TRIGGERING OF ACUTE CORONARY SYNDROMES

Developments in Cardiovascular Medicine

VOLUME 170

The titles published in this series are listed at the end of this volume.

Triggering of acute coronary syndromes

Implications for prevention

Edited by

STEFAN N. WILLICH Institute for Epidemiology, Social and Preventive Medicine, Humboldt University of Berlin, Klinikum Charite, Berlin, Germany

and

JAMES E. MULLER Institute for Prevention of Cardiovascular Disease, Deaconess Hospital, Harvard Medical School, Boston, U.S.A.

Kluwer Academic Publishers Dordrecht / Boston / London

Library of Congress Cataloging-in-Publication Data

Triggeri' g of "cute coronary syndromes: impl ications for prevention I edited by Stefan N. Willich and James E. Muller

p. cm. -- (Developments in cardiovascular medicine; v. 170) Inc I udes index.

1. Myocardial infarction. 2. Cardiac arrest. I. Muller. James E. II. Series.

[DNLM: 1. Coronary Disease--prevention & control. 2. Coronary Disease--epidemiology. 3. Coronary Disease--physiopathology. 4. Risk Factors. 6. Willich. Stefan N. W1 DE997VME v.170 1996 WG 300 T828 19961 RC686.I6T76 1996 616. 1 '23--dc20 DNLM/DLC for Library of Congress

ISBN-13: 978-94-010-7205-2 e-ISBN-13: 978-94-009-1577-0 DOl: 10.1007/978-94-009-1577-0

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96-21136

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To Tonya and Kathleen

Table of contents

About the editors x

List of contributors Xl

Foreword by E. Braunwald xv

Introduction by S.N. Willich, J.E. Muller xvii

PART ONE: Epidemiology

1. Magnitude of cardiovascular disease: impact and prevention in populations 1 Diane E. Bild & Lawrence Friedman

2. Secular trends and declining mortality rates from coronary heart disease in the United States 15 Robert J. Goldberg

3. Circadian variation in the incidence of transient myocardial ischemia 37 David Mulcahy & Henry Purcell

4. Circadian variation in the onset of myocardial infarction and sudden cardiac death 53 James E. Muller & Stefan N. Willich

5. Triggering of myocardial infarction by physical activity, emotional stress and sexual activity 71 Murray A. Mittleman

6. Physical activity, time of awakening, and other possible triggers of sudden cardiac death Stefan N. Willich & Hans-Richard Arntz 81

7. Subacute psychobiological factors predisposing to triggering of coronary syndromes 95 Sylvia Wassertheil-Smoller

Vlll Contents

PART TWO: Physiology

8. The genetic contribution to the onset of acute coronary heart disease 111 Fram;ois Cambien, Odette Poirier, Alun Evans, Dominique Arveiler, Gerald Luc, lean-Pierre Cambou & Laurence Tiret

9. Hemostatic risk factors for cardiovascular disease Praveen P. ladhav & Geoffrey H. Tofier

10. The imbalance of coagulation and fibrinolysis in coronary heart

135

disease and its relation to traditional risk factors 153 Kaj Winther, Steen Elkjrer Husted, Hans Krremmer Nielsen & 1 flJrn Dalsgaard Nielsen

11. Mechanisms contributing to the abrupt conversion from stable to unstable angina and myocardial infarction 175 lames T. Willerson

12. Circadian fluctuation of fibrinolytic factors in blood. Investigation, importance and clinical consequences 185 Felicita Andreotti & Alessandro Manzoli

13. The role of thrombosis in acute coronary heart disease 201 Antonio Fernandez-Ortiz & Valentin Fuster

14. The role of coronary vasomotor tone in coronary artery disease 219 Arshed A. Quyyumi

PART THREE: Pathology

15. Models of the intracoronary pathogenesis of acute coronary heart disease 237 loseph P. Jiang, Charles L. Feldman & Peter H. Stone

16. Some thoughts on the causes of coronary thrombosis in atherosclerotic arteries and on the research necessary for their future exploration 259 Paris Constantinides

17. Determinants of rupture of atherosclerotic coronary lesions 267 Pedro R. Moreno, Prediman K. Shah & Erling Falk

PART FOUR: Prevention

18. Primary prevention of triggering of coronary heart disease 285 Ira S. Ockene

Contents IX

19. Chronopharmacological aspects of coronary heart disease 295 Bjorn Lemmer & Klaus Witte

20. Pre hospital care of acute coronary heart disease 309 Hans-Richard Arntz, Richard Stern & Stefan N. Willich

21. Pharmacological and invasive therapy for acute myocardial infarction 331 Rolf Schroder

22. The role of electrophysiology and pharmacotherapy in prevention of factors triggering sudden cardiac death 347 Ralph Haberl, Peter Steinbigler & Gerhard Steinbeck

23. Secondary prevention of myocardial infarction: the roles of f3-adrenergic blockers, calcium-channel blockers, angiotensin converting enzyme inhibitors, and aspirin 367 William H. Frishman

24. Gene therapy for the vulnerable atherosclerotic plaque Laurent J. Feldman & Jeffrey M. Isner

Index

395

413

About the editors

Stefan N. Willich is Chair of the Institute for Epidemiology, Social and Preventive Medicine at Klinikum Charite, Humboldt University of Berlin. A graduate from Munich University Medical School and Harvard School of Public Health, Dr. Willich completed training in internal medicine, cardiology, and epidemiology in Berlin and Boston. As part of his focus on clinical epidemiology, Dr. Willich has developed the research field of triggering of cardiovascular disease in Germany, following work with Dr. James Muller's group in the mid 1980s.

James E. Muller is Chief of the Cardiovascular Division of Deaconess Hospital, Harvard Medical School. A graduate of the University of Notre Dame and the Johns Hopkins University School of Medicine, Dr. Muller has been engaged in research on the triggering of cardiovascular disease since 1985 when he and his colleagues reported the morning increase in onset of acute myocardial infarction. He is a Co-Director of the Institute for Prevention of Cardiovascular Disease that is conducting studies on the epidemiologic, pathophysiologic and basic science aspects of triggering of disease onset.

List of contributors

FELICIT A ANDREOTTI Lecturer, Istituto di Cardiologia, Universita Cattolica del Sacro Cuore, Policlinico Gemelli, Largo F. Vito, 1,1-00168 Rome, Italy

HANS-RICHARD ARNTZ Assistant Professor, Department of Medicine, Klinikum Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany

DIANEBILD Medical Officer, Division of Epidemiology and Clinical Applications, National Heart, Lung and Blood Institute, Federal Building, 7550 Wisconsin Avenue, Room 212, Bethesda, MD 20892, U.S.A.

EUGENE BRAUNW ALD Professor, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115-6195, U.S.A.

FRAN<;ms CAMBIEN Professor, INSERM, SC7, 17, rue du Fer a Moulin, F-75005 Paris, France

PARIS CONSTANTINIDES Professor em., Department of Clinical Anatomy, UBC Medical School, 903-540 Lonsdale, North Vancouver, BC, Canada V7M 2G7

ERLINGFALK Associate Professor, Institute of Forensic Medicine, Odense University, Odense, Denmark

CHARLES L. FELDMAN Lecturer, Cardiovascular Division, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, U.S.A.

LAURENT J. FELDMAN Fellow, Hopital Bichat, 46 Rue Henri Huchard, F-75018 Paris, France

xii List of contributors

ANTONIO FERNANDEZ-ORTIZ University Hospital San Carlos, Martin Lagos, 28040 Madrid, Spain

LAWRENCE FRIEDMAN Director, Division of Epidemiology and Clinical Applications, National Heart, Lung and Blood Institute, Federal Building, 7550 Wisconsin Avenue, Room 212, Bethesda, MD 20892, U.S.A.

WILLIAM H. FRISHMAN Professor, Division of Cardiology, Department of Medicine, The Albert Einstein College of Medicine/Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY 10461-2373, U.S.A.

VALENTIN FUSTER Professor, Division of Cardiology, Mt. Sinai Medical Center, Gustave L. Levy Place, New York, NY 10029, U.S.A.

ROBERTJ.GOLDBERG Professor, Department of Cardiovascular Medicine, University of Mas­sachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, U.S.A.

RALPH HABERL Assistant Professor, I Medical Clinic, Klinikum Grosshadem, Ludwig­Maximilians-University Munich, Marchionistr. 15, D-81377 Munich, Germany

JEFFREY M. ISNER Professor, Cardiovascular Research, Tufts University School of Medicine, St. Elizabeth's Medical Center, 736 Cambridge Street, Boston, MA 02135, U.S.A.

PRA VEEN P. JADHAV Fellow, Institute for Prevention of Cardiovascular Disease, Harvard Medical School, Deaconess Hospital, 5th floor, Kennedy Building, One Autumn Street, Boston, MA 02215, U.S.A.

JOSEPH P. JIANG Fellow, Cardiovascular Division, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, U.S.A.

BJORN LEMMER Professor, Institute for Pharmacology and Toxicology, Ruprecht-Karls­University Heidelberg, Maybachstr. 14-16, D-68169 Mannheim, Germany

List of contributors Xlll

ALESSANDRO MANZOLI Clinical Fellow, Istituto di Cardiologia, Universita Cattolica del Sacro Cuore, Policlinico Gemelli, Largo F. Vito, 1,1-00168 Rome, Italy

MURRAY A. MITTLEMAN Instructor, Institute for Prevention of Cardiovascular Disease, Harvard Medical School, Deaconess Hospital, One Autumn Street, 5th Floor, Boston, MA 02215, U.S.A.

PEDRO R. MORENO Fellow, Cardiac Catheterization Laboratories, Massachusetts General Hospital, Boston, MA 02114, U.S.A.

DAVID MULCAHY Consultant, Adelaide Hospital, Trinity College, Peter Street, Dublin 8, Ireland

JAMES E. MULLER Associate Professor, Institute for Prevention of Cardiovascular Disease, Deaconess Hospital, Harvard Medical School, One Autumn Street, 5th Floor, Boston, MA 02215, U.S.A.

IRA S. OCKENE Professor, Preventive Cardiology, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01655, U.S.A.

HENRY PURCELL Fellow, Royal Brompton Hospital, Sydney Street, London SW3, U.K.

ARSHED A. QUYYUMI Senior Investigator, Cardiology Branch, Building 10, NHLBI, National Institutes of Health, Bldg 10, 7B15, Bethesda, MD 20892, U.S.A.

ROLF SCHRODER Professor em., Klinikum Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, Haus II, D-12200 Berlin, Germany

PREDINIAN K. SHAH Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90077, U.S.A.

GERHARD STEINBECK Professor, I Medical Clinic, Klinikum Grosshadem, Ludwig-Maximillians­University Munich, Marchionistr. 15, D-81377 Munich, Germany

XIV List of contributors

PETER STEINBIGTER Fellow, I Medical Clinic, Klinikum Grosshadem, Ludwig-Maximilians­University Munich, Marchionistr. 15, D-81377 Munich, Germany

RICHARD STERN Instructor, Department of Medicine, Klinikum Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany

PETER H. STONE Associate Professor, Cardiovascular Division, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, U.S.A.

GEOFFREY H. TOFLER Assistant Professor, Institute for Prevention of Cardiovascular Disease, Harvard Medical School, Deaconess Hospital, One Autumn Street, 5th Floor, Boston, MA 02215, U.S.A.

SYLVIA W ASSERTHEIL-SMOLLER Professor, Division of Epidemiology & Biostatistics, The Albert Einstein College of Medicine, Belfer Building, Room 1312, 1300 Morris Park Avenue, Bronx, NY 10461-1602, U.S.A.

JAMES T. WILLERS ON Professor, Cardiology Research, Texas Heart Institute, MC 1-191, P.O. Box 20345, Houston, TX 77225-0345, U.S.A.

STEFAN N. WILLICH Professor, Institute for Epidemiology, Social and Preventive Medicine, Klinikum Charite, Humboldt University of Berlin, D-I0098 Berlin, Germany

KAJWINTHER Director, Department of Clinical Chemistry and Blood Transfusion, Kolding Hospital, DK-6000 Kolding, Denmark

KLAUS WITTE Fellow, Institute for Pharmacology and Toxicology, Ruprecht-Karls­University Heidelberg, Maybachstr. 14-16, D-68169 Mannheim, Germany

Foreword

Coronary artery disease, perhaps more than any other condition, may be considered the quintessential "twentieth century disease". When the century began, acute myocardial infarction was uncommon and the pathogenesis not clear. Early in the century the pathologic-clinical correlations between coronary atherosclerosis, coronary thrombosis and myocardial infarction were established, opening the door to much of the research that was to follow. The prevalence of coronary artery disease grew at an alarming rate. By mid-century it had reached epidemic proportions and had become the most common cause of death in industrialized nations. Soon, however, clues to the pathogenesis emerged and these led to massive campaigns to reduce the risk of coronary artery disease in populations. Simultaneously, the appli­cation of newly developed monitoring, pharmacologic, surgical and most recently catheter-based techniques reduced both death and disability in indi­vidual patients. By the mid-1960s the tide began to turn and the incidence of coronary deaths has declined steadily since then. However, despite this encouraging development, coronary artery disease remains the most impor­tant cause of death in North America and Europe.

We recognize two principal forms of coronary artery disease. The chronic form, due to gradual narrowing of the lumina of coronary arteries, is manifest as progressive, sometimes disabling, angina pectoris. This symptom can usu­ally be managed by pharmacotherapy or by coronary revascularization. The acute form, on the other hand, presents with a catastrophic event - sudden death, acute myocardial infarction or acutely disabling unstable angina. Until quite recently, little was known about the events that trigger the de novo occurrence of acute coronary events in previously asymptomatic persons or the conversion of chronic to acute coronary artery disease. However, largely through the pioneering efforts of one of the editors, Dr. Muller, the identifi­cation of such triggers and their possible prevention is now beginning to receive appropriate attention.

This book represents the first systematic review of this burgeoning new area of research. Drs. Willich and Muller deserve credit for having assembled experts in the several disciplines - genetics, physiology, pharmacology, cardi­ology, hematology, and epidemiology - which can contribute to an under­standing of the triggering of acute coronary events. In their contributions, each of the authors has provided an important building block to what is now an imposing edifice of knowledge.

Research into triggering of acute coronary events is of the utmost imp or-

XVI Foreword

tance and this book provides an important platform from which future work in this field can be launched. Given the overall success in managing chronic coronary artery disease, the next challenge is to prevent the development of acute coronary events. If this challenge is met successfully (and there are many provocative ideas in this book how this might be achieved), then we will have come full circle and should be able to enter the next century as we entered this one - with coronary artery disease low on the list of mankind's fatal, disabling illnesses.

Eugene Braunwald, M.D. Boston, Massachusetts

Introduction

STEFAN N. WILLICH and JAMES E. MULLER

To our knowledge, this is the first book devoted exclusively to the topic of triggering of acute coronary heart disease. This new research field is of great importance because coronary disease remains the leading cause of death in most industrial countries, accounting for approximately 25% of total mor­tality. Despite increasing insight into long-term risk factors for coronary disease and the dramatic improvement in acute in-hospital therapy during the past decades, the number of coronary deaths remains high, and in many countries is not declining. An important reason for this continuing high mortality is that approximately 50% of the deaths from coronary disease occur out-of-hospital and suddenly.

The need to identify the acute causes of sudden death and infarction has led to a rapid growth of interest over the last decade in the field of triggering research. Epidemiologic observations, newly identified acute and chronic risk factors for coronary artery disease, and pathophysiologic studies of the conversion of chronic coronary disease to an acute event have greatly ex­panded our knowledge of triggering mechanisms. As this literature develops and mechanisms are more fully understood, the prospects for design of more effective preventive therapy will be enhanced. The number of scientific publications on triggering of coronary artery disease has increased steadily since 1985, and the topic has been a focus of discussion at national cardiologic meetings and the National Heart, Lung, and Blood Institute in the United States.

This text is a compilation of the major advances in study of triggering of coronary heart disease that have taken place over the last decade. The triggering research, which is presented in the context of broader advances in the epidemiology and prevention of coronary heart disease is described by leading experts in the triggering field from both Europe and the United States.

The seven chapters of Part I describe the epidemiology of coronary artery disease, both in traditional terms and with regard to circadian variation and triggering. Drs. Bild, Friedman, and Goldberg present the magnitude of cardiovascular disease, and indicate important secular trends in its incidence and consequences. Drs. Mulcahy, Purcell, Muller, and Willich describe the marked circadian variation in the occurrence of transient myocardial is­chemia, myocardial infarction and sudden cardiac death. This well-docu­mented pattern of more frequent disease onset during the morning compared to other times of day forms the basis for the importance of external triggering

xviii Introduction

factors. Drs. Mittleman and Willich and Arntz present recent studies charac­terizing triggering of myocardial infarction and sudden cardiac death by physical activity. Finally, Dr. Wassertheil-Smoller presents data suggesting a role for psychological processes, such as depression, in increasing the subacute risk of disease onset.

The seven chapters of Part II describe advances in understanding the pathophysiology of coronary disease onset pertinent to triggering. Dr. Cam­bien and co-workers summarize the rapidly evolving insight into genetic factors contributing to risk for coronary artery disease. Drs. Jadhav and Tofler analyze the role of hemostatic variables as important independent predictors of coronary disease. Dr. Winther and co-workers examine the role of disturbances of the delicate balance between pro- and anti-thrombotic forces in the context of coronary syndromes. Dr. Willerson provides an update on the mechanisms contributing to the abrupt transition from stable angina to unstable angina and myocardial infarction. Drs. Andreotti and Manzoli focus on the role of endogenous fibrinolytic activity as an irpportant factor underlying the circadian variation of cardiac events. Drs. Femandez­Ortiz and Fuster summarize recent advances in characterization of the role of thrombosis in the acute coronary syndromes, and new approaches to preventive therapy. Dr. Quyyumi concludes this section with an in-depth analysis of the possible contribution of increased coronary vasomotor tone to disease onset, and implications of this mechanism for preventive therapy.

The three chapters of Part III focus on pathologic findings regarding the lesions responsible for acute coronary artery disease. Dr. Jiang and col­leagues propose state-of-the art models of intracoronary hemodynamic forces contributing to plaque disruption and acute coronary syndromes. Dr. Con­stantinides, who, in the 1960's, pioneered the study of plaque disruption as the underlying cause of myocardial infarction, describes future directions of research to identify the causes and mechanisms of plaque disruption and thrombosis. Dr. Moreno and colleagues provide an update on the determin­ants and risks of disruption of various types of atherosclerotic plaques.

The seven chapters of Part IV provide a comprehensive view of current and possible new methods for prevention of coronary artery disease. Dr. Ockene focuses on the means and importance of primary preventive mea­sures. Drs. Lemmer and Witte introduce chronopharmacology as a method to provide protective dosages and timing of cardiac medication to meet the temporal pattern of cardiac disease onset. The logistics and efficacy of prehospital treatment are described by Dr. Arntz and co-workers. Dr. Schroder assesses the relative importance of pharmacologic and invasive therapy for acute myocardial infarction based on recent clinical trials and studies. Dr. Haberl and co-workers give an in-depth view of the use of electrophysiology and pharmacotherapy to identify and reduce the risk of sudden cardiac death. The basis for secondary pharmacologic prevention of myocardial infarction is described by Dr. Frishman. The book concludes with a glimpse of genetic approaches provided by Drs. Feldman and Isner that

Introduction XIX

might, in the future, make it possible to stabilize the atherosclerotic plaque, decrease thrombotic tendency, and prevent acute cardiac events.

With chapters from authorities on each topic, this text provides a compre­hensive view of the new field of study of the triggers of disease onset and implications for prevention. While we believe that research in this field will be advanced by this text, and eventually be of great value, it is important at this early stage of the development of the field to note the following limitation of triggering information that is currently available.

A common initial reaction to recognition of a possible trigger is to assume that efforts will be made to urge patients to avoid such activity. In most cases this is not appropriate for two reasons. First, many potential triggers such as awakening in the morning, and unexpected physical and psychological stress cannot be avoided. Second, a recommendation for avoidance is often based on lack of consideration of the difference between relative risk and absolute risk difference. While relative risk may increase dramatically with a potential trigger (heavy exertion increases relative risk over 100-fold in an individual who is usually sedentary), absolute risk increases only a small amount, since baseline risk of an event occurring in any given hour is ex­tremely low (approximately 1 chance in a million per hour for a healthy 50-year old male). Such small increases in absolute risk make it unreasonable to recommend that a patient avoid a given activity at a particular time because of fear of triggering a coronary event. For example, physicians routinely perform exercise stress tests in patients known to be at risk of infarction, and only rarely does an event occur.

While results of triggering research should not be routinely used to recom­mend avoidance of a potential triggering situation, there is information cur­rently available that is useful for individual patient management. First, there are patients in whom an avoidable potential trigger occurs with such regu­larity that the accumulated risk (which corresponds to the area under a plot of risk versus time) becomes substantial and intervention may be helpful. For instance, a patient who experiences anger, a known trigger, many times per day, might benefit from stress management instruction.

Second, many clinicians now choose to be certain that patients taking agents proven to prevent infarction (such as aspirin, beta-adrenergic blocking agents and ACE inhibitors) have adequate pharmacologic coverage during the morning and other times of increased risk of infarction onset. While aspirin's effect lasts for at least 3 days making timing of administration inconsequential, chronotherapy with other agents is a logical approach. It is important to note, however, that there is as yet not a single study showing improved prevention of events based on timing of therapy.

Finally, triggering data can be used to reassure patients that an activity is highly unlikely to cause an infarct. Such reassurance is particularly important for patients considering resumption of sexual activity after a coronary event. The available data on the low absolute risk difference produced by sexual activity should be an aid in counseling.

xx Introduction

The lack of significance of triggering information as a grounds to advise against individual activities, and its relatively limited value for patient man­agement should not obscure the enormous importance of this field of research for prevention of cardiovascular disease. When triggering is assessed not in healthy individuals, but among those presenting with an infarction - a view from the opposite end of the telescope - the value of the field is apparent. Epidemiologic studies now indicate that an identifiable trigger is present in at least 15% of patients. An even larger number of infarcts are likely to have a trigger that could not be identified by the relatively insensitive methods available. Hence, triggering plays a role in a very large number of cardiac events. A better understanding of mechanism would greatly facilitate efforts to design therapy to sever the link between a potential trigger and its patho­logical consequences. It is our hope and that of our co-authors that this book will advance this new approach to understanding and prevention of this widespread and devastating disease.

We are most grateful for the excellent manuscripts provided by our co­authors which made the editorial work a rewarding experience. Nettie Dekker at Kluwer Academic Publishers has provided broad expertise, pati­ence, and invaluable guidance through the hurdles and challenges of this project.