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 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

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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

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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).

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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

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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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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

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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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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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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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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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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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28. Miyatake K, Okamoto M, Kinishita N, et al. Augmentation of atrial contribution to left ventricular inflow in aging as assessed by intracardiac Doppler flowmetry. Am J Cardiol 1984; 53:586–589. 29. Gardin JM, Rohan MK, Davidson DM, Dabestani A, Sklansky M, Garcia R, Knoll ML, White DB, Gardin SK, Henry WL. Doppler transmitral flow velocity parameters: relationship between age, body surface area, blood pressure and gender in normal subjects. Am J Noninvas Cardiol 1987; 1:3–10. 30. Dabestani A, Johnston WD, Tobis JM, et al. Relation between Doppler transmitral diastolic flow and left ventricular filling [abstr]. J Am Coll Cardiol 1984; 3:612. 31. Rokey R, Kuo LK, Zoghbi WA, et al. Determination of parameters of left ventricular diastolic filling with pulsed Doppler echocardiography: comparison with cineangiography. Circulation 1985; 71:543–550. 32. Mantero A, Gentile F, Azzollini M, Barbier P, Beretta L, Casazza F, Corno R, Faletra F, Giagnoni E, Gualtierotti C, Lippolis A, Lombroso S, Mattioli R, Morabito A, Ornaghi M, Pepi M, Pierini S, Todd S. Effect of sample volume location on Doppler-derived transmitral inflow velocity values in 288 normal subjects 20 to 80 years old: an echocardiographic, twodimensional color Doppler cooperative study. J Am Soc Echocardiogr 1998; 11:280–288. 33. Gardin JM, Rohan MK, Davidson D, Dabestani A, Sklansky MI, Garcia R, Knoll ML, White DB, Henry WL. Doppler transmitral flow velocity parameters: relationship between age, body surface area, blood pressure and gender in normal subjects. Am J Noninvas Cardiol 1987; 1:3– 10. 34. Appleton CP, Hatle LK. The natural history of LV filling abnormalities: assessment by twodimensional and Doppler echocardiography. Echocardiography 1992; 9:437–457. 35. Gentile F, Mantero A, Lippolis A, Ornaghi M, Azzollini M, Barbier P, Beretta L, Casazza F, Corno R, Faletra F, Giagnoni E, Gualtierotti C, Lombroso S, Mattioli R, Morabito A, Pepi M, Todd S, Pezzano A. Pulmonary venous flow velocity patterns in 143 normal subjects aged 20 to 80 years old. An echo 2D colour Doppler cooperative study. Eur Heart J 1997; 18:148–164. 36. Klein AL, Burstow DJ, Tajik AJ, Zacharia PK, Bailey KR, Seward JB. Effects of age on left ventricular dimensions and filling dynamics in 117 normal persons. Mayo Clin Proc 1994; 69: 212–224. 37. Rossvoll O, Hatle LK. Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993; 21:1687– 1696. 38. Klein AL, Abdalla I, Murray RD, Lee JC, Vandervoort P, Thomas JD, Appleton CP, Tajik AJ. Age independence of the difference in duration of pulmonary venous atrial reversal flow and transmitral A-wave flow in normal subjects. J Am Soc Echocardiogr 1998; 11:458–465. 39. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322:1561–1566. 40. 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. 41. Benjamin E, Levy D, Plehn J, Belanger A, D’Agostino R, Wolf P. Left atrial size: an independent risk factor for stroke [abstr]. Circulation 1989; 80(suppl 2):615. 42. Fried L, Borhani N, Enright P, Furberg C, Gardin JM, Kronmal R, Kuller L, Manolio T, Mittelmark M, Newman A, O’Leary D, Psaty B, Rautaharju P, Tracy R, Weiler P, for the CHS Collaborative Research Group. Cardiovascular Health Study: design and rational. Ann Epidemiol 1991; 1:263–276. 43. Gardin JM, Wong ND, Bommer W, Klopfenstein HS, Smith V-E, Tabatznik B, Siscovick D, Lobodzinski S, Anton-Culver H, Manolio TA. Echocardiographic design of a multicenter investigation of free-living elderly subjects: The Cardiovascular Health Study. J Am Soc Echocardiogr 1992; 5:63–72.

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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).

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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.

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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).

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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].

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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

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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

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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

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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

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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

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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

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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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Frishman et al.

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

Cardiovascular Drug Therapy

105

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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107

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

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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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121

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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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].

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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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16. Saltzberg S, Stroh JA, Frishman WH. Isolated systolic hypertension in the elderly: pathophysiology and treatment. Med Clin North Am 1988; 72:523–547. 17. Anderson RJ, Reed G, Kirk LM. Therapeutic considerations for elderly hypertensives. Clin Ther 1982; 5:25–38. 18. LaPalio LR. Hypertension in the elderly. Am Fam Physician 1995; 52:1161–1165. 19. Holzgreve H, Middeke M. Treatment of hypertension in the elderly. Drugs 1993; 46(suppl 2):24–31. 20. Aronow WS. Cardiovascular drug therapy in the elderly. In: Frishman WH, Sonnenblick EH, eds. Cardiovascular Pharmacotherapeutics. New York: McGraw Hill, 1997:1267–1281. 21. Amery A, Birkenhager W, Brixko P, et al. Morbidity and mortality results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985; 1:1349–1354. 22. Coope J, Warrender TS. Randomized trial of the treatment of hypertension in elderly patients in primary care. Br Med J 1986; 293:1145–1151. 23. Dahlof B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338:1281–1285. 24. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1992; 304:405–412. 25. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 255:3255–3264. 26. O’Rourke M. Arterial stiffness, systolic blood pressure, and logical treatment of arterial hypertension. Hypertens 1990; 15:339–347. 27. Stamler J, Neaton JD, Wentworth DN. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease. Hypertension 1989; 13(suppl 5):2–12. 28. Menard J, Day M, Chatellier G, Laragh JH. Some lessons from Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens 1992; 5:325–330. 29. Lenfant C. High blood pressure. Some answers, new questions, continuing challenges. JAMA 1996; 275:1604–1606. 30. Arima H, Tanizaki Y, Kiyohara Y, et al. Validity of the JNC VI recommendations for the management of hypertension in a general population of Japanese elderly: the Hisayama Study. Arch Intern Med 2003; 163:361–366. 30a. Whelton PK, He J, Appel LJ, et al., for the National High Blood Pressure Education Program Coordinating Committee. Primary prevention of hypertension. Clinical and public health advisory from the National High Blood Pressure Education Program. JAMA 2002; 288: 1882–1888. 31. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE) Cooperative research group. Am J Cardiol 1998; 82:1501–1508. 32. Appel J, Moore TJ, Obarzanek E, et al. for the DASH Collaborative Research Group. A Clinical Trial of the Effects of Dietary Patterns on Blood Pressure. Engl J Med 1997; 336:1117–1124. 33. Villareal H, Exaire JE, Revello A, Soni J. Effects of chlorothiazide on systemic hemodynamics in essential hypertension. Circulation 1962; 26:405–408. 34. Lund-Johaansen P. Hemodynamic changes in long term diuretic therapy of essential hypertension. Acta Med Scand 1970; 187:509–518. 35. Decavalho JGR, Dunn F, Frohlich ED. Hemodynamic correlates of prolonged thiazide therapy. Comparison of responders and nonresponders. Clin Pharmacol Ther 1979; 22:75–880. 36. National Heart Foundation of Australia. Treatment of mild hypertension in the elderly. Med J Australia 1981; 2:398–402. 37. Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA 1997; 278:212–216.

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38. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuetic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 1996; 276: 1886–1892. 39. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981–2997. 40. Neutel JM. Metabolic manifestations of low dose diuretics. Am J Med 1996; 101(suppl 3A): 71S–82S. 41. Frishman WH, Clark A, Johnson B. Effects of cardiovascular drugs on plasma lipids and lipoproteins. In: Frishman WH, Sonnenblick EH, eds. Cardiovascular Pharmacotherapeutics. New York: McGraw Hill, 1997:1515–1559. 42. Ekbom T, Dahlof B, Hansson L, et al. Antihypertensive efficacy and side effects of 3 beta blockers and a diuretic in elderly hypertensives. A report of the STOP Hypertension Study. J Hypertens 1992; 10:1525–1530. 43. Hansson L, Lindholm LH, Ekbom I, et al. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity in the Swedish Trial of Old Patients with Hypertension-2 Study. Lancet 1999; 354:1751–1756. 44. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomized trial against atenolol. Lancet 2002; 359:1004–1010. 45. Messerli FH, Grossman E, Goldbourt U. Are beta blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998; 279:1903–1907. 46. Frishman WH. Alpha- and beta-adrenergic blocking drugs. In: Frishman WH, Sonnenblick EH, Sica DA, eds. Cardiovascular Pharmacotherapeutics. 2d ed. New York: McGraw Hill, 2003:67–97. 47. Frishman WH, Sica DA. h-Adrenergic blockers. In: Izzo JL Jr, Black HR, eds. Hypertension Primer. 3rd ed. Dallas, American Heart Assn., 2003:417–420. 47a. Palatini P, THijs L, Staessen JA, et al., for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med 2002; 162:2313–2321. 48. Frishman WH, Sica DA. Calcium channel blockers. In: Frishman WH, Sonnenblick EH, Sica D, eds. Cardiovascular Pharmacotherapeutics. 2d ed. New York: McGraw-Hill, 2003:105– 130. 49. Keefe D, Frishman WH. Clinical pharmacology of the calcium blocking drugs. In: Packer M, Frishman WH, eds. Calcium Channel Antagonists in Cardiovascular Disease. Norwalk, CT: Appleton-Century-Crofts, 1984:3–19. 50. Frishman WH, Sonnenblick EH. Beta-adrenergic blocking drugs and calcium channel blockers. In: Alexander RW, Schlant RC, Fuster V, eds. Hurst’s The Heart. 9th ed. New York: McGraw Hill, 1998:1583–1618. 51. Frishman WH. Current status of calcium channel blockers. Curr Probl Cardiol 1994; 19:637– 688. 52. Frishman WH, Cheng-Lai A, Chen J. Current Cardiovascular Drugs. 3rd ed. Philadelphia: Current Medicine, 2000:148–166. 53. Erne P, Conen D, Kowski W, et al. Calcium antagonist induced vasodilation in peripheral, coronary, and cerebral vasculature as important factors in the treatment of elderly hypertensives. Eur Heart J 1987; 8(suppl K):49–56. 54. Busse JC, Materson BJ. Geriatric hypertension: the growing use of calcium-channel blockers. Geriatrics 1988; 43:51–58. 55. Forette F, Bert P, Rigaud A. Are calcium antagonists the best option in elderly hypertensives? J Hypertens 1994; 12(suppl 6):S19–S23. 56. Abernethy DR, Schwartz JB, Todd EL, et al. Verapamil pharmacodynamics and disposition

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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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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.

REFERENCES 1. 2. 3. 4.

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Landis DS. The Wealth and Poverty of Nations: Why Some Are So Rich and Some So Poor. New York: W.W. Norton and Company, 1998. Mukerji V, Holman AJ, Artis AK, Alpert MA, Hewett JE. Risk factors for coronary atherosclerosis in the elderly. Angiology 1989; 40:88–93. Kannel WB. Nutrition and the occurrence and prevention of cardiovascular disease in the elderly. Nutr Rev 1998; 46:68–78. Manolio TA, Ettinger WH, Tracy RP, Kuller LH, Borhani NO, Lynch JC, Fried LP. Epidemiology of low cholesterol levels in older adults. The Cardiovascular Health Study. Circulation 1993; 87:728–737. Rubin SM, Sidney S, Black DM, Browner WS, Hulley SB, Cummings SR. High blood cholesterol in elderly men and the excess risk of coronary heart disease. Ann Intern Med 1990; 113: 916–920. Kannel WB, Garrison RJ, Wilson PWF. Obesity and nutrition in elderly diabetic patients. Am J Med 1986; 80(suppl 5A):22–30. Corti M-C, Guralnik JM, Salive ME, Harris T, Ferrucci L, Glynn RJ, Havlik RJ. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older people. Ann Intern Med 1997; 126:753–760. LaRosa JC. Triglycerides and coronary risk in women and the elderly. Arch Intern Med 1997; 157:961–968. Ansell BJ. Cholesterol, stroke risk, and stroke prevention. Curr Athero Rep 2001; 2:92–96. Alcorn HG, Wolfson SK Jr, Sutton-Tyrrel K, Kuller LH, O’Leary D. Risk factors for abdominal aortic aneurysms in older adults enrolled in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1996; 16:963–970. Dayton S, Pearce ML, Hashimoto S, Dixon WJ, Tomiyasu U. A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 1969; 40(suppl II):1–63. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1998; 223:405–418. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282:2340–2346. Hebert PR, Gaziano M, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 1997; 278:313–321. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002; 360:7–22.

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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

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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

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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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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].

Diagnosis of CAD

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).

Diagnosis of CAD

265

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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74. 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. 75. Busby MJ, Shefrin EA, Fleg JL. Prevalence and long-term significance of exercise-induced frequent or repetitive ventricular ectopic beats in apparently healthy volunteers. J Am Coll Cardiol 1989; 14:1659–1665. 76. Hlatky MA, Pryor DB, Harrell FE, Califf RM, Mark DB, Rosati RA. Factors affecting sensitivity and specificity of exercise electrocardiography: multivariable analysis. Am J Med 1984; 77(1):64–71. 77. Newman KP, Phillips JH. Gradual exercise testing for diagnosis of coronary artery disease in elderly patients. South Med J 1988; 81:430–432. 78. Chaitman BR, Bourassa MG, Davis K, Rogers WJ, Tyras DH, Berger R, Kennedy JW, Fisher L, Judkins MP, Mock MB, Killip T. Angiographic prevalence of high-risk coronary artery disease in patient subsets (CASS). Circulation 1981; 64:360–367. 79. Arruda AM, Das MK, Roger VL, Klarich KW, Mahoney DW. Prognostic value of exercise echocardiography in 2,632 patients z65 years of age. J Am Coll Cardiol 2001; 37(4):1036–1041. 80. Glover DR, Robinson CS, Murray RG. Diagnostic exercise testing in 104 patients over 65 years of age. Eur Heart J 1984; 5(suppl E):59–61. 81. Mark DB, Shaw L, Harrell FE, Hlatky MA, Lee KL, Bengtson JR, McCants CB, Califf RM, Pryor DB. Prognostic value of a treadmill exercise score in outpatients wiht suspected coronary artery disease. N Engl J Med 1991; 325(12):849–853. 82. Kwok JMF, Miller TD, Hodge DO, Gibbons RJ. Prognostic value of the Duke treadmill score in the elderly. J Am Coll Cardiol 2002; 39:1475–1481. 83. Smith SC Jr, Gilpin E, Ahnve S, Dittrich H, Nicod P, Henning H, Ross JOutlook after acute myocardial infarction in the very elderly compared with that in patients aged 65 to 75 years. J Am Coll Cardiol 1990; 16(4):784–792. 84. Ciaroni S, Delonca J, Righetti A. Early exercise testing after acute myocardial infarction in the elderly: clinical evaluation and prognostic significance. Am Heart J 1993; 126:304–311. 85. Deckers JW, Fioretti P, Brower RW, Simoons ML, Baardman T, Hugenholtz PG. Ineligibility for predischarge exercise testing after myocardial infarction in the elderly: implications for prognosis. Eur Heart J 1984; 5(suppl E):97–100. 86. Vaitkevicius PV, Fleg JL. An abnormal exercise treadmill test in an asymptomatic older patient. J Am Geriatr Soc 1996; 44:83–88. 87. Iskandrian AS, Heo J, Decoskey D, Askenase A, Segal BL. Use of exercise thallium-201 imaging for risk stratification of elderly patients wiht coronary artery disease. Am J Cardiol 1988; 61(4):269–272. 88. Hilton TC, Shaw LJ, Chaitman BR, Stocke KS, Goodgold HM, Miller DD. Prognostic significance of exercise thallium-201 testing in patients aged z70 years with known or suspected coronary artery disease. Am J Cardiol 1992; 69(1):45–50. 89. Fleg JL, Gerstenblith G, Zonderman AB, Becker LC, Weisfeldt ML, Costa PT, Lakatta ED. Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardigraphy in asymptomatic volunteers. Circulation 1990; 81(2):428–436. 90. Quinones MA, Verani MS, Haichin RM, Mahmarian JJ, Suarez J, Zoghbi WA. Exercise echocardiography versus 102 Tl single-photon emission computed tomography in evaluation of coronary artery disease. Analysis of 292 patients. Circulation 1992; 85(3):1026–1031. 91. Crouse LJ, Harbrecht JJ, Vacek JL, Rosamond TL, Kramer PH. Exercise echocardiography as a screening test for coronary artery disease and correlation with coronary arteriography. Am J Cardiol 1991; 67(15):1213–1218. 92. Ranhosky A, Kempthorne-Rawson J, the Intravenous Dipyridamole Thallium-Imaging Study Group. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Circulation 1990; 81:1205–1209.

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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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72. Aronow WS. Commentary. Approach to symptomatic coronary disease in the elderly: TIME to change? Lancet 2001; 358:945–946. 73. Miettinen TA, Pyorala K, Olsson AG, Musliner TA, Cook TJ, Faegeman O, Berg K, Pedersen T, Kjekshus J, for the Scandinavian Simvastatin Study Group. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris. Findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997; 96:4211–4218. 74. Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, Limacher M, Kell S, Glasser SP, Grant J, Davis BR, Pfeffer MA, Braunwald E, for the CARE Investigators. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) Trial. Ann Intern Med 1998; 129:681–689. 75. The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339:1349– 1357. 76. Aronow WS, Ahn C. Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol 125 mg/dL treated with statins versus no lipid-lowering drug. Am J Cardiol 2002; 89:67–69. 77. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002; 360:7–22. 78. Willich SN, Lewis M, Lowel H, Arntz HR, Schubert F, Schroder R. Physical exertion as a trigger of acute myocardial infarction. N Engl J Med 1993; 329:1684–1690. 79. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on six-month survival. J Am Med Assoc 1993; 270:1819–1825. 80. Aronow WS. Exercise therapy for older persons with cardiovascular disease. Am J Geriatr Cardiol 2001; 10:245–252. 81. Schuler G, Schlierf G, Wirth A, Mautner HP, Scheurlen H, Thumm M, Roth H, Schwarz F, Kohlmeier M, Mehmel HC. Low-fat diet and regular supervised physical exercise in patients with symptomatic coronary artery disease: reduction of stress-induced myocardial ischemia. Circulation 1988; 77:172–181. 82. Frishman WH, Retter A, Mikailidis J, Ganem A, Sekhon J, Mohandas R, Khaski D, Sheikh F, Orlic D, Anversa P. Innovative pharmacologic approaches to the treatment of myocardial ischemia. In: Frishman WH, Sonnenblick EH, Sica D, eds. Cardiovascular Pharmacotherapeutics. 2d ed. New York: McGraw Hill, 2003. In press. 83. Frazier OH, Cooley DA, Kadipasaoglu KA, Pehlivanoglu S, Lindenmeier MI, Barasch E, Conger JC, Wilansky S, Moore WH. Myocardial revascularization with laser. Prelimary findings. Circulation 1995; 92(suppl II):II-58–II-65. 84. Donovan CL, Landolfo KP, Lowe JE, Clements F, Coleman RB, Ryan T. Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial laser revascularization in patients with refractory angina pectoris. J Am Coll Cardiol 1997; 30:607– 612. 85. Lauer B, Junghans U, Stahl F, Kluge R, Oesterle SN, Schuler G. Catheter-based percutaneous myocardial laser revascularization in patients with end-stage coronary artery disease. J Am Coll Cardiol 1999; 34:1663–1670. 86. Schofield PM, Sharples LD, Caine N, Burns S, Tait S, Wistow T, Buxton M, Wallwork J. Transmyocardial laser revascularization in patients with refractory angina: a randomised controlled trial. Lancet 1999; 353:519–524. 87. Oesterle SN, Sanborn TA, Ali N, Resar J, Ramee SR, Heuser R, Dean L, Knopf W, Schofield P, Schaer GL, Reeder G, Masden R, Yeung AC, Burkhoff D. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial. Lancet 2000; 356:1705– 1710.

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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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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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142. Oliva PB, Hammill SC, Edwards WD. Cardiac rupture, a clinically predictable complication of acute myocardial infarction: report of 70 cases with clinicopathologic correlations. J Am Coll Cardiol 1993; 22:720–726. 143. Harrison MR, MacPhail B, Gurley JC, et al. Usefulness of color Doppler flow imaging to distinguish ventricular septal defect from acute mitral regurgitation complicating acute myocardial infarction. Am J Cardiol 1989; 64:697–701. 144. Smyllie JH, Sutherland GR, Geuskens R, et al. Doppler color flow mapping in the diagnosis of ventricular septal rupture and acute mitral regurgitation after myocardial infarction. J Am Coll Cardiol 1990; 15:1449–1455. 145. Birnbaum Y, Fishbein MC, Blanche C, Siegel RJ. Ventricular septal rupture after acute myocardial infarction. N Engl J Med 2002; 347:1426–1432. 146. Blanche C, Khan SS, Chaux A, et al. Postinfarction ventricular septal defect in the elderly: Analysis and results. Ann Thorac Surg 1994; 57:1244–1247. 147. Clements SD, Story WE, Hurst JW, et al. Ruptured papillary muscle, a complication of myocardial infarction: clinical presentation, diagnosis, and treatment. Clin Cardiol 1985; 8:93– 103. 148. Vlodaver Z, Coe JI, Edwards JE. True and false left ventricular aneurysms. Propensity for the latter to rupture. Circulation 1975; 51:567–572. 149. Frances C, Romero A, Grady D. Left ventricular pseudoaneurysm. J Am Coll Cardiol 1998; 32:557–561. 150. Figueras J, Cortadellas J, Evangelista A, Soler-Soler J. Medical management of selected patients with left ventricular free wall rupture during acute myocardial infarction. J Am Coll Cardiol 1997; 29:512–518. 151. Raitt MH, Kraft CD, Gardner CJ, Pearlman AS, Otto M. Subacute ventricular free wall rupture complicating myocardial infarction. Am Heart J 1993; 126:946–955. 152. Califf RM, Bengtson JR. Cardiogenic shock. N Engl J Med 1994; 330:1724–1730. 153. Leor J, Goldbourt U, Reicher-Reiss H, et al. Cardiogenic shock complicating acute myocardial infarction in patients without heart failure on admission: incidence, risk factors, and outcome. Am J Med 1993; 94:265–273. 154. Goldberg RJ, Gore JM, Alpert JS, et al. Cardiogenic shock after acute myocardial infarction. Incidence and mortality from a community-wide perspective, 1975 to 1988. N Engl J Med 1991; 325:1117–1122. 155. Berger AK, Radford MJ, Krumholz HM. Cardiogenic shock complicating acute myocardial infarction in elderly patients: does admission to a tertiary center improve survival? Am Heart J 2002; 143:768–776. 156. Anderson RD, Ohman EM, Homes DR, et al. Use of intraaortic balloon counterpulsation in patients presenting with cardiogenic shock: observations from the GUSTO-I Study. J Am Coll Cardiol 1997; 30:708–715. 157. Paul SD, O’Gara PT, Mahjoub ZA, et al. Geriatric patients with acute myocardial infarction: cardiac risk factor profiles, presentation, thrombolysis, coronary interventions, and prognosis. Am Heart J 1996; 131:710–715. 158. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303:897–902. 159. DeWood MA, Stifter WF, Simpson CS, et al. Coronary arteriographic findings soon after non-Q-wave myocardial infarction. N Engl J Med 1986; 315:417–423. 160. Keen WD, Savage MP, Fischman DL, et al. Comparison of coronary angiographic findings during the first six hours of non-Q-wave and Q-wave myocardial infarction. Am J Cardiol 1994; 74:324–328. 161. Berger CJ, Murabito JM, Evans JC, et al. Prognosis after first myocardial infarction. Comparison of Q-wave and non-Q-wave myocardial infarction in the Framingham Heart Study. JAMA 1992; 268:1545–1551. 162. Krone RJ, Friedman E, Thanavaro S, et al. Long-term prognosis after first Q-wave (trans-

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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 6