over bony prominences such as the plantar aspect of the metatarsal heads need to be distinguished from neuroischemic ulcers, in which arterial insuﬃciency independently contributes to the pathological process. Liberal use of ultrasonic and angiographic investigations is warranted in diabetes when lower extremity circulation is an issue as the risks are so high. Current therapies and interventions for PAD include medical management, arterial reconstruction with surgery or endovascular methods, and ﬁnally, amputation. Medical Management of PAD Medical therapy entails reducing the impact of risk factors for atherosclerosis so as to slow disease progression, teaching proper local care of the foot, encouragement of exercise, and appropriate drug therapy. As tobacco use is a powerful promoter of disease progression, eﬀorts aimed at smoking cessation are most helpful. Even when tissue loss is present, tobacco cessation may lead to healing. Exercise regimens are very eﬀective for claudicants. If not restricted by other ailments, most can double their walking distance within 3 months by following a daily exercise routine, leading to multiple beneﬁts including improved joint mobility, better neuromuscular function, and a lower incidence of cardiovascular events [128]. The beneﬁcial eﬀects induced by exercise result from stimulation of arterial collateral vessels and changes in skeletal muscle enzymes, and possibly improved cardiac performance. With advancing age, ambulation consumes a greater proportion of the total energy expenditure an individual can generate. As a consequence, much of the beneﬁt of strenuous exercise in the young is achieved in the aged by simple walking [129]. The usual prescription for exercise therapy is a daily regimen of walking outside or on a treadmill, with gradual increases in the time spent with a target of 30 to 60 min. Repeated cycles of walking to maximum tolerated discomfort, recovery, and further walking should be part of the training. Patients must be careful to avoid minor trauma and wear properly ﬁtted shoes. Small objects inside a shoe may cause serious wounds. Careless nail clipping or injury from walking barefoot may lead to catastrophe. Feet should be washed daily and skin kept moist with topical emollients to prevent cracks and ﬁssures, which may become portals for bacterial infection. Similarly, fungal infections should be treated aggressively. Socks should be wool or other thick fabrics, and as necessary padding or shoe inserts should be employed to prevent pressure sores. When a wound of the foot develops, specialized foot gear, including casts, boots, and ankle foot orthoses are often helpful in unweighting the aﬀected area. The most important aspect is preventative care, as neuropathic and neuroischemic ulcers may become refractory to treatment, carrying a high risk of amputation despite appropriate care. Adjunctive pharmacological therapy for PAD has signiﬁcant potential eﬃcacy, but may not always be successful. Pentoxifylline leads to symptomatic improvement in an occasional claudicant, but is ineﬀective in most [130,131]. A new phosphodiesterase-3 inhibitor, cilostazol, has recently been introduced into clinical practice and appears to be more eﬀective than pentoxifylline in treadmill studies, providing signiﬁcant improvement in walking to about 50% of patients [132–134]. The pharmacological eﬀects of cilostazol on the cardiovascular system include direct relaxation of arterial smooth muscle leading to vasodilatation of both the macro and microcirculation, with preferential action on the lower extremity compared to other vascular beds. Headaches are a common early side eﬀect of the drug and appears to be associated with cerebrovascular vasodilation [135–137]. These

734

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headaches usually resolve after several weeks, but can limit patient acceptance of the medication. Other side eﬀects are diarrhea and superventricular tachycardia. Like other phosphodiesterase-3 inhibitors, cilostazol is a positive chronotrope and inotrope and induces an average increase in resting heart rate of about 5 beats per minute [138]. About 5% of claudicants treated with cilostazol will not be able to tolerate the drug due to tachycardia. Other noteworthy eﬀects of cilostazol include inhibition of smooth-muscle cell proliferation in vitro, inhibition of myointimal hyperplasia after endovascular interventions, and a beneﬁcial eﬀect on serum lipids (moderate increases in HDL and decreases in triglycerides [139–142]. Cilostazol also inhibits platelet aggregation and degranulation, comparable to aspirin, and thus carries a moderate risk of promoting hemorrhage. Like other antiplatelet agents, it should be used very cautiously in combination with warfarin, but probably can be safely used routinely with aspirin [143]. In addition to a proven eﬃcacy in claudication, anecdotal experience in many U.S. centers indicates that cilostazol can promote healing of chronic arterial ulcers; thus, it may be a useful intervention in some subjects with critical ischemia. It also appears to be eﬀective for Raynaud’s disease [144,145]. L-arginine is the precursor for endothelial cell production of the vasodilator nitric oxide. With divided doses of 8 to 16 g daily, L-arginine reportedly improves walking ability in claudicants [146]. The author’s experience with a moderate number of claudicants suggests that approximately one-third will experience signiﬁcant beneﬁt with arginine. Another medication, L-carnitine, is a mitochondrial cofactor for oxidative metabolism and appears to beneﬁt some claudicants at the dose of 1 g twice daily. Arginine is widely available as an over-the-counter food supplement in the United States. Carnitine is available as both a prescription drug and food supplement. A longer acting derivative, proprionyl-carnitine, is currently undergoing clinical trial evaluation [147]. A variety of prostaglandin E1 analogs are arterial vasodilators, and when administered intravenously are moderately eﬀective in promoting healing of chronic lower extremity arterial wounds [148,149], but none have been adopted into routine practice in the United States. Beroprost, an oral prostaglandin agent, is used in Europe for PAD [150]. Therapy with vascular endothelial growth factor (VEGF) has been shown in a few preliminary studies to promote angiogenesis in ischemic limbs and potentially could be a very useful agent for PAD [151]. Reconstruction Bypass surgery is the most common reconstruction employed for PAD of the lower limb. The results of all interventions are evaluated based on patency, limb salvage, and patient survival rates using life-table analysis. Patency refers to the continued function of a vascular conduit (bypass grafts or treated native vessels) at the end of a speciﬁed period. Primary patency represents uninterrupted blood ﬂow (function) without additional procedures employed to resurrect, maintain, or improve ﬂow from the time of initial implantation or treatment. Secondary patency is achieved if blood ﬂow (function) is present at the end of the time period under consideration, but secondary interventions have been performed to maintain or restore function. If a corrective procedure, such as balloon angioplasty or surgical patch angioplasty, is undertaken to maintain blood ﬂow without actual failure of the bypass graft or native vessel, assisted-primary patency is achieved. Limb salvage is achieved when no major amputation is required. A variety of materials are employed for bypass, with autologous saphenous vein (in either the reversed or in situ conﬁguration) and expanded polytetraﬂuoroethylene (ePTFE) being the most common conduits. Autologous veins are preferred over prosthetic conduits since they yield the best long-term patency. The

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common procedures are above knee femoropopliteal bypass, below knee femoropopliteal bypass, tibial (meaning distal anastomosis to a tibial vessel) bypass, and pedal or crural (ankle level or lower) bypass (Figure 7). Figure 8 shows the relations that emerge from numerous studies of lower extremity bypass [152–154]. Secondary patency is better than primary patency, as the former includes grafts resurrected after thrombosis. Limb salvage usually exceeds graft patency. This is particularly true if an operation is performed for intractable intermittent claudication— graft failure should not mandate limb loss. In addition, with gradual failure of a bypass, suﬃcient collaterals may develop such that when the graft completely occludes, suﬃcient perfusion is maintained to preserve the limb. Patient survival tends to be worse than patency or limb salvage rates because bypass patients are likely to succumb to accelerated cardiovascular disease. Most bypass patients die before recurrent ischemia necessitates amputation. Factors that inﬂuence patency, limb salvage, and survival after bypass are: (1) the severity of ischemia prior to operation; (2) the level of distal anastomosis; (3) the quality of the run-oﬀ arteries from the distal anastomosis (distal resistance); and (4) the conduit employed [155]. Long-term survival is highest when intractable claudication is the indication for bypass; intermediate with rest pain symptoms; and lowest when tissue loss is present at operation. The correlation between operative indications and mortality reﬂects the association between diﬀuse atherosclerotic disease in the lower extremities with more severe atherosclerosis in other territories. Similarly, if limb salvage is the chosen endpoint, the same relationship between operative indication and outcomes is observed—worse outcomes are

Figure 7 Arteriogram of distal reverse vein bypass to peroneal artery in patient presenting with limb-threatening condition.

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Figure 8 Life table analysis of results from infrainguinal bypass. The idealized relation between limb salvage, graft patency, and patient survival is shown. The relations shown could be for any particular bypass, such as above-knee saphenous vein femoropopliteal bypass. If a more distal anastomosis had been employed, overall rates of salvage, patency, and survival would be shifted downwards, but the relative positions of the curves would remain unchanged.

more likely with more advanced symptoms. Worse symptoms tend to be associated with more arterial segments being involved. Similarly, as more arterial segments are involved, the level of bypass required tends to become more distal, and worse outcomes result from the increased incidence of cardiovascular comorbidites associated with diﬀuse lower extremity arterial disease. The run-oﬀ resistance to ﬂow tends to be higher with more distal bypasses, exerting an independent negative impact on bypass graft patency. Even when bypass operations are immediately successful, more severe PAD strongly correlates with higher risks for subsequent graft thrombosis, limb loss, and death. Saphenous vein grafts to the popliteal artery provide 75 to 80% 5-year secondary patency, with higher patency rates resulting from intense graft surveillance and appropriate intervention. ePTFE grafts above-the-knee have an approximate 50% 5-year secondary patency, but have much poorer secondary patency (20 to 25%) when used below the knee. These prosthetic graft patencies have been reported to be improved with minor alterations in technique such as interpolating a patch of vein at the distal anastomosis [156]. The saphenous vein is highly preferred for distal bypass because of its better patency rates [155,157,158]. Due to the less favorable patency and limb salvage rates found with distal bypasses, procedures requiring reconstruction below the knee are generally reserved for critical ischemia with attendant limb threat. Such distal bypasses are generally avoided when uncomplicated claudication symptoms are the only indications for revascularization. Some of the complications of bypass include perioperative death, early graft failure, and wound complications. Thirty-day mortality (Table 4) after elective bypass is 2 to 5%, predominantly resulting from myocardial infarction [158,159]. Wound complications occur in as many as 20% of infrainguinal bypasses, but are generally minor, entailing superﬁcial

Peripheral Vascular Disease Table 4

737

Mortality of Lower Extremity Bypass

Author

Year

No. of patients

Mean age

30-day mortality

Rosenblatt Vieth Taylor Moody Whittemore

(1990) (1990) (1992) (1992) (1995)

[164] [165] [126] [166] [128]

171 857 484 226 3005

64 — 68 68 —

0 3.1 2.3 1.8 2.0

Plecha

(1985) [167]

Gregg

(1985) [143]

Bunt

(1994) [144]

2377 571 186 89 183

<75 >75 <70 >70 <70

2.2 6.7 3.5a 15.6a 2.2

a

Hospital mortality.

necrosis or infection, delayed healing, and ﬂuid accumulations from lymphatic disruption. Bypass graft infection is fortunately uncommon, with an incidence of only 1 to 2%, but can lead to a cascade of additional surgeries and even limb loss [160]. Besides bypass, endarterectomy and sympathectomy are occasionally employed. Endarterectomy in the lower extremity employs the same techniques required for carotid surgery. Optimal results are achieved with short arterial segments in the proximal arterial bed, with bypass being better than endarterectomy for longer, distal occlusions. Sympathetic denervation of the lower extremity can provide moderate improvements in symptoms of causalgia and in situations where arterial reconstruction is deemed impossible. It may occasionally be beneﬁcial in PAD. Sympathectomy requires excision of two ganglia in continuity and is adapted to minimally invasive endoscopic techniques. It should be reserved for otherwise inoperable patients with intact autonomous nervous system function (not routinely present in diabetics) and ABI greater than 0.3 [161,162]. Treatment of arterial lesions of the lower extremity may be amenable to either percutaneous transluminal angioplasty (PTA) or operative reconstruction [163]. Success or failure of PTA depends on (1) whether stenosis or complete occlusion is present; (2) lesion length; (3) severity of symptoms (i.e., claudication or limb threat); (4) position of the lesion (i.e., femoral, popliteal, or tibia); and (5) quality of the distal runoﬀ. The best results with PTA are achieved with short (<5 cm) focal stenoses in large arteries (e.g., iliac segments), and the worst results with long and distal occlusions (e.g., long superﬁcial femoral(SFA)popliteal occlusions). Five-year patency may be as high as 72% for iliac PTA if the runoﬀ is good (patent SFA) compared to only 51% when the SFA is occluded [164–166]. The quality of tibial runoﬀ (i.e., the presence of occlusion in the three tibial vessels) has a similar inﬂuence after popliteal PTA. Intraluminal stents may limit elastic recoil of atheroma into the lumen to prevent immediate restenosis and represent a major advance in endovascular therapy. A variety of balloon expandable and self-expanding stents are widely used clinically. The largest experience with stents in PAD has been with aortoiliac lesions. Compared to PTA alone, stenting improves 3-year patency by 26% [167,168]. Our center has been treating complete SFA-popliteal occlusions since 1994 with mechanical guidewire penetration and recanalization by PTA, followed by stent deployment throughout the area of occlusion. Compared

738

Fujitani et al.

to simple PTA which yields 1-year secondary patency of only 40% in our patients [169], the results achieved with adjunctive stenting of long occlusions have been signiﬁcantly better. Secondary patency has approached 70% at 3 years [170]. Our experience has shown that stenting is clearly superior to PTA alone for long occlusions with an acceptably low periprocedural morbidity from embolization and bleeding. Several recent, well-designed randomized clinical trials have shown no beneﬁt for stenting of short lesions (<5 cm) over PTA alone [171,172]. These observations indicate that the short-term improvement in patency aﬀorded by stent prevention of immediate recoil is balanced by increased stimulation of myointimal hyperplasia. Follow-up angiography in our series indicates that restenosis >50% within the stented segments occurs in the majority of cases by 1 year. This restenosis within the stent is generally progressive and not self-limited, leading to hemodynamic failure or thrombosis in the majority of patients by 3 years. This results in frequent additional treatments with thrombolysis or repeat PTA to maintain patency, limiting the value of stenting for infrainguinal occlusions. Our present practice is to employ bypass as the preferred intervention for chronic limb ischemia, reserving stenting of infrainguinal arteries for an occasional short lesion in a claudicant or for patients whose comorbidities make conventional surgery too risky. There is great current interest in the ability of adjunctive radiation and drug therapy to limit myointimal hyperplasia after PTA or stenting. Several studies, mostly by European groups, have shown that femoral restenosis after endovascular therapy is markedly inhibited by brief introduction into the arterial lumen of radioactive iridium wires and other radiation emitters [173]. Although the reported results are promising, there are practical problems associated with centering the radioactive source within the lumen to achieve uniform dosing, and safety issues that make adjunctive radiation less than ideally practical. More promising is the use of pharmacological agents for inhibiting hyperplasia. Several recent clinical trials demonstrated minimal hyperplasia developing within the ﬁrst 6 months after deployment of rapamycin-impregnated stents which deliver drug for several weeks to the adjacent arterial wall with minimal systemic levels. This eﬀect has been seen in both coronary and femoral stents [174,175], and is believed to be due to an eﬀect of the immunosurpressive drug on activation of leukocytes and other cells within the arterial wall [176,177]. Similar eﬀects on stent-induced hyperplasia have been reported with another antimetabolite, paxitaxol, which is used in cancer therapy [178]. Experiments in our lab show that oral administration of rapamycin inhibits the development of intimal hyperplasia after balloon injury of the rabbit aorta, and similar results have been reported in rabbits after systemic administration of a rapamycin congener following aortic stent deployment [179]. Drug-eluting stents are receiving great interest and may have a major impact the treatment of myointimal hyperplasia in these endovascular therapies. Despite these very promising developments in endovascular therapy for PAD, there will always remain signiﬁcant risks with these invasive procedures, including the precipitation of limb-threatening ischemia from distal embolization and bleeding complications from arterial access. The potential beneﬁts and risks of endovascular therapy must be tempered by the awareness that the results of medical therapy (medication and exercise programs) for claudicants are as good or better than those achieved with catheter-based endovascular techniques [180]. Amputation Amputation may be required when tissue loss has progressed beyond the point of salvage, when surgery is too risky, when life expectancy is very low, or when functional limitations

Peripheral Vascular Disease

739

obviate the beneﬁt of limb salvage. Amputation should remove all painful or nonviable tissue and lead to primary healing of the stump if possible. As greater limb length improves functional potential and the hopes for successful rehabilitation, as long a stump as possible should be fashioned. Minor toe amputation or transmetatarsal level foot amputation provides a suitable platform for walking without a prosthesis. Amputation at the midfoot level (Lisfranc or Chopart) is often technically feasible, but functional results tend not to be as good as with transmetatarsal amputation, even with the specialized shoe or braces required for midfoot levels. Similarly, preservation of the heel with Syme’s level amputation is associated with marginal function and stump ulceration, and is often unsuccessful in the elderly due to balance and strength limitations. The major amputations above the ankle; below knee (BKA), and above knee (AKA) entail increased costs and rehabilitation times compared to forefoot procedures, and the chances of recovering independent ambulation or even independent transfer with rehabilitation are much less. Death after vascular amputation is variably reported from 5 to 17% within 30 days, and is probably close to 15% (Table 5). Mortality is higher when sepsis is present or when an AKA is required. Thirty-day mortality ﬁgures do not adequately reﬂect the serious nature of amputation. An equivalent number of patients die during the second postopertive month as within the ﬁrst following major amputations [181]. Survivors of amputation have reduced longevity compared to age-matched controls. Table 6 shows long-term survival rates for vascular amputees. Survival after major amputations is approximately 50 to 60%, with BKA worse than AKA. Survival for those older than 70 was 50% at 1 year compared to 84% in younger patients. Five-year survival is 75% in patients under 60 compared to 24% in those older than 60 [182]. Approximately 20% of below-knee amputations and 10% of above-knee amputations fail to heal primarily, leading to prolonged hospitalization and repeated surgery [183,184]. These complications may result from inadequate arterial supply to the residual limb or other factors that impair wound healing, such as edema, diabetes, infection, and malnutrition, may also be important. Although higher level amputations have a higher likelihood of primary healing, there is still a critical tradeoﬀ between limb length and rehabilitation outcomes which often justify exposing the patient to the higher risk of wound-healing problems found with more distal amputation. Ambulation with prosthesis requires more energy expenditure than with an intact limb, and with higher amputations, even more energy is required. Table 7

Table 5

Mortality of Lower Extremity Amputation

Author

Year

Procedure

No. of patients

Mean age

Gregg

(1985) [143]

Rush

(1981) [169]

BKA AKA BKA AKA

Houghton

(1992) [110]

62 43 110 146 440

— — 64 67 72

Plecha

(1985) [167]

783

Bunt

(1994) [144]

212 253

<75 >75 <70 >70

a

Hospital mortality.

Mortality 8a 23a 7 16 17a 9.8 14.7 1.5 8.0

740

Fujitani et al.

Table 6 Long-Term Survival After Amputation or Revascularization for Critical Ischemia Author

Year

Procedure

No. of patients

Mean age

Rush

(1981) [169]

Bunt

(1994) [144]

Whittemore Vieth Taylor Hobson

(1995) (1981) (1990) (1985)

Ouriel

(1988) [151]

BKA AKA BKA + AKA BKA + AKA Bypass Bypass Bypass BKA Bypass BKA + AKA Bypass

121 146 212 253 230 522 498 172 375 158 204

64 67 <70 >70 65 — 68 67 66 70 68

[128] [170] [126] [171]

Survival 63% 51% 84% 50% 60% 48% 38% 58% 59% 54% 80%

at at at at at at at at at at at

5 5 1 1 5 5 5 5 5 3 3

years years year year years years years years years years years

shows the expected increased total energy requirement for ambulation with prosthesis. A unilateral BK amputee requires, on average, 33% more energy to walk than a normal subject, a unilateral AK amputee requires 87% more, and with bilateral BKAs more than a 100% increase in energy expenditure is required. The energy cost of ambulation, measured as oxygen consumption (mL O2/kg/min), remains fairly constant with age, but maximum potential energy expenditure steadily declines (Fig. 9). Consequently, the energy cost of normal ambulation increases from about 30% of maximum energy expenditure at age 25 to 55% of maximum energy expenditure at age 55 [185]. The consequence of the decline in maximum energy expenditure with age and the increased energy requirement of prosthetic ambulation is that the elderly tend not to achieve independent ambulation after major amputation. Less than one-third geriatric BK amputees will meet the physiological demands of walking with a prosthesis, and the prospects for AK amputees are much worse. Another problem is that, with advanced age, the average level for amputation rises. Patients less than 55 years of age require AKA 12.5% of the time; about half of those 55 to 74 years old require AKA; and those 75 years and older require AKA over two-thirds of the time [181]. A survey of British vascular amputees provides a grim, but useful, perspective. At eight centers, 440 patients (median age 72) underwent major amputation: 193 unilateral AKA,

Table 7 Energy Expenditure with Ambulation in Vascular Amputees Amputation Normals Unilateral symes Unilateral BKA Unilateral AKA Bilateral BKA a

Oxygen cost mL O2/kg-ma

% increase

0.15 0.17 0.20 0.28 0.31

— 13 33 87 106

Determined by oxygen consumption measurements during walking on a level surface at a comfortable walking speed. Source: From Ref. [172].

Peripheral Vascular Disease

741

Figure 9 Relation between age, ambulation, and maximal aerobic capacity. The height of each bar corresponds to the maximal sustained O2 consumption possible at each age. Hatched areas represent the rate of energy expenditure with ambulation. With increasing age the energy required for ambulation represents an increasing percentage of maximal energy expenditure. (From Walters et al, 1985[172], with permission.)

193 unilateral BKA, 54 other): 75 patients died in hospital; 113 were deemed unsuitable for rehabilitation; and the remaining 252 patients (57%) were referred for prosthesis ﬁtting. Of this latter group, only 12% achieved independent mobility without a wheelchair; another 29% were able to achieve limited mobility around their homes with the prosthesis. Nearly half the amputees actually ﬁtted never wore their prostheses. Only 5% of the entire group ultimately achieved independent ambulation; an additional 12% achieved partial rehabilitation. As would be expected, rates of successful rehabilitation were twice as high for BKA compared to AKA [186]. Arterial surgery should be reserved for limb-threat situations (rest pain or tissue loss) unless, based on anatomical considerations, the risk of surgery is low and the expected beneﬁt is high. With very severe claudication (e.g., the patient who experiences pain walking from bed to bath) and those incapacitated from employment, critical judgment is required. In an otherwise healthy patient with very severe claudication, an ABI of 0.5, and anatomy conducive to above-knee femoropopliteal bypass, surgery would probably be recommended by most U.S. surgeons. With identical symptoms but anatomy mandating bypass to the ankle, most patients would be advised to forego surgery. This conservative strategy is fairly standard. Much less uniform at the present time is the manner in which endovascular therapy is provided. Although less invasive in the short term, the risks of endovascular therapies (bleeding, embolization, thrombosis) are not trivial, and until new methods to combat myointimal hyperplasia are proven successful, the need for subsequent additional procedures to maintain patency will remain high. In the face of limb threat, the proposition that vascular surgery is better than amputation may seem self-evident. Nonetheless, based on comparative costs, morbidity,

742

Fujitani et al.

and mortality, primary amputation without prior revascularization may be the preferred approach in some, usually elderly patients. The initial costs associated with amputation are somewhat less than with bypass, in part due to the occasional need for secondary procedures to maintain bypass graft patency, and in part due to the signiﬁcantly increased total costs and hospital stays associated with unsuccessful bypass followed by amputation. Comparison of the outcomes from arterial surgery and amputation is confounded by selection bias, as older and sicker patients will tend to have amputation chosen in lieu of revascularization. Retrospective studies examining perioperative mortality show that revascularization has a low mortality (2 to 4%) compared to amputation (15%). When risk is analyzed by age (Tables 2–4), two trends emerge. First, mortality in the elderly is greater than in younger patients with either amputation or revascularization. Second, compared to arterial reconstruction, amputation at any age appears to be more dangerous. A study comparing outcomes weighted by preoperative risk found low- and intermediaterisk patients undergoing amputation and revascularization to have comparable low mortality (0 to 3%). In contrast, high-risk patients had signiﬁcantly greater ( p < 0.05) 30-day mortality with amputation than bypass (16% versus 6%). Most signiﬁcantly, 29% of highrisk amputees were alive at 3 years compared to 76% of high-risk bypass patients [151]. Amputation appears to decrease survival independent of other factors, plausibly because immobility leads to a hypercoaguable state with increased thromboembolism, and increased risk for coronary and cerebral thrombosis. The negative emotional and psychological impacts of amputation may well have an even greater impact on survival because the patient likely experiences depression, and health-care providers, perceiving diminished quality of life, may provide less aggressive care. Hospital charges for uncomplicated bypass operations are moderately higher than those for successful primary amputation. Length of stay is more diﬃcult to assess since rehabilitation may be provided either in or out of hospital, but probably the lengths of stay are comparable. When either revascularization or amputation fails, leading to more surgery, the total cost of treatment approximately doubles, and length of stay similarly increases [187–189]. One factor that should be incorporated into economic analyses is the cost of longterm care for amputees. Perhaps one-third of amputees require nursing home placement [190]. If one-third of successful revascularizations prevent a nursing home placement, each lasting 3 years on average, than a savings of about $45,000 should be associated with each successful arterial reconstruction (based on an estimated charge per diem of $130 for nursing home care in 1998). Overall, there is better quality of life aﬀorded by successful revascularization compared to amputation, with preservation of independence, better overall health, and improved satisfaction as a consequence of limb salvage [191,192]. Figure 10 shows the relation between angioplasty, bypass, and amputation utilization rates and age found in a recent study. Men were more likely than women at all ages to receive treatment for PAD by a factor of approximately 1.7. Those between the ages of 65 to 74 had the highest rate (70 per 100,000) for angioplasty. Those between ages 75 to 84 had the highest rate (250 per 100,000) for bypass surgery, and those over 85 had the highest rate (225 per 100,000) for amputation. Poor or black patients had higher rates of amputation and lower utilization of revascularization methods. Women were found to have lower ageadjusted rates for any intervention, but if requiring revascularization, were just as likely as men to have angioplasty or amputation. The study illustrates the age-related progression of disease severity and the results of the chosen therapy to age [193]. Analysis of hospital charges and length of stay indicates that age independently aﬀects resource consumption. Patients aged 80 to 84 admitted for PAD have hospital charges

Peripheral Vascular Disease

743

Figure 10 a) Inﬂuence of age and gender on utilization of angioplasty, b) bypass, and c) amputation. The histogram depicts the rate of procedure utilization (procedures per 100,000 per year) for individual age groups. Solid black bars represent men, stippled bars represent women. Note that the highest rate of angioplasty is in those aged 65–74, the highest rate of bypass is in those aged 75–84, and amputation rates are highest in those 85 and older. The data is drawn from all non-federal hospitals in Maryland over a two-year period. (From Tunis et al, 1993[158], with permission.)

744

Fujitani et al.

nearly twice that of those aged 55 to 64. Mean length of stay for 80 to 84-year-old patients is 24 days compared to 14 days for those aged 55 to 64. The diﬀerence in resource consumption cannot be attributed to the number of associated comorbid conditions, as older patients do not have more DRG or ICD-9 diagnoses [194,195]. Probably care of PAOD becomes more costly with age due to increased severity of comorbid conditions. Table 8 is a synopsis of the results of limb salvage surgery in octogenarians, most of whom (90%) had critical ischemia. When the high expected mortality associated with embolectomy for acute thrombosis is separated out, the 30-day mortality for bypass is about 5%. There is good agreement in the reported limb salvage rates, ranging from 80 to 92% at 1 year, and 71 to 83% at 3 years. Figure 11 shows limb salvage and bypass patency results from one study of octagenearians. These were not signiﬁcantly diﬀerent from those found in younger patients, nor was the survival of patients >80 requiring bypass signiﬁcantly diﬀerent than those <80. Survival of octogenarians requiring infrainguinal bypass is reduced compared to age-matched controls (Fig. 12). The average life expectancy of the octogenarian who requires bypass for limb threat is about 4 years, compared to an average life expectancy at 80 of 7.9 years and a life expectancy at 85 of 5.9 years [196,197]. Scher found that over 50% of octogenarians survived 2 or more years after bypass with the threatened limb intact, and 76% of the patients who eventually died had successful limb salvage [198]. O’Mara found 67% of octogenarians experienced amputation-free survival after distal bypass. Of eight patients dying more than 30 days after surgery, 75% had a functional limb [197]. Cogbill found 83% of survivors experienced limb salvage with graft patency conﬁrmed in 78%. Only one surviving patient was bedridden and 13 were fully ambulatory at 5 years. Only one-third of survivors were in nursing homes after bypass [196]. Given the relations between age and rehabilitation after amputation, eﬀorts toward limb salvage are more critical in the elderly than in young patients. The risks of bypass are not signiﬁcantly increased by age, and the results of surgery are not worsened appreciably. The modest decrease in life expectancy associated with PAOD does not justify reduced eﬀorts to preserve limbs, given the terribly morbid consequences of amputation.

CHRONIC VENOUS INSUFFICIENCY AND POSTPHLEBITIC SYNDROME The elderly are particularly prone to develop deep venous thrombosis as a consequence of prolonged immobilization and injuries leading to venous stasis. The long-term sequelae of acute deep venous thrombosis is the potential development of chronic venous insuﬃciency (CVI) and, subsequently, postphlebitic syndrome. However, it is estimated that in 20 to 50% of patients with symptoms and signs of chronic venous insuﬃciency, no history of deep venous thrombosis is obtainable. The classic physical ﬁndings are a chronically indurated ankle, dark stasis pigmentation in the distal medial leg (lipodermatosclerosis), and skin ulceration in some patients. Venous valvular incompetence or venous outﬂow obstruction is usually documented by venous plethysmography, duplex ultrasound, or venography. Postphlebitic syndrome or primary venous valvular incompetence can be very disabling, since leg dependency increases pain and swelling and may impede ulcer healing. Consequently, this can place signiﬁcant physical, social, and economic toll on the elderly [199,200]. It is estimated that chronic venous insuﬃciency aﬄicts at least 7 million individuals in the United States and that at least 500,000 U.S. citizens have venous leg ulcers [201]. A recent

(1987) [162]

(1987) [161]

(1989) [174]

O’Mara

Cogbill

Friedman

Unspeciﬁed interval.

(1986) [163]

Scher

a

Year

Author

84

84

21 50

84

85

84

Mean age

46

34

168

No. of patients

Table 8 Limb Salvage in Octagenarians

69

25

54

40

182

No. of procedures

16% inﬂow 84% infraing bypass

embolectomy

infraing bypass

13% inﬂow 13% angioplasty 85% infraing bypass tibial bypass

Procedure type

3%

19%

0%

5%

6%

Operative morality

year year year year

92% 1 year 83% 3 year

91% 1 81% 3 95% 1 87% 5 89%a

80% 1 year 71% 3 year

Limb salvage

90% 54% 85% 30% 67% 25% 92% 59%

1 3 1 5 1 3 1 3

year year year year year year year year

78% 1 year 54% 3 year

Survival

Peripheral Vascular Disease 745

746

Fujitani et al.

Figure 11 Limb salvage and graft patency rates in octagenarians. The patency and limb salvage rates were not signiﬁcantly different from those found with patients younger than 80. (From Ref. O’Mara et al, 1987[162], with permission.)

Figure 12 Cumulative survival after infrainguinal in octagenarians. Survival after infrainguinal bypass for limb salvage in octagenarians (circles) is plotted in comparison to survival of agematched controls (triangles). NS indicates not significant. The difference in survival at 5 years was significant. (From Cogbil et al, 1987[161], with permission.)

Peripheral Vascular Disease

747

retrospective cohort study utilizing the United Kingdom’s National Health Service GPRD data system found a 1.69% prevalence of venous leg ulceration in persons between 65 and 95 years of age [202]. In a 25-year population based retrospective review in the United States, Heit et al found the incidence of venous stasis syndrome and venous ulcer to be 76.1 and 18.0 per 100,000 person years, respectively [203]. This translates to approximately 150,500 new cases of venous stasis syndrome and 20, 500 new cases of venous ulcer annually in the United States. Additionally, the incidence of both venous stasis syndrome and venous ulcer was higher in females and increased with age for both sexes. The overall incidence in those over 65 years of age ranged from 40.6 to 125 per 100,000 person years compared to 1.8 to 32 per 100,000 person years for those 15 to 64 years of age. When stratiﬁed by age, those over 85 years old had a 20-fold increase of venous stasis ulcer compared with the youngest group. The average time from the diagnosis of venous stasis syndrome to the development of a venous ulcer was 5 years. The socioeconomic impact of CVI and postphlebitic syndrome cannot be underestimated. The elderly are often already burdened with multiple comorbidities requiring multiple prescription medications on a ﬁxed income. In addition to this, the relative physical decompensation that accompanies the aging process, and the burden of caring for a chronic wound, CVI and venous ulcer from postphlebitic syndrome have the greatest impact in the population that is least equipped to deal with them. Studies from the 1990s estimate the annual direct costs of $1735 and $7460 for each new case of venous stasis syndrome and venous ulcer [203,204]. This does not take into account the annual recurrence rate of 33% to 72% and the additional costs associated with each recurrence [203,205]. Estimated costs for ulcer treatment in the United States may be between $1.9 billion and $2.5 billion annually [205–207]. Olin et al. retrospectively found an average cost of $9685 (inpatient and outpatient costs; median $3036) per patient with venous stasis ulceration over 1 year. Home health care, hospitalizations, and home dressing changes accounted for 48%, 25%, and 21% of total costs, respectively, in this study [204]. Marston et al. reported a 10-week cost of outpatient compressive therapy of $1444 to $2771 [208]. These ﬁgures likely underestimate additional economic factors that impact the elderly, resulting from absence from work, forced disability, or early retirement [204]. Wissing et al. showed that elderly individuals with leg ulcers had signiﬁcantly lower mean values in psychic health, activities of daily living, cognition, time use, and social behavior as compared to age-matched controls that did not have leg ulcers [209,210]. The authors concluded that the life situation among elderly patients with leg ulcers was not as good when compared to the non-ulcer cohort and that those with ulcers were more vulnerable than elderly people of the same age. Similar results that show a negative correlation between venous ulceration in the elderly and their quality of life have been published. In a prospective study, Smith et al. identiﬁed four factors (social function, domestic activities, cosmesis, and emotional status) that adversely aﬀected an elderly population with venous ulcers and showed that their quality of life vis-a´-vis these factors improved as their ulcers healed [211]. Normally, blood ﬂows from the superﬁcial venous system (greater saphenous vein and lesser saphenous vein) to the deep venous system (popliteal and superﬁcial femoral vein) via perforator vessels. All these vessels possess oneway bicuspid valves that normally prevent reﬂux and ultimately drive venous ﬂow toward the heart. Normal venous pressures at the level of the ankle in a standing individual is approximately 80 mmHg, reﬂecting the hydrostatic pressure of the length of the column of blood from the heart. The calf muscle pump is a critical component of this system. Upon ambulation, contraction of the calf muscle causes compression of the deep venous system. This causes blood to ﬂow in a cephalad direction as the unidirectional valves close to prevent

748

Fujitani et al.

retrograde ﬂow as well as retrograde transmission of this venous pressure. The emptying of the deep system leads to a fall in deep venous pressures from 0 to 10 mmHg, which allows the valves to open and thus create the pressure diﬀerential that drives blood ﬂow from the superﬁcial to the deep system. [205,212–215]. The management of postphlebitic syndrome is based on our current understanding of its pathophysiology. The initial thrombophlebitis resulting from deep venous thrombosis damages the deep venous valves and often leaves them incompetent. The musculovenous pump can therefore no longer reduce ambulatory venous pressures. The venous valvular incompetence, obstruction, or both results in chronic elevation of venous pressures that are then transmitted to the superﬁcial venous system. In the pathological state, deep venous pressure may fall minimally or not at all with ambulation [205,212–215]. Consequently, the patient has chronic venous hypertension in the lower leg when he or she stands. These high venous pressures are transmitted through communicating veins from the deep to superﬁcial venous system, with development of lipodermatosclerosis, and ultimately skin breakdown and ulceration. The exact means by which this chronic venous hypertension causes stasis skin changes and ulceration is still unclear. The most recent evidence suggests that local capillaries leak ﬁbrinous protein that is not adequately removed by ﬁbrinolysis. Lipodermatosclerosis occurs and local tissue oxygen diﬀusion may be impeded. This results in tissue necrosis and skin ulceration. Thus chronic venous hypertension (chronic venous insuﬃciency) results from three general mechanisms: (1) dysfunction of superﬁcial or perforator valves secondary to congenital absence or acquired incompetence; (2) dysfunction of the deep venous valves secondary to the above causes; and (3) muscle dysfunction/calf muscle failure [205,212–215]. Venous ulceration is typically seen near the medial malleolusal, though it may be on either side and may even be circumferential. In advanced CVI, the extremity may resemble an ‘‘inverted champagne bottle’’ with the proximal calf being swollen and the distal leg appearing shrunken. Areas where there is a paucity of capillaries (atrophie blanche) are prone to develop ulceration [212]. As leg ulceration may be common in the elderly population, it is important to diﬀerentiate its many causes. The most common causes of ulceration in the elderly are venous disease (70 to 90%), arterial disease (5 to 20%), diabetes (2 to 5%), and vasculitis (2 to 5%) [216]. Venous ulcers must be distinguished from those caused by arterial disease, diabetic neuropathy, immune or aoutoimmune processes, or trauma. In addition, combinations of venous and arterial disease are not uncommon in the elderly [217,218]. The history, location, presentation, and appearance of ulcers can be useful clinically. Patients with venous ulceration/CVI complain of chronic swelling and aching of the legs which is exacerbated by standing and alleviated by limb elevation [205]. Pain, odor, and weepy drainage from the wound with pruritus are also common, as well as a history of recurrent ulceration, often in the same location [205,219]. Venous ulcers typically occur in the gaiter/medial malleolar region, whereas arterial ulcers usually occur along bony prominences in the distal foot or heel. Diabetic ulcers are not associated with pain and are typically surrounded by callus and located along the plantar surface of the foot or on the weight-bearing area of the heel. Age is certainly a risk factor for the development of CVI and postphlebitic syndrome [199]. Scott et al. demonstrated additional risk factors to be male sex, obesity, a history of phlebitis, and a history of serious leg injury [220]. Other risk factors are the degree and pattern of venous insuﬃciency such that insuﬃciency of the superﬁcial and perforators in combination carries a greater risk of CVI than insuﬃciency of the superﬁcial system alone. Congenital absence of valves, valve degeneration, prior surgery of

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varicose veins, and arteriovenous shunts are further risk factors for developing CVI [205,212,215,220]. The diagnosis of CVI and venous stasis ulceration may be made by clinical criteria alone in a majority of cases. Arterial or neuropathic causes usually can be ruled out by history and physical examination supported with normal ankle brachial indices, pre- and postexercise. Historically, examination for CVI utilized the Trendelenbeg and Perthes tests. However, hand-held continuous-wave Doppler and, more importantly, duplex ultrasonography have largely supplanted these tests. Incompetent vessels in the superﬁcial, perforator, or deep systems, presence or absence of obstruction, and retrograde ﬂow as well as anatomical location can be demonstrated by duplex ultrasonography [221,222]. Air plethysmography (APG), which reliably measures extremity venous volumes, can then be used to quantify these abnormalities. APG-derived variables such as venous ﬁlling index (VFI) and residual volume fraction (RVF) are directly related to venous ulceration. Nicolaides et al. have shown that patients with VFIs >10 mL/s have a 76% incidence of venous ulceration and that patients with RVFs >80% had an 88% incidence of venous ulcerations[212–214]. Schina et al., measuring various APG variables, demonstrated that the eﬃciency of the calf muscle pump diminishes with increasing age, possibly contributing to an increased risk of deep venous thrombosis in the elderly, both of which, in turn, would increase the risk of CVI [223]. The above-mentioned exams are all noninvasive. If needed, however, invasive ambulatory venous pressure (AVP) testing can be performed. Again, these have a direct linear correlation with venous ulceration, with AVPs greater than 80 mmHg (normal AVP 15 to 30 mmHg) having a 73% incidence of venous ulceration. Descending and ascending phlebography are still other invasive means of delineating venous pathology. Currently, the combination of anatomical data supplied by duplex ultrasonography and hemodynamic data derived from APG is a comprehensive method of evaluating CVI [212]. In 1994, the International Consensus Committee on Chronic Venous Disease created the CEAP classiﬁcation in an eﬀort to standardize venous disease reporting. Chronic venous disease was classiﬁed according to clinical severity (grades 0 to 6); etiology (congenital, primary, secondary); anatomical location (superﬁcial, perforator, deep); and pathophysiology (reﬂux, obstruction, or both). Table 9 summarizes the CEAP classiﬁcation. In additional, these grades are supplemented by (A) when asymptomatic and (S) when symptomatic [212–214]. Current management and treatment of venous stasis ulceration utilize mechanical, topical, systemic, and surgical modalities, often in combination. Although extremity elevation and bed rest undoubtedly help in relieving extremity edema, they are often impractical in terms of patient compliance. Compression remains the mainstay of therapy. Compression therapy is thought to improve the venous pump mechanism and in doing so improves venous hypertension. Duplex ultrasound has shown that reﬂux in the deep system is decreased with external compression [205,224]. Compression therapy has also been demonstrated to improve blood ﬂow through patent superﬁcial and deep venous systems as well as enhance ﬁbrinolysis [205,225,226]. Other theoretical considerations include beneﬁts such as reapproximation of previous incompetent valves as well as decreasing macromolecular extravasation [205,227]. In a recent meta-analysis of 24 prospective, randomized controlled trials evaluating diﬀerent methods of compression therapy for venous ulcers, Fletcher et al. determined that many of these trials suﬀered from poor methodology and inadequate sample size [228]. Despite these limitations, they concluded the following: (1) compression treatment increases the healing rate of ulcers as compared to no

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Table 9 CEAP Classification Clinical signs

Grades 0–6 (see table below)

Etiology Anatomical distribution Pathophysiology

Congenital, primary, secondary Superﬁcial, deep, perforator alone or in combination Reﬂux, obstruction alone or in combination

Classa 0 1 2 3 4 5 6

Physical signs No visible or palpable signs of venous disease Telengiectasias, reticular veins, malleolar ﬂares Varicose veins Edema without skin changes Skin changes: pigmentation, eczema, lipodermatosclerosis Healed ulceration Active ulceration

a Further designated by (A) for asymptomatic and (S) for symptomatic. Source: Modiﬁed from Ref. 214.

compression; (2) high compression (pressures) are more eﬀective than low compression in the absence of signiﬁcant arterial disease; (3) no signiﬁcant diﬀerences in types of high compression methods (various multilayer versus traditional Unna’s boot) were noted; and (4) intermittent pneumatic compression may be of beneﬁt as an adjunctive therapy. Compression therapy is relatively contraindicated with signiﬁcant peripheral arterial disease (ABI <0.8) [205,212–215,217,218]. An external pressure of 35 to 40 mmHg at the ankle is considered necessary for compression therapy to be successful. Acutely, one may use rigid high-pressure therapy (i.e., Unna boot or 4-layered compression) and then slowly transfer to graduated compression stockings once the acute edema resolves and the ulcer shows signs of healing. These graduated compression stockings should be then tailored to the patient’s clinical needs. For example, 20 to 30 mmHg is suitable for varicose veins and mild edema, 30 to 40 mmHg for moderate venous insuﬃciency or severe varicose veins, and 40 to 50 mmHg for severe edema and CVI [205,229,230]. Time-to-ulcer healing, risk factors for recurrence or delayed healing, and follow-up are quite variable in the literature. In a prospective study of 252 patients with clinical or duplex evidence of CVI and an ulcer subjected to outpatient compressive therapy, Marston et al. demonstrated a healing rate of 96% with healed at 16 weeks. Factors associated with delayed healing in this study were initial ulcer size and moderate arterial insuﬃciency (ABI 0.5 to 0.8) [208]. In a retrospective review of 71 patients, Erickson et al. showed that 91% of ulcers healed completely in a median time of 3.4 months [231]. However, this study also showed a 57% recurrence at a median of 10.4 months. Venous reﬁll time of 10 s or less as well as inadequate compliance predicted delayed healing. In a prospective multicenter trial, 70 patients were randomized to conventional dressing and compression versus hydrocolloid and compression. In this study, only 34% of ulcers healed with a mean time of 7 weeks and 8 weeks for the hydrocolloid and conventional dressing, respectively [232]. Percent area reduction greater than 30% within the ﬁrst 2 weeks was predictive of healing in this study. Adjuncts in the treatment of venous stasis ulceration include diﬀerent methods of ulcer debridement using gels, proteolytic enzymes (papain, trypsin, collagenase, tissue plasmi-

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nogen activator), and mechanical debridement as well as growth factors, topical antibiotics, and systemic pharmacotherapy. No diﬀerences in ulcer healing have thus far been conclusively demonstrated with respect to gels or proteolytic enzyme [205,233–237]. Mechanical or sharp surgical debridement is rarely necessary in the treatment of venous ulcerations as they are rarely necrotic in nature [205,238]. With the possible exception of cadexomer iodine, topical antibiotics and antiseptics have not been shown to improve ulcer healing, nor have systemic antibiotics except in cases where there is a cellulitic component to venous ulceration or wound infection via quantitative tissue culture [205,239–241]. Stanozol, an androgenic steroid with ﬁbrinolytic properties, has demonstrated eﬀectiveness in the treatment of lipodermatosclerosis but has not been shown to increase rate of ulcer healing. Pentoxifylline, typically used in lower extremity (arterial) claudication, has been studied in venous ulcer disease, but with conﬂicting results [242]. In a prospective, randomized doubleblind placebo-controlled trial, Dale et al. failed to demonstrate statistical signiﬁcance with pentoxifylline (n = 101) 400 mg three times a day versus placebo (n = 99). Complete healing of pure venous ulcers occurred in 64% of the pentoxyfylline arm and in 53% of the placebo arm. Falanga et al., however, in another prospective double-blind placebo-controlled trial comparing outcomes of time-to-healing with 400 mg versus 800 mg pentoxifylline three times a day to placebo were able to show a statistical diﬀerence [243]. Median time-tohealing was 100 days for placebo versus 83 and 71 days for the 400 mg and 800 mg doses of pentoxifylline, respectively. Disabling chronic venous insuﬃciency and venous ulcers that fail the above-mentioned therapies may be treated with surgical interventions. Adjunctive procedures include skin grafting of the ulcers using autogenous or tissue-engineered skin with or without venous surgery. However, long-term success minimizing recurrence of the ulcers usually requires treatment of the underlying pathophysiological processes. Venous surgery may include ligation and stripping of greater and lesser saphenous veins, open or subfascial endoscopic perforator ligation (SEPS), deep venous valve reconstruction or transplant, or venous bypass procedures.The eﬀectiveness of these varying surgical procedures to ulcer healing and recurrence rates are promising. Venous ulceration in the context of isolated superﬁcial venous incompetence was prospectively studied by Bello et al. [244]. Patients underwent saphenofemoral and/or saphenopopliteal procedures that yielded 6-, 12-, and 18-month ulcer healing rates of 57%, 74%, and 82%, respectively. Unfortunately, no control group or standard therapy was simultaneously assessed. Barwell et al. studied 236 patients with venous ulceration and isolated superﬁcial reﬂux, where 131 were nonrandomly assigned to surgery and 105 assigned to compressive four-layer therapy [245]. This study found no signiﬁcant diﬀerences in time-to-healing with surgery but did ﬁnd a signiﬁcant diﬀerence in ulcer recurrence of 40% compared to 26% at 3 years for the nonoperative versus operative group. With respect to venous ulceration with associated deep or perforator insuﬃciency, open or endoscopic perforator ligation in combination with a superﬁcial procedure has been advocated. Gloviczki et al. reported on 133 patients with venous ulceration who underwent SEPS, 71% of whom had simultaneous superﬁcial procedures [246,247]. Ulcer healing at 1 year was 88%, with a 1-year and 2-year recurrence of 16% and 28%, respectively. They concluded that interruption of perforators with a simultaneous superﬁcial procedure was eﬀective in decreasing symptoms of CVI and resulted in rapidly healing ulcers. This analysis, however, also lacked a standard control group. In a small comparison of open (modiﬁed Linton) versus SEPS for the ulcer treatment, Sybrandy et al. demonstrated that long-term results were comparable between the two procedures. They further found that deep venous

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incompetence did not signiﬁcantly aﬀect ulcer recurrence but that it signiﬁcantly inﬂuenced the development of new incompetent perforators [248]. Chronic venous insuﬃciency and venous ulceration continue to pose a major challenge to health-care practitioners in terms of their physical, social, and economic costs. They disproportionately aﬀect the elderly who are often least equipped to deal with them. Even with all available treatments, a signiﬁcant proportion will develop recurrent ulceration and recalcitrant disease. A combined approach utilizing primary-care practitioners as well as specialists focused on early diagnosis, and patient-tailored therapy based on sound clinical evidence will maximize the beneﬁt for this segment of the population.

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31 Perioperative Cardiovascular Evaluation and Treatment of Elderly Patients Undergoing Noncardiac Surgery Rita A. Falcone, Roy C. Ziegelstein, and Lee A. Fleisher The Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Over 30 million patients undergo noncardiac surgery annually in the United States, 4 million of whom are at risk of having coronary artery disease (CAD) on the basis of clinical risk factors. More than 1 million patients have cardiovascular complications postoperatively [1]. The health-care costs associated with these adverse cardiac outcomes have been estimated to be in excess of $10 billion annually in the United States. Cardiovascular complications continue to be a signiﬁcant etiology of adverse outcome in elderly patients undergoing noncardiac procedures in spite of improvements in surgical and anesthetic techniques and perioperative medical management. This is related to a high prevalence of CAD in older patients and to the changes in the cardiovascular system that occur with aging, including a greater prevalence of systolic hypertension (HTN), diastolic left ventricular dysfunction, and blunted responses to the hemodynamic stressors of surgery. The preoperative evaluation and preparation of the elderly patient undergoing noncardiac surgery represents a unique challenge for the primary-care physician, cardiologist, anesthesiologist, and surgeon. The elderly not only have a higher prevalence of cardiovascular disease but also are more likely to need urgent or emergent noncardiac surgical procedures. Therefore, the preoperative evaluation is frequently more complicated and may need to be performed on a more urgent basis. In approaching the elderly surgical patient, the fundamental assumption is that the preoperative evaluation will result in changes in perioperative management. Since each practitioner has a diﬀerent perspective with regard to potential perioperative complications, it is important that the various consultants communicate with each other in order to reduce an individual patient’s risk. For example, the internist or cardiologist may be most concerned with the need for preoperative interventions or with assessing the risks versus beneﬁts of a surgical intervention. From the anesthesiologist’s perspective, information regarding the patient’s ventricular reserve and cardiac ischemic potential is critical in determining the optimal intraoperative management. Therefore, communication is essential in order to achieve the optimal perioperative outcome. 765

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It is important to realize that the preoperative evaluation may also represent the patient’s initial cardiovascular, and sometimes medical, evaluation. Therefore, strategies to assess and modify perioperative cardiac risk may also have important long-term consequences for the patient. In order to provide the practitioner with an understanding of some of the issues and concerns for the anesthesiologist and medical caregivers, this chapter will review those factors that identify the high-risk elderly patient and the preoperative and perioperative interventions that may modify that risk.

ASSESSMENT OF THE PATIENT BEFORE NONCARDIAC SURGERY History Since the highest risk to any elderly patient undergoing noncardiac surgery is related to cardiovascular complications, a thorough history should focus on cardiovascular risk factors and symptoms or signs of unstable cardiac disease states such as myocardial ischemia, congestive heart failure (CHF), valvular heart disease, and signiﬁcant cardiac arrhythmias. Coronary Artery Disease Symptoms of cardiovascular disease should be carefully determined, especially characteristics of chest pain, if present. In patients with symptomatic CAD, the preoperative evaluation may lead to the recognition of an increase in the frequency or pattern of anginal symptoms. It is important to realize that certain populations of patients, such as the elderly, women, or those with diabetes mellitus (DM), may present with more atypical symptoms of angina pectoris. If unstable angina is present, there is associated high perioperative risk of myocardial infarction (MI) [2]. Even when angina symptoms are ‘‘stable,’’ there may be a sizeable risk of perioperative myocardial ischemia so that additional preoperative cardiovascular testing or perioperative monitoring may be required. In addition to identifying the the severity and stability of CAD, if present, it is also necessary to know any prior medical or surgical cardiac interventions that have been performed. Congestive Heart Failure In virtually all studies to date, the presence of symptomatic CHF preoperatively has been associated with an increased incidence of perioperative cardiac morbidity [3–5]. Stabilization of symptoms of pulmonary congestion is prudent prior to elective surgery. It is important to determine the etiology of the left heart failure since the type of perioperative monitoring and treatments would be diﬀerent for such conditions as ischemic or nonischemic cardiomyopathy or mitral or aortic valvular insuﬃciency and/or stenosis. Myocardial Infarction Traditionally, perioperative risk assessment for noncardiac surgery was based upon the time interval between an MI and the surgery. Although many earlier studies demonstrated an increased incidence of reinfarction if surgery is performed within 6 months of an MI [6–8], this time interval may no longer be valid in the current era of thrombolytics, endovascular stenting, and aggressive medical management options after an acute MI. The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Perioperative Evaluation of the Cardiac Patient Undergoing Noncardiac Surgery considers those with an acute MI within 7 days of the surgical procedure to be at highest risk, while those

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with a prior MI within 7 to 30 days are considered to have an increased, but somewhat lower, risk [9,10]. Peripheral Arterial Disease Peripheral arterial disease has been shown to be associated with CAD in multiple studies since the same risk factors are often responsible for disease in all vascular territories. Hertzer and colleagues studied 1000 consecutive patients scheduled for major vascular surgery and found that approximately 60% of patients had a least one coronary artery with a critical stenosis [11]. Diabetes Mellitus Diabetes mellitus is common in the elderly and frequently results in noncardiac complications that necessitate urgent or emergent surgery. Patients with DM have a greater likelihood of having multivessel CAD, which is often clinically silent [12]. Eagle et al. demonstrated that DM is an independent risk factor for perioperative cardiac morbidity [13]. Diabetes that is either longstanding or associated with end-organ dysfunction is felt to place the patient at higher perioperative risk than uncomplicated or newly developed DM. The requirement for insulin has also been associated with increased perioperative risk [14]. Autonomic neuropathy has recently been found to be the best predictor of silent cardiac ischemia [15]. Since patients with DM are at risk for silent MI, a preoperative electrocardiogram (ECG) should be obtained to examine for the presence of prior MI. Hypertension Hypertensive patients with left ventricular hypertrophy who undergo noncardiac surgery are at a higher perioperative risk than nonhypertensive patients [16]. Individuals with left ventricular hypertrophy and ‘‘strain pattern’’ on ECG may have a greater prevalence of CAD than those without this pattern [17]. Hypertension (HTN) is common and its prevalence increases with age [18]. It is estimated that 24% of the adult population of the United States has HTN and, by age 70, the prevalence increases to more than 60% [18,19]. Hypertension can result in a more severe form of diastolic dysfunction, which may predispose to CHF. Hypertension is a known risk factor for cardiovascular, renal, and neurological disease [20]. A large multivariate analysis did not establish mild-to-moderate HTN as an independent predictor of postoperative cardiac complications [3,21], but a hypertensive crisis in the postoperative period, deﬁned as a diastolic blood pressure >120 mmHg and clinical evidence of impending or actual end-organ damage [22], poses a deﬁnite risk of MI and cerebrovascular accident. Several precipitants of hypertensive crises have been identiﬁed [22], including pheochromocytoma, abrupt clonidine withdrawal prior to surgery, and the use of chronic monoamine oxidase inhibitors with or without sympathomimetic drugs in combination [23]. Chronic HTN may indirectly predispose patients to perioperative myocardial ischemia since CAD is more prevalent in these patients. Even in the absence of CAD, patients with chronic HTN may have episodes of myocardial ischemia [24], perhaps due to impaired coronary vasodilator reserve and autoregulation [25], such that higher arterial pressures are required to maintain adequate perfusion of vital organs. The Study of Perioperative Ischemia Research Group showed that a history of HTN was an independent predictor of postoperative ischemia and increased postoperative mortality [16,26]. Patients with a history of HTN had almost twice the risk of developing

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postoperative myocardial ischemia [16] and almost four times the risk of postoperative death [26] than did patients without HTN in the ﬁrst 48 h postoperatively. The link between systemic HTN and perioperative cardiac complications may relate to an increased risk of silent myocardial ischemia, which has been shown to be a major predictor of postoperative cardiac morbidity [27,28]. In patients who underwent ambulatory ECG ST-segment monitoring to determine the incidence of silent myocardial ischemia before elective noncardiac surgery, at least one episode of ST-segment depression consistent with silent ischemia occurred in 20% of patients [29]. Patients with HTN despite antihypertensive therapy were at particularly high risk, with more than a 50% incidence of silent myocardial ischemia. However, continuous ECG ST-segment monitoring may overestimate the incidence of myocardial ischemia in the setting of left ventricular hypertrophy [29,30]. In patients with signiﬁcant diastolic HTN (diastolic blood pressure >110 mmHg,) the potential beneﬁts of delaying surgery in order to optimize antihypertensive medications should be weighed against the risk of delaying the surgical procedure [31,32]. Isolated systolic HTN (systolic blood pressure greater than 160 mmHg and diastolic blood pressure less than 90 mmHg) has been identiﬁed as a risk factor for cardiovascular complications in the general population, and treatment has been shown to reduce the future risk of stroke [33]. However, there has been only one study to directly assess the relationship between cardiovascular disease and preoperative isolated systolic HTN. In a multicenter study of patients undergoing coronary artery bypass grafting (CABG), the presence of isolated systolic HTN was associated with a 30% increased incidence of cardiovascular complications [34]. In summary, noncardiac surgery should not be postponed or canceled in the otherwise uncomplicated patient with mild-to-moderate HTN [9]. Antihypertensive medications should be continued perioperatively and blood pressure should be maintained near preoperative levels to reduce the risk of myocardial ischemia [9,25]. More severe or poorly controlled HTN (systolic blood pressure z180 mmHg or diastolic blood pressure z110 mmHg), should be controlled before any elective noncardiac surgery [10]. Continuation of antihypertensive treatment throughout the perioperative period is indicated.

Physical Examination A complete preoperative physical examination is necessary for every patient undergoing noncardiac surgery. Blood pressure and heart rate should be determined in both the supine and standing positions to assess intravascular volume status or autonomic dysfunction. Careful cardiac auscultation should be performed to detect clinically important cardiac ﬁndings, including the presence of an S3 gallop suggestive of CHF and murmurs suggestive of signiﬁcant valular disease, particularly aortic stenosis. The pulmonary exam and evaluation for jugular venous distention and lower extremity edema can also help determine intravascular volume status and the presence of CHF. Peripheral arterial pulses and bruits may suggest cardiac valvular disease or the presence of occult atherosclerotic disease.

ESTIMATION OF PERIOPERATIVE CARDIAC RISK Identifying Surgery-Specific Risk The type of surgical procedure itself has a signiﬁcant impact on perioperative cardiac risk. Knowledge of the urgency, type, and anticipated duration of the surgical procedure and the

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expected blood loss and intravascular volume shifts is necessary to make perioperative management plans. Three classiﬁcations of surgical risk have been suggested by the ACC/AHA Task Force (Table 1) [10]. Surgical procedures which are not emergent and are not associated with signiﬁcant blood loss are not associated with a high risk of cardiac ischemia. For example, cataract surgery is associated with minimal cardiac stress and exceedingly low cardiac morbidity and mortality rates, even after a recent MI [35]. Similarly, outpatient procedures have also been shown to be associated with a low incidence of cardiac morbidity and mortality [36]. In such patients, changes in perioperative management are rarely needed unless the patient demonstrates unstable angina or signs or symptoms of CHF. On the other hand, intra-abdominal, orthopedic, and intrathoracic procedures are associated with an intermediate cardiac risk. In this group, the duration of surgery and extent of ﬂuid shifts may modify the need for further cardiac evaluation. In contrast, the patient undergoing a noncardiac surgical procedure associated with a high risk of cardiac morbidity and mortality may beneﬁt from a more extensive preoperative cardiac evaluation. For example, peripheral vascular surgery is associated with a high risk of cardiac morbidity [37]. Since further determination of cardiac status may alter perioperative care, the beneﬁt of further evaluation and treatment would be expected to be greater than the associated costs or risks of such testing. Identifying Clinical Risk Predictors Several approaches can be used to estimate perioperative cardiac risk in patients before noncardiac surgery. In early studies, clinical parameters associated with CAD were proven predictors of perioperative morbidity and mortality. In a landmark study in 1977 by Goldman et al. [3], there were nine independent clinical correlates of postoperative cardiac complications in patients undergoing noncardiac surgery. A point system was assigned to each Table 1 Cardiac Riska Stratification for Noncardiac Surgical Procedures High

Intermediate

Lowb

a

Reported cardiac risk often >5% Emergent major operations, particularly in the elderly Aortic and other major vascular Peripheral vascular Anticipated prolonged surgical procedures associated with large ﬂuid shifts and/or blood loss Reported cardiac risk generally <5% Carotid endarterectomy Head and neck Intraperitoneal and intrathoracic Orthopedic Prostate Reported cardiac risk generally <1% Endoscopic procedures Superﬁcial procedure Cataract Breast

Combined incidence of cardiac death and nonfatal myocardial infarction. Do not generally require further preoperative cardiac testing. Source: Reproduced with permission from Ref. 10.

b

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clinical predictor and a cardiac risk index score was calculated to help stratify patients at highest risk perioperatively. Detsky [4] validated these criteria a decade later in a small patient population using a modiﬁed version of the index. In 1999, six other independent clinical predictors of risk were included in a Revised Cardiac Risk Index: high-risk type of surgery, history of ischemic heart disease, history of CHF, history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine >2.0 mg/dL [14]. Unlike the original risk index, points were not assigned for diﬀerent clinical predictors, although rates of major cardiac complications were found to increase with an increasing number of these speciﬁc risk factors. Unfortunately, the sensitivity of these cardiac indices is not very high and many cardiac events occur even in patients with low risk scores. In 1996, an ACC/AHA Task Force developed Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery [9]. These guidelines were developed to provide a framework for cardiac risk stratiﬁcation for those undergoing noncardiac surgery, acknowledging the lack of prospective, randomized trials in this area. The guidelines were recently updated in 2002 [10]. These guidelines assess clinical risk predictors (Table 2),

Table 2 Clinical Predictors of Increased Perioperative Cardiovascular Risk (Myocardial Infarction, Congestive Heart Failure, Death) Major Unstable coronary syndromes Recent myocardial infarctiona with evidence of important ischemic risk clinical symptoms or noninvasive study Unstable or severeb angina (Canadian Class III or IV)c Decompensated congestive heart failure Signiﬁcant arrhythmias . High-grade atrioventricular block . Symptomatic ventricular arrhythmias in the presence of underlying heart disease . Supraventricular arrhythmias with uncontrolled ventricular rate Severe valvular disease Intermediate Mild angina pectoris (Canadian Class I or II) Prior myocardial infarction by history or pathological Q-waves Compensated or prior congestive heart failure Diabetes mellitus Chronic renal insuﬃciency Minor Advanced age Abnormal ECG (left ventricular hypertrophy, left bundle branch block, ST-T abnormalities) Rhythm other than sinus (e.g., atrial ﬁbrillation) Low functional capacity (e.g., inability to climb one ﬂight of stairs with a bag of groceries) History of stroke Uncontrolled systemic hypertension Abbreviations: ECG=electrocardiogram. a The American College of Cardiology National Database Library deﬁnes recent MI as greater than 7 days but less than or equal to 1 month (30 days). b May include ‘‘stable’’ angina in patients who are unusually sedentary. c Campeau L. Grading of angina pectoris. Circulation 1976; 54:522–523. Source: Reproduced with permission from Ref. 10.

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exercise tolerance (Table 3), and type of surgery (Table 1) to be performed in an algorithm model to assist in decision making for further preoperative cardiac testing (Fig. 1).

Defining Exercise Tolerance Exercise tolerance is one of the most important determinants of perioperative risk and the need for invasive monitoring [38]. A high exercise tolerance, even in patients with stable angina, is associated with a low perioperative cardiac risk. Estimated energy requirements for various activities can be deﬁned by MET (metabolic equivalent) levels, where one MET equals resting energy expenditure, f3.5 mL oxygen/k/min. Exercise tolerance can be assessed with formal treadmill testing or with a questionnaire that assesses activities of daily living (Table 3) [9]. Perioperative cardiac risk is increased in patients unable to achieve 4 METs during normal daily activities [9,26]. For example, if a patient can walk a mile without developing chest discomfort or unusual shortness of breath, then the probability of severe CAD is small. On the other hand, if a patient develops chest pain during minimal exertion, then the probability of extensive CAD is high as is the perioperative risk [39]. In one study of outpatients referred for evaluation before major noncardiac procedures, patients were asked to estimate the number of blocks they could walk and ﬂights of stairs they could climb without experiencing cardiac symptoms [40]. Patients who could not walk four blocks and climb two ﬂights of stairs were considered to have poor exercise tolerance and were found to have more perioperative cardiovascular complications. The likelihood of a serious complication occurring was

Table 3 1 MET

| | z

4METs

Estimated Energy Requirement for Various Activities Can you take care of yourself? Eat, dress, or use the toilet? Walk indoors around the house? Walk a block or two on level ground at 2–3 mph or 3.2–4.8 km/h? Do light work around the house like dusting or washing dishes?

4 METs

| | z

Climb a ﬂight of stairs or walk up a hill? Walk on level ground at 4 mph or 6.4 km/h? Run a short distance Do heavy work around the house like scrubbing ﬂoors or lifting or moving heavy furniture? Participate in moderate recreational activities like golf, bowling, dancing, doubles tennis, or throwing a baseball or football? Participate in strenuous sports like swimming, singles tennis, football, basketball, or skiing?

>10 METs

Abbreviations: MET-metabolic equivalent. Source: Adapted from the Duke Activity Status Index and AHA Exercise Standards. Reproduced with permission from Ref. 10.

Figure 1 The American Heart Association/American College of Cardiology Task Force on Perioperative Evaluation of Cardiac Patients undergoing Noncardiac Surgery has proposed an algorithm for decisions regarding the need for further evaluation. This represents one of multiple algorithms proposed in the literature. It is based upon expert opinion and incorporates six steps. First, the clinician must evaluate the urgency of the surgery and the appropriateness of a formal preoperative assessment. Next, he or she must determine whether the patient has had a previous revascularization procedure or coronary evaluation. Those patients with unstable coronary syndromes should be identiﬁed, and appropriate treatment should be instituted. The decision to have further testing depends on the interaction of the clinical risk factors, surgery-speciﬁc risk, and functional capacity. (Reproduced with permission from Ref. 10.)

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inversely related to the number of blocks that could be walked or ﬂights of stairs that could be climbed.

NONINVASIVE TESTING BEFORE NONCARDIAC SURGERY General Comments The approach to the preoperative evaluation of an elderly patient for noncardiac surgery includes consideration of noninvasive cardiac stress testing. The sensitivity, speciﬁcity, and accuracy of the stress-testing modality and its cost must be considered along with the prevalence of CAD in the population. A positive stress test for myocardial ischemia may not have the same meaning in a population with a low prevalence of CAD as in a population with a high prevalence of CAD. The optimal approach for cardiac risk stratiﬁcation for patients undergoing noncardiac surgery remains controversial. Several algorithms exist for approaching cardiac risk assessment. Some studies raise questions about the usefulness of preoperative noninvasive stress testing before noncardiac surgery, while other studies consider it useful in speciﬁc populations [13,41–43]. In general, the negative predictive values of the speciﬁc stress testing modalities studied in these patient populations are high. Therefore, in a patient with a negative stress test for myocardial ischemia, the risk of a perioperative cardiac event is relatively low. On the other hand, the positive predictive values of available stress tests are consistently low so that a patient with evidence of stress-induced myocardial ischemia often still has a good perioperative outcome. This may be explained by the fact that an acute MI is often caused by the rupture of a non-ﬂow-limiting, unstable coronary artery plaque [44]. Stress testing detects ﬂow-limiting coronary artery stenoses (>50 to 70% arterial lumen narrowing), but cannot detect stenoses that are non–ﬂow limiting. Approach to the Patient Importantly, no preoperative cardiovascular testing should be performed if the results will not change perioperative management. The algorithm to determine the need for cardiac stress testing proposed by The ACC/AHA Task Force is based upon observational or retrospective studies and expert opinion before the decision to proceed to further cardiac testing is made [9,10] (Fig. 1). An alternative approach was developed by the American College of Physicians and attempts to apply an evidence-based approach for the determination of preoperative cardiac risk [45]. The initial decision point is the assessment of risk using the Detsky modiﬁcation of the Cardiac Risk Index [4] and other clinical factors [13,46].

NONINVASIVE PREOPERATIVE CARDIAC TESTING Although cardiac risk for noncardiac surgery is increased with preexisting CAD, the indications for cardiac testing to evaluate the presence of CAD are not based on adequately contolled or randomized clinical trials. Thus, the optimal strategy for testing is based on a conservative approach where the use of testing and treatment is best done only if the results will change preoperative management of the patient. The indications for resting and ambulatory ECG, evaluation of systolic and diastolic left ventricular function, and, ﬁnally, preoperative cardiac stress testing are discussed below.

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Resting Electrocardiography All patients undergoing preoperative evaluation for noncardiac surgery should have a resting ECG in order to identify preexisting cardiac disease. It has been estimated that up to 30% of MIs are silent and only detected on routine ECG, especially in diabetics and patients with HTN. The baseline ECG has limited applicability in the assessment of myocardial ischemia but may be useful to detect signiﬁcant conduction disturbances and arrhythmias. Electrocardiographic abnormalities may not always lead to delay of a noncardiac surgical procedure but may lead to increased vigilance by the anesthesiologist intraoperatively. High-grade atrioventricular block, symptomatic ventricular arrhythmias in the presence of underlying heart disease, and supraventricular arrhythmias with uncontrolled ventricular rate are considered high-risk clinical predictors by the ACC/AHA Guidelines [9]. Pathological Q-waves are considered intermediate-risk clinical predictors. The presence of left ventricular hypertrophy, left bundle branch block, ST-segment abnormalities, and rhythm other than sinus are considered minor risk predictors. Assessment of Left Ventricular Function In general, an assessment of baseline left ventricular function should be reserved for those with unexplained cardiopulmonary symptoms, using echocardiography, radionuclide angiography, and/or contrast ventriculography. Left ventricular ejection fraction has been correlated with short- and long-term prognosis in multiple studies in patients undergoing noncardiac surgery; in general, the lower the ejection fraction, the greater the perioperative risk [9]. Some recent studies have found that left ventricular systolic dysfunction does not predict cardiac complications after vascular surgery [9,47–49]. Importantly, Halm and colleagues were unable to demonstrate that preoperative echocardiographic information added to clinical risk factors for risk stratiﬁcation [50]. The ACC/AHA Task Force Guidelines recommend that preoperative assessment of left ventricular systolic function prior to noncardiac surgery should be limited to patients with current or poorly controlled CHF, but not as a routine test in patients without prior CHF [9,10]. Among patients with a history of CHF and with dyspneas of unknown etiology, the indications are less clear. Continuous ECG ST-Segment Monitoring Multiple studies have demonstrated the association between major cardiac events and perioperative ST-segment changes detected by continuous ECG monitoring. The duration of perioperative ST-segment changes has been shown to be the strongest predictor of poor outcome [51,52]. Continuous ST-segment monitoring is typically used during the intraoperative period for high-risk patients, although ST-segment changes may not always indicate myocardial ischemia [53,54]. The value of continuous ECG ST-segment monitoring for all patients is unclear. In one study, preoperative myocardial ischemia detected by this method was found to be the most signiﬁcant independent predictor of adverse postoperative cardiac events [55]. The absence of ischemia was associated with a very high negative predictive value. Cardiac events occurred more often in patients with higher postoperative heart rates or if patients had a history of diabetes, clinical manifestations of CAD, or were older than 70 years of age.

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Intraoperative ECG ST-segment changes consistent with ischemia, on the other hand, were a signiﬁcant, but relatively weak, predictor of postoperative events, especially in patients with a low prevalence of CAD. Since it is unclear whether early detection of STsegment changes will lead to improved treatment and patient outcome, the utility of continuous ECG ST-segment monitoring is unclear, and it should not be used routinely in the perioperative period. In fact, overly aggressive treatment of ST-segment changes of nonischemic origin could theoretically increase morbidity, costs, or both.

PREOPERATIVE NONINVASIVE CARDIAC STRESS TESTING Early studies assessed only clinical parameters from a population with a relatively low risk of CAD [3,4]. Applying these clinical indexes to elderly patients undergoing vascular surgery in whom the prevalence of CAD is high and exercise capacity is limited may not be as reliable [49]. The ultimate goal of a preoperative cardiac stress test is to identify patients with myocardial ischemia in whom further cardiac interventions would signiﬁcantly lower perioperative cardiac risks. In patients undergoing major vascular surgery, which carries the highest perioperative cardiac risk, noninvasive cardiac testing has been found to be helpful for cardiac risk stratiﬁcation [13,41,43,56–61]. Unfortunately, there are few prospective, randomized studies that establish the value of preoperative testing and that clearly demonstrate that therapy based on these test results aﬀects perioperative outcomes. An important aspect of cardiac stress testing relies on Bayes’ theorem, which states that the correct interpretation of the results of noninvasive stress testing requires estimating the pretest probability of CAD in the patient being studied [62,63]. False-positive stress test results are more common in those in whom CAD is unlikely to be present and false-negative results are more common in those with a high likelihood of CAD. Therefore, determining the probability of CAD in a speciﬁc patient will often guide decision making even before a stress test is considered. A limited number of prospective studies have investigated the predictive value of noninvasive cardiac stress tests in determining the risk of postoperative cardiac events. The positive predictive values of all stress testing modalities are poor (10 to 20%), so that a patient with evidence of myocardial ischemia often will not have a postoperative cardiac event even though the estimated cardiac risk is high. On the other hand, negative predictive values are high (95% to 100%), so that patients without evidence of ischemia are at the lowest risk for an adverse perioperative outcome. The likelihood of an adverse cardiac event after noncardiac surgery, even in patients with evidence of CAD, is less than 10% [64,65]. Stress testing should generally be limited to patients in whom the risk of signiﬁcant CAD is high and to those undergoing the highest risk surgical procedures. The ACC/AHA Task Force Guidelines 2002 update states that the choice of specialized testing in the preoperative evaluation for noncardiac surgery in ambulatory patients is the exercise treadmill ECG to determine functional capacity and to detect myocardial ischemia [9,10]. In patients with baseline ECG abnormalities or in those who are unable to ambulate, nuclear scintigraphic or echocardiographic imaging should be used, depending on the expertise of the interpreters. Dobutamine echocardiography, stress treadmill echocardiography, and dipyridamole thallium have been shown to have similar positive and negative predictive values, sensitivities, and speciﬁcities when performed by clinicians with expertise [66–69].

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Exercise ECG Cardiac Stress Testing In patients with a normal baseline ECG without a prior history of CAD, the exercise ECG response is abnormal in up to 25% of cases. In those with a prior history of MI or an abnormal resting ECG, the exercise ECG response can be abnormal in up to 50% of cases [70]. If an ischemic response occurs at a low cardiac workload, the positive predictive value of the test for determining a high cardiac risk is further increased [38,71,72]. Reduced exercise duration and exercise-induced ST-segment depression, in most [43,71] but not all [73], studies have been shown to correlate with an increased likelihood of postoperative cardiac events [43,71]. In the general population, the usefulness of treadmill ECG test without imaging is somewhat limited. The mean sensitivity and speciﬁcity are 68% and 77% for detection of single-vessel disease, 81% and 66% for detection of multivessel disease, and 86% and 53% for detection of three-vessel or left main CAD [9]. The older age of patients undergoing noncardiac and vascular surgery reduces the sensitivity and prognostic utility of exercise stress testing in this group [70,74]. Often these patients will have a submaximal treadmill exercise study, not being able to achieve their maximum predicted heart rate due to medical therapy, such as beta-blocker use, or to comorbid states, which can limit the results. Patients with intermediate- to high-risk clinical proﬁles who reach a cardiac workload >5 METs or a heart rate greater than 75 to 85% of maximum age-predicted with a nonischemic ECG response are at low-risk for postoperative cardiac events [38,74]. A patient’s performance on a treadmill or bicycle ergometer may also be predictive of postoperative cardiac outcomes [75]. The level at which ischemia is evident on the exercise ECG can be used to estimate an ‘‘ischemic threshold’’ for a patient to guide perioperative medical management. This may support further intensiﬁcation of perioperative medical therapy in highrisk patients, which may impact on perioperative cardiovascular events [76]. Pharmacological Cardiac Stress Testing Pharmacological stress testing has been advocated for preoperative cardiac risk assessment for patients in whom exercise tolerance is limited. Often, these patients may not exercise suﬃciently during daily life to provoke symptoms of myocardial ischemia or CHF. Pharmacological stress tests with echocardiographic or nuclear scintigraphic imaging have been studied extensively in preoperative cardiac risk assessment for noncardiac, and especially vascular, surgery and will be brieﬂy reviewed here [9]. Nuclear Scintigraphy Myocardial Perfusion Imaging An abnormal preoperative dipyridamole-thallium scintigraphy scan has been shown to be a sensitive predictor of postoperative cardiac events [41,43,56,58,61,63,77–80]. Pooled data, though, show that the positive predictive value for adverse cardiac outcomes is low, ranging from 36 to 45%. The negative predictive value, on the other hand, is high (up to 97%). In several studies, the presence of a ﬁxed defect was shown to have no predictive value for adverse postoperative cardiac outcomes [41,43,46,56,58,61,77,81] although, in two studies, there was a higher risk compared to patients with no ischemic defect [62,65]. Preoperative dipyridamole thallium scintigraphy was found to be superior to the clinical assessment alone for the determination of cardiac risk in early studies [56]. More recent studies support the use of preoperative dipyridamole thallium scintigraphy, in combination with clinical parameters, to identify patients at high risk for adverse cardiac outcomes after noncardiac surgery. In the initial study by Eagle et al. of patients

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undergoing vascular surgery, an abnormal preoperative dipyridamole thallium scan was the most signiﬁcant predictor of postoperative ischemic events. The likelihood of an ischemic event was 7% if the scan was negative and 45% if it revealed ischemia [41]. Clinical predictors of postoperative events were pathological Q-waves on ECG and evidence of redistribution defects. Patients with no clinical predictors were at low perioperative cardiac risk, and their perioperative outcomes were not aﬀected by the results of preoperative stress testing. In a second study by Eagle [13] in a similar patient population, ﬁve clinical variables were predictive of postoperative cardiac events: age >70 years, Q-waves on baseline ECG, history of angina, ventricular ectopic activity requiring therapy, and DM. Dipyridamole thallium scintigraphy was found to be most useful in further stratifying patients considered at intermediate clinical risk (one or two clinical variables). In this group, the presence of a redistribution defect was associated with a 30% event rate compared to a 3% event rate in those without a thallium redistribution defect. In more than 50% of cases, the dipyridamole thallium stress test did not add incremental information to the preoperative assessment after clinical variables were evaluated. One study by Lette [74] has challenged the ﬁndings of Eagle [13]. Using 18 clinical parameters and several scoring systems, clinical variables were not found to predict postoperative events. Dipyridamole thallium scintigraphy was the only predictor of adverse postoperative events. Patients without evidence of ischemia or with only a ﬁxed defect had no adverse cardiac outcomes. Some studies have also found that dipyridamole thallium scintigraphy scans with a large number and size of redistribution defects, presence of left ventricular dilatation after stress, or pulmonary radiotracer uptake are predictive of a higher postoperative cardiac risk [61,74,77,81]. The accuracy of dipyridamole thallium scintigraphy in the preoperative evaluation of patients before noncardiac surgery has been challenged by more recent trials [82–85]. In one study, intraoperative myocardial ischemia was assessed using continuous ECG monitoring and transesophageal echocardiography in patients undergoing vascular surgery [82]. All had dipyridamole thallium scintigraphy preoperatively, and all treating physicians were blinded to the results. There was a 5% incidence of adverse postoperative cardiac outcomes, with no association between redistribution defects and adverse cardiac outcomes. The sensitivity and speciﬁcity of thallium scintigraphy for all adverse outcomes were low (40 to 54% and 65 to 71%, respectively). The positive predictive value was low (27 to 47%) and the negative predictive value relatively high (61 to 82%). It was proposed that routine use of dipyridamole thallium scans for preoperative screening of patients before vascular surgery may not be warranted. A study by Baron [83] using SPECT, which has been found to have an increased sensitivity for the detection of CAD, conﬁrmed these ﬁndings. Initial data using technetium 99m sestamibi, a newer myocardial perfusion tracer, indicate that it has the same diagnostic accuracy as thallium 201 for the detection of myocardial ischemia [86]. There are few studies that evaluate the long-term postoperative outcomes of patients with abnormal dipyridamole thallium scans. In one study [60], an abnormal dipyridamole thallium scan was associated with a signiﬁcantly increased risk of cardiac death in the perioperative period and in late follow-up in comparison to those with a normal scan. A reversible defect was the only predictor of death or MI during late follow-up and was associated with a twofold greater risk of a cardiac event than if the defect was ﬁxed. The number of perfusion defects, a history of angina, and the presence of chest pain during the study were independent predictors of perioperative cardiac events. Fleisher et al. utilized criteria from the TIMI-IIIB trials for quantiﬁcation of dipyridamole thallium results [39].

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They reported a signiﬁcantly increased long-term risk only in the subset of patients with high-risk thallium markers, including increased lung uptake and multiple segments with reversible defects. Recently, the ACC/AHA Task Force algorithm was applied to high-risk patients before major vascular surgery [87]. An evaluation of functional status was also incorporated, and patients were stratiﬁed according to predicted cardiac risk. Overall mortality was 3.5% and cardiac mortality was 1%. There was no signiﬁcant diﬀerence in cardiac morbidity between groups and no single independent predictor of morbidity. This algorithm for highrisk patients proved to be a safe and economical strategy. One study of patients who underwent elective aortic abdominal surgery over an 8-year period [88] compared data of two consecutive 4-year periods (1993–1996 (control period) versus 1997–2000 [intervention period] based upon the ACC/AHA Guidelines including perioperative medical therapy). Implementation of ACC/AHA Guidelines in the second time period resulted in more preoperative myocardial scanning and coronary revascularization, fewer cardiac complications (11.3% versus 4.5%), and higher event-free survival at 1 year after surgery (98.2% versus 91.3%). In a small, prospective, randomized trial, 99 patients undergoing elective vascular surgery were randomized to preoperative cardiac stress testing or to no stress testing and followed for up to 12 months postoperatively for adverse cardiac outcomes [89]. There were three perioperative adverse cardiac events, no perioperative deaths, and two additional adverse cardiac events during 12-month follow-up. There was no diﬀerence in postoperative adverse cardiac outcomes between these two groups, suggesting that preoperative cardiac stress was unnecessary in this patient group, who had a high functional capacity at baseline. Larger randomized clinical trials are needed to conﬁrm these ﬁndings. Dobutamine Stress Echocardiography Dobutamine stress echocardiography (DSE) involves the identiﬁcation of new or worsening myocardial wall motion abnormalities using two-dimensional echocardiography during infusion of intravenous dobutamine. This technique has been shown to have the same accuracy as dipyridamole thallium scintigraphy for the detection of CAD [69,90–92]. More recently, DSE has been found to be useful for the assessment of preoperative cardiac risk among patients undergoing noncardiac surgery [9,67,93,94]. The estimated low positive predictive values (17 to 43%) and high negative predictive values (93 to 100%) are similar to those for dipyridamole thallium [41,56,58,67,69,82,95]. There are several advantages to DSE compared to dipyridamole thallium scintigraphy; DSE can also assesses left ventricular function and valvular abnormalities. The cost of DSE is signiﬁcantly lower [67,69], there is no radiation exposure, the duration of the study is signiﬁcantly shorter, and results are immediately available. Several studies have assessed the value of DSE in preoperative risk assessment. In one of the ﬁrst studies, postoperative cardiac events were noted in 21% of patients undergoing noncardiac surgery who had evidence of preoperative dobutamine stress-induced myocardial ischemia, while no patient had a cardiac even if ischemia was not induced [59]. Other authors have reported similar ﬁndings [68,69,96]. The results of DSE add signiﬁcantly to the clinical risk assessment of patients undergoing major vascular surgery [69], particularly in patients with intermediate clinical risk [96]. As with other forms of preoperative risk assessment, however, DSE has a relatively low positive predictive value [68] and many patients with abnormal test results do not have adverse postoperative cardiac events.

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Presently, there are few studies that report long-term cardiac outcomes after noncardiac surgery among patients with abnormal preoperative DSE. In one study, patients were followed for up to 2 years after major vascular surgery [67]. There were two cardiac events (3%) among patients with negative DSE. Among patients with positive DSE, 68% subsequently underwent coronary revascularization before the noncardiac surgery was performed. There were no perioperative events in the group of patients with positive DSE who underwent coronary revascularization before noncardiac surgery. By contrast, 40% of those with positive DSE who did not undergo coronary revascularization had perioperative adverse cardiac outcomes. In this study, DSE predicted perioperative and long-term outcome among patients undergoing major vascular surgery, with a high negative predictive value. In a second study, patients undergoing major vascular surgery were evaluated by clinical parameters and results of DSE and followed for an average of 19 months postoperatively [97]. The presence of extensive dobutamine-induced wall motion abnormalities and a previous history of MI independently predicted late cardiac events, increasing risk up to 6-fold. A meta-analysis of 15 studies to compare dipyridamole-thallium and DSE for risk stratiﬁcation before vascular surgery in intermediate-risk patients found that the prognostic value of both techniques is comparable, but that the accuracy varies with CAD prevalence [95]. In summary, the ACC/AHA guidelines recommend that exercise or pharmacological cardiac stress testing be performed before noncardiac surgery with the same indications as for those who are not undergoing noncardiac surgery [10].

CORONARY ANGIOGRAPHY AND REVASCULARIZATION BEFORE NONCARDIAC SURGERY Coronary Angiography An abnormal noninvasive study in the preoperative period may lead to coronary angiography and revascularization, to changes in anesthetic technique, to utilization of expensive resources such as intensive care units, or to aggressive treatment of hemodynamic ﬂuctuations [98]. Historically, the use of coronary angiography as a screening procedure before elective peripheral vascular surgical procedures was advocated [11] due to the high perioperative mortality associated with the high prevalence of CAD in this patient group [60]. Many argue that using coronary angiography as a preoperative screening tool is too costly and places patients at further risk due to the cumulative risks of these procedures, especially in the elderly with signiﬁcant comorbid diseases. This has led to increased interest in preoperative noninvasive cardiac stress testing to assist in risk-stratifying patients before elective noncardiac surgery [99]. It is generally assumed that coronary angiography should be performed preoperatively in patients with evidence of ischemia on stress testing [41,56,58,60], although there are no published randomized trials to support this approach. The present indications for coronary angiography in the preoperative evaluation before noncardiac surgery are adapted from the ACC/AHA Guidelines for coronary angiography in the general population [100]. Coronary angiography should be considered in patients with unstable symptoms of angina pectoris, with high-risk or equivocal preoperative noninvasive stress test results, or in patients with multiple clinical risk parameters who are undergoing a high-risk noncardiac surgical procedure. It is generally agreed

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that performance of coronary angiography is not indicated in patients with low-risk results on preoperative noninvasive cardiac stress testing, in those who are asymptomatic up to 5 years after prior coronary revascularization, or for CAD screening without a prior noninvasive cardiac stress test.

Percutaneous Coronary Intervention The role of percutaneous coronary intervention (PCI) before noncardiac surgery to reduce the incidence of perioperative cardiac events has not been studied in a prospective randomized fashion. In a small, retrospective study of patients who underwent PCI prior to noncardiac surgery, 10% required urgent CABG [101]. Successful preoperative PCI in highrisk patients was shown to be associated with a low perioperative cardiac risk during noncardiac surgery. In a large 10-year study of patients who underwent PCI and/or CABG prior to elective abdominal aortic aneurysm surgery from 1980 to 1990, there were no perioperative deaths in patients with prior coronary revascularization compared to a 2.9% perioperative mortality for the group as a whole [102]. Three-year survival was similar with either revascularization procedure (92% PCI versus 83% CABG), although patientswith PCI had a signiﬁcantly higher number of late events at 3 years (56.5% versus 27.3%). This study suggests that coronary revascularization before high-risk vascular surgery may improve perioperative outcomes in a select group of patients. Posner et al. [103] retrospectively analyzed hospital discharge abstracts, matching patients with CAD undergoing noncardiac surgery with and without prior PCI. In this nonrandomized study, they noted a signiﬁcantly lower rate of 30-day cardiac complications in patients who underwent PCI at least 90 days before the noncardiac surgery. PCI performed within 90 days of noncardiac surgery was not associated with improvement in outcome. These results suggest that PCI performed ‘‘to get the patient through surgery’’ may not improve perioperative outcome, although this study did not control for CAD severity, medical management, or comorbidities. One study evaluated the value of multivessel coronary angioplasty on subsequent noncardiac surgery a median of 29 months after the most recent coronary revascularization procedure [104]. Mortality or non-fatal MI occurred in 4 of the 250 surgery-assigned patients and 4 of the 251 angioplasty-assigned patients. Therefore, there does not appear to be an optimal choice of revascularization procedure for multivessel disease, although a larger scale study will be necessary to conﬁrm these ﬁndings. Evidence regarding the value of coronary stent placement is currently lacking. Of importance, the outcome in 40 patients who underwent coronary stent placement less than 6 weeks before noncardiac surgery requiring a general anesthesia was recently reported [105]. There were 7 myocardial infarctions, 11 major bleeding episodes, and 8 deaths. All deaths and MIs, as well as the majority of bleeding episodes, occurred in patients subjected to surgery fewer than 14 days from the stent procedure. Four patients expired after undergoing surgery 1 day after stenting. The time between stenting and surgery appeared to be the main determinant of outcome, and the authors recommend that a minimum of 2 weeks, and preferably 4 weeks, elapse before elective surgery. The risk of signiﬁcant complications during PCI limits its generalized use, especially in elderly patients [101,102,106]. The indications for the use of PCI before noncardiac surgery should therefore be considered similar to the indications for PCI in other settings [107].

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Coronary Artery Bypass Graft Surgery Studies have shown that the preoperative presence of CAD signiﬁcantly increases the risk for a perioperative cardiac event after noncardiac surgery [108–111], although there are no randomized trials to assess whether preoperative CABG lowers this risk [112]. Some evidence exists that preoperative revascularization may decrease postoperative cardiac risk two- to four-fold in patients undergoing elective vascular surgery [113–115]. In one study, CABG surgery was performed in 216 patients before noncardiac surgery with a 5.2% mortality [11]. The overall surgical mortality for both the cardiac and noncardiac procedures combined in the total cohort of 1000 patients was 2.6%. This indicates that a signiﬁcant proportion of patients had inoperable or severe CAD. The risk of adverse cardiac outcomes after noncardiac surgery in these patients may be reduced with CABG surgery, but with the added risk of the CABG procedure itself. Many patients referred for noncardiac surgery, and especially for vascular surgery, are elderly with comorbid conditions, and it is in these patients that the risks of CABG itself are signiﬁcant [11,116]. Several studies suggest that preoperative CABG can reduce postoperative risk if the patient is felt to be at low risk for the CABG itself [11,117–122]. In a subset of patients in the Coronary Artery Surgery Study (CASS) Registry enrolled from 1978 to 1981, the inﬂuence of CABG on perioperative cardiac risks prior to noncardiac surgery was studied [122]. The operative mortality for patients with CABG prior to noncardiac surgery was 0.9% but was signiﬁcantly higher at 2.4% among patients without prior CABG. However, there was a 1.4% mortality rate associated with the CABG procedure itself [112]. Eagle and colleagues reported a long-term analysis of patients in the CASS registry who received medical or surgical therapy for CAD and who subsequently underwent 3368 noncardiac operations over the next 10 years [123]. The rate of perioperative MI and death was stratiﬁed by the type of surgical procedure. Speciﬁcally, low-risk surgeries such as skin, breast, urological, and minor orthopedic procedures were associated with a total morbidity and mortality of less than 1%, and prior revascularization did not aﬀect outcome. Intermediate-risk surgery, such as abdominal or thoracic procedures or carotid endarterectomy, was associated with a combined morbidity and mortality of 1 to 5%, with a small, but signiﬁcant, improvement in outcome among patients who underwent prior coronary revascularization. The most signiﬁcant improvement in outcome was noted among patients undergoing major vascular surgery who underwent prior coronary revascularization. Therefore, in this nonrandomized study, CABG was beneﬁcial in selected subgroups if they survived the initial coronary revascularization operation. Few data support the use of CABG solely to improve perioperative outcomes among patients undergoing noncardiac surgery. The indications for CABG are based on ACC/ AHA Task Force Guidelines and indications for CABG for the general population [100]. Timing of CABG prior to noncardiac surgery is an individualized decision, and there are no prospective, randomized data to suggest the optimal strategy. An alternative approach to determine the optimal strategy for medical care is construction of decision analyses. Decision analyses have been published on cardiovascular testing before major vascular surgery [115,124,125]. All analyses assumed that patients with signiﬁcant CAD would undergo CABG surgery prior to noncardiac surgery. The models indicated that the optimal decision was sensitive to local morbidity and mortality rates within the clinically observed range. These models suggest that preoperative testing for the purpose of coronary revascularization is not the optimal strategy if the anticipated perioperative morbidity and mortality are low.

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First and foremost, the primary cost of preoperative testing and revascularization is the revascularization procedure itself. Therefore, the indications for revascularization, and thus the frequency of its use, has a signiﬁcant impact on the model. Second, potential long-term beneﬁts of coronary revascularization in this population were not included in the analysis, potentially biasing against the revascularization arm. If long-term survival is included in the models, then coronary revascularization may lead to improved overall outcome and be a cost-eﬀective intervention. However, a patient’s age should be included in the equation. For example, an 80-year-old diabetic patient with signiﬁcant comorbid diseases may gain little additional life-years by undergoing coronary revascularization. By contrast, a 55-year-old man with an abdominal aortic aneurysm who is found to have occult left main coronary disease would have a substantial increase in both the length and quality of his life from preoperative cardiovascular testing and coronary revascularization.

PERIOPERATIVE INTERVENTIONS TO REDUCE RISK Table 4 indicates strategies to reduce risk of noncardiac surgery. Intra-Aortic Baloon Counterpulsation Among patients with unstable angina or severe CAD, placement of an intra-aortic balloon counterpulsation device has been used before induction of anesthesia in patients considered high-risk for noncardiac surgical procedures. In several small case series, perioperative morbidity and mortality was low [126]. Perioperative CHF It is critical to optimize the medical management of CHF, both systolic and diastolic, before an elective noncardiac surgical procedure. For patients with left ventricular systolic dysfunction, this often involves the use of diuretics, angiotensin-converting enzyme inhibitors, and beta-blockers. These medications can alter hemodynamic and metabolic parameters that may impact on perioperative cardiac risk. Patients at risk for CHF postoperatively are those with a history of arrhythmia and DM and those undergoing prolonged surgical procedures [3,122]. Patients who develop isolated CHF postoperatively have a better long-term prognosis than those in whom a postoperative myocardial ischemic event occurs [127]. Pharmacological Agents Beta-Blockers Several studies in the late 1970s indicated that beta-blocker therapy could be safely continued preoperatively, often resulting in a reduction in the incidence of myocardial ischemia [128]. These studies, and the concern for beta-blocker withdrawal-induced tachycardia, HTN, and myocardial ischemia [129,130], led to recommendations to continue beta-blocker therapy before surgery [131]. By decreasing adrenergic stimulation of the heart, beta-blockers may reduce the incidence of perioperative arrhythmias and myocardial ischemia. In a study of patients with

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mild-to-moderate HTN undergoing general anesthesia, the use of a single low-dose oral beta-blocker produced a 13-fold reduction in the incidence of intraoperative myocardial ischemia by ECG [132]. Among patients not receiving beta-blocker therapy, ischemia was detected in 28%. All episodes were either during tracheal intubation or emergence from anesthesia. In those treated with beta-blocker therapy, only 2.2% had evidence of myocardial ischemia. Those who received beta-blockers more frequently had bradycardia, had a greater fall in mean arterial pressure during premedication, and had less of a pressor response during tracheal intubation and emergence from anesthesia. The prophylactic use of beta-blocker therapy in patients at high risk of postoperative cardiac complications appears to be safe and eﬀective [133]. The ﬁrst well-designed randomized, placebo-controlled study in high-risk noncardiac surgical patients involved the perioperative use of atenolol, which was administered beginning 2 days preoperatively and continued for 7 days postoperatively [76,134]. A signiﬁcantly lower incidence of perioperative ischemia and improved event-free 6-month survival was observed in the atenolol group. No diﬀerence in perioperative MI or cardiac death was noted between groups. Of note, several risk factors and medications were not equally distributed in the two groups, with the placebo group having a higher risk proﬁle. Further research is required to conﬁrm these ﬁndings. In a study of the perioperative use of bisoprolol in elective major vascular surgery, this medication was administered at least 7 days perioperatively, titrated to achieve a resting heart rate V60 beats per minute, and continued postoperatively for 30 days [135]. Of note, the study was conﬁned to patients with one or more clinical markers of cardiac risk (prior MI, DM, angina pectoris, CHF, age >70 years or poor functional status), and with myocardial ischemia on DSE. Patients with large zones of myocardial ischemia were excluded from the trial. Bisoprolol led to an approximate 80% reduction in perioperative MI or cardiac death. The eﬃcacy of bisoprolol in the highest risk group, those who would be considered for coronary revascularization or modiﬁcation or cancellation of the surgical procedure, is unknown. However, the event rate in the placebo group (nearly 40%) suggests that all but the highest risk patients were enrolled in the trial. The same data were then reevaluated with respect to clinical factors, DSE results and beta-blocker usage [136]. A clinical risk score was calculated by assigning one point for each of the following characteristics: age z 70 years, current angina, MI, CHF, prior cerebrovascular, DM, and renal failure. Importantly, DSE was performed only in patients with a signiﬁcant number of risk factors. Those patients who demonstrated new wall motion abnormalities had higher event rates compared to those without new wall motion abnormalities, for the same clinical risk score. When the risk of death of MI was stratiﬁed by perioperative beta-blocker usage, there was no signiﬁcant improvement in those without any of the prior risk factors (Fig. 2). In those with fewer than three clinical risk factors, the use of beta-blockers was associated with a lower rate of cardiac events (0.8% versus 2.3%), and beta-blocker therapy was very eﬀective in reducing cardiac events in those with limited stress-induced ischemia on DSE (33% versus 2.8%). By contrast, beta-blocker therapy had no eﬀect in those patients with more extensive stress-induced ischemia on DSE. Several recent reviews also highlight the importance of perioperative beta-blocker therapy, although there is lack of strong evidence regarding the optimal agents or timing [137]. A scientiﬁc review provides recommendations regarding the use of perioperative betablocker therapy [138]. If patients are taking beta-blockers preoperatively, then it is important to continue them in the perioperative period. If patients are undergoing vascular surgery and demonstrate areas of myocardial ischemia on preoperative cardiac stress

Patients requiring calcium channel blockers to control angina and/or provocable ischemia Patients previously requiring nitrates to control angina and/or provocable ischemia; patients developing perioperative ischemia without hypovolemia

Calcium channel blockers

Nitrates

Patients with existing CAD undergoing vascular surgery

Patients already on; evidence of existing CAD (prior MI, angina or its equivalent, and/or provocable myocardial ischemia in presence of risk factors for CAD

Patient selection

Alpha-2 agonists

Medical Therapy Beta-blockers

Category

Table 4 Strategies to Reduce Cardiac Risk of Noncardiac Surgery

Continue prior regimen; institution of intravenous delivery

Continue prior regimen

Continue prior regimen; ideally begin treatment days to weeks preoperative (e.g., atenolol 25–50 mg q.d. or metoprolol 25–50 mg b.i.d. titrating to achieve heart rate V60 beats per minute) 2 Ag/kg of clonidine orally as premedication; mizaverol (not commercially available) given to achieve a target concentration of 20 ng/mL

Speciﬁc therapy

Data on clonidine supports reduction in myocardial ischemia, not MI or death; mivazerol only demonstrates eﬃcacy in subset of large clinical trial Not well studied; no convincing data to support eﬃcacy Limited trial data; no convincing prophylactic value

Most convincing data exist for patients undergoing vascular surgery with known CAD and provocable ischemia on stress test

Quality of supporting data

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Coronary artery bypass surgery

Percutaneous coronary intervention

Patient with poorly controlled angina despite maximal medical therapy; patients with large zones of provocable myocardial ischemia on preoperative stress test, particularly when already on maximal medical therapy and undergoing high stress noncardiac surgery Patients with poorly controlled angina despite maximal medical therapy; Patientswith signiﬁcant (>50%) left main coronary stenosis; Patients with severe 2- or 3- vessel coronary artery disease with involvement of the proximal left anterior descending artery and easily provocable myo cardial ischemia on stress testing and/or impaired left ventricular systolic function at rest

All data are observational, based on small sample sizes or utilize administrative databases

All data are observational; much is old (e.g. >10 years ago)

PCI is justiﬁed independent of noncardiac surgery; dilation and stenting of severe lesions—allow 4 weeks of post-stent antiplatelet therapy and coronary endothelial healing before elective noncardiac surgery CABG is justiﬁed independent of noncardiac surgery; CABG should generally be performed before elective, high stress noncardiac surgery to reduce risk of perioperative cardiac events

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Figure 2 Perioperative cardiac risk and death in dierent populations of patients enrolled in the DECREASE trial. Risk is deﬁned according to clinical risk and use of beta-blockers both as part of the randomized and nonrandomized cohort of individuals. Patients with risk factors and a positive stress test demonstrating 1 to 4 areas of regional wall motion abnormality on dobutamine stress echocardiography were randomized to perioperative bisoprolol titrated preoperatively to a heart rate <60 beats per minute versus standard care. For all other patients who were not randomized but were on preoperative beta-blockers, the medication was switched to bisoprolol targeted to a heart rate <60 beats per minute. (Reproduced with permission from Ref. 136.)

testing, then beta-blocker therapy should be initiated several days or weeks in advance and titrated to a heart rate of 60 to 70 beats per minute. Among patients who were not previously on beta-blocker therapy and who are unstable or were monitored in the intensive care unit, the use of short-acting agents such as esmolol is suggested. When patients are hemodynamically stable and will tolerate longer acting beta-blockers, oral agents should be used. A majority of patients who present for noncardiac surgery, including vascular surgery, have not been started on beta-blockers [139,140]. This limits the anesthesiologist to the acute administration of beta-blocking agent the day of surgery in some cases. The eﬀect of acute heart rate decrease coupled with the induction of anesthesia in a patient who had previously been beta-blocker naive has anecdotally been associated with marked bradycardia and hypotension. Treatment of these events could lead to wide swings in heart rate and blood pressure. The ACC/AHA guidelines recommend beta-blockers for patients previously taking these agents and/or for those undergoing vascular surgery with a positive stress test for

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coronary ischemia [10]. These guidelines favor the use of beta-blockers in patients with known CAD or with risk factors undergoing noncardiac surgery. One approach to perioperative beta-blocker therapy is shown in Figure 3. Nitroglycerin Continuous intravenous infusions of nitroglycerin, a venodilator, are most useful for the management of perioperative HTN. The postoperative patient with CHF and/or ischemic heart disease may also beneﬁt from its use. Nitroglycerin may also reduce preload and improve myocardial oxygen supply. Prolonged use should be avoided due to potential tachyphylaxis. Nitroglycerin has been a mainstay of anti-ischemic therapy, but its value during the perioperative period is controversial. Two randomized clinical trials have focused on highrisk noncardiac surgery patients. Coriat et al. studied a cohort of patients undergoing carotid endarterectomy using a high-dose narcotic anesthetic technique [141]. They demonstrated a signiﬁcantly reduced incidence of myocardial ischemia with 1.0 Ag/kg/min of nitroglycerin compared to 0.5 Ag/kg/min; however, there were no patients who sustained a perioperative MI. Another study compared nitroglycerin at 1.0 Ag/kg/min to placebo in high-risk patients undergoing noncardiac surgeries and demonstrated no diﬀerence in perioperative myocardial ischemia or infarction [142]. Many of the eﬀects of nitroglycerin are mimicked by the anesthetic agents, minimizing nitroglycerin’s potential beneﬁcial eﬀects and potentially leading to more profound hypotension. Therefore, the evidence does not support the routine prophylactic use of this agent. Alpha-2 Agonists Alpha-2 agonists have received a great deal of attention as adjuvants to the anesthetic management. Clonidine stimulates central alpha2-receptors and thereby decreases sympathetic nervous outﬂow to the vasculature, producing vasodilation and lowering blood pressure [22]. Clonidine has been shown to signiﬁcantly decrease the incidence of intraoperative but not postoperative ischemia compared to placebo in patients undergoing noncardiac surgery [143]. Another study of patients undergoing elective vascular surgery demonstrated a signiﬁcantly reduced incidence of perioperative myocardial ischemia with fewer nonfatal myocardial infarctions among patients treated with clonidine versus placebo [144]. Clonidine may be useful for the management of postoperative HTN since it is available for oral and transdermal use and should be continued in the patient taking clonidine preoperatively in order to avoid a withdrawal syndrome [145]. Clonidine should not be used in patients with high-grade atrioventricular conduction disturbances [146]. Calcium Channel Antagonists Calcium channel blockers may be useful in the management of postoperative HTN, but some may produce reﬂex tachycardia; this is particularly true of the dihydropyridine compounds like nifedipine [147]. The use of sublingual nifedipine capsules for the treatment of hypertensive emergencies may be dangerous, since there have been numerous reports of drug-induced cerebrovascular ischemia and infarction, acute MI, and death [148]. Management of Permanent Pacemakers Over 460,000 individuals in the United States have permanent pacemakers, 85% of whom are over the age of 65 [149]. It is important that the type of pacemaker implanted is known in order to guide perioperative management if issues arise. Major pacemaker manufacturers provide technical support for particular devices, as does the cardiologist who implanted the

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Figure 3 One proposed algorithm for the administration of beta-blockers. (Reproduced with permission from Fleisher LA. Optimizing Perioperative Outcomes. IAPS Refresher Course Lecture; 2003.)

device, if available. A conservative recommendation is that a pacemaker be interrogated at least 2 months prior to an elective procedure. Indications for use of perioperative pacemakers and management of preexisting devices are generally based on expert opinion. No established evidence-based guidelines are available. In general, noncardiac surgery should be delayed for 48 h after permanent pacemaker implantation, if possible, to minimize the risk of acute dislodgment of the pacemaker leads.

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In general, perioperative temporary pacemaker placement is indicated for high-grade conduction abnormalities and intraventricular conduction delays with associated symptoms. In cases where symptoms are not present and an intraventricular conduction delay is not present, easy access to temporary transvenous pacemaker equipment in the operating room is advised. Recommendations for temporary or permanent pacemaker implantation in patients undergoing noncardiac surgery are the same as those for elective pacemaker implantations for patients not undergoing surgical procedures. As with all invasive procedures, the risk of temporary pacemaker placement must be considered. Electrocautery may interfere with pacemakers by causing oversensing in patients with unipolar and, rarely, bipolar systems. In this case, it is recommended that the electrocautery electrode be kept at least 4–6 inches away from the pacemaker to minimize electrical interference [150]. A pacemaker could be programmed to a ﬁxed-rate mode to avoid reprogramming problems. Preoperatively, in cases of emergent surgery or situations in which the pacemaker is not able to be interrogated, a magnet should be placed over the pacemaker and an ECG recorded to evaluate the back-up mode and function of the pacemaker. A programming device speciﬁc for the interrogation of the pacemaker being used should be available in the operating room when the potential for electrocautery interference is high, the use of deﬁbrillation or cardioversion is expected, or when there has been a noted change in the function and pacing mode of the pacemaker. Pacing thresholds may be decreased due to hypoxia and myocardial ischemia and may be raised due to hyperkalemia and acid/base disturbances [150]. Endocarditis prophylaxis for patients with permanent pacemakers before noncardiac surgery is not indicated in most cases [151]. Management of Automatic Implantable Cardiac Defibrillators Management of the automatic implantable cardiac deﬁbrillator (AICD) in the perioperative setting is also based predominantly on expert opinion. The consultant should know the manufacturer of the device. In general, the device should be inactivated, and appropriate resuscitation equipment should be available in the operating room. If the electrophysiologist who implanted the device is available, he or she could provide expert assistance. Also, the technical support provided by the major AICD manufacturers may provide speciﬁc recommendations. The AICD can be left in the inactivated mode until the patient is transferred to an unmonitored hospital bed. Endocarditis prophylaxis for patients with an AICD is not generally recommended [151].

SPECIFIC MEDICAL CONDITIONS Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy is uncommonly encountered. Patients with this condition typically have marked degrees of left ventricular hypertrophy, reduced ventricular compliance, hyperdynamic left ventricular systolic function and systolic anterior motion of the mitral valve leaﬂet, with or without a dynamic pressure gradient in the subaortic area. Therefore, it is important to identify this condition preoperatively, since there may be increased risk of hemodynamic compromise in the perioperative period. There may be a family history of cardiomyopathy or of sudden, unexpected death at a young age. A history of cardiac symptoms should be carefully determined, especially chest pain, dyspnea, and syncope. The systolic murmur of hypertrophic cardiomyopathy is quite characteristic, and dynamic auscultation during passive leg elevation or with the patient

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changing from the standing to the squatting position typically demonstrates a decrease in the intensity of the murmur [152]. Doppler echocardiography is useful in the identiﬁcation of this condition. There is little published information available that deﬁnes the perioperative risk of patients with hypertrophic cardiomyopathy. Although based on limited evidence, it has been recommended that spinal anesthesia be avoided in these patients because it can decrease systemic vascular resistance and increase venous capacitance [153,154]. As a result of the pathophysiology of hypertrophic cardiomyopathy, these patients are particularly susceptible to factors that alter left ventricular ﬁlling, such as diminished intravascular volume, alterations in systemic vascular resistance, and increases in heart rate. Special care should be taken to maintain adequate intravascular volume, minimize pain and anxiety, and avoid treatment with catecholamines [9]. Intensive care unit monitoring may be useful postoperatively to limit periods of hypotension and avoid volume depletion, which may include pulmonary artery catheter monitoring, although the usefulness of these has not been established.

Diastolic Dysfunction The hypertensive heart is characterized by concentric left ventricular hypertrophy, normal or above-normal systolic function, and diastolic dysfunction [155]. In the elderly patient with marked concentric left ventricular hypertrophy and small end-systolic chamber sizes, diastolic dysfunction can lead to pulmonary congestion [156]. This population may be particularly sensitive to factors that aﬀect diastolic ﬁlling of the left ventricle, such as increased heart rate, atrial ﬁbrillation, or volume depletion. Identifying chronically hypertensive patients with diastolic dysfunction with reliable echocardiography parameters [156– 158] could guide optimal perioperative ﬂuid and blood pressure management. Echocardiography should be considered in the patient with chronic HTN and a history of exertional or stress-induced dyspnea, particularly if there is evidence of left ventricular hypertrophy on the ECG. Exercise may produce a suboptimal increase or even a decrease in left ventricular ejection fraction in these individuals, apparently in some cases due to impaired diastolic ﬁlling [159]. The hemodynamic response to the stress of anesthesia and surgery might be expected to produce a similar response. Increased sympathetic nervous system activity producing increases in blood pressure and heart rate may occur as the patient emerges from anesthesia [160]. This response may compromise diastolic ﬁlling, so it is critical to assess volume status at this time. In certain patients, this may be extremely diﬃcult without continuous invasive hemodynamic monitoring. While a pulmonary artery catheter cannot be routinely recommended, it may provide important information.

Valvular Heart Disease Valvular heart disease is frequently encountered in elderly patients undergoing surgical procedures. The known prevalence of valvular heart disease might be greater today due to the more widespread use of echocardiography. Mitral and aortic valvular disease are more likely to be associated with perioperative cardiac events. The ACC/AHA Guidelines indicate that severe valvular disease is a major clinical predictor of increased perioperative cardiovascular risk [10]. A very early study of only 23 patients considered severe aortic

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stenosis, deﬁned by physical examination criteria and by other supportive data when available, to be the most signiﬁcant valvular lesion [3]. A later study in which all patients underwent echocardiography showed that selected patients with moderate-to-severe aortic stenosis can undergo noncardiac surgical procedures at a relatively low risk [161]. Patients with mitral regurgitation, mitral stenosis, or aortic regurgitation may have an increased risk of developing new or worsening CHF but do not appear to have an increased risk of perioperative cardiac mortality [21]. All of these valvular conditions are reviewed below. Mitral Stenosis The major concerns in the patient with mitral stenosis undergoing noncardiac surgery are: (1) maintaining hemodynamic stability; (2) decreasing the incidence of perioperative arrhythmia such as atrial ﬁbrillation; and (3) prevention of infective endocarditis. Increases in heart rate reduce left ventricular ﬁlling across the stenotic mitral valve and increase the transmitral pressure gradient [162]. Patients with mitral stenosis can become symptomatic with activities associated with tachycardia and, similarly, during tachycardias induced during the perioperative period. Beta-blockers may be used to reduce heart rate in an attempt to optimize hemodynamic conditions. Antiarrhythmic agents may be considered to prevent the development of atrial ﬁbrillation since this arrhythmia is particularly likely in these patients. Unrecognized mitral stenosis must be included in the diﬀerential diagnosis of the patient who develops acute pulmonary edema in the perioperative period. Patients with acquired mitral stenosis should receive antibiotic prophylaxis against infective endocarditis for certain surgical procedures [151]. Mitral valve balloon valvuloplasty is often a reasonable alternative to mitral valve surgery in patients who require intervention for symptoms due to signiﬁcant mitral stenosis before proceeding to noncardiac surgery. Mitral Regurgitation Mitral regurgitation is more common than mitral stenosis. When the regurgitation is severe, left ventricular function is often reduced, left atrial and pulmonary vascular pressures are elevated, and atrial ﬁbrillation may be present. Mitral regurgitation is less likely than mitral stenosis to cause abrupt clinical deterioration in the perioperative period unless there are associated valvular lesions, such as aortic stenosis or left ventricular dysfunction. In one study, mitral regurgitation was a signiﬁcant univariate correlate of cardiac perioperative morbidity and postoperative mortality, but the predictive value did not persist after controlling for other criteria of heart disease in a multivariate analysis [21]. Patients with mitral valve prolapse with an associated mitral regurgitation murmur should receive antibiotic prophylaxis against infective endocarditis for certain surgical procedures [151]. For those with physiological mitral regurgitation and normal mitral valve leaﬂets by echocardiography but without a mitral regurgitation murmur, endocarditis prophylaxis is not generally recommended. Aortic Stenosis The patient with suspected aortic stenosis merits further evaluation prior to noncardiac surgery, since those with severe aortic stenosis are considered to be at high risk [3,9,21]. Aortic stenosis is more common in men, is particularly a condition of the elderly, and usually results from degenerative calciﬁc aortic valve disease or calciﬁcation of a congenitally bicuspid valve [163]. Although cardiac output may increase normally with exercise in asymptomatic patients with aortic stenosis, stroke volume may decrease [164]. Thus, a normal hemodynamic response to exercise or to the stress of the perioperative period may be

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critically dependent on an increase in heart rate. In symptomatic and more severe aortic stenosis, the cardiac output may not increase normally with increasing metabolic demand. Patients with moderate-to-severe valvular aortic stenosis typically develop concentric left ventricular hypertrophy and diastolic left ventricular dysfunction. There are recommendations for antibiotic prophylaxis against infective endocarditis for patients with bicuspid and acquired aortic valve diseases for certain surgical procedures [151]. Asymptomatic patients with signiﬁcant aortic stenosis may be considered for valve replacement prior to noncardiac surgery unless this is not feasible due to the urgent nature of the procedure or due to unacceptably high risk [165]. The ACC/AHA Guidelines recommend that elective noncardiac surgery be postponed or canceled until aortic valve replacement is performed in patients with severe, symptomatic aortic stenosis [10], although there are reports that selected patients with aortic stenosis, even when severe, may be able to safely undergo noncardiac surgery with meticulous perioperative monitoring and care [161]. Cardiac stress testing may be indicated prior to noncardiac surgery in patients with aortic stenosis since it may be diﬃcult to distinguish whether chest pain or dyspnea is due to signiﬁcant aortic stenosis or myocardial ischemia. The safety of exercise stress testing in patients with aortic stenosis has been questioned since exercise-induced cardiac events, particularly eﬀort syncope, have been described [166]. The ACP/ACC/AHA Task Force Statement on exercise testing lists severe aortic stenosis as a general contraindication to exercise testing [70]. Nevertheless, some studies have indicated that patients with varying degrees of valvular aortic stenosis may safely undergo treadmill stress testing [164,167–169]. One study of a small number of patients suggests that adenosine nuclear scintigraphy may be safely performed in patients with moderate-to-severe aortic stenosis [170]. Dobutamine echocardiography has also been safely performed in patients with severe aortic stenosis [171]. General anesthesia may be preferable to spinal anesthesia in asymptomatic patients with mild aortic stenosis since the hemodynamic eﬀects of spinal anesthesia may be undesirable [165]. Patients with moderate-to-severe aortic stenosis may also beneﬁt from close postoperative hemodynamic monitoring in an intensive care unit. The long-term outcome of patients who undergo percutaneous aortic balloon valvuloplasty for signiﬁcant aortic stenosis is generally poor [172,173] due primarily to restenosis [174]. This procedure may be used for palliation prior to noncardiac surgery [175]. Aortic valvuloplasty may improve the severity of aortic stenosis [172,173], but the procedure has signiﬁcant risk. Fatal cardiac arrest complicating the procedure has been reported in approximately 3% of patients [174]. In one report, 4.9% of patients died within the ﬁrst 24 h after valvuloplasty and 7.5% died during the hospitalization [176]. Acute catastrophic complications including ventricular perforation, acute severe aortic regurgitation, cerebrovascular accident, and limb amputation have been reported in approximately 6% of patients [177]. In a study of elderly patients, Doppler echocardiography showed that while the aortic valve mean gradient decreased signiﬁcantly after the procedure, it increased to near preprocedure levels approximately 6 months later [173]. In contrast to aortic valvuloplasty, percutaneous mitral valve balloon valvuloplasty is often a reasonable alternative to mitral valve surgery. Results have been favorable, especially in younger patients with mitral stenosis but without severe mitral valve leaﬂet thickening or signiﬁcant subvalvular calciﬁcation [178,179]. Aortic Regurgitation Patients with chronic aortic regurgitation may have marked degrees of left ventricular hypertrophy and dilatation and eventually develop systolic dysfunction. As is true of patients with mitral regurgitation, those with isolated chronic aortic regurgitation typically

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do not deteriorate abruptly in the perioperative period. Patients with acquired aortic regurgitation should receive antibiotic prophylaxis against infective endocarditis for certain surgical procedures [151]. Prosthetic Heart Valves More than 60,000 cardiac valve replacements are performed each year in the United States [180]. Issues important in the perioperative period for those with prosthetic valves include the management of chronic anticoagulation therapy, reducing the risk of infective endocarditis [151], preventing valve thrombosis, and identifying valve-related hemolysis. There are two major types of mechanical prosthetic heart valves, the caged-ball and the tilting-disk valves. The St. Jude valve, a type of tilting-disk valve, is the most commonly used prosthetic valve in the world [181]. While mechanical prosthetic valves have greater durability than bioprosthetic valves, they are more thrombogenic. The risk of valve thrombosis is greatest in patients with caged-ball prosthetic valves (Starr-Edwards) [180]. Single-tilting-disk prosthetic valves (Bjork-Shiley, Medtronic-Hall, and Omnicarbon) have an intermediate risk of valve thrombosis, and bileaﬂet tilting-disk prostheses (St. Jude, Carbomedics, Edwards Duromedics) pose the lowest risk of the mechanical prosthetic valves [180]. The possibility of prosthetic valve dysfunction may be suggested by new cardiac symptoms and abnormal auscultatory ﬁndings on physical examination. Mechanical prosthetic valves may be evaluated with cineﬂuoroscopy. Echocardiography or cardiac catheterization may be warranted in some situations [180]. The management of chronic warfarin anticoagulation in the perioperative period is of major importance in patients with mechanical prosthetic heart valves. The risk of temporarily discontinuing anticoagulation must be weighed against the beneﬁt of a reduced risk of perioperative bleeding for all patients on chronic anticoagulation, especially those with prosthetic heart valves. In general, the incidence of thromboembolism in patients with valvular heart disease depends on the valve involved, the type of prosthetic heart valve, the existence of concomitant heart disease, the presence of left atrial enlargement, and whether atrial ﬁbrillation is present [182]. For most elective noncardiac surgical procedures in which blood loss is anticipated, it is generally recommended that patients with prosthetic valves who are taking warfarin have this therapy stopped 3 to 5 days before surgery [180]. Some have recommended brieﬂy reducing the level of warfarin anticoagulation to the low therapeutic or subtherapeutic range for minimally invasive surgical procedures [183] and then resuming the usual warfarin dose after the procedure, but this recommendation can only be made with information about the potential for blood loss if the surgery does not go as planned. Those patients with the greatest risk of thromboembolism should be therapeutically anticoagulated with intravenous heparin during the 3 to 5 preoperative days in which warfarin is discontinued [184]; the heparin infusion should be continued until several hours before surgery [180,184]. Warfarin should be restarted as soon as possible following surgery, and intravenous heparin should be resumed and continued until oral anticoagulation is in the therapeutic range.

INTRAOPERATIVE MANAGEMENT Anesthetic Agents There are many diﬀerent approaches to the anesthetic care and intraoperative monitoring of the patient with CAD, depending upon the integration of patient- and surgery-speciﬁc

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factors [9]. The type of anesthesia used was not found to be an independent predictor of 30day mortality in a multivariate analysis [185]. There are three classes of anesthetics: general, regional, and local/sedation or monitored anesthetic care (M.A.C.). Outcome studies speciﬁcally addressing anesthetic technique in high-risk patients will be discussed after a review of the pharmacology of speciﬁc agents. General Anesthesia General anesthesia can best be deﬁned as a state including unconsciousness, amnesia, analgesia, immobility, and attenuation of autonomic responses to noxious stimulation, which can be achieved with inhalational agents, intravenous agents, or their combination. General anesthesia can be achieved with or without an endotracheal tube. Traditionally, laryngoscopy and intubation were thought to be the time of greatest stress and risk for myocardial ischemia, but recent studies suggest that extubation is the time of greatest risk [186]. There are ﬁve approved inhalational anesthetic agents in the United States, all of which have reversible myocardial depressant eﬀects and decrease myocardial oxygen demand, depending on their concentration and eﬀects on systemic vascular resistance and baroreceptor responsiveness (Table 5). Overall, there appears to be no one best inhalation anesthetic for patients with CAD. The available agents are brieﬂy reviewed below. Halothane is rarely used because of its slow onset and oﬀset and its association with hepatitis. Enﬂurane moderately decreases systemic vascular resistance and depresses baroreceptor function, while isoﬂurane is a more potent vasodilator and has minimal eﬀects on baroreceptor function. Isoﬂurane has become the most widely used anesthetic, even for patients with CAD. Isoﬂurane has vasodilating properties and has been shown to cause a coronary artery steal phenomenon leading to myocardial ischemia in an animal model [187], which led to concern for its use in patients with CAD [188]. However, several large-scale studies of these inhalational agents in patients undergoing CABG have not demonstrated any increased incidence of myocardial ischemia or infarction [189,190]. In a subsequent analysis, those patients who demonstrated steal-prone anatomy on coronary angiography did not have a higher incidence of myocardial ischemia [191]. Two newer inhalation agents, desﬂurane and sevoﬂurane, are available. Desﬂurane has the fastest onset and is commonly used in the outpatient setting, although it has been shown to be associated with airway irritability leading to tachycardia [192]. In a large-scale study comparing a narcotic-based anesthetic to desﬂurane, the desﬂurane group had a signiﬁcantly higher incidence of myocardial ischemia [193]. By including narcotics with desﬂurane, this tachycardia can be avoided. Sevoﬂurane is the newest approved agent for use in the United States. High-dose narcotics are an alternative form of anesthesia and oﬀer an advantage of hemodynamic stability and lack of myocardial depression [194]. The disadvantage is the requirement for postoperative ventilation. Recently, an ultra-short-acting narcotic (remifentanil) was introduced, negating the need for prolonged ventilation. There has been no diﬀerence in survival or major morbidity between a high-dose narcotic technique and inhalation-based technique. Therefore, most anesthesiologists use a ‘‘balanced’’ technique of lower doses of narcotics with an inhalational agent. An alternative anesthetic agent is intravenous propofol, which is an alkyl phenol that can be used for both induction and maintenance of general anesthesia. It can result in profound hypotension secondary to reduced arterial blood pressure with no change in

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Table 5 Clinical Qualities of Inhaled Anesthetics Agent Nitrous oxide

Halothane

Advantages Rapid uptake and elimination Minimal respiratory depression Minimal circulatory depression Odorless, nonpungent Potent anesthetic Nonpungent Stable heart rate

Enﬂurane

Stable heart rate Skeletal muscle relaxation

Isoﬂurane

Decreases cerebral metabolic rate

Desﬂurane

Cardiac output maintained Rapid uptake and elimination

Sevoﬂurane

Rapid uptake and elimination Nonpungent Less depression of myocardial contractility Stable heart rate

Disadvantages Supports combustion Expansion of closed air spaces Inactivates vitamin B12 Lack of anesthetic potency Requires preservatives Slow uptake and elimination Undergoes biotransformation Idiosyncratic hepatic necrosis Sensitization to catecholamineinduced cardiac dysrhythmias EEG seizure activity Depression of myocardial contractility Tachycardia at greater concentration Airway irritation Tachycardia with rapid increase in inspired concentration Requires specialized vaporizer for administration Expensive unless low ﬂows are used Reacts with CO2 absorbents Inorganic ﬂuoride release Expensive unless low ﬂows are used

heart rate. It has a rapid clearance with few residual eﬀects on awakening; however, it is expensive. Regional Anesthesia Regional anesthesia includes the techniques of spinal and epidural anesthesia, as well as peripheral nerve blocks. Peripheral techniques oﬀer the advantage of being associated with minimal or no hemodynamic eﬀects. In contrast, spinal or epidural techniques are associated with sympathetic blockade, which can lead to reduction in blood pressure, reﬂex sympathetic activation above the level of the blockade, and slowing of heart rate. The associated autonomic eﬀects of spinal anesthesia occur sooner than the same anesthetic agent administered epidurally. Since a catheter is usually left in place for epidural anesthesia, it can be more easily titrated. Improved outcomes have been demonstrated with a combined regional and general anesthetic approach for patients with CAD, particularly in patients undergoing vascular surgery [195]. One study noted a decreased incidence of allcause cardiac morbidity with no diﬀerence in acute MI or cardiac death in patients receiving combined general plus regional anesthesia for infrainguinal surgery [196]. Another study using epidural anesthesia for infrainguinal surgery followed by epidural analgesia versus

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general anesthesia plus postoperative intravenous patient-controlled analgesia showed no diﬀerence in cardiac morbidity between the two groups [197]. A third study randomized patients to epidural, spinal, and general anesthesia and found no diﬀerence in cardiac outcome [198]. Importantly, those patients who had a failed regional technique had the highest incidence of cardiac morbidity. An informal meta-analysis of these data suggest that no diﬀerence in cardiac morbidity could be detected between regional and general anesthesia [199]. The same ﬁndings are true for patients undergoing aortic surgery [200]. Local anesthesia monitored anesthesia care (M.A.C.) encompasses local anesthesia administration by the surgeon, both with or without sedation. In a large-scale epidemiological study, M.A.C. was associated with increased 30-day mortality in a univariate analysis, although it did not remain signiﬁcant in multivariate analysis [185]. The major concern with M.A.C. is the ability to adequately block the stress response, including tachycardia. Although M.A.C. can supplement analgesia, the ability to provide good local anesthesia is important.

Pulmonary Artery Catheterization Historically, pulmonary artery (PA) catheters were widely used in high-risk patients undergoing major noncardiac surgery, with the assumption that better understanding of cardiac ﬁlling pressures and cardiac output would lead to improved outcomes [201]. However, there have been several randomized studies in which placement of a PA catheter perioperatively did not alter cardiac morbidity [202–204]. More recent studies have shown a threefold increased incidence of major postoperative cardiac events [205,206] and a higher rate of pulmonary embolism in the PA catheter group than in those in the standard care group [206]. The American Society of Anesthesiologists advocates reserving use of the PA catheter for those circumstances in which there is a high-risk patient undergoing a high-risk surgery, when the PA catheter will make a diﬀerence in medical management [207].

Hemodynamic Changes Increases in heart rate cause increases in myocardial oxygen demand that can precipitate myocardial ischemia in patients with known CAD. Studies have supported a causal relationship between tachycardia and intraoperative myocardial ischemia [208]. Attenuation of the heart rate response and control of exaggerated sympathetic responses in the perioperative period may limit the development of myocardial ischemia and infarction.

Anemia Anemia has also been associated with an increased incidence of perioperative myocardial ischemia. In a small retrospective study of patients undergoing infrainguinal bypass surgery, a hematocrit <27% was associated with a signiﬁcantly increased risk of postoperative MI [209]. A higher rate of myocardial ischemia was noted in patients undergoing radical prostatectomy who had a hematocrit V28% compared to those with a higher hematocrit, although there was no diﬀerence in the rate of major morbidity [210]. Until deﬁnitive randomized trials are conducted to determine the value of preoperative transfusions, con-

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servative use of blood products is recommended, especially because of concerns of disease transmission [9]. Maintenance of Body Temperature Hypothermia has also been associated with an increased incidence of myocardial ischemia in vascular surgery patients [211]. In a randomized trial involving patients either undergoing vascular surgery or with known risk factors for CAD, use of forced air warming to maintain normothermia was associated with a signiﬁcant reduction in cardiac morbidity and myocardial ischemia for the ﬁrst 24 postoperative hours [212]. Therefore, maintenance of normothermia should be a goal of perioperative management. Perioperative Arrhythmias The incidence of arrhythmias during noncardiac surgery varies widely [76] and their prognostic importance is unclear [213]. High-grade atrioventricular block, symptomatic ventricular arrhythmias in the presence of underlying heart disease, and supraventricular arrhythmias with an uncontrolled ventricular response are considered major clinical predictors of increased perioperative risk [10]. The management of perioperative ventricular arrhythmias is not well studied and is generally considered to be the same as that for the nonsurgical patient. Reversible causes such as electrolyte disturbances, acid–base abnormalities, or decompensated CHF should be corrected. A search for underlying cardiac or pulmonary disease or for potential drug toxicity is essential. Signiﬁcant perioperative ventricular arrhythmias do not often require therapy unless they are associated with myocardial ischemia, signiﬁcant valvular disease, left ventricular dysfunction, or hemodynamic compromise [10]. No studies support the suppression of preoperative arrhythmias with antiarrhythmics to reduce surgical morbidity and mortality. The use of perioperative beta-blockers may be beneﬁcial [76]. One study in patients undergoing noncardiac surgery showed that major ventricular arrhythmias (>30 ventricular ectopic beats/h or ventricular tachycardia) detected with the use of continuous ECG monitoring occurred in 44% of patients and were not associated with clinical symptoms [213]. Patients with CHF, ECG evidence of MI, or a history of tobacco use had a higher incidence of preoperative arrhythmias. Nonfatal myocardial ischemia or cardiac death was not more frequent in patients with these arrhythmias so that aggressive perioperative therapy may not be required. Surveillance for Perioperative MI The optimal and most cost-eﬀective strategy for monitoring high-risk patients for major cardiac morbidity after noncardiac surgery is unknown. Postoperative myocardial ischemia or infarction is often clinically silent, most likely due to the confounding eﬀects of analgesics. Creatine kinase (CK)-MB has been shown to be less speciﬁc than cardiac troponins for the detection of MI postoperatively [214]. Non-ST-elevation MI occurs more often than ST-elevation MI perioperatively [52,215]. In one study of diabetic and hypertensive patients, a postoperative daily ECG plus symptom-directed CK-MB isoenzymes yielded the best sensitivity and speciﬁcity for detecting MI [216]. Myocardium-speciﬁc enzymes such as cardiac troponins (I or T) are quite sensitive in the detection of perioperative MIs. In one study of patients undergoing high-risk surgery,

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eight patients sustained a perioperative MI, as conﬁrmed by the presence of new segmental wall motion abnormalities, and all had elevations of cardiac troponin I, while six patients had elevated CK-MB [217]. Troponin I had a speciﬁcity of 99%, while CK-MB had a speciﬁcity of 81%. Other studies have conﬁrmed the clinical utility of cardiac troponins in the perioperative setting [218,219]. Traditionally, perioperative MI was associated with a 30 to 50% short-term mortality [6,220]. With greater perioperative surveillance, more asymptomatic myocardial infarctions are being detected. More recent series have reported that perioperative MI is associated with a short-term mortality of up to 20% [51,52]. One study demonstrated signiﬁcantly worse survival in those patients who sustained a perioperative cardiac event compared to those who did not [221]. A retrospective study of a cohort of patients who underwent major vascular surgery found that survival was signiﬁcantly less for those patients who had a symptomatic perioperative myocardial infarction [222]. By contrast, asymptomatic MI, diagnosed by elevated cardiac enzymes, was not associated with worse survival. Elevated troponin-T levels have been shown to be associated with an increased incidence of cardiovascular complications within 6 months of surgery [223]. In a study of patients undergoing vascular surgery, where cardiac troponin I levels were measured immediately after surgery and on three consecutive postoperative days, 12% had elevated troponin I levels, which was associated with a sixfold increased risk of 6-month mortality and a 27-fold increased risk of MI [224]. Further research will be required to determine the implications of elevated postoperative cardiac enzymes on outcomes. The ACC/AHA guidelines recommend the use of cardiac biomarkers for patients at high risk and those with clinical, ECG, or hemodynamic evidence of cardiovascular dysfunction [10].

POSTOPERATIVE ANALGESIA If postoperative tachycardia and catecholamine surges lead to cardiac events, the more intense analgesia regimens may be beneﬁcial in improving perioperative outcomes. Additionally, there is growing interest in the role of postoperative analgesia in reducing the hypercoagulable state. Several studies comparing general with regional anesthesia have demonstrated reduced platelet aggregability in the epidural group [196,225]. Future research will focus on how to best deliver postoperative analgesia.

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deFilippi C, Willett D, Brickner M, Appleton C, Yancy C, Eichhorn E, Grayburn P. Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am J Cardiol 1995; 75:191–194. 172. Otto C, Mickel M, Kennedy J, Alderman E, Bashore T, Block P, Brinker J, Diver D, Ferguson J, Holmes D, Lambrew C, McKay C, Palacios I, Powers E, Rahimtoola S, Weiner B, Davis K. Three-year outcome after balloon aortic valvuloplasty: insights into prognosis of valvular aortic stenosis. Circulation 1994; 89:642–650. 173. Nishimura R, Holmes D Jr, Reeder G, Orszulak T, Bresnahan J, Ilstrup D, Tajik A. Doppler evaluation of results of percutaneous aortic balloon valvuloplasty in calciﬁc aortic stenosis. Circulation 1988; 78:791–799. 174. Litvack F, Jakubowski A, Buchbinder N, Eigler N. Lack of sustained clinical improvement in an elderly population after percutaneous aortic valvuloplasty. Am J Cardiol 1988; 62:270–275. 175. Levine M, Berman A, Saﬁan R, Diver D, McKay R. Palliation of valvular aortic stenosis by balloon valvuloplasty as preoperative preparation for noncardiac surgery. Am J Cardiol 1988; 62:1309–1311. 176. Holmes D, Nishimura R, Reeder G. In-hospital mortality after balloon aortic valvuloplasty: frequency and associated factors. J Am Coll Cardiol 1991; 17:189–192. 177. Isner J. Acute catastrophic complications of balloon aortic valvuloplasty. J Am Coll Cardiol 1991; 17:1436–1444. 178. Wilkinans G, Weyman A, Abscal V, Black P, Palacios I. Percutaneous mitral valvotomy: analysis of echocardiographic variables related to outcome and the mechanism of dilatation. Br Heart J 1988; 60:299–308. 179. Palacios I, Tuzcu M, Weyman A, Newell J, Block P. Clinical follow-up of patients undergoing percutaneous mitral balloon valvotomy. Circulation 1995; 91:671–676. 180. Vongpatanasin W, Hillis L, Lange R. Prosthetic heart valves. N Engl J Med 1996; 335:407–416. 181. Braunwald E, ed. Valvular Heart Disease. 5th ed. Philadelphia: WB Saunders, 1997. 182. Chesebro J, Adams P, Fuster V. Antithrombotic therapy in patients with valvular heart disease and prosthetic heart valves. J Am Coll Cardiol 1986; 8:41B–56B. 183. Stein P, Alpert J, Copeland J, Dalen J, Goldman S, Turpie A. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1992; 102:445S–455S. 184. Gohlke-Barwolf C, Acar J, Burckhardt D, Oakley C, Butchart E, et al. Ad Hoc Committee of the work group on valvular heart disease, European Society of Cardiology. Guidelines for prevention of thromboembolic events in valvular heart disease. J Heart Valve Dis 1993; 2:398–410. 185. Cohen M, Duncan PG, Tate RB. Does anesthesia contribute to operative mortality? JAMA 1988; 260:2859–2863. 186. Abalos A, Leibowitz AB, Distefano D, Halpern N, Iberti TJ. Myocardial ischemia during the weaning period. Am J Crit Care. 1992;1:32–36. 187. Buﬃngton CW, Romson JL, Levine A, Duttlinger ND, Huang AH. Isoﬂuorane induces coronary steal in a canine model of chronic coronary occlusion. Anesthesiology 1987;66:280–292. 188. Becker LC. Is isoﬂurane dangerous for the patient with coronary artery disease? [editorial]. Anesthesiology 1987; 66:259–261. 189. Slogoﬀ S, Keats AS. Randomized trial of primary anesthetic agents on outcome of coronary artery bypass operations. Anesthesiology 1989; 70:179–188. 190. Leung JM, Goehner P, O’Kelly BF, Hollenberg M, Pineda N, Cason BA, Mangano DT. Isoﬂurane anesthesia and myocardial ischemia: comparative risk versus sufentanil anesthesia in patients undergoing coronary artery bypass graft surgery. The SPI (Study of Perioperative Ischemia) Research Group. Anesthesiology 1991; 74:838–847. 191. Slogoﬀ S, Keats AS, Dear WE, Abadia A, Lawyer JT, Moulds JP, Williams TM. Steal-prone coronary anatomy and myocardial ischemia associated with four primary anesthetic agents in humans. Anesth Analg 1991; 72:22–27.

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192. Ebert TJ, Muzi M. Sympathetic hyperactivity during desﬂurane anesthesia in healthy volunteers. A comparison with isoﬂurane. Anesthesiology 1993; 79:444–453. 193. Helman JD, Leung JM, Bellows WH, Pineda N, Roach GW, Reeves JDd, Howse J, McEnany MT, Mangano DT. The risk of myocardial ischemia in patients receiving desﬂurane versus sufentanil anesthesia for coronary artery bypass graft surgery. The S.P.I. Research Group. Anesthesiology 1992; 77:47–62. 194. Lowenstein E, Hallowell P, Levine FH, Daggett WM, Austen WG, Laver MB. Cardiovascular response to large doses of intravenous morphine in man. N Engl J Med 1969; 281:1389–1393. 195. Yeager MP, Glass DD, Neﬀ RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in highrisk surgical patients. Anesthesiology 1987; 66:729–736. 196. Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel RV, Ivankovich AD. Eﬀects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 1991; 73:696–704. 197. Christopherson R, Beattie C, Frank SM, Norris EJ, Meinert CL, Gottlieb SO, Yates H, Rock P, Parker SD, Perler BA, et al. Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology 1993; 79:422–434. 198. Bode RH Jr, Lewis KP, Zarich SW, Pierce ET, Roberts M, Kowalchuk GJ, Satwicz PR, Gibbons GW, Hunter JA, Espanola CC. Cardiac outcome after peripheral vascular surgery. Comparison of general and regional anesthesia. Anesthesiology 1996; 84:3–13. 199. Go AS, Browner WS. Cardiac outcomes after regional or general anesthesia. Do we have the answer? [editorial]. Anesthesiology 1996; 84:1–2. 200. Baron JF, Bertrand M, Barre E, Godet G, Mundler O, Coriat P, Viars P. Combined epidural and general anesthesia versus general anesthesia for abdominal aortic surgery. Anesthesiology 1991; 75:611–618. 201. Berlauk JF, Abrams JH, Gilmour IJ, O’Connor SR, Knighton DR, Cerra FB. Preoperative optimization of cardiovascular hemodynamics improves outcome in peripheral vascular surgery: a prospective, randomized clinical trial. Ann Surg 1991; 214:289–297. 202. Joyce WP, Provan JL, Ameli FM, McEwan P, Jelenich S, Jones DP. The role of central haemodynamic monitoring in abdominal aortic surgery: a prospective randomized study. Eur J Vasc Surg 1990; 4:633–636. 203. Isaacson IJ, Lowdon JD, Berry AJ, Smith RBd, Knos GB, Weitz FI, Ryan K. The value of pulmonary artery and central venous monitoring in patients undergoing abdominal aortic reconstructive surgery: a comparative study of two selected, randomized groups. J Vasc Surg 1990; 12:754–760. 204. Bender J, Smith-Meek M, Jones C. Routine pulmonary artery catheterization does not reduce morbidity and mortality of elective vascular surgery: results of a prospective, randomized trial. Ann Surg 1997; 226:229–236. 205. Polanczyk CA, Rohde LE, Goldman L, Cook EF, Thomas EJ, Marcantonio ER, Mangione CM, Lee TH. Right heart catheterization and cardiac complications in patients undergoing noncardiac surgery: an observational study. JAMA 2001; 286:309–314. 206. Sandham JD, Hull RD, Brant RF, Knox L, Pineo GF, Doig CJ, Laporta DP, Viner S, Passerini L, Devitt H, Kirby A, Jacka M. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 2003; 348:5–14. 207. Anonymous. Practice guidelines for pulmonary artery catheterization. A report by the American Society of Anesthesiologists Task Force on Pulmonary Artery Catheterization. Anesthesiology 1993; 78:380–394. 208. Mangano DT, Goldman L. Preoperative assessment of patients with known or suspected coronary disease. N Engl J Med 1995; 333:1750–1756. 209. Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med 1993; 21:860–866.

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32 Ethical Decisions and Quality of Life in Older Patients with Cardiovascular Disease Lofty L. Basta Clearwater Cardiovascular and Interventional Cardiovascular Consultants and Project GRACE, Clearwater, Florida, U.S.A.

Henry D. McIntosh Lakeland, Florida, U.S.A.

Death is the only certainty in life. Doctors have to learn to allow their patients to make the most out of their living but not to ﬁght dying. It is the job of a good physician to guide his patients’ health and as long as a measure of happiness is achievable, and to make their passing comfortable and digniﬁed when death is near and unavoidable [1]. After all, life is measured by the richness of its experiences rather than by the length of its days. It is not a great achievement to prolong the years of mindless existence in a state deemed by the patient to be a fate worse than death [2]. Research ought to focus on prolonging life worth living. The World Health Organization has shown that the health care of Americans cost three times that of the British ($4200 versus $1400 per year) per individual per year. Americans live an average of 76 years, of which less than 70 is independent. By contrast, the British live an average of more than 77 years, of which more than 70 years are spent in independent worthwhile living. The Japanese live more than an average of 80 years, more than 75 of which are independent living, and less than 5 years spent in institutionalized, dependent care. In Japan, the country that has the best health-care, the cost per individual is $2300 per year [3]. More dollars do not equate to more health. The United States may have the best doctors and hospitals, and the most advanced technology, but not the best health-care system [4]. The 2000 report of the World Health Organization ranked the U.S. health-care system at thirty-seventh of the nations—somewhere between Costa Rica and Slovania—is based upon dollars spent in relation to the health care provided. Ten percent of American children lack basic health coverage and more than 15% of American citizens lack health insurance. Furthermore, review of multiple textbooks reveals that a minority of them have chapters on end-of-life medical care although they may show ﬁgures of mortality in subsets of patients with certain organ system disease [5]. This is a mistake that needs to be addressed and corrected by the medical establishment. In this chapter, we shall focus attention on how ethical factors can and should inﬂuence the management of cardiovascular disease in elderly individuals. But we shall 811

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also urge thoughtful and caring physicians, regardless of their practice orientation or the age of their patients, to direct attention to identifying or ruling out the presence of cardiovascular diseases or risk factors thereof. Once identiﬁed, the caring physician should initiate eﬀorts to minimize the potentially adverse eﬀects of these factors in ALL their patients and in society at large.

PREVENTIVE EFFORTS Most cardiovascular diseases can be classiﬁed as epidemic [6]. Therefore, the occurrence of such diseases should likely be preventable or modiﬁable, provided the individual recognizes early enough the existence of potentially serious adverse lifestyles and resolves to correct them. Such a goal is more likely to be attained if all physicians involved in a individual’s care focus attention on obesity, lack of physical activity, and smoking. According to Massie [7], 60% of adults in the United States are obese. Clearly, an eﬀort should be made, at any age, to reduce, if not eradicate, the obesity and other adverse lifestyles. It would obviously be highly desirable if the physician did not possess the adverse lifestyle (i.e., obesity, morbidly sedentary lifestyle, or smoking) when counseling the patient. Members of the medical profession should obviously seek to ‘‘heal themselves.’’ With little additional eﬀort, the presence of signiﬁcant hypertention can be documented. No longer can even a midly elevated systolic blood pressure (BP), even in older persons, be considered a ‘‘normal’’ or a ‘‘physiological’’ component of the aging process. This conclusion has been reached despite more than one-half of individuals, aged 65 years or older, having a BP z 140/90 mmHg [8]. The persistence of such elevated a pressure should not be ignored. Rather, the potential cause should be sought and, when identiﬁed, the appropriate therapy should be introduced. The Framingham data indicate that the risk of coronary heart disease increases, even with lower diastolic BP, at levels of systolic BP z 120 mmHg [9]. If not already established or ruled out, impaired glucose tolerance and/or dyslipidemia should be identiﬁed or excluded by scheduling appropriate studies [6]. The sooner appropriate therapy for such an adverse risk factor is initiated, the better the patient’s quality of life. If a physician does not have the necessary time or is not qualiﬁed to render the indicated care, that physician should refer the patient to an appropriate caregiver who can institute the necessary therapy to prevent the progression of an epidemic cardiovascular disease. Clearly, prevention of cardiovascular disease is more beneﬁcial than treatment of the complications of an adverse cardiovascular process years later. Doctors should not ignore the beneﬁcial assistance they can oﬀer to patients even if they are only responsible for limited care of given patients. Also, health-care systems should approve the added cost of evaluation consultations, including special studies.

EVOLUTION OF THE PRACTICE OF INFORMED CONSENT Now the keystone to the ethical consideration of informed consent in the practice of medicine evolved from the use of human subjects in clinical investigation. Today the patient

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must be informed as to procedures and expected outcomes of the procedures, and consent must be given to proceed with the outlined plan. This practice was not required prior to 1973 [10]. That year, to insure that this practice would become established, Senator Edward Kennedy introduced legislation to establish the National Commission for the Protection of Human Subjects. Soon thereafter, the Doctrine of Informed Consent was established [10,11]. During the early 1970s it became accepted by members of both the medical profession and society at large that all the knowledge and skills that had been acquired did not have to be used in all individuals at all times: not all births were a blessing and sometimes death could be a blessing. Furthemore, it became clear that society at large was not willing to let physicians have unlimited supremacy in caring for all medical problems. Assistance from the courts was sought to resolve many areas of conﬂict and even to deﬁne the authority of physicians under certain conditions.

COURTS RESOLVE MEDICAL CONFLICTS In the early 1970s, many physicians as well as lay people questioned whether all pregnancies should be guided toward a full-term delivery. For example, should an infant in vitro, with serious structural and/or functional abnormalities, be delivered prematurely with the goal of spontaneous death or should society and/or physicians demand that every eﬀort be made to maintain the fetus in vitro, seeking a full-term birth and survival, even with an anticipated markedly compromised quality of life. Until that time it was widely accepted that ‘‘everything possible’’ should be done to preserve all life, including that of an unborn, deformed fetus [12]. This question was ﬁnally considered by the U.S. Supreme Court, under the legal action of Roe v. Wade. The court ruled that ‘‘a woman has the right to an abortion without interference from the government in the ﬁrst trimester of pregnancy.’’ Furthermore, the court concluded that ‘‘it is a part of her right to privacy,’’ although the court maintained that the ‘‘right to privacy is not absolute.’’ Furthermore, the court granted the States the right to intervene in the second and third trimesters of pregnancy. Since then, many States have established laws regarding interruption/protection of pregnancy in the second and third trimesters [11]. The complexity of care for an individual with persistent loss of consciousness was recorded in the terminal history of Karen Ann Quinlan. On the night of April 15, 1975, that 22-year-old woman suddenly slipped into a coma and was admitted to a New Jersey hospital emergency department [11,13]. Some evidence suggested that the coma evolved as a result of ingesting a combination of prescription medication and alcohol [14]. Shortly after admission to the hospital, the patient was placed on a respirator. After several months of hoping against hope, the patient’s parents asked the physician to take their daughter oﬀ the respirator. The Quinlans were practicing Catholics and had sought guidance from the Church regarding continuous use of the respirator. They were told by their priest that the respirator could be deﬁned as ‘‘extraordinary care’’ and that returning Karen to her ‘‘natural state,’’ (i.e., taking her oﬀ the respirator) was a morally correct action, even if she should die [13]. The primary physician at ﬁrst agreed to remove the respirator, but then feared that if Karen died there could be legal ramiﬁcations of his actions. He therefore refused to remove the assist device.

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The Quinlans asked a lower court in New Jersey to order the physician and the hospital to remove the respirator, but the court refused to accept the case. So the Quinlans sought help from the Supreme Court of the State of New Jersey. That court heard the case in June 1976 and agreed that the family did have the right to order that the respirator be removed. This was the ﬁrst time that a court gave orders regarding the therapy for a speciﬁc patient that did not support the order of the physician. Ms. Quinlan survived in a comatose state for 9 years after removal of the respirator. The clinical course demonstrates how diﬃcult it can be, even for highly qualiﬁed physicians, to predict when death will actually occur. This was indeed a landmark case. It involved not just the patient’s right to die or the concept of living wills. It involved a far more basic issue—who rules at the bedside [13]? Indeed, the Quinlan case was a contest between physicians, on the one hand, and patients and families and legal advisors on the other. Until that case, the physician was presumed to represent the patient. As a result of the Quinlan case, the court and the lawyers became the spokespersons and the respirator was removed against the doctor’s wish. The New Jersey Supreme Court referred to the fact that 3 years earlier, in the Roe v. Wade decision, the United States Supreme Court had reduced the supremacy of the physician. The Court stated that: Presumably the Right to Privacy is broad enough to encompass a patient’s decision to decline medical treatment under such circumstances, in much the same way that it is broad enough to encompass a woman’s decision to terminate pregnancy under certain conditions.

One additional landmark case should be cited [11,14–16] Nancy Cruzan, a woman in her twenties, lost control of her car in 1983. The vehicle overturned and Ms. Cruzan was found lying face down in a ditch, without detectible respiratory or cardiac function. It was later estimated that she had been deprived of oxygen for about 12 to 14 mins. Paramedics were able to restore her respiratory function and she was taken to a hospital and given maximum acute care. She remained in a coma for 3 weeks and then progressed to a conscious state and was able to ingest nutrients. But she did not relate intelligently to her environment and was diagnosed as being in a persistent vegetative state. A gastrostomy tube was implanted to improve her nutrition. After several weeks, the parents asked the hospital authorities to remove the tube and let their daughter die peacefully [17]. The remaining life of Nancy Cruzan will be described in some detail because it emphasizes the importance of a person, even in her twenties, having an advance care plan. Nancy had completed no such document, but she allegedly had made statements to a friend and roommate that she ‘‘would not want to live as a vegetable.’’ The parents were conﬁdent that indeed Nancy would rather die than live as she was. But the doctors and hospital authorities refused to honor the parents’ request without court approval, which was sought by the parents. The trial court approved termination of the stomach tube. But that decision was contested, and the case was taken to the United States Supreme Court. That court accepted the Missouri court’s decree and stated that individual states do have the right to demand that a person must have life-sustaining treatment if, while competent, that person established clearly and convincingly that he or she would not want to be kept alive by artiﬁcial means. Thus, because Ms. Cruzan had no advance directive, she had to continue to receive artiﬁcial hydration and nutrition and continue to exist in a vegetative state.

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Despite the lack of support by the U.S. Supreme Court, the parents persisted with their desire to terminate the life of their comatose daughter. They identiﬁed new, more persuasive witnesses. The parents then took the case back to the original trial court in Missouri. After hearing the testimony from the new witnesses, the Judge ruled that there was now clear and convincing evidence that Ms. Cruzan would not want to continue to live in a vegetative state. The gastrostomy tube, which had kept the patient alive for 7 years, was removed and 12 days later Ms. Cruzan died. The activities related to Ms. Cruzan had been widely publicized. Large segments of society favored removal of the tube and possibly hastening death, while many others favored maintaining nutrition and maintaining life even if in a vegetative state. As a result, when Nancy Cruzan died in the Missouri Rehabilitative Center, 35 armed guards patrolled the premises to keep the euthanasia opponents, who were camped outside, from breaking into Nancy Cruzan’s room to forcefully reinsert the tube. The police arrested 19 individuals who had stormed the center in an attempt to ﬁnd Ms. Cruzan’s room. Several relevant cases that came before the American courts were treated similarly. Even Nancy Cruzan was allowed to die peacefully upon withdrawal of life support. Soon after the Supreme Court hearings, the State of Missouri withdrew from the Cruzan case, stating, ‘‘It has no interest in the outcome of this litigation.’’ The Missouri law was changed by the state legislature and no longer requires the ‘‘clear and convincing evidence’’ standard. This was welcomed legislation that received wide support from the citizens and the media, and provided a welcome relief to the Cruzan family. In spite of the seemingly conﬂicting court rulings on this issue of futile care, it must be stated that no physician has ever been indicted, let alone convicted, for withholding care deemed unnecessary by reasonable medical standards. This may seem odd when one considers the prevailing view among practicing physicians that they should overtreat patients for fear of legal repercussions. In the case of People v. Barber, heard by a Los Angeles court in 1983, nurses complained to the state prosecutor that physicians withdrew treatment, including feeding and hydration, from a terminally ill patient and ‘‘watched him die’’ [18]. The court dismissed this case on the basis that there was no evidence in the record to show that the defendants were acting either in a malignant, selﬁsh, or foolhardy manner to take the life of another. In this case, we do not have willful starvation as the proximate cause of the patient’s death. To say that the attending physician sat back and watched a person starve to death is to ignore the state of bad health of the patient, Mr. Herbert.

In no case was the support for the physician withholding treatment as strong as in the case of Spring v. Massachusetts Supreme Judicial Court in 1980 [19]. In this case, the court not only upheld that an incompetent person has the same right to respect, dignity, and freedom of choice as competent people, but also took upon itself to send a message to treating physicians: ‘‘. . .little need be said about criminal liability; there is precious little precedent, and what there is suggests that the doctor will be protected if he acts in a good faith judgment that is not grievously unreasonable by medical standards.’’ The legal scholar, Dr. Allan Meisel, Professor of Law and Medicine at the University of Pittsburgh and the author of Right to Die legal compendium in 1989, summed up a developing legal consensus in an article in 1992 [20]. He indicated that the bulk of court opinions have been generally supportive of a general principle that determination of the futility of care is a decision to be made by the medical profession. Artiﬁcial feeding and nutrition are treated no diﬀerently from other intrusive medical treatments when it comes to

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end-of-life care. This is explicit in the Supreme Court ruling regarding Cruzan. These opinions would suggest that physicians are under no obligation to seek consent from patients or families before withholding or withdrawing care that is deemed ineﬀective. Also, physicians are not exposing themselves to legal liability if their decision is reasonable by conventional medical standards. But obviously, a caring, thoughtful physician would keep responsible members of the patient’s family informed about such important decisions. One of the lessons learned from the Supreme Court discussions is that if Ms. Cruzan had had a routine living will, it would not have altered the course of action for her in Missouri or in many other states. It is of interest that the United States Supreme Court rejected the wishes of the family to terminate life support of Ms. Cruzan by a split vote of 5:4. In dissenting, Justice William J. Brennan stated eloquently [14]: Too few people execute living wills or equivalent formal directives for such an evidentiary rule to ensure adequately that the wishes of an incompetent person will be honored. When a person tells family or close friends, however, that she does not want her life sustained artiﬁcially, she is expressing her wishes in the only terms familiar to her. To require more is unrealistic for all practical purposes. It precludes the rights of the patient to forgo life-sustaining treatment.

Teno et al. [15] summed it up by saying that a minority of Americans execute living wills, 50% of those who elected to forego cardiopulmonary resuscitation (CPR) have no such orders on their chart and almost 90% have living wills that are not medical scenariospeciﬁc. People die from potentially reversible disease even if they have a terminal condition. Most die of a fractured hip, cardiopulmonary arrest, or pneumonia, all of which are potentially reversible. The Project GRACE Advance Care Plan is medical scenario-speciﬁc and enables primary-care physicians to make the right choices that patients have chosen for themselves at the end of life [14]. It should be noted that it was and is usually considered that living wills are intended for members of the older segment of our society. But Nancy Cruzan was in her twenties when she needed it [14]. A living will that does not tell us whether to treat your pneumonia by machines when you have advanced dementia (you do not recognize yourself, environment, and loved ones, irretrievably and terminally) is worthless. There are now many that urge all individuals, 18 years and older, to have a well-documented Advance Care Plan [21–23]. These and other similar cases prompted, Dr. Lofty L. Basta to focus on the complexities of facing death and managing dying individuals. He recorded many of his observations under the title of ‘‘Life and Death on Your Own Terms’’ [14]. This publication prompted us to organize a State of Florida based Consensus Development Conference to lay the groundwork for the evolution of a document stating the individual’s wishes for care at the end of life [21,22]. This document contains an Advance Care Plan that can be adopted by an individual to instruct their doctor(s) and other health-care providers on how they wish to be treated during the last days of their life should they develop: (1) an unconscious state; (2) permanent confusion; (3) total dependence; and (4) an end-stage disease or other debilitating end-stage condition(s). Would the individual, when experiencing any of the stated conditions, wish or not wish to receive cardiopulmonary resuscitation (CPR), surgery, blood, antibiotics or tube feeding? Furthermore, the document indicates the need for identifying, the name, address, and telephone numbers of a surrogate for health-care aﬀairs.

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The usefulness of the document, after excessive testing, has been widely accepted and is easily available [21,22]. An individual’s wishes for care at the end of life, as stipulated on the document, can be stored for immediate access at an Emergency Information Storage Center [23]. Clearly, now when an individual has indicated that he/she would welcome a graceful exit, that individual, if admitted to a hospital, should have included in the orders for management a Do Not Resuscitate (DNR) order.

SUDDEN CARDIAC DEATH Sudden cardiac death is a common occurrence. It is well established that the mechanism in the vast majority of individuals is due to a ventricular tachyarrhythmia, principally ventricular ﬁbrillation [24]. With the absence of any eﬀective contraction of the ventricle of the heart, there is no cardiac output. Thus, there is a total absence of blood ﬂow and tissue perfusion and no supply of glucose or oxygen resulting in profound ischemia. If prolonged, cellular and tissue damage occurs; after approximately 4 mins, cellular damage becomes irreversible and death of tissue and the patient ensues, unless there is prompt restoration of organized electrical activity and eﬀective pumping action with resumption of tissue perfusion with a suﬃcient supply of oxygen. Deﬁbrillation, with resumption of an eﬀective cardiac rhythm, can frequently be accomplished by an appropriately applied electrical shock. But the success of the procedure lessens as the seconds become minutes. A key to successful CPR is reestablishing and maintaining a patent airway and providing artiﬁcial ventilation by means of rescue breathing and maintaining artiﬁcial circulation by means of external compression. The interval between onset of cardiac arrest and the restoration of normal cardiac rhythm will determine the success of the deﬁbrillation and the extent of neurological damage as well as achievement of long-term survival. It is of interest that Bernard Lown [25], in 1979, reported that 350,000 to 500,000 persons died in this country each year as a result of sudden cardiac arrest. But by 1990, the National Heart, Lung and Blood Institute reported that, despite the expanding aging population, the incidence of such sudden deaths had been reduced to 300,000 per year [26]. This gratifying reduction was due to the reduction of the incidence of potentially fatal arrhythmias and the correction of the serious arrhythmia that did develop by timely deﬁbrillation. Clearly, the potentially corrective measures that were previously described should be instituted as promptly as possible. For not only is successful resuscitation and long-term survival of a patient dependent on the age of the patient, the nature and extent of the underlying heart disease and the presence and severity of other chronic disease states, such as hypertension, diabetes, renal and liver disease, and central nervous system dysfunction, but the duration of the ventricular ﬁbrillation [26].

DO NOT RESUSCITATE For many individuals, a sudden, essentially painless, death might be a highly desirable event, if not even a blessing. Such would be the case for a patient with widespread carcinoma or extensive neurological impairment.

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In 1974, the American Heart Association proposed that in some individuals with advanced debilitating diseases there should be documented, in the patient’s record, a DNR order [13]. In 1976, the Clinical Care Committee of the Massachusetts General Hospital developed recommendations for the treatment of hopelessly ill patients and for orders not to resuscitate [27]. The DNR orders intended that, in the event that the heart stopped contracting or the lungs ceased to function, no eﬀort should be undertaken to revive the heart or place the patient on an assisted ventilation device. The patient’s chart should be clearly marked to indicate the plan. But it should be noted that the Committee determined that DNR orders were appropriate only when the patient’s disease had fulﬁlled all three of the following criteria: 1. 2.

3.

The disease is ‘‘irreversible’’ in the sense that no known therapeutic measures can be eﬀective in reversing the course of the illness. The physical status of the patient is ‘‘irreparable’’ in the sense that the course of illness has progressed beyond the capacity of existing knowledge and techniques to stem the process. The patient’s death is ‘‘imminent’’ in the sense that in the ordinary course of events, death will occur within a period not exceeding 2 weeks.

The Committee also stipulated that the initial medical judgment regarding DNR orders be made by the physician primarily responsible for the patient’s care, after discussion with an ad hoc committee consisting not only of the other physicians attending the patient, nurses, and other health-care professionals active in the care of the patient, but also of at least one other staﬀ physician not previously involved in the patient’s care [27]. Even with the medical staﬀ’s recommendation, the Committee deemed that a DNR order would become eﬀective only upon the informed choice of a competent patient. If the patient was incompetent, all appropriate family members must be in agreement with the views of the involved staﬀ. Clearly, those guidelines represented a tremendous burden on the treating physician so they were rarely followed to the letter. But it became clear that unanimous approval of all involved family members was highly desirable. Experience has shown that in considering CPR for a given patient, it should be used only for those patients who have a good chance of being restored to a conscious living state in which some degree of autonomy, even if limited, can be anticipated [24]. The decision to undertake CPR can be a diﬃcult one to make for a physician or other healthcare provider. Clearly, the practice of both inpatient and out-of-hospital CPR created considerable discussion and in many instances conﬂict between those favoring and those disapproving the practice. The courts were not infrequently called upon to resolve conﬂicting opinions regarding the practice of DNR. But the success of attempts to resuscitate is not great. Schneider and coworkers [28] reported a meta-analysis of 98 reports involving in-hospital CPR performed on 19,955 patients. Fifteen percent of the patients survived to be discharged from the hospital. Thompson and coworkers [29] reviewed data on 316 patients with an average age of 63 years who were treated in the Seattle Heart Watch Program. They reported 117 patients (37%) died prior to hospitalization (at the scene, in the ambulance, or in the emergency room); 106 patients (34%) died in the hospital despite successful resuscitation. Thus, only

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93 patients (29%) of the original patients who were successfully resuscitated lived to survive hospitalization and be discharged. Physicians are trained from their earliest medical experience to act in favor of sustaining life. But this objective can conﬂict with another fundamental objective of medicine, the relief of suﬀering. So it is not surprising that for many years the public was not urged by physicians to establish such directives regarding their preference for treatment as death became imminent. But the physician should have a frank and open discussion with not just elderly patients, but all patients and family member designated to assume the role of decision maker for the patient about the matter of attempting resuscitation if a cardiac arrest evolve [21,30]. Current policies in most hospitals will require statements regarding such treatment to be included in the orders of the patient’s hospital chart. But they do not need to be as detailed as those recommended by the Massachusetts General Hospital in 1976 [14]. To sum it up, roughly 5% of all victims of cardiac arrest, 3% of those over age 65 and 1 to 2% of the frail elderly, are rescued with CPR outside the hospital. In the hospital, CPR is three times as successful (as out-of-hospital CPR), depending upon where it is conducted and the morbid status of the patient. It remains to be seen whether prudential well thought-out decisions by informed citizens support or refute the presumed consent hypothesis for CPR and life support interventions under these circumstances. Wagg et al. [31] have shown that physicians and nurses in America and in Britain estimate a success rate of at least double the actual number of in-hospital resuscitation. Add to this the misinformation provided by television to the public of a success rate of almost 70% [32]. This leads to exaggerated promises from health-care providers and unrealistic expectations by the lay public, all of which inevitably lead to unreasonable demands followed by disappointments and blame seeking when loved ones are lost. When the frail elderly are informed that only 1 to 2% survive after out-of-hospital resuscitation, many opt to forego CPR when they suﬀer cardiopulmonary arrest in a nursing home or wherever they spend their ﬁnal days [33]. It is hoped, however, that most individuals have given careful thought to the adoption of an Advance Care Plan. As has been indicated, Project GRACE has made available such a form [14,21,22]. This should become a part of each individual over 16 years’ important personal papers and medical/hospital records. Each caring physician should have a frank discussion with the patient and responsible relatives about their wishes for treatment should death become imminent and establish appropriate documents [21–23].

EUTHANASIA Similar diﬃculties by men of zeal, well-meaning but with poor understanding, came in the way of elective legislation for physician-assisted suicide in the states of Washington and California. In 1995, Oregon for the second time, ratiﬁed the Death with Dignity Act. In 1997, the United States Supreme Court ruled that American citizens do not have a constitutional/liberty right to physician-assisted suicide. The court further stipulated that states are free to ban it or to permit it. Oregon has chosen to permit physician-assisted suicide in certain circumstances. The Oregon ‘‘Death with Dignity Act,’’ passed in October 1997 [34], allows the physician who has primary responsibility for managing a patient’s terminal illness to prescribe a dose of lethal medication that the patient may administer provided certain conditions are met: death, conﬁrmed by a consultant, should be expected

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within 6 months. Also, the patient must make two oral requests and one written request for assisted suicide over a period of 15 days. Referral to a mental health professional is required if either the attending physician or the consultant is concerned that the patient’s judgment may be impaired by a mental disorder. In 1998, 24 Oregonians were given prescriptions for lethal doses of medication. Of these, 16 died after ingesting their medicine [35]. The rest either died naturally without taking the lethal medicine or elected not to take it at all. In 1999, of 33 Oregonians who were given such prescriptions, 27 took their own lives. Participation was not found to be associated with low educational level, lack of health insurance, or poor access to hospice care. Only 12% of the 1998 patients were married, raising concern that physician-assisted suicide would be asked mostly from patients lacking social support. In 1999, the percentage of married patients was 44. Autonomy and the desire to control the moment of dying was the most important factor driving terminally ill patients to ask for assisted suicide. In 1999, over half the patients who asked for physician-assisted suicide raised the issue of pain and suﬀering as a contributing factor. In many instances, however, the fear of suﬀering was more pressing than present pain. Doctors have granted one in six requests for lethal medications, and only one in ten requests eventually resulted in suicide. ‘‘Physicians frequently made palliative care interventions which were helpful to patients and caused them to change their minds about assisted suicide,’’ reported Dr. Linda Ganzini, a geriatric psychiatrist at the Portland Veterans Medical Center and her colleagues in a recent article [36]. One-third of patients had to go to more than one doctor for help. More importantly, however, is that of the 165 patients who asked to be helped with suicide, more than one-third did so because they perceived themselves to be a burden to others. Only three of these received a prescription, suggesting that the physicians were reluctant to accede to requests for assistance under these circumstances. In the same issue of the New England Journal of Medicine, Drs. Amy Sullivan, Katrina Hedberg, and David Fleming [35] from the Oregon Health Division of the Centers for Disease Control and Prevention reported on the second year’s experience with legalized physician-assisted suicide in Oregon. The authors concluded, ‘‘In the second, as compared with the ﬁrst year of legalized physician-assisted suicide in Oregon, the number of patients who died after ingesting lethal medications increased, but it remained small in relation to the total number of persons in Oregon who died. Patients who requested assistance with suicide appear to be motivated by several factors, including loss of autonomy and a determination to control the way in which they die.’’ The Oregon experience has lent credence to both sides of the debate for and against physician-assisted suicide. On the one hand, the law to legalize physician-assisted suicide in Oregon did not open the ﬂoodgates to mass executions or to a slippery slope by which the undesirable go ﬁrst. Less than 4 out of every 10,000 deaths occurred by lethal drug prescription. Most of these deaths were quick and uneventful. On the other hand, the experience shows clearly that with adequate attention to pain and anguish, it would not be necessary to consider the option of ending the life of another; indeed, most of those who pursued this course turned out to have control issues, a need for autonomy and a desire to be in command of all aspects of their life and death. Dr. Dick L. Willems and colleagues of Vrige Universiteit, Amsterdam, The Netherlands [37] compared physicians’ attitudes in the United States to those from The Nether-

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lands regarding physician-assisted suicide. They noted that physicians from The Netherlands are much less strict in allowing physician-assisted suicide, particularly to patients who perceive themselves to be a burden to others. We do not advocate euthanasia nor physician-assisted suicide, but a more natural course by which the patient is neither punished by unnecessary technological interventions nor made to die. The narrative skills, ability to communicate with patients and families about end-oflife issues, as well as understanding of what constitutes quality of care for the dying cardiac patient is paramount. When asked, patients indicate that they want to be free of pain and suﬀocation, not have the dying process artiﬁcially prolonged by high technology, not a burden to others, have a capacity to interact with loved ones and maintain a sense of control [38]. Cardiologists should understand that emphasis on quality and seeing through the patients’ eyes are imperative to caring for the individuals as they become near the end of life. The colleges of cardiology are expected to answer the following questions: 1.

2. 3.

4. 5.

In patients with multiple disabilities (e.g., a patient with an ejection fraction of 20%, moderate dementia, carotid disease, moderate renal failure, and abdominal aortic aneurysm), which of these should be treated by the cardiologist [39]? Recent data suggests that prevalence, expenditures, and complications of multiple chronic conditions in the elderly is very high: complications are 90 times as frequent with four conditions as with one condition. Which patients with heart failure should receive an AICD and biventricular pacing, if any? Is it cost eﬃcient? This applies to all high technology discoveries. Compare inotropic therapy, external counter pulsation to other modalities including palliative and spiritual caring at the end of life. The practice of abandoning the control groups while paying attention only to treated groups enters unnecessary bias toward intervention. Proper advance care planning for patients with heart failure or poor ventricular function and in patients with heart failure. Nutritional and other over-the-counter supplements of questionable beneﬁt or which may have high sodium content or interfere with absorption of drugs for patients with advanced heart disease [40].

After all, to die well is the height of wisdom of life [41].

REFERENCES 1. 2. 3. 4. 5. 6.

Morrison RS, Siu AL, Leipzig RM, Cassel CK, Meier DE. The hard task of improving the quality of care at the end of life. Arch Intern Med 2000; 160:743–747. Fried TR, Bradley HE, Towle VR, Allore H. Understanding the treatment preferences of seriously ill patients. N Engl J Med 2002; 346(14):1061–1066. World Health Report 2000. Available at http://www.who.int/whr/2000/en/report.htm; accessed June 28, 2000. Starﬁeld B. Is US health really the best in the world? J Am Med Assoc 2000; 284:483–485. Rabow MW, Hardie GE, Fair JM, McPhee SJ. End-of-life care content in 50 textbooks from multiple specialties. J Am Med Assoc 2000; 283:771–778. Stamler J. Established major coronary risk factors. In: Marmot M, Elliot P, eds. Coronary Heart Disease Epidemiology, From Etiology to Public Health. New York: Oxford University Press, 1992:45–46.

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Basta and McIntosh Massie BM. Editorial–obesity and heart failure–risk factor or mechanism? N Engl J Med 2002; 346:358–359. Franklin SS, Guotin WG, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D. Hemodynamic patterns of age-related changes in blood pressure: the framingham heart study. Circulation 1977; 96:308–315. Sander GE. High blood pressure in the geriatric population: treatment considerations. Am J Geriatr Cardiol 2002; 11:223–232. Beechner HK. Ethics and clinical research. N Engl J Med 1966; 274:1354–1369. McIntosh HD. Attaining and maintaining autonomy. In: Chesler E, ed. Clinical Cardiology in the Elderly. Armonk, NY: Futura Publishing Co. Inc., 1994:547–563. Drainan SJ. Abortion and the law. In: Vaux K, ed. Who Shall Live? Medicine, Technology, Ethics. Philadelphia, PA: Fortress Press, 1970:52–75. Rothman DJ. Strangers at the Bedside. A History of How Law and Bioethics Transformed Medical Decision-Making. New York, NY: Basic Books, 1991:199–213. Basta LL. Life and Death on Your Own Terms. New York: Promethius Books, 2000. Teno JM, Licks S, Lynn J, Wenger N, Connors AF Jr, Phillips RS, O’Connor MA, Murphy DP, Fulkerson WJ, Desbiens N, Knaus WA. Do advance directives provide instructions that direct care? J Am Geriatr Soc 1997; 45:508–512. Saultz J. Routine discussion of advance health care directives: are we ready? an aﬃrmation view. J Fam Pract 1990; 31:653–655. Rodriquez GS. Routine discussion of advance health care directives: are we ready? an opposing view. J Fam Pract 1990; 31:656–659. Barber v. Superior Court of State of California. Cal Rptr, 1983. In re Spring 380 Mass. 629 405 NE 2nd 115, 119 (1980). Miesel A. The legal consensus about forgoing life-sustaining treatment: its status and its prospects. Kennedy Inst Ethics J 1992; 29:309–312. Brooks RG, Basta LL, McIntosh HD, Doty WD, Walker RM, Geldart MD, Kalb I, Shashy R, Schonwetter R, Redmond L, Lowell J, Roscoe L, Bruno S, McGrew D, Leonard W. Project GRACE: Guidelines for resuscitation and care at end-of-life. Clin Cardiol 2000; 23(II):1–28. Project GRACE, 401 Corbett Street, Suite 250, Clearwater, FL 33756. Toll-Free 1-877-99GRACE. IMRI, Inc., P.O. Box 1855, Dunedin, FL 34697-1855. Toll-Free 1-866-87-4674. Baum RS, Alverez H, Cobb LA. Survival after resuscitation from an out of hospital ventricular ﬁbrillation. Circulation 1974; 50:1231–1235. Lown B. Sudden cardiac death: the major challenge confronting contemporary cardiology. Am J Cardiol 1979; 43:313. National Heart, Lung and Blood Institute. Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Disease. Washington, DC: US Department of Health and Human Services, 1990. Rabkin MT, Dillerman G, Rice NR. Orders not to resuscitate. N Engl J Med 1976; 294:364– 366. Schneider AP, Nelson DJ, Brown DD. In-hospital cardiopulmonary resuscitation: a 30-year review. J Am Board Fam Pract 1993; 6:191. Thompson RG, Hallstrom AT, Cobb LA. Bystander initiated cardiopulmonary resuscitation in the management of ventricular ﬁbrillation. Ann Intern Med 1979; 9:737. Podrid PJ. Cardiopulmonary resuscitation in the elderly. In: Chesler E, ed. Clinical Cardiology in the Elderly. Armonk, NY: Futura Publishing Co. Inc., 1994:777–795. Wagg A, Kininirons M, Stewart K. Cardiopulmonary resuscitation doctors and nurses expect too much. J R Coll London 1995; 29:20–24. Diem SJ, Lantos JD, Tulsey JA. Cardiopulmonary resuscitation on television: miracles and misinformation. N Engl J Med 1996; 334:1578–1582. Murphy DJ, Burrows D, Santilli S, Kemp AW, Tenner S, Kreling B, Teno J. The inﬂuence of

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probability of survival on patients’ preferences regarding cardiopulmonary resuscitation. N Engl J Med 1994; 330:545–549. Oregon Death with Dignity Act, Oregon Revised Statutes 1997; §127:800–897. Sullivan AD, Hedberg K, Fleming D. Legalized physician-assisted suicide in Oregon—the second year. N Engl J Med 2000; 342:598–600. Ganzini L, et al. Physicians’ experiences with the Oregon death with dignity act. N Engl J Med 2000; 342:557–563. Willems DL, et al. Attitudes and Practices Concerning the end-of-life, a comparison between Physicians from the United States and from the Netherlands. Arch Intern Med 2000; 160:63– 68. Singer PA, Martin DK, Kelner M. Quality end-of-life care, patients perspectives. J Am Med Assoc 1999; 281:163–168. Wolﬀ JL, Starﬁeld B, Anderson G. Prevalence expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med 2000; 162:2269–2276. Adams K, Cohen MH, Eisenberg D, Jonsen AR. Ethical considerations of complementary and alternative medical therapies in conventional medical settings. Ann Intern Med 2002; 137(8): 660–664. Strathern P. Kierkegaard in 90 Minutes. Chicago: Ivan R. Dee Inc, 1997.

Index

Abciximab acute coronary syndromes, 173 route of elimination, 100 Abdominal aortic aneurysms, 718–722 abdominal roentgenograms, 724 aortography, 719–720 arteriography, 725 barium studies, 724–725 celiotomy, 726 computed tomography, 719 endovascular stent-graft prostheses, 721 ultrasound, 719 ACAS, 638, 712 Accelerated atrioventricular junctional rhythm, 575 Acebutolol angina, 279 route of elimination, 102 ACE inhibitors (see Angiotensin-converting enzyme (ACE) inhibitors) ACTION, 144 Acute coronary syndromes, 173–175 adjunctive therapy, 173–174 Acute coronary thrombosis, 230 Acute Infarction Ramipril Eﬃcacy (AIRE), 309, 340 Acute ischemic syndrome, 282 Acute myocardial infarction (see also Myocardial infarction) angiotensin converting enzyme inhibitors, 308–309 angiotensin receptor blockers (ARB), 309 antiarrhythmic drugs, 310 anticoagulants, 683 antithrombotic agents, 303–307 calcium antagonists, 308 complications, 305, 309–315 coronary angioplasty, 302–303

[Acute myocardial infarction] coronary arteries, 75 ethical issues, 316–317 ﬁbrinolytic therapy, 299–302 magnesium, 309–310 nitrates, 307–308 percutaneous intervention, 395–396 risk stratiﬁcation, 316 statins, 310 therapy, 297–318 Adenosine route of elimination, 99 Adenosine echocardiography, 265 Advanced glycation end products, 11 Adventitia media, 227 Aerobic capacity, 24, 25 Aerobic exercise, 261, 411 Aerobic training, 407–409 AFASK, 571, 572 AFCAPS/TexCaps, 178 African Americans, 629, 636 AICD myocardial infarction, 342–343 noncardiac surgery, 789 AIRE, 309, 340 Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCaps), 178 Airway obstruction stroke, 639 Aldosterone antagonists, 145 Allbutt, Cliﬀord, 357 ALLHAT [see Antihypertensive Lipid Lowering Heart Attack Trial (ALLHAT)] Allopurinol congestive heart failure dilated cardiomyopathy, 505 825

826 Alpha adrenergic blockers, 113–114 Alpha-2 agonists noncardiac surgery, 787 Alprostadil route of elimination, 104 Alteplase, 301 route of elimination, 100 Alzheimer’s type, 631 Amaurosis fugax, 635 Ambulatory electrocardiography, 256–260 Ambulatory venous pressure, 749 American Heart Association Committee on Vascular Lesions, 221 Amiloride, 142 route of elimination, 101 Amiodarone, 115, 342, 499, 595 acute myocardial infarction, 309 arrhythmias, 313 atrial ﬁbrillation, 564, 567, 569 atrial ﬂutter, 573 myocardial infarction, 342 restrictive cardiomyopathy, 493 route of elimination, 99 ventricular arrhythmias, 594–595 Amlodipine, 113, 139 angina, 282 route of elimination, 102 Amphetamines avoidance, 122 Ampicillin endocarditis, 485 Amputation peripheral vascular disease, 738–746 Amrinone heart failure, 311 systolic heart failure, 545 Amyloid angiopathy, 631, 632 Anagrelide route of elimination, 100 Anemia noncardiac surgery, 796–797 Anesthesia noncardiac surgery, 793–796 Aneurysms inﬂammatory, 720 mycotic, 720 Angina, 92, 191, 252, 273–290, 378, 419 (see also Stable angina; Unstable angina) drug therapy, 275–283 equivalent, 252 evaluation, 274–275

Index [Angina] management, 274–275 new approaches, 289–290 natural history, 358–360 recognition, 356–357 Angina With Serious Operative Mortality Evaluation (AWESOME), 397 Angioplasty, 395 outcomes, 392 predictors, 391 vs. surgery, 392–393 Angiotensin antagonists, 11 Angiotensin-converting enzyme (ACE) inhibitors, 11, 107, 111–112, 138, 177, 331, 332 acute coronary syndrome, 174 acute myocardial infarction, 309, 317 alcohol, 121 angina, 283 congestive heart failure dilated cardiomyopathy, 504 diastolic heart failure, 548 distribution, 97 interactions, 120 myocardial infarction, 339 restrictive cardiomyopathy, 493 systolic heart failure, 543–544 Angiotensin receptor blockers (ARB), 112 acute myocardial infarction, 309 diastolic heart failure, 548 systolic heart failure, 544 Anistreplase route of elimination, 100 Ankle-brachial index, 710 Antiarrhythmic drugs, 114 acute myocardial infarction, 310 Antiarrhythmics Versus Implantable Deﬁbrillators (AVID), 342 Anticardiolipin antibody, 630 Anticoagulants (see also Oral anticoagulants) dose adjustment, 678–679 surgical procedures, 680–681 Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT), 683 Anticoagulation, 677–682 Antihypertensive Lipid Lowering Heart Attack Trial (ALLHAT), 113, 115, 136, 140, 144, 145, 156, 177 Antithrombotic therapy, 173 Aorta

Index [Aorta] ﬂow velocity, 51, 52, 53 root diameter, 12 Aortic aneurysms (see also Abdominal aortic aneurysms) thoracoabdominal, 722–723 Aortic annuli calciﬁcation, 25 Aortic regurgitation, 429–436 chest roentgenography, 431 Doppler echocardiography, 431 echocardiography, 431 electrocardiography, 431 etiology and prevalence, 429 medical and surgical management, 434–436 natural history, 434 noncardiac surgery, 792–793 pathophysiology, 429–430 signs, 430–431 symptoms, 430 Aortic root late diastole, 48 Aortic stenosis aortic valve replacement, 427–428 balloon aortic valvuloplasty, 428 chest roentgenography, 421 Doppler echocardiography, 421–425 echocardiography, 421–425 electrocardiography, 421 etiology and prevalence, 417–418 medical management, 427 natural history, 424–427 noncardiac surgery, 791–792 pathophysiology, 418–419 signs, 420–421 symptoms, 419–420 syncope, 661–662 Aortic systolic ejection murmur (ASEM), 420 Aortic valve annulus size, 46 calciﬁed, 83 disease, 417–436 stenosis, 82 Aortocaval ﬁstulae, 721 Apathetic hyperthyroidism, 30 Apoptosis, 234–235 APPROACH, 389–390 Aprindine atrial ﬁbrillation, 569 myocardial infarction, 341

827 ARB [see Angiotensin receptor blockers (ARB)] Ardeparin route of elimination, 99 Argatroban route of elimination, 99 Arginine, 734 Arrhythmias, 25–26, 30–34, 253 (see also Bradyarrhythmias; Dysrhythmia; Ventricular arrhythmias) acute myocardial infarction, 312–313 age and mortality, 33 atrial, 30 exercise-induced, 31 perioperative noncardiac surgery, 797 Arterial pressure, 5–10, 132 Arterial Revascularization Therapy Study (ARTS), 397 Arterial stiﬀness, 5–10, 15 Arterial thrombosis, 729–731 arteriography, 730–731 embolectomy, 730 MRI, 241 Arteriovenous malformations, 645 Artery of Adamkiewicz, 723 ARTS, 397 ASEM, 420 Asians, 629 ASPECT, 683 Aspiration pneumonia stroke, 639 Aspirin, 677 acute coronary syndromes, 173 acute myocardial infarction, 303, 317 angina, 282–283 atrial ﬁbrillation, 571 avoidance, 117, 122 myocardial infarction, 336 route of elimination, 100 stroke, 636 unstable angina, 286 Asthma, 138 Asymptomatic Carotid Atherosclerosis Study (ACAS), 638, 712 Asymptomatic carotid stenosis surgery, 714 Atenolol, 138 acute myocardial infarction, 299 angina, 279 noncardiac surgery, 783 route of elimination, 102

828 Athero-occlusive disease lower extremities, 731–746 Atherosclerosis, 251, 274, 708 classiﬁcation, 221 initiation, 217–221 progression, 221–228 risk factors, 217 vascular aging, 3 Atherothrombosis, 217 ATLAS, 169 Atorvastatin route of elimination, 103 Atrial arrhythmias, 30 Atrial ﬁbrillation, 30, 89, 107, 494–495, 559–573, 571, 684–687, 685 antiarrhythmic drugs, 568–569 anticoagulants, 687–688 antithrombotic therapy, 571–573 associated risks, 560–562 clinical symptoms, 562 diagnostic tests, 562 elective cardioversion, 566–568 nondrug therapy, 564–565 oral anticoagulants, 688 pacing, 565 predisposing factors, 560 prevalence, 559–560 rapid ventricular rate, 563–564 risk factors for thrombotic stroke, 570–571 treatment, 562 ventricular rate control, 569–570 very rapid ventricular rate, 563 Wolﬀ-Parkinson-White syndrome, 565–566 Atrial Fibrillation, Aspirin, Anticoagulation (AFASK), 571, 572, 685 Atrial ﬂutter, 573–574 Atrial tachyarrhythmias, 724 Atrioventricular (AV) block, 28, 607, 614–617, 662–663 Atrioventricular junctional rhythm accelerated, 575 Atrioventricular (AV) node, 25–26 Atropine route of elimination, 99 Automatic implantable cardioverter deﬁbrillator (AICD) myocardial infarction, 342–343 noncardiac surgery, 789 Autonomic nervous system dysfunction, 170–171 AVID, 342 A-waves, 57–58 AWESOME, 397

Index Azathioprine interactions, 119 Back pain abdominal aortic aneurysms, 720 Balloon angioplasty, 391 Baltimore Longitudinal Study of Aging (BLSA), 2, 12, 17, 18, 586 right bundle branch block (BBB), 29 BARI [see Bypass Angioplasty Revascularization Investigation (BARI)] Barnard, Christiaan, 362 Basta, Lofty, 816 BBB, 28 Baltimore Longitudinal Study of Aging (BLSA), 29 Beck, Claude, 361 Beck poudrage, 362 Benazepril route of elimination, 98 Bendroﬂumethiazide route of elimination, 103 Benzodiazepines avoidance, 122 Benzothiazepines, 139 Benzthiazide route of elimination, 103 Bepridil route of elimination, 102 Bernard, Claude, 358 Beroprost, 734 Beta adrenergic blockers, 108–109 atrial ﬁbrillation, 563 diastolic heart failure, 549 systolic heart failure, 544–545 Beta-adrenergic stimulation, 22–25 Beta-adrenoreceptor blockers acute coronary syndrome, 174 Beta blockade, 331, 332 acute myocardial infarction, 305–306, 317 congestive heart failure dilated cardiomyopathy, 504 hyperthyroidism, 516 hypertrophic obstructive cardiomyopathy (HOCM), 494 myocardial infarction, 337–339, 342 noncardiac surgery, 782–787 restrictive cardiomyopathy, 493 Beta Blocker Heart Attack Trial (BHAT), 108, 110, 337, 338 Beta Blocker Pooling Project, 337 Beta blockers, 177 acute myocardial infarction, 298

Index [Beta blockers] adverse eﬀects, 118 angina, 278–280 avoidance, 117 complex ventricular arrhythmias, 110 stable angina, 288 unstable angina, 286 Betaxolol route of elimination, 102 BHAT [see Beta Blocker Heart Attack Trial (BHAT)] Bile acid sequestrants, 159 Bileaﬂet tilting-disk prostheses, 793 Bisoprolol route of elimination, 102 Bivalirudin route of elimination, 99 Bjork-Shiley, 793 Blood lipids, 200–202 Blood pressure hypertension, 197–200 systemic, 194, 198 systolic, 193 Blood pressure control dysautonomic disorders, 666–667 neurally mediated disorders, 667–669 BLSA [see Baltimore Longitudinal Study of Aging (BLSA)] Body temperature noncardiac surgery, 797 Body weight coronary heart disease, 204–206 Bosentan route of elimination, 101 Boston Area Anticoagulation Trial for Atrial Fibrillation, 470 Bowel infarction, 724 Bradyarrhythmias, 313, 607–621, 662–663 diagnosis, 607–608 electrocardiography, 608 electrophysiological testing, 609–610 history, 607–608 physical examination, 608 provocative testing, 608–609 Bradycardias, 280 pacemakers, 617–621 codes, 618–620 follow-up, 620 future, 620–621 indications, 617–618 Bretylium route of elimination, 99 Bronx Aging Study, 332–333

829 Bumetanide acute myocardial infarction, 299 route of elimination, 103 Bundle of His, 611 Bypass cost, 742 Bypass Angioplasty Revascularization Investigation (BARI), 174–175, 367–368 CABG [see Coronary artery bypass graft (CABG)] Caged ball-prosthetic valves, 793 Calcium channel antagonists, 138 diastolic heart failure, 548–549 noncardiac surgery, 787 Calcium channel blockers, 113, 177 angina, 280–282 chronic ischemic heart disease, 174–175 hypertrophic obstructive cardiomyopathy (HOCM), 494 myocardial infarction, 340–341 restrictive cardiomyopathy, 493 CAMIAT, 342, 595 CAN, 170 Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), 342, 595 Candesartan, 144 route of elimination, 98 CAPPP, 144 Captopril route of elimination, 98 Captopril Prevention Project (CAPPP), 144 Captopril renography, 727 Carbamazepine interactions, 119 Carbomedics, 793 Carcinoid syndrome, 492 Cardiac amyloidosis, 79–80, 87 Cardiac Arrest in Seattle Conventional Versus Amiodarone Drug Evaluation Study, 342, 569 Cardiac Arrhythmia Suppression Trial (CAST), 110, 111, 341, 588–589 Cardiac disability, 405–407 Cardiac index cycle exercise, 20 Cardiac sarcoidosis, 492 Cardiac stress testing noncardiac surgery, 792 Cardioembolic stroke prevention, 638–639 Cardiogenic shock, 396 acute myocardial infarction, 315

830 Cardiomyopathies, 489–505 Cardiopulmonary resuscitation, 816, 818 Cardiovascular autonomic neuropathy (CAN), 170 Cardiovascular disease MRI, 238 prevention, 155–157, 812 Cardiovascular Health Study (CHS), 61, 62–63, 417, 529, 560, 687 Cardiovascular syncope, 654 Cardiovascular system normal aging, 1–34 arrhythmias, 30–34 cardiac structure, 11–25 electrocardiography and arrhythmias, 25–26 methodological issues, 2 vascular aging, 3–11 physical ﬁndings, 15–16 CARE, 178, 333, 334 Carnitine, 734 Carotid artery disease, 637–638 Carotid artery upstroke, 15 Carotid bifurcation, 707 Carotid endarterectomy (CEA), 712 morbidity and mortality, 715–716 Carotid sinus hypersensitivity, 614, 667–668 Carotid sinus massage, 668 CARS, 336 Carteolol route of elimination, 102 Carvedilol route of elimination, 102 CASS [see Coronary Artery Surgery Study (CASS)] CAST [see Cardiac Arrhythmia Suppression Trial (CAST)] Catecholamines, 22 CEA, 712 morbidity and mortality, 715–716 CEAP classiﬁcation, 749 Ceftriaxone endocarditis, 485 Central ﬁbrous body calciﬁcation, 25 Cerebral circulation, 626–627 Cerebrovascular disease, 625–646 Cerivastatin, 159 Charcot-Bouchard aneurysms, 630 Chest pain, 253, 255 acute myocardial infarction, 299 Chicago Stroke Study, 329

Index Chlorothiazide route of elimination, 100 Chlorpropamide interactions, 119, 120 Chlorthalidone, 113, 135, 136, 138 route of elimination, 100 Cholesterol, 154–155, 194, 200 intervention, 155–160 Cholesterol and Current Events Trial, 115 Cholesterol and Reoccurring Events (CARE), 178, 333, 334 Cholesterol Reduction in Seniors Program (CRISP), 115 Cholestyramine, 157 route of elimination, 101 Chronic ischemic heart disease, 174–175 revascularization therapy, 174–175 Chronic mesenteric ischemia, 726 Chronic obstructive pulmonary disease, 138 Chronic venous insuﬃciency, 746–749 CHS [see Cardiovascular Health Study (CHS)] 11-C-hydroxyephedrine, 171 Cigarette smoking (see Smoking) Cilostazol, 733, 734 route of elimination, 104 Circle of Willis, 627 Circulatory collapse, 695 Cloﬁbrate route of elimination, 103 Clonidine, 145 avoidance, 117 noncardiac surgery, 787 route of elimination, 98 Clopidogrel (Plavix), 174 acute myocardial infarction, 304–305 angina, 283 chronic ischemic heart disease, 174–175 route of elimination, 100 transient ischemic attack (TIA), 636–637 unstable angina, 286 Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), 174, 286 Cluster headache, 278 Cockcroft-Gault formula, 105 Coﬁbrate, 155 Colesevelam route of elimination, 102 Colestipol, 157 route of elimination, 101 Complete heart block, 77

Index Complete left bundle branch block, 89 Complete right bundle branch block, 89 Complex ventricular arrhythmias prevalence, 585–586 Compression therapy, 750 Computed tomographic arteriography (CTA) peripheral vascular disease, 711 Conduction system, 25–26, 610–612 Congestive heart failure, 78, 87, 107, 111, 169–170, 255, 419 acute myocardial infarction, 299 coronary arteries, 75 dilated cardiomyopathy, 504–505 noncardiac surgery, 766 perioperative, 782 CONSENSUS II, 174, 308 Continuous electrocardiography ST-segment monitoring noncardiac surgery, 774–775 Controlled-Onset Verapamil Investigation of Cardiovascular Events (CONVINCE) trial, 140, 142 Cooperative Cardiovascular Project, 560–561 Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II), 174, 308 Coronary angiography, 252 noncardiac surgery, 779–780 Coronary angioplasty acute myocardial infarction, 302–303 Coronary arteries, 74, 79, 86 acute myocardial infarct, 75 calciﬁed, 73, 76, 83, 85 congestive heart failure, 75 narrowing, 78 Coronary artery bypass graft (CABG), 174, 358, 368–371, 389 costs, 379–380 indications, 380 morbidity, 373–374 noncardiac surgery, 781–782 operative mortality, 371–373 outcome, 371–379 survival, 374–377 unstable angina, 287 Coronary artery disease, 167–168 diagnosis, 251–266 noncardiac surgery, 766 pathophysiology, 215–241, 357–358 prevalence, 355 randomized studies outcomes, 362–364

831 [Coronary artery disease] silent, 3 surgery, 353–380 costs, 379–380 evolution, 360–362 quality of life, 377–379 treatment evolution, 355–358 Coronary Artery Surgery Study (CASS), 236, 365–366, 781 Coronary events prevention, 682–683 risk factors, 329–330 Coronary heart disease, 190–192 epidemiology, 189–209 primary prevention, 208–209 risk factors, 192–207 Coronary steal phenomenon, 282 Costs health care, 811 Coumadin, 336 restrictive cardiomyopathy, 493 Coumadin Aspirin Reinfarction Study (CARS), 336 Coumarin pharmacology, 677–678 Courts, 813–817 Creatine kinase, 797 CRISP, 115 Cruzan, Nancy, 814–816 Cryoablation atrial ﬁbrillation, 564 Cycle ergometry, 18, 261 end-diastolic volume index, 24 Cycle exercise, 20 Cyclosporine interactions, 119 d, l-sotalol myocardial infarction, 341–342 DAIS, 178 Dalteparin route of elimination, 100 Danaparoid route of elimination, 100 DASH, 135 DCCT, 166, 179, 203 Death with Dignity Act, 819 Decadron intracranial hemorrhage, 644 stroke, 641 Depression, 139

832 Desﬂurane noncardiac surgery, 794 Diabetes Atherosclerosis Intervention Study (DAIS), 178 Diabetes Control and Complications Trial (DCCT), 166, 179, 203 Diabetes mellitus, 163–180, 635, 708, 732 cardiovascular complications, 166–171 cardiovascular disease management, 172–176 clinical consequences, 167–171 glucose tolerance, 203 glycemic control, 179–180 hypertension, 176–177 lipid disorders, 177–179 myocardial infarction, 335 noncardiac surgery, 767 pathophysiological changes, 166–167 pathophysiology, 164–166 Diarrhea, 733 Diastolic dysfunction, 489–490 noncardiac surgery, 790 Diastolic heart failure pharmacotherapy, 546–549 Diastolic hypertension, 330 Diastolic pressure, 5–10, 193, 198 Diazoxide route of elimination, 104 Diet cholesterol, 155, 157 heart failure, 541 Dietary Approaches to Stop Hypertension (DASH), 135 Diethylenetriamine pentaacetic acid (DTPA), 727 Digitalis atrial ﬁbrillation, 563 Digoxin, 106–107 adverse eﬀects, 118 atrial ﬂutter, 574 avoidance, 117, 121 congestive heart failure dilated cardiomyopathy, 504 diastolic heart failure, 548 distribution, 97 hypertrophic obstructive cardiomyopathy (HOCM), 494 interactions, 119, 120 paroxysmal supraventricular tachycardia (PSVT), 575 restrictive cardiomyopathy, 493 route of elimination, 101 sick sinus syndrome, 614 systolic heart failure, 545

Index Dihydropyridine, 139 Dilated cardiomyopathy, 500–505 symptoms, 500–505 Diltiazem, 113, 139 angina, 281, 282 atrial ﬁbrillation, 563 atrial ﬂutter, 573, 574 avoidance, 117 paroxysmal supraventricular tachycardia (PSVT), 575 route of elimination, 102 Dipyridamole avoidance, 122 route of elimination, 100 transient ischemic attack (TIA), 637 Dipyridamole stress imaging, 264–265 Disopyramide, 97 atrial ﬁbrillation, 567, 569 avoidance, 121, 122 hypertrophic obstructive cardiomyopathy (HOCM), 494 interactions, 119 myocardial infarction, 341 route of elimination, 99 Diuretics, 107–108, 331, 332 congestive heart failure dilated cardiomyopathy, 504 heart failure, 311 restrictive cardiomyopathy, 493 systolic heart failure, 544–545 Dizziness, 632 DNR, 817–819 Dobutamine, 265 acute myocardial infarction, 299 heart failure, 311 hypotension, 312 route of elimination, 101 systolic heart failure, 545 Dobutamine stress echocardiography noncardiac surgery, 778–779 Dofetilide atrial ﬁbrillation, 567 route of elimination, 99 Do not resuscitate (DNR), 817–819 Dopamine, 612 acute myocardial infarction, 299 hypotension, 312 route of elimination, 101 systolic heart failure, 545 Doppler aortic ﬂow velocity left ventricular systolic performance, 51–54 echocardiography, 54–55

Index Doppler mitral valve velocity, 58 Doppler transmitral ﬂow-velocity left ventricle diastolic performance, 56–60 Doppler ultrasound peripheral vascular disease, 710 Doxazosin, 113, 114 route of elimination, 98 Drug-alcohol interactions, 121 Drug-disease interactions, 118 Drug-drug interactions, 119–120 Drugs, 95–122 adverse eﬀects, 117 avoidance, 117–118, 121, 122 pharmacodynamics, 105–106 pharmacokinetics, 95–105 absorption, 95 bioavailability, 95–97 distribution, 97 excretion, 97–98 half-life, 97 metabolism, 97 physiological changes aﬀecting, 96 prudent use, 120–122 route of elimination, 98–104 d-Sotalol myocardial infarction, 341–342 DTPA, 727 Duplex ultrasound peripheral vascular disease, 710 Dyslipidemia, 166, 202, 332–333 Dyspnea, 252, 254, 274, 695, 696 Dysrhythmia, 494–495 EAFT, 571, 685 EAST, 176, 366–367 Echocardiography, 12, 260–261 epidemiological studies, 61–64 left ventricular systolic performance, 51–54 Doppler aortic ﬂow-velocity, 54–55 M-mode, 43–51, 85 regression equations, 47 without clinical heart disease, 43–64 ECST, 712 Edema, 139 EDRF angina, 275–276 EDVI, 16, 18, 21 cycle ergometry, 24 Edwards Duromedics, 793 EECP angina, 289

833 Ejection fraction cycle exercise, 20 maximal exercise, 19 Ejection time, 51 Elderly American population growth, 2 Electrocardiography ambulatory, 256–260 exercise, 262–263 exercise stress testing noncardiac surgery, 776 maximal treadmill exercise, 263 resting, 26, 256 noncardiac surgery, 774 signal-averaged, 260 Electrocautery pacemakers, 789 Electrophysiological study (EPS), 654 Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM), 594 ELITE II, 112, 544 EMIAT, 342, 595 Emory Angioplasty versus Surgery Trial (EAST), 176, 366–367 Enalapril, 112, 141, 174, 308 diastolic heart failure, 548 route of elimination, 98 Enalaprilat adverse eﬀects, 311 Encainide, 114 atrial ﬁbrillation, 567, 569 myocardial infarction, 341 End-diastolic volume index (EDVI), 16, 18, 21 cycle ergometry, 24 Endocarditis, 477–485 Endothelial dysfunction, 5–10, 219, 222 Endothelium-derived relaxing factor (EDRF) angina, 275–276 End-systolic pressure (ESP-ESV), 21 End-systolic volume index (ESVI), 16–18 Enﬂurane noncardiac surgery, 794 Enhanced external counter pulsation (EECP) angina, 289 Enoxaparin route of elimination, 100 EPESE, 332, 530 Epinephrine, 612 route of elimination, 101 EPISTENT, 176

834 Eplerenone route of elimination, 101 Epoprostenol route of elimination, 104 Eprosartan route of elimination, 98 EPS, 654 EPTFE, 734 Eptiﬁbatide route of elimination, 100 unstable angina, 286 Erectile dysfunction, 139 Esmolol route of elimination, 102 ESP-ESV, 21 Established Populations for Epidemiologic Studies of the Elderly (EPESE), 332, 530 Estrogen, 343 Estrogen Replacement and Atherosclerosis trial, 343 ESVEM, 594 ESVI, 16–18 Ethacrynic acid avoidance, 117 route of elimination, 103 Ethics, 811–821 European Atrial Fibrillation Trial (EAFT), 571, 685 European Carotid Surgery Trial (ECST), 712 European Coronary Surgery Study Group, 364–368 European Myocardial Infraction Amiodarone Trial (EMIAT), 342, 595 European Working Party Study on High Blood Pressure in the Elderly (EWPHE), 134, 135 Euthanasia, 819–821 Evaluation of Platelet IIb/IIIa Inhibitors for Stenting Trial (EPISTENT), 176 E-wave peak velocity mitral annulus, 57 E-waves, 57–58 EWPHE, 134, 135 Exercise, 261–262, 733 aerobic, 261, 411 capacity, 17–21 cycle, 20 exhaustive upright, 24 ﬂexibility, 411 maximal ejection fraction, 19 stable angina, 289

Index Exercise cardiac imaging, 263–264 Exercise electrocardiography, 262–263 maximal treadmill, 263 noncardiac surgery, 776 Exercise-induced arrhythmias, 31 Exercise-induced ventricular ectopic beats (VEB), 33 Exercise stress testing, 263 Exercise tolerance noncardiac surgery, 771–773 Exercise training, 405–413 myocardial infarction, 335–336 Exhaustive upright exercise, 24 Expanded polytetraﬂuoroethylene (ePTFE), 734 Extracranial carotid disease, 712–713 Ezetimibe route of elimination, 102 Falls syncope, 658 Familial amyloidosis, 492 Fatty streaks, 224 Felodipine, 113, 139, 141 angina, 282 route of elimination, 102 Fenoﬁbrate, 159 route of elimination, 103 Fenoldopam route of elimination, 104 Fibrinoid degeneration, 357 Fibrinolysis acute myocardial infarction, 317 Fibrinolytic Therapy Trialists (FTT), 172, 300 Flecainide, 114 atrial ﬁbrillation, 567, 569 myocardial infarction, 341 route of elimination, 99 Flexibility exercise, 411 Fluvastatin route of elimination, 103 Fondaparinux route of elimination, 100 Forssmann, Werner, 358 Fosinopril route of elimination, 98 Framingham Heart Study, 51, 167, 168, 189, 193, 194, 200–201, 206, 253, 256, 331, 332, 405, 529, 560, 561 Frank-Starling mechanism, 17, 446 FRISC II, 173 FTT, 172, 300

Index Furosemide acute myocardial infarction, 299 avoidance, 117 route of elimination, 103 Gemﬁbrozil, 157, 159, 178 route of elimination, 103 Gender, 411–412 cholesterol, 154–155 Gentamicin endocarditis, 485 Gibbon, John, 361 GISSI-2, 168 GISSI-3, 308 Global Registry of Acute Coronary Events (GRACE), 396 Global Utilization of Streptokinase and tPA for Occluded Arteries (GUSTO-I), 172, 301 Global Utilization of Streptokinase and tPA for Occluded Arteries (GUSTO-III), 301 Glucose tolerance diabetes mellitus, 203 Glycoprotein IIb/IIIa inhibitors, 393 acute myocardial infarction, 304, 317 non-ST-elevation myocardial infarction, 316 Glycoproteins, 11, 97 acute coronary syndromes, 173 distribution, 97 Goteborg Trial, 338 GRACE, 396 Graham-Steele murmur, 447 Group A beta-hemolytic streptococci, 480 Guanabenz route of elimination, 98 Guanadrel route of elimination, 103 Guanethidine route of elimination, 103 Guanfacine route of elimination, 98 GUSTO-I, 172, 301 GUSTO-III, 301 Halothane noncardiac surgery, 794 HDL, 194, 218, 223–224, 280, 332–333 Headache, 277–278, 644, 733 cluster, 278 Health care costs, 811 Heart calcium, 76

835 [Heart] morphological features, 69–93 cardiac necropsy, 76–80 causes of death, 71–75 clinical ﬁndings, 71 methods, 70–71 results, 71 structure, 11–25 Heart and Estrogen/Progestin Replacement Study (HERS), 116, 343 Heart failure, 529–549 acute myocardial infarction, 298, 311–312 comorbidities, 533 diagnosis and clinical ﬁndings, 539–541 epidemiology and risk factors, 529–530 pathophysiology, 532–538 precipitants, 538–539 prognosis, 531–532 surgery, 546 treatment, 541–542 Heart Outcomes Prevention Evaluation (HOPE), 144, 174, 339, 340 Heart Protection Study (HPS), 156, 288, 333, 334 Heart rate coronary heart disease, 206 cycle exercise, 20 Heberden, 356 Helsinki Aging Study, 417 Helsinki Heart Study, 178 Helsinki Policeman Study, 165 Hematocrit, 206 Hemoptysis, 696 Hemorrhage intracerebral, 630 intracranial, 301, 644 Hemorrhagic stroke management, 644 Heparin acute myocardial infarction, 303–304 arterial thrombosis, 730, 731 non-ST-elevation myocardial infarction, 316 route of elimination, 99 stroke, 640 unstable angina, 286 HERS, 116, 343 HHC, 496–499 High-density lipoprotein cholesterol (HDL), 194, 218, 223–224, 280, 332–333 Hindgut ischemia, 726 Hippocrates, 356 HMG CoA reductase inhibitors, 115, 157, 178

836 [HMG CoA reductase inhibitors] interactions, 120 HOCM, 493–496 echocardiography, 494 Home exercise vs. supervised exercise, 412 Honolulu Heart Program, 329, 335 HOPE, 144, 174, 339, 340 Horner’s syndrome, 717 HOT, 140, 142 HPS, 156, 288, 333, 334 Hunter, John, 356–357 Hydralazine route of elimination, 104 systolic heart failure, 544 Hydrochlorothiazide, 108, 135 route of elimination, 100 Hydroﬂumethiazide route of elimination, 100 Hydrophilic drugs distribution, 97 Hydroxyephedrine, 171 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, 115, 157, 178 interactions, 120 Hypercholesterolemia, 202, 218 drug therapy, 333–335 hypothyroidism, 520 Hyperglycemia, 166, 218 Hyperlipidemia drug therapy, 153–160 Hypertension, 258, 330–332, 635 alpha-adrenergic blocking agents, 145 angiotensin converting (ACE) inhibitors, 144 angiotensin receptor blockers (ARB), 144–145 beta-adrenergic blockers, 137–139 blood pressure, 197–200 calcium blockers, 139–143 trials, 140–141 centrally acting agents, 145 combination therapy, 145–146 concomitant medical conditions, 132 deﬁned, 132 diabetes mellitus, 176–177 diuretics, 136–137 noncardiac surgery, 767–768 renovascular, 727 systemic, 131–147 systolic, 330 treatment nonpharmacological, 135

Index [Hypertension] pharmacological, 136–146 rationale, 132–134 trials, 133–134 venous, 748 Hypertensive hemorrhage, 631 Hypertensive hypertrophic cardiomyopathy (HHC), 496–499 Hyperthyroidism, 511–516 apathetic, 30 cardiac complications, 514–515 clinical ﬁndings, 511–512 hemodynamic changes, 513–514 management, 516 mechanism of action, 512–513 subclinical, 515–516 Hypertriglyceridemia, 333 Hypertrophic cardiomyopathy, 493–499 noncardiac surgery, 789–790 Hypertrophic obstructive cardiomyopathy (HOCM), 493–496 echocardiography, 494 Hypoglycemia, 658 Hypokalemia, 108 Hypomagnesemia, 108 Hyponatremia, 108, 112 Hypotension, 277 acute myocardial infarction, 298–299, 312 orthostatic, 16, 666–667 postural, 139 Hypothyroidism, 516–521 clinical manifestations, 518–519 management, 521 myxedema coma, 521 subclinical, 519–520 Ibutilide arrhythmias, 313 atrial ﬁbrillation, 567 route of elimination, 99 ICAM, 222–223 IEL, 227 Imipramine atrial ﬁbrillation, 569 myocardial infarction, 341 IMPACT, 588 Inamrinone route of elimination, 101 Indapamide route of elimination, 100 Independent living, 811

Index Inﬂammatory aneurysms, 720 Informed consent, 812–813 INR, 516 high values, 679 INSIGHT, 140, 142 Insulin resistance, 164–166 Insulin resistance syndrome, 165–166 Internal carotid artery occlusion, 628 Internal elastic lamina (IEL), 227 International Mexilitine and Placebo Antiarrhythmic Coronary Trial (IMPACT), 588 International Nifedipine Study Intervention as a Goal in Hypertension Treatment (INSIGHT), 140, 142 International Normalization Ratio (INR), 516 high values, 679 International Stroke Trial, 642 Intimal medial thickening, 3–5 drug/diet interventions, 11 Intraaortic balloon counterpulsation noncardiac surgery, 782 Intracerebral hemorrhage, 630 Intracranial hemorrhage, 301, 644 Intraluminal stents, 737 Intravascular ultrasound, 236 Intrinsic sympathetic stimulation (ISA), 279 Irbesartan route of elimination, 98 ISA, 279 Ischemia silent, 167 Ischemic stroke CAT scan, 634 medical complications, 639–640 MRA, 634 MRI, 634 pathophysiology, 627–631 therapy, 634–636 transcranial Doppler, 634 transesophageal echocardiography (TEE), 634 treatment, 639–644 ISDN route of elimination, 104 ISIS-1, 305–306 ISIS-4, 308 ISMN route of elimination, 104 Isoﬂurane noncardiac surgery, 794 Isoniazid alcohol, 121

837 Isoproterenol, 612 route of elimination, 101 Isosorbide dinitrate systolic heart failure, 544 Isosorbide mononitrate angina, 276–277 Isoxsuprine route of elimination, 104 Isradipine, 139, 141 route of elimination, 102 Jenner, Edward, 356–357 Kent bundle, 611 Kuopio Ischemic Heart Disease Risk Factor Study, 165 Labetalol route of elimination, 102 L-arginine, 734 Late diastolic peak transmitral ﬂow velocity, 56 L-carnitine, 734 LDL, 194, 218, 223, 280 Left atrium, 90 late diastole, 48 Left ventricle, 90 (see also LV) afterload, 21–22 diastolic performance, 14, 59, 64 Doppler transmitral ﬂow-velocity, 56–60 dysfunction, 169–170 ejection fraction, 50 end-diastole, 49 end-systole, 49 ﬁlling natural history, 60 late diastole, 49 mass, 50 echocardiography, 61–62 noncardiac surgery, 774 systolic performance, 14 volume cycle exercise, 20 wall motion echocardiography, 62 Left ventricular hypertrophy (LVH), 132, 196, 204, 258 Left ventricular mass, 13 magnetic resonance imaging (MRI), 12 Left ventricular systolic performance Doppler aortic ﬂow velocity, 51–54 echocardiography Doppler aortic ﬂow-velocity, 54–55

838 Lepirudin route of elimination, 100 Lev’s disease, 611 Lidocaine, 97, 114 acute myocardial infarction, 309 atrial ﬁbrillation, 569 interactions, 119 myocardial infarction, 341 route of elimination, 99 LIFE, 137, 138 Life expectancy, 1 Lifestyle modiﬁcations cardiovascular autonomic dysfunction, 171 hypertension, 135 Ligation, 751 Limb salvage deﬁned, 734 Lincomycin interactions, 120 Lipid disorders diabetes mellitus, 177–179 Lipid-lowering drugs, 115–116, 157 LIPID trial, 178 Lipophilic drugs distribution, 97 Lipoprotein disorders cardiovascular risk, 154–155 Lisinopril, 141, 174 route of elimination, 98 LMWH, 173 acute myocardial infarction, 304, 317 Local atherogenic risk factors, 220–221 Long-term electrocardiographic monitoring, 663–664 Long-Term Intervention with Pravastatin in Ischaemic Disease Study, 333, 334 Loop diuretics, 107, 108 Los Angeles Veterans Administration Study, 155 Losartan, 112, 138 diastolic heart failure, 548 route of elimination, 98 systolic heart failure, 544 Losartan Heart Failure Survival Study (ELITE II), 112 systolic heart failure, 544 Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE), 137, 138 Lovastatin route of elimination, 103 Low-density lipoprotein cholesterol (LDL), 194, 218, 223, 280

Index Lower extremities athero-occlusive disease, 731–746 Low molecular weight heparin (LMWH), 173 acute myocardial infarction, 304, 317 L-sotalol myocardial infarction, 341–342 L-thyroxine, 520, 521 LV free-wall thickness at end-diastole (LVPWd), 43–44 LVH [see Left ventricular hypertrophy (LVH)] LV internal dimensions at end-diastole (LVIDd), 43 LV internal dimensions at end-systole (LVIDs), 43 LVPWd, 43–44 Macrophage colony stimulating factor (M-CSF), 219 MADIT, 342–343, 546, 596 Magnesium acute myocardial infarction, 309–310 Magnetic resonance arteriography (MRA) peripheral vascular disease, 711 Magnetic resonance imaging (MRI) left ventricular mass, 12 Mannitol intracranial hemorrhage, 644 stroke, 641 Marie, Pierre, 357 MAT, 575–576 Matrix metalloproteinases (MMP), 225–227, 231–232 Maximal exercise ejection fraction, 19 Maximal treadmill exercise electrocardiography, 263 Maximum oxygen consumption rate (VO2max), 18, 19 MCP-1, 219, 226 M-CSF, 219, 226 Mecamylamine route of elimination, 103 Medical conﬂicts court resolution, 813–817 Medical Outcomes Study, 406 Medical Research Council, 136 Medical Research Trial on Treatment of Hypertension in Older Adults (MRC), 134, 137 Medications (see Drugs) Medtronic-Hall, 793 Meisel, Allan, 815

Index Mesenteric ischemia, 723–726 Meta-iodobenzylguanidine (MIBG), 171 Metaraminol route of elimination, 101 Methotrexate interactions, 119 Methoxamine route of elimination, 101 Methyclothiazide route of elimination, 100 Methyl-D-aspartate receptor, 644 Methyldopa avoidance, 117, 121 route of elimination, 98 Metolazone, 108 route of elimination, 100 Metoprolol acute myocardial infarction, 299, 307 angina, 279, 280 myocardial infarction, 337 route of elimination, 102 Metropolitan Relative Weight, 197 Mexiletine atrial ﬁbrillation, 569 myocardial infarction, 341 Mexilitine, 588 route of elimination, 99 MIBG, 171 Midodrine avoidance, 117 route of elimination, 101 Milrinone heart failure, 311 route of elimination, 101 Minoxidil route of elimination, 104 MIRACL, 156, 546 Mitral annular calciﬁcation, 25, 83, 456–470 atrial ﬁbrillation, 463 bacterial endocarditis, 466–467 cardiac events, 467 cerebrovascular events, 468–470 chamber size, 461 conduction defects, 463 diagnosis, 458–460 mitral regurgitation, 463–464 mitral stenosis, 464–466 mitral valve replacement, 467 predisposing factors, 457–458 prevalence, 457 Mitral annulus, 83, 85 E-wave peak velocity, 57

839 Mitral peak ﬂow velocity in early diastole (PFVE), 56 Mitral regurgitation etiology, 443, 444 laboratory ﬁndings, 449–450 natural history, 450–451 noncardiac surgery, 791 pathophysiology causing symptoms, 445–447 regurgitant oriﬁce formation, 445–446 signs, 449 surgery, 453–456 symptoms, 448 Mitral stenosis balloon valvotomy, 451–453 etiology, 443 laboratory ﬁndings, 448 natural history, 450 noncardiac surgery, 791 open commissurotomy, 453 oral anticoagulants, 688 pathophysiology, 444–445 signs, 447 symptoms, 447 Mitral valve normal ﬂow velocity, 57 Mitral valvular regurgitation, 252 M-mode echocardiography, 43–51, 85 MMP [see Matrix metalloproteinases (MMP)] Mobility, 92 Moexipril route of elimination, 98 Molecular enhancer MRI, 241 MONICA study, 167 Monocyte chemoattractant protein-1 (MCP-1), 219, 226 Monocyte colony stimulating factor (M-CSF), 226 Moricizine, 114 atrial ﬁbrillation, 569 myocardial infarction, 341 route of elimination, 99 Morphine acute myocardial infarction, 298, 299 heart failure, 311 unstable angina, 285–286 MRA peripheral vascular disease, 711 MRC, 134, 137 MRFIT, 134, 169

840 MRI left ventricular mass, 12 Multicenter Automatic Deﬁbrillator Implantation Trial (MADIT), 342–343, 546, 596 Multicenter Chest Pain Study, 255 Multicenter Diltiazem Post Infarction, 282, 337, 341 Multicenter Study of Myocardial Ischemia, 336 Multifocal atrial tachycardia (MAT), 575–576 Multi-infarct dementia, 639 Multiple Risk Factor Intervention Trial (MRFIT), 134, 169 Mycotic aneurysms, 720 Myocardial contractility, 21 Myocardial infarction, 78–79, 107, 109, 167, 191 [see also Acute myocardial infarction angiotensin converting enzyme (ACE)] inhibitors, 339 antiarrhythmic therapy, 341–343 anticoagulants, 337 calcium channel blockers, 340–341 complications, 256 diagnosis, 253–256 exercise electrocardiography, 263 hormone replacement therapy, 343–344 management, 329–344 nitrates, 339 noncardiac surgery, 766–767 perioperative noncardiac surgery, 797–798 revascularization, 344 stroke, 639 Myocardial ischemia, 109, 167, 252 diagnosis, 251–253 syncope, 662 Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL), 156, 546 Myocardial revascularization unstable angina, 287 Myocardial rupture, 313–314 Myocardium, 132 Nadolol route of elimination, 102 Nafcillin endocarditis, 485 NASCET, 712 National Cooperative Study Group, 366 National Heart Foundation of Australia, 135 Nesiritide heart failure, 311

Index [Nesiritide] route of elimination, 101 Netherlands, 820 Niacin, 155 Nicardipine, 139 route of elimination, 102 Nicorandil angina, 289 Nicotinic acid, 157 Nifedipine, 113, 139, 142 angina, 281, 282 route of elimination, 103 Nimodipine, 139 route of elimination, 103 Nisoldipine route of elimination, 103 Nitrates, 108, 113 acute myocardial infarction, 298 adverse eﬀects, 277–278 alcohol, 121 angina, 275–276 chronic ischemic heart disease, 174–175 heart failure, 311 myocardial infarction, 339 non-ST-elevation myocardial infarction, 316 restrictive cardiomyopathy, 493 Nitrendipine, 139, 141 Nitroglycerin, 357 acute myocardial infarction, 299 angina, 276–277 heart failure, 311 noncardiac surgery, 787 route of elimination, 104 Nitroprusside heart failure, 311 route of elimination, 104 N-methyl-D-aspartate receptor (NMDA), 644 Noncardiac surgery exercise tolerance, 771–773 intraoperative management, 793–798 noninvasive testing before, 773 perioperative cardiovascular evaluation and treatment, 765–798 perioperative interventions reducing risk, 782–789 perioperative risk, 768–773 Noninvasive preoperative cardiac testing, 773–775 Nonocclusive mesenteric ischemia, 724 Non-Q-wave myocardial infarction, 255, 283 Non-ST-elevation myocardial infarction, 315–316

Index Nonsteroidal anti-inﬂammatory drugs (NSAID), 677 adverse eﬀects, 118 Nonsustained ventricular tachycardia, 109 NORDIL, 140 Norepinephrine, 22 acute myocardial infarction, 299 hypotension, 312 route of elimination, 101 North American Symptomatic Carotid Endarterectomy Trial (NASCET), 712 Norwegian Multicenter Study, 338 Norwegian Timolol Study, 109 NSAID, 677 adverse eﬀects, 118 Nuclear scintigraphy myocardial perfusion imaging noncardiac surgery, 776–778 OASIS, 168 Obesity myocardial infarction, 335 Olmesartan route of elimination, 98 Omnicarbon, 793 Oral anticoagulants bleeding, 680 clinical applications, 681 indications, 688–689 optimum duration, 682 Oregon, 819–820 Orthostatic hypotension, 16, 666–667 Orthostatic stress, 16–17 Osler, William, 357 Oxygen acute myocardial infarction, 298, 299 heart failure, 311 unstable angina, 285 Pacemaker cells, 25 Pacemakers noncardiac surgery, 787–789 Papaverine route of elimination, 104 Parodi, Juan, 721 Paroxysmal atrial tachycardia atrioventricular block, 575 Paroxysmal supraventricular tachycardia (PSVT), 30–32, 574–576 Patency deﬁned, 734 Paxitaxol, 738

841 Penbutolol route of elimination, 102 Penicillin endocarditis, 485 Pentoxifylline, 733 route of elimination, 104 Percutaneous coronary intervention, 389–399 characteristics, 390–391 contemporary, 393 noncardiac surgery, 780 Percutaneous renal angioplasty, 729 Percutaneous transluminal coronary angioplasty (PTCA), 362 acute myocardial infarction, 302–303 peripheral vascular disease, 710–711 Perindopril route of elimination, 98 Perioperative arrhythmias noncardiac surgery, 797 Perioperative congestive heart failure, 782 Perioperative myocardial infarction noncardiac surgery, 797–798 Peripheral arterial disease noncardiac surgery, 767 Peripheral vascular disease, 171, 707–751 amputation, 738–746 bypass surgery, 734–735 clinical presentations, 712–731 diagnosis, 709–711 medical management, 733–734 reconstruction, 734–735 risk factors, 708 saphenous vein grafts, 736 PFVE, 56 Pharmacodynamics, 105–106 Pharmacokinetics, 95–105 Pharmacological cardiac stress testing noncardiac surgery, 776–779 Pharmacological Intervention in Atrial Fibrillation, 569–570 Pharmacological stress testing, 261–262, 264–266 Phenylephrine route of elimination, 101 Phenytoin alcohol, 121 atrial ﬁbrillation, 569 interactions, 119, 120 myocardial infarction, 341 Phosphodiesterase inhibitors heart failure, 311 Physical activity coronary heart disease, 206

842 [Physical activity] heart failure, 541–542 myocardial infarction, 335–336 Physical examination, 92 Physician-assisted suicide, 820 Pindolol angina, 279 route of elimination, 102 Plaque clinical consequences, 235–237 disruption, 228–232 morphological characteristics, 229 passive, 230–231 rapid growth, 226–227 slow progression, 226 thrombosis, 233 in vivo visualization, 237–241 Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptors Suppression Using Integrilin Therapy (PURSUIT), 561 Plavix [see Clopidogrel (Plavix)] Pneumonia aspiration stroke, 639 Polytetraﬂuoroethylene, 734 Polythiazide route of elimination, 100 Popliteal artery endarterectomy, 736–737 percutaneous transluminal angioplasty (PTA), 737 saphenous vein grafts, 736 sympathectomy, 736–737 Postoperative analgesia noncardiac surgery, 798 Postphlebitic syndrome, 746–749 Postural hypotension, 139 Pravastatin, 115, 116 route of elimination, 103 Prazosin route of elimination, 98 PREDICT, 140, 142 Prednisone interactions, 120 Preoperative noninvasive cardiac stress testing, 775–779 Pressor stress, 17 Preventive cardiology, 412–413 Primary arrhythmic syncope, 662–666 Primary neurological syncope, 669

Index Primary Percutaneous Coronary Intervention, 172 P-R interval, 27–28 Procainamide, 114 atrial ﬁbrillation, 567, 569 interactions, 119 myocardial infarction, 341 route of elimination, 99 Progestin, 343 Project GRACE Advance Care Plan, 816 Propafenone atrial ﬁbrillation, 567 route of elimination, 99 Propofol noncardiac surgery, 794 Propranolol, 97, 108, 109 acute myocardial infarction, 307 angina, 279, 280 atrial ﬁbrillation, 563 interactions, 119 myocardial infarction, 337 paroxysmal supraventricular tachycardia (PSVT), 575 route of elimination, 102 Prospective Randomized Evaluation of Diltiazem CD Trial (PREDICT), 140, 142 Prospective Study of Pravastatin in Elderly at Risk (PROSPER), 117, 156 PROSPER, 117, 156 Prosthetic heart valves anticoagulants, 683–684 noncardiac surgery, 793 Protein C, 630 Protein S, 630 Pro-urokinase, 642–643 PSVT, 30–32, 574–576 PTCA, 362 acute myocardial infarction, 302–303 peripheral vascular disease, 710–711 Pulmonary angiography complications, 700 Pulmonary artery catheterization noncardiac surgery, 796 Pulmonary edema, 252 Pulmonary embolism, 695–703 anticoagulants, 701–702 blood gases, 698 chest radiograph, 698–699 clinical assessment, 699 contrast-enhanced spiral computed tomography, 700

Index [Pulmonary embolism] diagnosis, 701 electrocardiography, 697–698 gadolinium-enhanced magnetic resonance angiography, 700–701 predisposing factors, 695 pulmonary angiography, 700 signs, 696–697 stroke, 639 symptoms, 696 syndromes, 695–696 thrombolytic therapy, 702–703 ventilation/perfusion lung scans, 699–700 Pulmonary hemorrhage syndrome, 695 Pulmonary infarction syndrome, 695 Pulmonary venous ﬂow pulsed Doppler, 59 Pulsed Doppler pulmonary venous ﬂow, 59 Pulse pressure, 5–10 Pulse-wave velocity (PWV), 7–9 Purkinje ﬁbers, 611 PURSUIT, 561 P waves, 27 PWV, 7–9 QRS complex, 28–29, 89, 92 Quality of life, 811–821 Quinapril route of elimination, 98 Quinethazone route of elimination, 100 Quinidine, 114 atrial ﬁbrillation, 567–569 avoidance, 117 interactions, 119, 120 myocardial infarction, 341 route of elimination, 99 Quinlan, Karen, 813–814 Q waves, 29, 254 Radioactive iodine hyperthyroidism, 516 Radiofrequency catheter atrial ﬁbrillation, 564 RALES, 112 Ramipril, 144, 309, 340 route of elimination, 98 Randomized Aldactone Evaluation Study (RALES), 112 Ranolizine

843 [Ranolizine] angina, 289 Rapamycin, 738 Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group, 570 Recurrent stroke prevention, 641–642 Refractory atrial ﬁbrillation, 115 Regional anesthesia noncardiac surgery, 795–796 Renal function, 132 Renal function-related resistance, 108 Renovascular arterial disease, 726–729 arteriography, 728 renal duplex scanning, 728 Renovascular hypertension, 727 Repolarization, 29–30 Reserpine, 138 avoidance, 117 route of elimination, 103 Resistance training, 409–411 Respiratory sinus arrhythmia, 26, 27 Resting electrocardiography, 26, 256 noncardiac surgery, 774 Rest pain, 732 Restrictive cardiomyopathy, 490–493 etiology, 490–492 presentation and diagnosis, 492–493 treatment, 493 Reteplase, 301 route of elimination, 100 Revascularization, 362, 397–399 Reversible ischemic neurological deﬁcit, 712 Rhabdomyolysis, 159 Rifampin alcohol, 121 endocarditis, 485 Right bundle branch block (BBB), 28 Baltimore Longitudinal Study of Aging (BLSA), 29 Right ventricular infarction, 313 Rose Angina and Claudication Questionnaire, 62–63 4S, 178, 333, 334 SAECG, 260 Salvage and Ventricular Enlargement (SAVE), 309 SAVE, 309 SAVE trial, 111, 339, 340

844 Scandinavian Simvastatin Survival Study (4S), 178, 333, 334 Screening, 411 Seattle Heart Watch Program, 818 Sedatives alcohol, 121 Seizures, 658, 669 SEPS, 751 Serum total cholesterol, 332 Serum triglycerides, 333 Sevoﬂurane noncardiac surgery, 794 S4 gallop, 15 Shear stress, 221 SHEP, 107, 134, 136–139, 177, 200 SHOCK study, 168 Shoes, 733 Short-term electrocardiographic monitoring, 663 Sick sinus syndrome, 26, 607, 613–614, 662–663 Signal-averaged electrocardiography (SAECG), 260 Sildenaﬁl route of elimination, 104 Silent cardiac disease, 711 Silent coronary artery disease (CAD), 3 Silent ischemia, 167, 259 Simvastatin, 156, 178 [see also Scandinavian Simvastatin Survival Study (4S)] route of elimination, 103 Single-tilting-disk prosthetic valves, 793 Sinoatrial exit block, 612–613 Sinus arrest, 612 Sinus bradycardia, 26, 612 Sinus node electrocardiography, 26–27 Sinus node dysfunction, 612–614 SISH, 140 Sixty Plus Reinfarction Group, 116, 337, 683 SMC, 219, 232, 233 SMILE, 308, 340 Smoking, 203, 206, 329–330, 636, 732 Smoking cessation, 708, 733 Smooth muscle cells (SMC), 219, 232, 233 Socks, 733 Soft basal ejection, 15–16 SOLVD, 111, 561–562 Sones, Mason, 358, 361 Sotalol arrhythmias, 313 atrial ﬁbrillation, 567 myocardial infarction, 341–342 route of elimination, 99

Index SOVLD, 169 SPAF, 638, 685 SPIRIT, 681 Spironolactone congestive heart failure dilated cardiomyopathy, 504 route of elimination, 101 SPORTIF, 688 St. Jude, 793 Stable angina, 287–289 prevention, 288 Staphylococcus aureus, 466, 478–480, 483 Starr Edwards, 793 Statins, 155, 157, 178 acute myocardial infarction, 310, 317 intimal medial thickening, 11 MRI, 238–241 side eﬀects, 159 ST-elevation myocardial infarction (STEMI), 172, 174 reperfusion therapy, 172–173 Stents, 393–395, 396–397 intraluminal, 737 Stiﬀ heart, 18, 24 Stockholm Secondary Prevention Study, 155 STONE, 141 STOP, 134, 137 STOP-2, 137, 138, 140, 141 Streptococcus bovis, 483 Streptococcus faecalis, 483 Streptococcus viridans, 478, 480–483 Streptokinase, 301, 396 route of elimination, 100 Stress cardiovascular response, 16 Stress testing noncardiac surgery, 776 unstable angina, 287 Stripping, 751 Stroke, 155, 625, 669, 684 diabetes, 168–169 diagnosis, 631–634 mitral annular calciﬁcation, 468–470 prevention, 154–155 progression prevention, 640–641 risk factors for, 570–571 symptom reversal, 642–644 Stroke Prevention in Atrial Fibrillation Study (SPAF), 114, 590, 638, 685 Stroke Prevention Using Oral Thrombin Inhibition in Atrial Fibrillation (SPORTIF), 688

Index Stroke volume cycle exercise, 20 Stroke volume index (SVI), 16, 17 Strong Heart Study, 170 Studies of Left Ventricular Dysfunction (SOLVD), 111, 561–562 Study of Perioperative Ischemia Research Group, 767–768 Subarachnoid hemorrhage, 631, 645 Subclavian steal syndrome, 717 Subclinical disease, 3, 62–63 Subfascial endoscopic perforator ligation (SEPS), 751 Substance intoxication, 658 Sudden cardiac death, 817 Sudden death, 419 Sulfonylureas alcohol, 121 Superior mesenteric artery occlusion, 724 Supervised exercise vs. home exercise, 412 Supraventricular tachyarrhythmias, 111, 559–576 atrial ﬁbrillation, 559–573 Survival and Ventricular Enlargement (SAVE) trial, 111, 339, 340 Survival of Myocardial Infraction Long-term Evaluation (SMILE), 308, 340 Survival with Oral d-Sotalol (SWORD), 342, 593 SVI, 16, 17 Swedish Trial in Old Patients with Hypertension (STOP), 134, 137 Swedish Trial in Old Patients with Hypertension 2 (STOP)-2, 137, 138, 140, 141 SWORD, 342, 593 Syncope, 419, 653–672 diagnosis, 660, 669–670 diﬀerential diagnosis, 655 electrocardiography, 659–660 electrophysiological study, 664–665 epidemiology, 653–654 etiology, 654–670 history, 658–659 impact, 654 initial workup, 656, 660 physical examination, 659 structural cardiovascular disorders, 661–662 unexplained, 106 vasovagal, 667 Syst-China, 141

845 Systemic atherogenic risk factors, 218–220 Systemic blood pressure, 194, 198 Systemic hypertension, 131–147 Systemic inﬂammatory markers, 235 Syst-Eur, 141 Systolic blood pressure, 193 Systolic heart failure pharmacotherapy, 544–546 Systolic hypertension, 330 Systolic Hypertension in China (Syst-China), 141 Systolic Hypertension in Europe (Syst-Eur), 141 Systolic Hypertension in the Elderly (SHEP), 107, 134, 136–139, 177, 200 Systolic pressure, 5–10, 131 Tachyarrhythmias, 662 Tachypnea, 696 TACTICS-TIMI, 18, 173 Tamsulosin, 113 Technetium 99m diethylenetriamine pentaacetic acid, 727 Telmisartan route of elimination, 98 Temporary pacing, 313 Tenecteplase, 301 route of elimination, 100 Terazosin route of elimination, 98 Tetracycline interactions, 120 Thiazolidinediones, 179 Thiazolium, 11 Thienopyridines acute myocardial infarction, 304–305 Thiocyanate adverse eﬀects, 311 Thoracoabdominal aortic aneurysms, 722–723 Thrombolysis in Myocardial Infarction (TIMI-II), 306 Thrombolysis in Myocardial Infarction (TIMI-III), 173, 396 Thrombosis inﬂammation, 235 Thrombosis Prevention Trial, 682 Thrombus formation, 232–235 Thyroid disease, 511–522 Thyroxine, 520 TIA [see Transient ischemic attack (TIA)] Ticlid [see Ticlopidine (Ticlid)] Ticlopidine (Ticlid) acute myocardial infarction, 304–305

846 [Ticlopidine] angina, 283 avoidance, 121, 122 route of elimination, 100 transient ischemic attack (TIA), 636 Tilt table testing (TTT), 654, 668 TIMI-II, 306 TIMI-III, 173, 396 Timolol, 109 acute myocardial infarction, 307 route of elimination, 102 TIMP, 225, 231–232 Tinzaparin route of elimination, 100 Tiroﬁban route of elimination, 100 unstable angina, 286 Tissue factor, 233–234 Tissue inhibitors of the metalloproteinase families (TIMP), 225, 231–232 Tissue plasminogen activator (TPA), 395, 642, 702–703 TMLR, 289 Tobacco use cessation, 708 Tocainide atrial ﬁbrillation, 569 myocardial infarction, 341 route of elimination, 99 Tolbutamide interactions, 119, 120 TONE, 135 Torsemide route of elimination, 103 TPA [see Tissue plasminogen activator (TPA)] Trandolapril route of elimination, 98 Trandolapril Cardiac Evaluation Study, 340 Transient ischemic attack (TIA), 669, 688, 712 platelet antiaggregant therapy, 636–637 Transmyocardial laser revascularization (TMLR) angina, 289 Treadmill testing, 261 left ventricular systolic performance, 54–55 Trial of Nonpharmacologic Intervention in the Elderly (TONE), 135 Triamterene route of elimination, 101 Trichlormethiazide route of elimination, 100

Index Tricyclic antidepressants adverse eﬀects, 118 avoidance, 122 Triglycerides, 280 Trimethaphan route of elimination, 104 Troponins, 797 TTT, 654, 668 Type 1 diabetes mellitus, 164–165 Type 2 diabetes mellitus, 165 UA/NSTEMI, 173 Unexplained syncope, 106 United Kingdom Prospective Diabetes Study (UKPDS), 166, 169, 177, 179 Unstable angina, 366 interventional therapy, 286–287 management, 283–287 Unstable Angina and Non-ST-Elevation Myocardial Infarction (UA/NSTEMI), 173 Urokinase route of elimination, 100 VALHEFT systolic heart failure, 544 Valsartan route of elimination, 98 Valvular heart disease noncardiac surgery, 790–793 Vancomycin endocarditis, 485 Vasa vasorum, 228 Vascular aging, 3–11 arterial pressure, 5–10 arterial stiﬀness, 5–10 endothelial dysfunction, 5–10 intimal medial thickening, 3–5 prevention, 10–11 Vascular compliance, 131 Vascular endothelial growth factor (VEGF), 734 Vascular endothelium, 131 Vasodilators stable angina, 288 Vasovagal syncope, 667 VA Stable Angina Study, 363 VA Unstable Angina Study, 364 VCAM, 222–223, 226, 234 VEB, 32 exercise-induced, 33 VEGF, 734 Venous hypertension, 748 Venous stasis ulceration, 748–749

Index Venous thromboembolism, 724 prevention and treatment, 682 Venous ulceration, 751 Ventricles dilation, 79 Ventricular arrhythmias, 32–33, 109, 253, 258, 313, 585–598 angiotensin-converting enzyme inhibitors, 593 automatic implantable cardioverterdeﬁbrillator (AICD), 595–598 beta-blockers, 591–593 calcium channel blockers, 590 class 1 antiarrhythmic drugs, 588–590 class III antiarrhythmic drugs, 593–595 complex prevalence, 585–586 invasive intervention, 595–598 prognosis, 586–587 therapy, 586–595 Ventricular ectopic beats (VEB), 32 exercise-induced, 33 Ventricular septal internal dimensions at end-diastole (VSd), 43–44 Ventricular tachycardia (VT), 32, 115 noninvasive assessment of risk for, 665–666 nonsustained, 109 Verapamil, 113, 139, 140, 142 adverse eﬀects, 118 angina, 281, 282 atrial ﬁbrillation, 563 atrial ﬂutter, 573, 574 avoidance, 117 paroxysmal supraventricular tachycardia (PSVT), 575 route of elimination, 103 Vertebrobasilar disease, 714 Vertebrobasilar insuﬃciency, 717–718 Vertigo, 658 Very low-density lipoprotein cholesterol (VLDL), 194 Veterans Administration Cooperative Study, 115, 426, 571, 712

847 Veterans Aﬀairs Diabetes Feasibility Trial, 179 Vineberg implant procedures, 362 Vital capacity coronary heart disease, 206 Vitamins alcohol, 121 VLDL, 194 VO2max, 18, 19 VSd, 43–44 VT, 32, 115 noninvasive assessment of risk for, 665–666 nonsustained, 109 Walking, 733 Warfarin, 97, 470, 677–678, 682, 686 acute myocardial infarction, 305 alcohol, 121 arterial thrombosis, 731 atrial ﬁbrillation, 570, 571 hyperthyroidism, 516 interactions, 119, 120 noncardiac surgery, 793 nonhemorrhagic adverse eﬀects, 681 route of elimination, 100 stroke, 642 Warfarin Reinfarction Study (WARS), 337, 681, 683 Wenckebach block, 615 West of Scotland Coronary Prevention Study (WOSCOPS), 178 WHI, 343–344 WHO study, 168 Wide pulse pressure, 131 Willems, Dick, 820 Wolﬀ-Parkinson-White syndrome, 611 Women cholesterol, 154–155 Women’s Health Initiative (WHI), 343–344 World Health Organization (WHO) study, 168 WOSCOPS, 178 Ximelagatran, 688