The Health Consequences Of Smoking CARDIOVASCULAR DISEASE a report of the Surgeon General 1983 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVCES Ptt4icHedthService ONiceonSmokngdHeelth RockWe, MaryW9857 TC THE READERS OF THIS VOLUME: Provisions of the Public Health Cigarette Smoking Act of 1969 (P.L. 91-222) require the Secretary of Health and Human Services to submit an annual report to the Congress on the health conse- quences of smoking. Attached is the 1983 report, Health Conse- quences of Smoking: Cardiovascular Disease. This volume is an indepth analysis of the scientific evidence of the relationship between cigarette smoking and multiple cardiovascular diseases. This relationship is quantitatively the most serious of the health consequences of smoking, but is poorly recognized by the public. This report represents the consolidated work of many widely- recognized experts known for their contribution to understanding cardiovascular disease. It is a scientific reference document to serve as a state-of-the-art source for medical and behavioral scientists and researchers. Smoking-related cardiovascular disease is estimated to account for more deaths than,any other smoking-related disease, including cancer. This report clearly establishes that cigarette smoking increases the risks for a number of cardiovascular diseases, partic- ularly coronary heart disease, the largest single cause of deaths in the United States. In addition, smoking +s related to an increased risk for stroke, atherosclerosis, and other circulatory diseases. The report clearly demonstrates that cigarette smoking is a major risk factor for coronary heart disease in the United States. There are 55 million persons who smoke, a larger population than those who have hypertension or elevated cholesterol, the other major risk factors for this disease. Smokers ' death rates from coronary heart disease are 70 percent greater than those of non- smokers. Simply by quitting smoking, these men and women drsmati- tally reduce their risk of premature death from this disease. The economic and social toll these smoking-related deaths extract from the Nation's health is immeasurable. The report `a findings re-emphasize the importance of this Department's continued educational efforts to enable a fully-informed choice by indlvid- uals on whether to begin or to continue t.o smoke. In my view, this volume is a solid scientific work and a contri- bution to the prevention efforts of this Department. Heckler FOREWORD The 1983 Report is the second volume in The Health Consequences of Smoking series that focuses on specific diseases. The 1982 Report reviewed in depth the association between tobacco use and various cancers; the 1983 Report is a comprehensive review of the relation- ship between smoking and cardiovascular disease. The ability to draw a conclusion from the scientific evidence on the causal relationship between smoking and cardiovascular disease was reached more recently than it was from the evidence on the relationship between smoking and cancer. The latter relationship was first established scientifically 30 years ago, particularly for lung cancer. At the time the Advisory Committee on Smoking and Health was formed in 1962, the scientific evidence linking tobacco use, particularly cigarettes, with respiratory cancers was overwhelming. A causal link between cigarette use and lung cancer was both clear and compelling. A number of epidemiological studies on the relation- ship between smoking and coronary heart disease (CHD) existed at that time, but the Committee felt that the evidence was insufficient to make a judgment of a causal relationship. Nevertheless, the Committee found the evidence compelling enough to caution that even though the causal role of cigarette smoking in coronary heart disease was not proved, countermeasures were warranted, and the Committee counseled against postponing action until no uncertainty remained. The evidence was reviewed again in the 1971 Surgeon General's Report and was, by this time, clearly strong enough to establish cigarette smoking as a major risk factor for coronary heart disease in men. By 1979, when the 15th year anniversary Report of the Surgeon General was published, there was no longer any doubt that cigarette smoking was directly related to coronary heart disease for both men and women in the United States. The Importance of Cardiovascular Disease The importance of cardiovascular disease, particularly coronary heart disease, to the health of the American public is evident. In 1980 cardiovascular disease accounted for approximately half of all U.S. deaths-980,000 out of 1,980,OOO total deaths. Of these, slightly . . . ill over 565,000 were due to coronary heart disease; that is, approxi- mately 30 percent of all deaths and almost 60 percent of all cardiovascular deaths were due to CHD. The age-adjusted CHD death rate peaked in 1963, and by 1980 had declined 30 percent. In the period between 1968 and 1978 alone, the age-adjusted rate declined 26.5 percent, with a greater decline noted for the younger age groups. In comparison, the total number of all cancer deaths was slightly over 416,000 in 1980. Thus, deaths from CHD exceeded all cancer deaths, and deaths from all cancers numbered less than one-half the total of all cardiovascular deaths. Last year this Department issued a report in which it was estimated that tobacco use, particularly cigarette smoking, was related to 30 percent of all cancer deaths in the United States-a projected 129,000 premature deaths. The findings of this year's Report, however, should be considered even more alarming, in that the number of cardiovascular deaths that are reasonably estimated to be cigarette related is even higher. A number of investigators' have estimated that 30 percent, or more, of CHD deaths could be attributed to cigarette smoking because of the higher CHD death rates experienced by ever-smokers compared with never-smokers. If 30 percent of coronary heart disease deaths are attributed to cigarette smoking, 170,000 Americans will die prematurely of CHD each year. Smokers also experience increased death rates owing to other cardiovascular diseases such as stroke, peripheral vascular disease, aortic atherosclerosis, and other vascular problems. Findings of the 1983 Report-Coronary Heart Disease and Cigarette Smoking Each of the three major risk factors poses approximately the same increase in risk of CHD for the person with the risk factor, but cigarette smoking is far more prevalent as a risk factor for CHD in the American population than either hypertension or elevated serum cholesterol. Thus, the overall finding of this Report is clear: Cigarette smoking should be considered the most important of the known modifiable risk factors for coronary heart disease in the United States. For over 25 years, cigarette smoking has been linked epidemiologi- tally with an increased risk of dying from coronary heart disease. As early as 1954, a strong, statistically significant association between cigarette use and CHD was demonstrated. In the intervening years, additional studies have confirmed this association. An examination of only the major prospective studies, involving more than 20 million `Report of the Royal College of Physicians. London. 1978; Sogot and Murray, Public Health Reports. 1980; Ganinkel, Proceedings of the Fourth World Conference on Smoking and Health, Stackbolm, 1980. See Section 3 for additional discussion. iv person-years of observation, indicates that smoking has been consis- tently shown to elevate CHD mortality rates. Overall, smokers have a 70 percent greater CHD mortality than nonsmokers. Heavy smokers, those who consume more than two packs per day, experi- ence CHD mortality rates almost 200 percent greater than nonsmok- ers. In the National Pooling Project study, a unique study that combined data from five of the Nation's largest incidence studies on heart disease, smokers of a pack or more per day were found to have a greater than 2.5fold increased risk of developing a major coronary event compared with nonsmokers. This study also found that smokers who have other major risk factors experience a greater increased risk than would be expected from the summation of the independent risks. Thus, cigarette smoking interacts with the other major risk factors in a manner that greatly increases the risk of CHD. The risk of developing and dying from CHD is directly related to the total dosage of cigarette smoke exposure. A dose-response relationship has been established for the number of cigarettes smoked per day, the total years of cigarette smoking, and the degree of inhalation; CHD risk is inversely related to the age of initiation. CHD mortality ratios are also greater at the younger age groups; thus, preventive efforts could truly have a decided impact on extending life-expectancy-if large numbers of smokers could be persuaded to quit smoking. The decrease in elevated CHD risk with cessation, coupled with the prevalence of smoking as a risk factor in the U.S. population, means that the elimination of cigarette usage could have a greater impact on CHD morbidity and mortality than any other preventive measure. Sudden Cardiac Death Smokers are at a two to four times greater risk for sudden cardiac death @CD) than are nonsmokers. The risk for sudden death increases with increasing daily exposure, as measured by the number of cigarettes consumed per day. Stroke The association between cigarette smoking and cerebrovascular disease (CVD) is largely confined to the younger age groups, with little evidence of an effect after age 65. The number of stroke deaths in 1980 totaled 170,000; even a small percentage of such deaths represents thousands of premature deaths. V Women For women who both smoke cigarettes and used oral contracep- tives, a strong association exists between their use and one form of stroke-subarachnoid hemorrhage. Smoking and oral contraceptive use appear to interact synergistically to greatly increase the risk of subarachnoid hemorrhage and of CHD, compared with the risk for those women who neither smoke nor use oral contraceptives. Other Cardiovascular Disease Cigarette smoking contributes to the development of aortic atherosclerosis and arteriosclerotic peripheral vascular disease (APVD). Ninety percent of patients with APVD are cigarette smokers, and the successful management of this disease includes complete smoking cessation by such patients. Changing Trends in Smoking Behavior and Coronary Heart Disease Demographers have noted a reduction in mortality rates from heart disease for several years. However, a sharp decline in these rates occurred in the late 1960s for reasons that are not entirely known. Significantly, declines in cigarette smoking prevalence among adults were first noted in 1964, the year of the first Surgeon General's Report, with declines in prevalence accelerating between 1966 and 1970. By 1980, overall adult smoking prevalence had declined by nearly 25 percent. While the magnitude of the impact of these changes in smoking behavior on the decline in CHD death rates is uncertain, the direction and nature of that impact is not. The substantial changes in smoking beh.avior that have occurred over the last 20 years have exerted, and will continue to exert, a substantial beneficial effect on the incidence of CHD in the U.S. population. We know from cohort mortality studies, incidence studies, and, more recently, intervention trials that smoking cessation results in a reduction in CHD mortality. Data from the Multiple Risk Factor Intervention Trial (MRFIT) have shown that those cigarette smokers who reported quitting at their first-year interview (after an average of 6 years of followup) reduced their relative risk for CHD mortality by almost half compared with those smokers who continued to smoke. Mortality from all causes was almost 30 percent lower among those who quit smoking compared with those who continued to smoke. These data correlate well with those observed in the cohort mortality studies, which have consistently shown a decline in CHD mortality among former smokers compared with continuing smokers. In some studies vi a substantial improvement in mortality within the first few years after smoking cessation was demonstrated. Public Perception of the Scientific Link Between Cigarette Smoking and CHD A recent staff report by the Federal Trade Commission revealed that a substantial proportion of the American public is not aware of the link between cigarette smoking and heart disease. When asked to respond to the statement "Cigarette smoking is a major cause of heart disease," 40 percent of adults responded "false" or "don't know," including almost half of the adult smokers (45 percent). This concurs with results from a 1980 Roper survey, which found that 53 percent of the population and 58 percent of smokers did not know that smoking causes many cases of heart attack; a surprising 20 percent were not even aware that smoking causes some cases. It is apparent that for a significant segment of the general public, a large gap exists in its understanding of the relationship between cigarette smoking and heart disease, a relationship that accounts for the largest number of excess deaths of all the diseases associated with cigarette smoking. In last year's Report, I stated that the education of our citizens regarding the health hazards of smoking cannot be left solely to government. The findings of this Report and previous ones compel me again to ask for an increased commitment by the health care community, voluntary health agencies, schools, and other groups in our society to join this Department and the Public Health Service in our continuing efforts to reduce the premature death and disability associated with cigarette smoking through renewed efforts of education and information. Edward N. Brandt, Jr., M.D. Assistant Secretary for Health vii PREFACE In 1982, the Public Health Service's Report on the health consequences of smoking dealt with the relationship between smoking and cancer. This 1983 Report turns its attention to the relationship between cigarette smoking and cardiovascular disease, one that imposes an even greater burden of disease and premature death. In preparing this Report, the Public Health Service has reviewed a world literature that goes back more than 40 years and has examined the results of epidemiological observations covering many millions of person-years. This evidence permits us to affirm again what was said in our 1979 Report and what is the consensus of other scientific bodies here and across the world. Cigarette smoking is causally related to heart disease; it and elevated levels of serum cholesterol and hypertension consti.tute the major risk factors for contracting and dying from this disease. Since 1979, much additional information has accumulated to support this judgment. From a public health viewpoint, the most important is the new and further evidence presented in this volume that when one quits smoking, the risk of dying from heart disease begins to recede almost immediately and eventually becomes no greater than that experienced by scmeone who has never smoked at all. This is an encouragement to personal action and a justification for much greater research and program effort by government and voluntary agencies in helping people to quit smoking. As in all previous Reports, the Public Health Service has turned to many people and agencies within the research and clinical communi- ty in developing this statement. On behalf of the Service, I express my respect and gratitude to them. C. Everett Koop, M.D. Surgeon General ix ACKNOWLEDGEMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Joanne Luoto, M.D., M.P.H., Director. Manag- ing Editor was Dona` i R. Shopland, Technical Information Officer, Office on Smoking and Health. Consulting scientific editors were David M. Burns, M.D., Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, Califor- nia; John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medical Center, Salt Lake City, Utah; and Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer Prevention Program, Division of Cancer Control, Jonsson Compre- hensive Cancer Center, University of California at Los Angeles, Los Angeles, California. The editors wish to acknowledge their appreciation to the Nation- al Heart, Lung, and Blood Institute, Claude Lenfant, M.D., Director, for their assistance. In particular, the editors wish to acknowledge Peter L. Frommer, M.D., Deputy Director, and Gardner C. McMillan, M.D., Ph.D., Associate Director for Arteriosclerosis, Hypertension and Lipid Metabolism Program, for their assistance in the planning of the Report and for their careful review of the manuscripts. Special recognition is due Thomas L. Robertson, M.D., Chief, Cardiac Diseases Branch, for his substantial contribution to the Report. The following individuals wrote portions of the Report: Robert W. Barnes, M.D., F.A.C.S., Professor and Chairman, Depart- ment of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas Joseph T. Doyle, M.D., Professor of Medicine and Head of the Division of Cardiology, and Attending Cardiologist, Albany Medi- cal Center Hospital, Albany Medical College, Albany, New York James E. Enstrom, Ph.D., M.P.H., School of Public Health, Universi- ty of California at Los Angeles, Los Angeles, California Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Hyattsville, Maryland Nancy J. Haley, Ph.D., Associate, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York xi Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York Ilse Hoffmann, Research Coordinator, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York William B. Kannel, M.D., Professor of Medicine, Chief, Section of Preventive Medicine and Epidemiology, Boston University Medi- cal Center, Boston, Massachusetts Paul E. Leaver-ton, Ph.D., Acting Director, Epidemiology and Biome- try Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Margaret H. Mushinski, M.A., American Cancer Society, Depart- ment of Epidemiology and Statistics, New York, New York Jeffrey Newman, M.D., M.P.H., Medical Epidemiologist, Behavioral Epidemiology and Evaluation Branch, Centers for Disease Control, Public Health Service, Atlanta, Georgia Judith K. Ockene, Ph.D., Director, Division of Preventive and Behavioral Medicine, Department of Medicine, University of Massachusetts Medical School, Worchester, Massachusetts Oglesby Paul, M.D., Professor of Medicine, Harvard Medical School, Boston, Massachusetts Thomas L. Robertson, M.D., Chief, Cardiac Diseases Branch, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Jack P. Strong, M.D., Boyd Professor and Head, Department of Pathology, Louisiana State University Medical Center, New Orleans, Louisiana Thomas J. Thorn, Statistician, Epidemiology and Biometry Program, National Heart, Lung, and Blood. Institute, National Institutes of Health, Bethesda, Maryland The editors acknowledge with gratitude the followiT g distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Henry Blackburn, M.D., Professor ,and Director, Division of Epide- miology, School of Public Health, University of Minnesota, Minne- apolis, Minnesota William Castelli, M.D., Chairman and Medical Director, Framing- ham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts Thomas B. Clarkson, D.V.M., Professor of Comparative Medicine and Director, Arteriosclerosis Research Center, Department of Com- xii parative Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina D. Layten Davis, Ph.D., Director, University of Kentucky Tobacco and Health Research Institute, University of Kentucky, Lexing- ton, Kentucky Joseph T. Doyle, M.D., Professor of Medicine and Head of the Division of Cardiology, and Attending Cardiologist, Albany Medi- cal Center Hospital, Albany Medical College, Albany, New York William H. Foege, M.D., Director, Centers for Disease Control, Atlanta, Georgia Gary D. Friedman, M.D., Assistant Director for Medical Methods Research, Epidemiology and Biostatistics, Kaiser-Permanente Medical Group, Inc., Oakland, California Peter L. Frommer, M.D., Deputy Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Michael R. Guerin, Ph.D., Section Head, Bio-Organic Analysis Section, Analytical Chemistry Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts Lawrence E. Hinkle, Jr., M.D., Professor of Medicine and Director, Division of Human Ecology, Department of Medicine, The New York Hospital-Cornell Medical Center, New York, New York Stephen B. Hulley, M.D., M.P.H., Professor in Residence, Systolic Hypertension in the Elderly Program Coordinating Center, De partment of Epidemiology and International Health, School of Medicine, University of California at San Francisco, San Francis- co, California Hershel Jick, M.D., Boston University Medical Center, Boston Collaborative Drug Surveillance Program, Waltham, Massachu- setts Lewis H. Kuller, M.D., Dr.P.H., Professor and Chairman, Depart ment of Epidemiology, Graduate School of Public Health, Univer- sity of Pittsburgh, Pittsburgh, Pennsylvania Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Joseph L. Lyon, M.D., M.P.H., Department of Family and Communi- ty Medicine, University of Utah School of Medicine, Salt Lake City, Utah Henry C. McGill, Jr., M.D., M.P.H., Professor, Department of Pathology, University of Texas Health Science Center, and Scien- tific Director, Southwest Foundation for Research and Education, San Antonio, Texas . . . XIII Gardner C. McMillan, M.D., Ph.D.,, Associate Director, Arteriosclero sis, Hypertension and Lipid Metabolism Program, Division of Heart and Vascular Disease, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Kenneth M. Moser, M.D., Professor of Medicine and Director, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at San Diego, San Diego, California Mark Novitch, M.D., Acting Commissioner of the Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, Maryland John A. Oates, M.D., Professor `of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee C. Tracy Orleans, Ph.D., Division of Psychosomatic Medicine, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Oglesby Paul, M.D., Professor of Medicine, Harvard Medical School, Boston, Massachusetts Terry F. Pechacek, Ph.D., Assistant Professor, Division of Epidemiol- ogy, University of Minnesota, Minneapolis, Minnesota William Pollin, M.D., Director, National Institute on Drug Abuse, U.S. Department of Health and Human Services, Rockville, Maryland James A. Schoenberger, M.D., Professor and Chairman, Department of Preventive Medicine, Rush-PresbyterianSt. Luke's Medical Center, Chicago, Illinois Sam Shapiro, Professor, Health Services Research and Development Center, Department of Health Policy and Management, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland Roger Sherwin, M.D., Professor, Department of Epidemiology and Preventive Medicine, University d Maryland School of Medicine, Baltimore, Maryland John A. Spittell, Jr., M.D., F.A.C.C., F.A.C.P., Mary Lowell Leary Professor of Medicine, Mayo Medical School, and Consultant, Cardiovascular Division, Internal Medicine, Mayo Clinic, Roches- ter, Minnesota Jeremiah Stamler, M.D., Chairman, Department of Community Health and Preventive Medicine, Northwestern University Medi- cal School, Chicago, Illinois John F. Williams, Jr., M.D., H.H. Weiner-t Professor of Medicine, University of Texas Medical Branch, Galveston, Texas Robert W. Wissler, M.D., Ph.D., Donald N. Pritzker Distinguished Service Professor of Pathology, and Senior Scientist of the Specialized Center of Research in Atherosclerosis, Department of Pathology, University of Chicago Medical Center, Chicago, Illinois xiv Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Spe- cialist, Office on Smoking and Health, Rockville, Maryland Leena Kang, Date Entry Operator, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland William R. Lynn, Program Operations Technical Assistance Officer, Office on Smoking and Health, Rockville, Maryland Kurt D. Mulholland, Graphic Artist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock- ville, Maryland Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Roberts A. Roeder, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Shari G. Simons, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Linda R. Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Evelyn L. Swarr, Administrative Secretary, Data Processing Ser- vices, Informatics General Corporation, Rockville, Maryland Debra C. Tate, Publications Systems Specialist, Informatics General Corporation, Riverdale, Maryland Jill Vejnoska, Writer-Editor, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Aileen L. Walsh, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Dee Whitley, Computer Operations, Data Processing Services, Infor- matics General Corporation, Rockville, Maryland Robert Winning, Graphic Artist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Louise Wiseman, Technical Information Specialist, Office on Smok- ing and Health, Rockville, Maryland xvi Robert S. Hutchings, Associate Director for Information and Pr+ gram Development, Office on Smoking and Health, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Spe- cialist, Office on Smoking and Health, Rockville, Maryland Leena Kang, Data Entry Operator, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland William R. Lynn, Program Operations Technical Assistance Officer, Office on Smoking and Health, Rockville, Maryland Kurt D. Mulholland, Graphic Artist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock- ville, Maryland Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Roberta A. Roeder, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Shari G. Simons, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Linda R. Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Evelyn L. Swarr, Administrative Secretary, Data Processing Ser- vices, Informatics General Corporation, Rockville, Maryland Debra C. Tate, Publications Systems Specialist, Informatics General Corporation, Riverdale, Maryland Jill Vejnoska, Writer-Editor, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Aileen L. Walsh, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Dee Whitley, Computer Operations, Data Processing Services, Infor- matics General Corporation, Rockville, Maryland Robert Winning, Graphic Artist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Louise Wiseman, Technical Information Specialist, Office on Smok- ing and Health, Rockville, Maryland xvi TABLE OF CONTENTS Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii Preface .................................................................. ix Acknowledgements .................................................. xi 1. Introduction, Overview, and Conclusions.. . . . . . . . . . . . . . . . . . 1 2. Arteriosclerosis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3. Coronary Heart Disease.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 4. Cerebrovascular Disease.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 5. Atherosclerotic Peripheral Vascular Disease and Aortic Aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 6. Pharmacological and Toxicological Implications of Smoke Constituents on Cardiovascular Disease.. . . . . . .203 7. Changes in Cigarette Smoking Behavior in Clinical and Community Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _ . .241 8. The Effect of Cigarette Smoking Cessation on Coro- nary Heart Disease.............................................291 A. Trends in Cardiovascular Diseases ....................... 327 B. Trends in U.S. Cigarette Use, 1965-1980 .............. 361 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375 xvii SECTION 1. INTRODUCTION, OVERVIEW, AND CONCLUSIONS Introduction Organization and Development of the 1983 Report The content of the Report is the work of numerous scientists and experts within the Department of Health and Human Services as well as from outside the organization. Individual manuscripts were written by experts nationally and internationally recognized for their scientific contributions to the understanding of cardiovascular diseases. These manuscripts were reviewed individually by other experts, within and outside the U.S. Public Health Service, and the entire Report was reviewed by a broad-based panel of distinguished cardiovascular scientists. The 1983 Report includes a Foreword by the Assistant Secretary for Health of the Department of Health and Human Services and a Preface by the Surgeon General of the U.S. Public Health Service. The body of the report consists of eight sections and two appendices, as follows: 0 Section 1. Introduction, Overview, and Conclusions 0 Section 2. Arteriosclerosis 0 Section 3. Coronary Heart Disease 0 Section 4. Cerebrovascular Disease o Section 5. Atherosclerotic Peripheral Vascular Disease and Aortic Aneurysm o Section 6. Pharmacological and Toxicological Implications of Smoke Constituents on Cardiovascular Disease 0 Section 7. Changes in Cigarette Smoking Behavior in Clini- cal and Community Trials o Section 8. The Effect of Cigarette Smoking Cessation on Coronary Heart Disease a Appendix A. Trends in Cardiovascular Diseases o Appendix B. Trends in U.S. Cigarette Use, 1965 to 1980 Historical Perspective Early reports linking smoking with a greater risk of developing cardiovascular disease occurred around the turn of the century. An early series of studies, initiated in 1904 by Erb, found a much higher percentage of smokers than of nonsmokers with intermittent claudi- cation; only 10 percent of his patients with claudication were nonusers of tobacco. As early as 1934, Howard made the observation that the increasing prevalence of coronary heart disease noted since the first World War might be a result of the greatly increased use of cigarettes. By the turn of the century, numerous studies had demonstrated clinically and experimentally that cigarette smoking or cigarette smoke constituents, most notably nicotine, caused an elevation in blood pressure and heart rate during smoking. 3 The first major prospective study results were made public in 1954 in the United States by Hammond and Horn and found a strong association between cigarette use among men and coronary heart disease (CHD). Overall, smokers were found to carry a 70 percent greater risk of dying from CHD than nonsmokers; heavy smokers had CHD mortality rates almost two and one-half times greater than nonsmokers. Hammond and Horn also noted a consistent dose- response relationship with the number of cigarettes consumed per day. In the intervening 30 years, numerous additional epidemiological mortality studies were undertaken to examine this issue. These included studies in the United Kingdom, Canada, Sweden, Japan, and Switzerland in addition to the United States. In total, they represent more than 20 million person-years of observation. Find- ings from these studies have been remarkably uniform: smokers have much higher death rates from coronary heart disease than do nonsmokers, despite the fact that these studies were conducted in varying populations, were geographically diverse, and involved differing methodologies. The first major U.S. Public Health Service review of the relation- ship between smoking and heart disease was conducted by the Surgeon General's Advisory Committee on Smoking and Health in 1984. Although the Committee noted that male smokers had higher death rates from coronary heart disease, it was unable to conclude that the association had causal significance. However, it was noted in the report that "the causative role of these factors [risk factors including cigarette smoking] in coronary disease, though not proven, is suspected strongly enough to be a major reason for taking countermeasures against them. It is also more prudent to assume that the established association between cigarette smoking and coronary disease has causative meaning than to suspend judgement until no uncertainty remains." Since the release of the original Report of the Surgeon General in 1984, additional studies dealing with. cigarette smoking and CHD have been summarized in the series of annual reports of the Surgeon General The Health Consequences of Smoking. By 1979, the magni- tude of the epidemiological, pathological, clinical, and experimental evidence had grown to the point that the Surgeon General's Report concluded: "Smoking is causally related to coronary heart disease in the common sense of that idea and for the purposes of preventive medicine." Overview In 1980, diseases of the circulatory system were responsible for approximately one-half of the total U.S. mortality. CHD was the 4 single most important cause of death, accounting for approximately 30 percent of all U.S. deaths. Cigarette smoking is one of the three major independent CHD risk factors. The magnitude of the risk associated with cigarette smoking is similar to that associated with the other two major CHD risk factors, hypertension and hypercholesterolemia; however, because cigarette smoking is present in a larger percentage of the U.S. population than either hypertension or hypercholesterolemia, ciga- rette smoking ranks as the largest preventable cause of CHD in the United States. Cigarette smoking also acts synergistically with the other major risk factors to greatly increase the risk for CHD. Arteriosclerosis is the predominant underlying cause of cardiovas- cular disease, and atherosclerosis is the form of arteriosclerosis that most frequently causes clinically significant disease, including CHD, atherothrombotic brain infarction, atherosclerotic aortic disease, and atherosclerotic peripheral vascular disease. Cigarette smoking contributes both to the development of atherosclerotic lesions and to the clinical manifestations of atherosclerotic vascular disease, in- cluding sudden death. Although the precise pathophysiologic basis of these clinical manifestations is not understood, it may be related to several deleterious cardiovascular effects of cigarette smoking, including production of an imbalance between myocardial oxygen supply and demand, a decrease in the threshold for ventricular fibrillation, and an increase in platelet aggregation. Nicotine and carbon monoxide are the tobacco smoke constituents most closely associated with these adverse effects; other cigarette smoke constitu- ents such as hydrogen cyanide, oxides of nitrogen, and carbon disulfide are being studied for possible pathogenic cardiovascular effects. Cigarette smoking is the most important risk factor for atheroscle- rotic peripheral vascular disease, which usually involves the lower extremities. Smoking cessation is probably the single most impor- tant intervention in the management of this disorder. The effect of cigarette smoking to aggravate and accelerate the development of atherosclerosis is more striking in the aorta than in any other vessels. Cigarette smoking is associated with an increased risk for cerebrovascular disease, especially in younger age groups, but this effect is less marked than for atherosclerotic disease at other sites. Women cigarette smokers experience an increased risk for subarach- noid hemorrhage; the use of both cigarettes and oral contraceptives greatly increases this risk. Smoking cessation is associated with decreased mortality and morbidity from atherosclerotic vascular disease. Prospective epide- miologic studies have shown that former cigarette smokers reduce their CHD death risk from that of current smokers to that of nonsmokers over approximately a 15-year period after stopping 5 smoking. The beneficial effects of quitting are not explained by differences in baseline characteristics between quitters and continu- ing smokers. CHD intervention trials have successfully demon- strated the feasibility of reducing cigarette consumption; these trials also documented a significant reduction in CHD mortality. Conclusions of the 1983 Report The purpose of this Report is to review in depth the many sources of scientific evidence relating cigarette smoking to individual cardiovascular disease entities. Listed below are the major findings of this review. Arteriosclerosis 1. A preponderance of evidence both from prospective studies with autopsy followup and from autopsy studies with retrospec- tive smoking data indicates that cigarette smoking has a significant positive association with atherosclerosis. This evi- dence suggests that cigarette smoking has the effect of aggravating and accelerating the development of atherosclerot- ic lesions in the artery wall and that its effect is not limited to those events related to the occlusive episode. The effects are most striking for aortic atherosclerosis; a significant positive relationship also exists between cigarette smoking and athero sclerotic lesions in the coronary arteries, at least for most high risk populations. Cigarette smoking could also be associated with other factors that precipitate thrombosis, hemorrhage, or vasoconstriction leading to occlusion and ischemia. 2. Some evidence exists that cigarette smoke alters total serum cholesterol concentrations and lipoprotein composition in ways that would be expected to increase the development of athero sclerosis. Recent studies of the effects of smoking on the hemostatic system indicate effects on platelet function. 3. Although the specific mechanisms by which tobacco smoke affects arteriosclerosis have not been clearly delineated, the effects of cigarette smoking on the atherosclerotic lesions that underlie cardiovascular disease seem well established. Coronary Heart Disease 1. Cigarette smoking is a major cause of coronary heart disease in the United States for both men and women. Because of the number of persons in the population who smoke and the increased risk that cigarette smoking represents, it should be considered the most important of the known modifiable risk factors for CHD. 6 2. Overall, cigarette smokers experience a 70 percent greater CHD death rate than do nonsmokers. Heavy smokers, those who consume two or more packs per day, have CHD death rates between two and three times greater than nonsmokers. 3. The risk of developing CHD increases with increasing exposure to cigarette smoke, as measured by the number of cigarettes smoked daily, the total number of years one has smoked, and the degree of inhalation, and with an early age of initiation. 4. Cigarette smokers have a twofold greater incidence of CHD than do nonsmokers, and heavy smokers have an almost fourfold greater incidence. 5. Cigarette smoking is a major independent risk factor for CHD, and it acts synergistically with other risk factors (most notably, elevated serum cholesterol and hypertension) to greatly in- crease the risk of CHD. 6. Women have lower rates for CHD than do men. In particular, CHD rates for women are lower prior to the menopause. A part of this difference is due to the lower prevalence of smoking in women, and for those women who do smoke, to the tendency to smoke fewer cigarettes per day and to inhale less deeply. Among those women who have smoking patterns comparable to male smoking patterns, the increments in CHD death rates are similar for the two sexes. 7. Women who use oral contraceptives and who smoke increase their risk of a myocardial infarction by an approximately tenfold factor, compared with women who neither use oral contraceptives nor smoke. 8. Cigarette smoking has been found to significantly elevate the risk of sudden death. Overall, smokers experience a two to four times greater risk of sudden death than nonsmokers. The risk appears to increase with increasing dosage as measured by the number of cigarettes smoked per day and diminishes with cessation of smoking. 9. The CHD mortality ratio for smokers compared with nonsmok- ers is greater for the younger age groups than for the older age groups. Although the smoker-to-nonsmoker mortality ratio narrows with increasing age, smokers continue to experience greater CHD death rates at all ages. 10. Cigarette smoking has been estimated to be responsible for up to 30 percent of all CHD deaths in the United States each year. During the period 1965 to 1980 there were over 3 million premature deaths from heart disease among Americans attrib uted to cigarette smoking. Unless smoking habits of the American population change, perhaps 10 percent of all persons now alive may die prematurely of heart disease attributable to 7 their smoking behavior. The total number of such premature deaths may exceed 24 million. 11. Cessation of smoking results in a substantial reduction in CHD death rates compared with those of persons who continue to smoke. Mortality from CHD declines rapidly after cessation. Approximately 10 years following cessation the CHD death rate for those ex-smokers who consumed less than a pack of cigarettes daily is virtually identical to that of lifelong non- smokers. For ex-smokers who had smoked more than one pack per day, the residual risk of CHD mortality is proportional to the total lifetime exposure to cigarette smoke. 12. Epidemiologic evidence concerning reduced tar and nicotine or filter cigarettes and their effect on CHD rates is conflicting. No scientific evidence is available concerning the impact on CHD death rates of cigarettes with very low levels of tar and nicotine. 13. Smokers who have used only pipes or cigars do not appear to experience substantially greater CHD risks than nonsmokers. Cerebrovascular Disease 1. Data from numerous prospective mortality studies have shown an association between cigarette smoking and cerebrovascular disease. This risk is most evident in the younger age groups, and the effect diminishes with increasing age, with little or no effect noted after age 65. No consistent dose-response effect has been demonstrated. 2. Women cigarette smokers experience an increased risk for subarachnoid hemorrhage. However, the use of both cigarettes and oral contraceptives greatly increases the risk for subarach- noid hemorrhage among women. Atherosclerotic Peripheral Vascular Disease and Aortic Aneurysm 1. Cigarette smoking is the most powerful risk factor predisposing to atherosclerotic peripheral arterial disease. 2. Smoking cessation plays an important role in the medical and surgical management of atherosclerotic peripheral vascular disease. 3. Death from rupture of an atherosclerotic abdominal aneurysm is more common in cigarette smokers than in nonsmokers. Pharmacological and Toxicological Implications of Smoke Constituents on Cardiovascular Disease 1. Over 4,000 different compounds have been identified in tobacco smoke. 8 2. Nicotine exerts an effect on ganglionic cells, producing tran- sient excitation. The pharmacological effects are small, but are reinforced several times daily in habitual smokers. The exact mechanisms whereby nicotine might influence cardiovascular events are unknown, but a lowering of the ventricular fibrilla- tion threshold is dose related to nicotine levels. 3. Carbon monoxide may act to precipitate cardiac symptomatolo- gy or ischemic episodes in individuals already compromised by coronary disease. In addition, carbon monoxide binds to hemoproteins, potentially inhibiting their functions. 4. Several studies have shown that smokers may alter their smoking behavior when they switch to low-yield cigarettes. This compensatory behavior may lead to the increased uptake of gas phase constituents including carbon monoxide, hydrogen cyanide, and nitrous oxides. 5. It is unlikely that a "safe cigarette" can be developed that will reduce cardiovascular risk. Changes in Cigarette Smoking Behavior in Clinical and Community Trials 1. Smokers involved in intervention programs demonstrate high- er smoking cessation rates than those in control groups. 2. In general, the success of smoking intervention programs is related to the amount of intervention provided. The Effect of Cigarette Smoking Cessation on Coronary Heart Disease 1. In the four intervention trials involving mortality followup of individual men for 5 to 10 years, the intervention groups had a combined total of 10 percent fewer CHD deaths than did the comparable control groups. Differences for other causes of death or for total deaths were not significant. 2. In these trials, the amount of cigarette smoking has been reduced 10 to 50 percent more in the intervention group than in the control group, demonstrating that intervention can alter smoking behavior. 3. In the two trials involving morbidity followup, the intervention groups had 4 and 45 percent lower total CHD incidence than did the respective control groups. 4. The relative reductions in CHD mortality in each of the four intervention studies involving individual followup are reason- ably consistent with the reduction in CHD risk factors, and for a combination of all four studies, the reduction is statistically significant. 9 5. Numerous studies ha-.-e shown that those who quit cigarette smoking experience a substantial decrease in CHD mortality and an improvement in life expectancy. 6. A number of prospective epidemiological studies indicate that former cigarette smokers substantially reduce their CHD and total death rates from that of current smokers. Trends in Cardiovascular Diseases The evidence supports the conclusion that changes in smoking habits have contributed to substantial improvement in mortality rates from the cardiovascular diseases in the United States. Trends in U.S. Cigarette Use, 19651980 1. The proportion of current regular smokers declined steadily between 1965 and 1980. The decline was steeper among males (from 52.1 to 37.9 percent) than among females (from 34.2 to 29.8 percent). 2. The proportion of never smokers increased steadily from 1965 to 1980 among males (27.6 to 31.6 percent), except those 45 years old and older. Among females, only 20- to 34-year-ok% showed an increase in proportion of never smokers. 3. The mean number of cigarettes smoked per day by current smokers increased slightly from 1970 to 1980 (from 20 to 21.7 cigarettes). 4. Males smoked a higher mean number of cigarettes throughout the 1970-1980 period, but the number for males and females increased about the same amount. 5. Heaviest daily consumption was in the middle-aged group (35- 65 years). The greatest mean increase was observed among women aged 35 to 44. 6. The proportion of current smokers who smoked less than 20 cigarettes per day decreased between 1970 and 1980 (39.8 to 33.8 percent); the proportion smoking one pack exactly (20 cigarettes) remained constant (34.9 to 34.8 percent); the propor- tion smoking from 21 to 39 cigarettes increased slightly (13.7 to 14.5 percent); and the proportion smoking two or more packs per day increased from 11.4 to 16.8 percent. 7. The proportion of current smokers who attempted to quit three or more times decreased slightly from 1966 to 1980 (41.2 to 38.7 percent). 8. The proportion of former smokers having made three or more attempts to quit increased sharply (36 to 53.2 percent) from 1966 to 1975. 9. The proportion of current smokers who had attempted to quit during the past year increased from 1966 to 1980 (26.0 to 36.7 percent). 10 10. Among current smokers, younger persons and females were more likely than older persons and males to have attempted to quit during the previous 12 months. 11. The proportion of former smokers who had attempted to quit during the previous 12 months decreased from 1966 to 1975 (13.8 to 9.8 percent). 12. Among former smokers, younger persons and females were more likely than older persons and males to have quit during the previous 12 months. 11 SECTION 2. ARTERIOSCLEROSIS Introduction and Definition of Terms Arteriosclerosis is the predominant underlying cause of cardiovas- cular diseases, including coronary heart disease (CHD), cerebral infarction, arteriosclerotic peripheral vascular disease, and athero- sclerotic aortic aneurysm. The specific relationships of tobacco use and these conditions, as well as an overview of known and suspected risk factors for cardiovascular disease, are reviewed in other sections. Because arteriosclerosis is sometimes used in a broad sense to cover a variety of arterial lesions, the nomenclature and terminology used in this section will be defined. Arteriosclerosis is a generic term that includes practically any arterial disease that leads to thickening and hardening of arteries of any size. Atherosclerosis is a specific form of arteriosclerosis. Its most distinctive feature is the accumulation of lipid in the intima of large elastic arteries (aorta) and medium-sized muscular arteries (coro- nary, femoral, carotid, and others). In addition to lipid, cells, connective tissue fibers, and various blood components accumulate in the lesions. A number of complications, including thrombosis, hemorrhage into a plaque, and ulceration, can also occur in or upon the lesions. The hallmarks of atherosclerosis are its intimal location during the initial stage, the involvement of large- and medium-sized arteries, and the accumulation of fat in the lesion. Atherosclerosis is the form of arteriosclerosis that most frequently causes clinically significant disease. Mbnckeberg's medial calcific sclerosis, characterized by calcifica- tion of the medial layer of muscular arteries, and arteriolosclerosis, characterized by thickening, fibrosis, hyalinization, and narrowing of arterioles, are other types of arteriosclerosis quite distinct from atherosclerosis. They are beyond the scope of this section. Medial and arteriolar lesions have sometimes caused confusion in interpret- ing experimental studies, principally those in which rabbits and rats have been used. Only the intimal lesions that contain lipid and connective tissue elements in large elastic and medium-sized muscu- lar arteries are models of human atherosclerosis. The term atheroma has been used in several different ways, sometimes to refer to the entire process of atherosclerosis and sometimes to describe a specific lesion. Some pathologists use the word to mean a large atherosclerotic plaque containing a pool of necrotic cells, lipid, and connective tissue. Atheroma has also been used to refer to any lesion of atherosclerosis, including fatty streaks, fibrous plaques, or complicated or calcified lesions. The following working definitions are offered for different types of atherosclerotic lesions detectable grossly after staining vessels with Sudan IV or other fat stains. 15 A fatty streak is a fatty intimal lesion that is stained distinctly by Sudan IV and shows no other underlying change. Fatty streaks are flat or only slightly elevated in opened fresh or immersion fmed vessels. They do not significantly narrow the lumina of blood vessels. A fibrous plaque is a firm, elevated intimal lesion that in the fresh state is usually gray-white, glistening, and translucent. Human fibrous plaques characteristically contain fat. A thick fibrous connective tissue cap containing varying amounts of lipid covers a more concentrated "core" of lipid. If a lesion also contains hemor- rhage, thrombosis, ulceration, or calcification, that lesion is classi- fied according to one of the next two categories. A complicated lesion is an intimal plaque in which there is hemorrhage, ulceration, or thrombosis with or without calcification. A calcified lesion is an intimal plaque in which insoluble mineral salts of calcium are visible or palpable without overlying hemor- rhage, ulceration, or thrombosis. The term raised atherosclerotic Lesion is sometimes used as a measure of atherosclerosis to include the sum of fibrous plaques, complicated lesions, and calcified lesions. Raised lesions are contrast- ed with fatty streaks, which typically show little or no elevation above the surrounding intimal surface. Although this classification scheme implies a pathogenetic se- quence, it can be used for descriptive purposes regardless of the theoretical pathogenetic interrelationships among the lesions. Certain other intimal lesions are sometimes considered as sub- types of atherosclerosis or as lesions predisposing to atherosclerosis. These include musculoelastic or fibromuscular intimal thickening, gelatinous or edematous lesions, and organizing mural thrombi on an otherwise normal intima. The pathogenetic relationship of atherosclerosis and its clinical manifestations is less well established for these lesions, and quantitative information related to the natural history, topography, and geographic pathology is not available. "Rhythmic" or periodic wrinkling of the intimal surface of the aortas of children and adolescents is another change whose relationship to atherosclerosis has not been established. Clinical Significance of Atherosclerosis Atherosclerosis is the underlying cause of coronary heart disease (coronary occlusion, coronary thrombosis, myocardial infarction, and angina pectoris) and of one major type of stroke (cerebral thrombosis with infarction). Atherosclerosis also causes aortic aneurysms by weakening the aortic media via encroachment from primarily intimal lesions. Atherosclerosis also sets the stage for arteriosclerot- ic peripheral vascular disease by occlusive-thrombotic disease of the 16 distal aorta and by atherosclerotic lesions in the iliac-femoral vessels. Previous Literature Reviews The history of our knowledge about atherosclerosis was reviewed by Long (39). The morphology and pathogenesis of human atheroscle- rotic lesions were reviewed in detail by Duff and McMillan (201, and the gross and microscopic features of typical coronary and aortic human lesions at various ages were illustrated by McGill et al. (44). Data on the worldwide distribution of atherosclerotic lesions among different human populations were published in 1968 (41). Strong et al. (72, 73) reviewed the development of atherosclerosis by age, sex, and race, by the geographic variation in prevalence and extent of atherosclerosis, and by the relationship of atherosclerotic lesions to risk factors for coronary heart disease. A monograph on arterial smooth muscle cells by Geer and Haust (22) contains an extensive review of publications on the nature of cells in atherosclerotic lesions, descriptions of the histologic and ultrastructural features of arterial lesions, and electron micrographs illustrating atherosclerot- ic lesions. The published proceedings of international symposia on atherosclerosis (25, 34, 63, 64, 65, 86) contain review articles and reports of investigative work in atherosclerosis. Natural History and Topography Atherosclerosis begins in childhood, but does not usually become clinically manifest through its ischemic complications until later in life. The simple fatty streak is considered to represent the earliest lesion of atherosclerosis that can be easily recognized either grossly or histologically. The fatty streak is gradually converted into a fibrous plaque in which there is abundant connective tissue as well as lipid. These more advanced intimal lesions with increased amounts of mesenchymal tissue may enlarge to cause progressive stenosis of the vascular lumen. These lesions may undergo sufficient enlargement by accumulated lipid and connective tissue or superim- nosed mural thrombus to further narrow the lumen, or the lesions may become vascular&d and undergo intramural hemorrhage or may become ulcerated and covered by thrombus. In these last instances, rapid occlusion of the artery may result. Under certain circumstances and in certain arterial segments, the lesion may so weaken the underlying media that an aneurysm is produced, or the lesion may become calcified-a change that may represent a healing process, but nevertheless reflects an advanced stage of the athero sclerotic process. 17 The strong association between cigarette smoking and the clinical manifestations of atherosclerosis is examined in other sections of this Report. This section examines the relationship between ciga- rette smoking and the development of atherosclerotic lesions and other stages of occlusive arterial disease. A brief description of the topographic distribution of atherosclero- sis in different arterial segments provides additional background information for this section. The topographic distribution of athero- sclerotic lesions was reviewed by Duff and McMillan (20) and by Glagov and Ozoa (23). Schwartz and Mitchell (68) described selective involvement of some arteries and areas of localization of arterial plaques in their necropsy survey. Those studies were generally consistent, finding that lesions occur earliest and most extensively in the aorta. Pathologically demonstrable lesions usually develop later and less extensively in the coronary and cerebral arteries; the renal, mesenteric, and pulmonary arteries are the least susceptible to atherosclerotic lesions. A diagrammatic representation of the usual localization of arterial involvement by atherosclerosis is depicted in Figure 1, taken from the National Heart and Lung Institute (NHLI) task force report on arteriosclerosis (79). Studies in the International Atherosclerosis Project (IAP) led to the following conclusions concerning atherosclerosis in the aorta and in the coronary, carotid, vertebral, and intracranial arteries (43). The severity of atherosclerosis in one artery does not predict the severity in another artery for an individual case. On a cross-cultural basis, however, the average predilection of a population to raised lesions in one artery is correlated with the predilection in other arteries. The rank order of location-race groups in the IAP is approximately the same regardless of whether the ranking is based on raised lesions in the coronary arteries, the thoracic aorta, the abdominal aorta, or the cerebral arteries. This finding is consistent with the hypothesis that environmental conditions predominantly determine the severity of atherosclerosis in a population, despite large differences in susceptibility to lesions among individuals or among different anatomic loci within the arteries of each person. In general, the development of atherosclerosis follows a definite sequence. The aorta is involved first, beginning in infancy with fatty streaks that increase rapidly during puberty; fibrous plaques begin in the aorta in the third decade. Fatty streaks begin in the coronary arteries during puberty. They begin to increase significantly and become converted into fibrous plaques in the third decade of life in high risk populations. The carotid arteries begin to be involved with fatty streaks at approximately the same age as does the aorta. The other cerebral arteries begin to be involved at approximately the same age as do the coronary arteries. Raised lesions develop in the 18 FIGURE l.-Common sites of atherosclerotic lesions SOURCE: U.S. Public Health Service (79). carotid arteries at roughly the same age as in the aorta, but do not develop in the vertebral and intracranial arteries until much later. Hypotheses of Atherogenesis A succinct review of the major hypotheses concerning the athero sclerotic process (47) summarized various theories of atherogenesis with emphasis on the two major hypotheses-the lipid hypothesis, and the hypothesis that regards atherogenesis as a process involving the conversion of arterial mural thrombi into atherosclerotic plaques. The lipid hypothesis is based on the frequent occurrence of excessive amounts of cholesterol and lipid in lesions, the positive association between elevated serum lipids and atherogenesis in man and in animals, the association of dietary saturated fats and cholesterol with atherogenesis in man and in experimental animals, 19 and the association between specific diseases and genetic disorders that affect lipid metabolism and atherogenesis. The hypothesis concerning the conversion of mural thrombi into atherosclerotic plaques through tissue organization of the mural thrombi (the Duguid-Rokitansky concept) is based largely on patho- logical observations in man that show morphological evidence compatible with this view of atherogenesis. Such evidence is most convincing in relation to the middle or late development of plaques rather than to their early stages. Many investigators of atherosclero- sis have accepted this theory as a basis for plaque progression or complication rather than as a theory of plaque initiation. The demonstration that platelets are capable of interacting with intimal smooth muscle cells to stimulate them to proliferate has now extended this theory to encompass the initiation of atherogenesis without necessarily invoking the classical sequence of thrombosis (59). McMillan (47) pointed out that there has been a tendency for the proponents of one or the other of these theories to emphasize the rather exclusive importance of one hypothesis when considering various factors that are thought to be of particular importance for atherogenesis (such as cigarette smoking, hypertension, diabetes mellitus, or hyperlipoproteinemia). That is, the atherogenic factors often have been relegated to one or the other theory as independent factors that promote either lipid or thrombotic atherogenesis. Nevertheless, as McMillan (47) indicates, the two major theories are not mutually exclusive, but may complement one another in the initiation and progression of atherogenesis. There is much support for the view that atherosclerosis is best accounted for by the known facts if it is regarded as a multifactorial disease and, in the words of McMillan, "polyetiologic and polypatho genetic." The finding that some individual fibrous plaques are uniform for one or other of the sex-linked isoenzymes of 6-GPD (12, 13, 14) suggests that each mature plaque derives from a single cell and is the basis for a new theory of atherogenesis, the monoclonal hypothesis. This theory suggests that plaques may result from the transformation, genetic or otherwise, of individual cells of the vessel wall into a cell that will react to stimulation and form a plaque. Other observations that fatty streaks are not monotypic (55) and that thin plaques tend to be heterotypic, while thicker ones from the same aorta tend to be monotypic (76), suggest that the phenomenon of cell adaptation and selection rather than that of transformation may be the basis for plaque monotypism. The arterial endothelium obviously has a key role in both the lipid and the thrombotic theories. In the lipid theory, the lipoprotein molecules traverse the endothelium in some fashion prior to being 20 accumulated in a plaque. The thrombotic theory also includes endothelial participation as an essential phenomenon. Endothelial damage or loss may be manifest either as increased permeability to macromolecules or as a focus for platelet adhesion, aggregation, and release; thus, these changes may be atherogenic stimuli. Exposure of the intima to lipoproteins and platelets may be mitogenic for smooth muscle cells, and can affect the arterial lesion by modulating the cellular production of collagen and glycosaminoglycans. This se- quence of events indicates how the lipid and thrombotic theories can interrelate in early atherogenesis. The most popular hypothesis to account for the accumulation of lipid in plaques involves the introduction of excessive amounts of plasma lipoproteins through the endothelial barrier to the intima. The lipoproteins, particularly low density lipoproteins (LDL), are internalized by smooth muscle and other connective tissue cells and are not metabolized rapidly; therefore, the lipid components accumu- late in the cells. The sterols that are liberated in the cell lysosomes of arterial cells may become so excessive that high density lipoproteins (HDL) are unable to remove them from the cells and from the intima. With progressive cellular lipid accumulation, cellular necro- sis may occur, causing lipid to be dispersed into the extracellular portions of the arterial wall. Thus, lipid may accumulate both intracellularly and extracellularly and may act as a local cause of injury. When weighing the evidence linking tobacco usage with the development of atherosclerotic lesions, one should consider these theories of atherogenesis as well as the natural history of atheroscle- rosis presented earlier in order to make judgments about possible mechanisms and the stages at which the process might be affected. Epidemiological Evidence Linking Cigarette Smoking With Atherosclerosis Cigarette smoking is a major risk factor for coronary heart disease, peripheral vascular disease, and other clinically significant sequelae of atherosclerosis. A key question is whether cigarette smoking has an effect on the development of the arterial lesions, the terminal occlusive events, or both. Until the recent past, few investigators specifically designed studies to answer questions dealing with the association between cigarette smoking habits and the development of atherosclerotic lesions in the aorta and coronary arteries. In the 1971 Report of the Surgeon General The Health Conse- quences of Smoking (801, reports of such studies were reviewed and summarized. Since that time, a number of additional reports have been published dealing with the relationship between cigarette smoking and atherosclerosis of the coronary arteries, aorta and 21 peripheral arteries, arterioles within the myocardium, and cerebral vessels. The evidence relating cigarette smoking and autopsy evi- dence of atherosclerotic disease in each of these areas is reviewed separately and summarized in individual tables in this section. coronary Arteries Table 1 summarizes the studies that have examined the relation- ship between cigarette smoking and autopsy evidence of atheroscle- rosis in the coronary arteries. Auerbach et al. (6) found more coronary atherosclerosis in smokers than in nonsmokers and a concomitant increase in the amount of atherosclerosis with the amount of cigarette smoking. An interim report by Strong et al. (75) concluded that atherosclerotic involvement of aortas and coronary arteries was greatest in heavy smokers and least in nonsmokers among autopsied men in New Orleans. A report by Vie1 et al. (81) on accidental deaths in Chile stated that there was no relationship between atherosclerotic lesions and the use of tobacco; however, examination of the data indicated that heavy smokers in the 50- to 54year and 55- to 59-year age groups exhibited higher percentages of the left anterior descending coronary intima involved by atheroscle- rotic lesions than did nonsmokers. Apparently these differences were not statistically significant. A detailed study of smoking and atherosclerosis in deceased men in New Orleans has been conducted. Several reports based on the findings of that study, as well as various interpretations of those findings, have been published. Strong and Richards (74) reported the basic findings on the association of cigarette smoking and atheroscle- rosis in 1,320 autopsied men in New Orleans, 25 to 64 years of age. Coronary lesions were evaluated visually in coded specimens and objectively by analysis of post mortem radiographs. Using schedules that had been tested on pairs of living persons (49, interviewers obtained estimates of cigarette smoking habits of the deceased men from surviving relatives. Data were compared for black men and white men and also were analyzed in groups according to the presence or absence of diseases thought to be associated with smoking or with coronary heart disease (emphysema, lung cancer, myocardial infarction, hypertension, diabetes mellitus, stroke, etc.). Atherosclerotic involvement of the coronary arteries was greatest in heavy smokers and least in nonsmokers for both races in the total sample and in the basal group (those cases least influenced by the bias of autopsy selection). The data for these groups are presented in Table 1. The study by Strong and Richards (74) included approximately the same number of autopsied subjects from New Orleans as had the previously reviewed study by Auerbach et al. (6) in East Orange, New Jersey. Even though the methods of evaluation of arterial 22 TABLE l.-Autopsy studies of atherosclerosis involving the coronary arteries Data collection Measure of Study Population method atherosclerosis Resulta Smoking No atherosclerosis * Moderate Advanced Auerbach et al. 1,372 autopsies of Interview with Visual protocol None 5.6 57.3 21.8 15.3 (6) men who did not relatives (20 2.6 30.9 37.3 29.2 die of CND 20-34 .8 19.7 42.1 37.4 40+ .6 18.1 35.4 45.9 Avtandilov 259 males and Not specified Not specified Comparative size of mean area of atherosclerotic lesions in inner coat of coronary arteries (8) 141 female autopsies Right coronary artery Left coronary artery Smoker Nonsmoker Smoker Nonsmokers 3lL39 15.5 (30)' 1.3 (32) 6.3 ' 2.2 40-49 23.6 (34) 11.5 (27) 15.8 ' 4.4 50-59 36.3 (39)' 14.6 (39) 27.9 ' 9.9 60-69 31.9 (321' 23.6 (36) 26.5 ' 22.5 70-79 41.9 (16) 31.7 (36) 26.1 35.8 NOTE The results concerning aortrc athercscleroels are gwen in form of ligure Presentation Of rid&analysis. Vie1 et al. (81) 1,150 males and 290 Interview with females autopsied relatives following violent death Not specified Graphic data presentation only. but no association noted E TABLE l.-Continued. Study Population Data collection Measure of method atherosclerosis ReSUlta Strong et al. (75) Strong and Richards (74 747 New Orleans males 20-64 years of age at death 1,320 autopsies of males aged 25-64 Interviews wth IAP protocol. next of kin visual grading, within 8 weeks and optical of death scanning Interview with Visual grading Mean percent of coronary artery intimal surface involved with raised lesions for total next of kin and optical sample, males scanning Average number cigarettes smoked per day Age 0 l-24 25+ 25-34 3 35-44 21 4L54 32 5.%64 36 25-34 4 35-44 12 45-54 19 55-64 32 White males 6 27 37 45 Black males 4 16 31 31 10 26 39 47 12 23 35 33 TABLE I.-Continued. Data collection Measure of Study Population method atherosclerosis Results Auerbach et al. 1,056 autopsies of Interview with Visual and Distribution (in percentages) of degrees of fibrous thickening, of atheroma, and of cal- (4 male veterans relatives micrcacopic cification by smoking habits standardized for age (microscopic coronary study) evaluation Current cigarette smokers Never EX- Degree of smoked < pack l-2 packs 2+ pa& Cigar/ cigarette findings regularly per day per day per day pipe smokers Fibrous thickening None 50.1 3.9 0.6 0.4 4.5 5.0 Slight 20.1 26.5 8.0 5.1 24.4 30.6 Moderate 29.0 59.1 72.6 72.3 54.8 57.4 Advanced 0.8 10.5 18.6 22.2 16.3 7.0 -4theroma None 82.5 74.5 69.9 66.1 68.2 12.0 Slight 4.1 4.0 3.7 3.1 4.5 3.9 Moderate 13.1 19.2 20.6 20.8 23.4 21.5 Advanced 0.3 2.3 5.8 10.0 3.9 1.6 Calcification None 85.8 81.5 7A.l 73.5 75.5 79.2 Slight 4.5 4.1 3.8 4.3 6.2 4.3 Moderate a.4 10.3 11.1 11.2 13.4 12.7 Advanced 1.3 4.1 7.0 11.0 4.9 3.8 TABLE I.-Continued. Study Population Data collection method Measure of atherosclerosis Results Distribution by percentage of degree of atherosclerosis by smoking habits standardized for age (macroscopic study) Current cigarette smokers Degree of atherosclerosis NWW EX- smoked < pack l-2 packs 2+ packs Cigar/ cigarette regularly per day per day per day pipe smoker Lif&.ic (371 894 autopsies of males 20-79 at death in Yalta Interview with relatives Visual grading None or minimal 59.8 45.2 36.6 32.6 36.3 50.9 Slight 24.7 26.9 27.9 21.5 28.4 25.5 Moderate 10.2 16.2 16.0 16.5 21.0 12.6 Advanced 5.3 ii.7 lY.5 23.4 14.3 11.0 Total 100.0 loo.0 loo.0 1OQ.O 1Oil.o loo.0 Ratio of the extent of atherosclerotic lesions in the average coronary artery between nonsmokers and smokers Total Compli- athero- Fatty Fibrous cated Calcified Raised sclerosis streak plaque lesion lesion lesion Nonsmoker to heavy smoker Nonsmoker to smoker 1.0 1.1 1.0 1.5 0.6 1.0 1.0 1.1 1.1 1.0 0.6 1.0 TABLE l.-Continued. Data collection Measure of Study Population method atherosclerosis Results Schettler Autopsies of 89 Interview with Visual grading Stenosis et al. males aged 60-94 relatives (63) at death in Tokyo Smoking No Yes Total No 6 8 14 Yes, daily 8 67 75 Total 14 75 89 Rhoads et al. 109 sutop&s of Interview with AHA panel Mean coronary atherosclerosis grade versus selected attributes (56) Japanese American subject male8 born 1900- Regression coefficients 1919 who parti- cipated in Honolulu Examination variables Simple Multiple ' heart study Relative weight 1%) 0.031 J 0.025O Cigarettes/day 0.022* 0.024 3 Cholesterol(mg/dl) 0.011 3 0.0093 Triglycerides(mg/dlI o.Oo22 NS' Glucose(mg/dl) 0.004 2 NS' Hematirit 1%~ o.069z NS ' `Multiple regreaxon was done by B stepw.ee ehmmatmn procedure begmnmg wth the set of vanables shown: coefficwnts are for the final step. Multiple correlation (final step1~0.46 IN- 108l ~Slgnlficant at on5 level ~S1gmficant at 0 01 level `NS. vanable included ,n timt step. deleted an not slgmficant at 0.05 level. TABLE l.-Continued. Study Population Data collection method Measure of atherosclerosis ReSUlti 35-44 X 4.4 a.4 x 32.2 32.1 X 60.3 62.1 2 8 12 45-54 X 5.5 0.4 x 25.1 31.4 x 65.7 70.4 2 25 12 55-64 a.1 47 7.2 31.4 31.1 20.8 60.3 57.4 62.4 11 15 9 ' ATL as percent surface fatty streaks (F) plus raised lesions (Rl: FaF=F - (100 - R%E in percentage units explained in the text; X indicates subgroups having fewer than five members Holme et al. (29) 129 autopsies from Interview with Visual grading Correlation coefficient between number of cigarettes and raised lesions in the coronary 16,2CGC males aged subject arteries = ,039, not significant. 4M9 in Oslo prospective CHD stwiv Sternby (711 60 autopaiea of 703 Interview with Visual grading Smoking and stenosis or atherosclerosis in the left anterior descending coronary artery males in CHD subject study in Malmo. LAD Coronary SW&n Smoking category Number rased lesions artery stenosis Non 3 68 33 Ex 8 52 38 Light 18 45 39 Heavy 17 54 59 TABLE l.-Continued. Study Population Data collection method Measure of atherosclerosis Results Sorlie et al. ( 70) 139 autopsies of Interview with Visual grading Association of atherosclerosis in coronary arteries with antemortem characteristics: 9,824 Puerto Rican sub@ simple correlation coefficients (Puerto Rico heart health program) males aged 35-79 m a prospective study Correlation coefficients Characteristics measured at exam 1 Total (139) Rural (36) Urban ( 103) Systolic blood pressure Diastolic blood pressure Serum cholesterol Age, exam 1 Relative weight Physical activity Blood glucose Hematocrit Education level Income Cigarettes smoked Calories (24.hour recall) Starch (24.hour recall) Alcohol (24.hour recall) Total fata (24.hour recall) Triglycerides (fasting) Ventricular rate Vital capacity 0.22 0.07 0.30 0.26 0.09 0.30 0.42 0.59 0.38 0.01 0.32 4.08 0.21 JJ.15 0.25 -0.18 0.06 -0.22 0.20 4.04 0.21 0.14 0.36 0.12 0.14 a.40 0.24 0.16 4 17 0.16 4.16 xl.05 xl.22 a.14 a.43 407 -0.17 -0.29 -0.09 a.10 -9.10 a.13 -0.04 xl.53 0.03 0.23 0.49 0.19 0.13 0.20 0.08 -0.19 a.13 4.16 lesions were not identical, the findings from both of these large studies of autopsied men in the United States were remarkably similar. Both studies reported more extensive coronary atherosclero- sis among the cigarette smokers than among the nonsmokers, and for the major comparisons, with only rare exceptions, there was an orderly progression of least extensive lesions in nonsmokers, inter- mediate extent of lesions in light or moderate smokers, and most extensive lesions in heavy smokers. In the New Orleans study (741, lesions were measured not only by visual evaluation, but also by optical electronic scanning of radio- graphic images of the flattened arteries. The measurements of lesions from radiographs-relative mean coronary wall thickness and percentage of the coronary artery intima involved with calcifica- tion-were consistently greater for the heavy smokers than for the nonsmokers. A variety of statistical analyses on smoking measures and atherosclerotic lesions were performed to determine the signifi- cance of the various differences and trends. These analyses con- firmed that the major differences between the heavy smokers and the nonsmokers in extent of raised atherosclerotic lesions (the sum of fibrous plaques, complicated lesions, and calcified lesions) were significant. A one-way multivariate analysis of nine atherosclerotic variables clearly indicated that there were statistically significant differences among the three categories of smokers (heavy, light to moderate, and nonsmokers) for mean coronary wall thickness, raised lesions in the coronary arteries, percentage of cases positive for fibrous plaques, percentage of cases positive for complicated lesions, and percentage of cases positive for calcified lesions, with lower values in nonsmokers and higher values in the heavy smokers. Pate1 et al. (53) evaluated this same data on smoking and atherosclerotic lesions to examine further the interrelationships with measures of obesity. The confounding effects of diseases such as hypertension and diabetes mellitus were controlled by excluding such cases from the analysis. The confounding effects of age and measures of smoking habits on the association between atherosclero- sis and obesity were controlled by multivariate regression analysis. This analysis disclosed an inverse relationship between smoking habits and obesity. There was also a weak positive association- when age and smoking were controlled for-between measures of obesity and mean coronary wall thickness and raised lesions in the coronary arteries among whites, but not among blacks. In the black men, again with age and smoking controlled in the analysis, a weak association between fatty streaks in the coronary arteries and obesity was found. This analysis confirmed the previously reported relationships between smoking habits and atherosclerosis, as mea- sured by mean coronary wall thickness, coronary calcifications, and raised lesions in the coronary arteries. 31 Since their first report in X65, Auerbach and his associates have investigated the relationship of cigarette smoking to microscopic findings in the coronary arteries (4). This study indicated that lesions were most extensive in cigarette smokers and confirmed earlier studies by Auerbach et al. (6) and Strong and Richards (74). The microscopic portion of the Auerbach et al. study (4) showed that fibrous thickening, atheroma, and calcifications of the coronary arteries all increased with increasing number of cigarettes smoked per day. They also found that the fibrous thickening of arteries increased in relation to the number of cigarettes smoked per day as the size of the artery decreased; i.e., it was least in the coronary arteries and greatest in the myocardial arteries. Lifsic (37) reported on the relationship of cigarette smoking to coronary atherosclerotic lesions based on the Yalta sample from the World Health Organization (87) autopsy study of five cities in Europe. Information on cigarette smoking was obtained by means of interviews with the subjects' near relatives. The prevalence and extent of atherosclerotic lesions were evaluated in autopsies of 865 men, aged 20 to 79 years, out of the 1,220 deaths occurring in Yalta residents of this age and sex group during the period of study. There was a positive association of smoking with the extent of coronary calcification; however, the author explained this association as being related to coexisting alcohol consumption and stated that smoking alone tended to be negatively associated with coronary calcification. The following paragraph from Lifiic's discussion provides additional, information from this report. There was little significant difference between smokers and nonsmok- ers in the prevalence and extent of atherosclerotic lesions in the coronary arteries. Thus, of the total of 210 comparisons of different indices of the prevalence and extent of atherosclerotic lesions between subgroups X and W, significant differences positively correlated with smoking were found in only 20. The tendency toward a positive correlation of coronary atherosclerosis with smoking was found mainly in subjects up to the age of 50, but after 60 the opposite tendency prevailed. These age peculiarities agreed with data from other studies showing that differences in the degree of atherosclerosis between smokers and nonsmokers. . . are more distinct below age 60. The author also mentioned a positive association between smoking and coronary calcification in "strenuous workers." A note added in proof to LifGic's article states, "Additional study of this material by individually matched case-control analyses revealed a marked trend toward a positive association between smoking and atherosclerotic raised lesions in the coronary arteries" (82). Thus, while the author's abstract does not indicate an important relationship of smoking and coronary atherosclerosis, there are findings in the study that do 32 indicate significant relationships between smoking and coronary atherosclerosis, especially in the younger subjects. A subsequent study by Vikhert et al. (83) on material from five cities in the U.S.S.R. evaluated the effect of nutritional status and tobacco smoking on atherosclerotic changes in the coronary arteries as measured by a visual planimetric method. This material was also utilized for a WHO-sponsored epidemiological study of atherosclero- sis (87). The vessels examined were from 430 men 40 to 69 years of age. The major analyses concerning tobacco smoking were made from 313 male heavy smokers and 82 nonsmokers. The investigators studied both manual workers and white-collar workers and found that tobacco smoking in combination with overnourishment had a much more positive effect on the development of coronary athero- sclerosis in white-collar workers than in the manual workers. Prospective epidemiologic studies of cardiovascular disease with autopsy followup provide additional information concerning the relationship of smoking to atherosclerotic lesions in the artery wall. The epidemiological studies in Oslo, Puerto Rico, and Honolulu are characterized by careful documentation of selected major risk factors, including cigarette smoking habits during life, and by standardized evaluation of atherosclerotic lesions at autopsy (29, 56, 70). Each of these three studies reported findings on the relationship of CHD risk factors to atherosclerotic lesions in more than 100 autopsies of deceased men who had been part of larger cohorts that had been examined and followed during life. In addition, a smaller study from Malmo, Sweden, had some of the same features as these larger studies (71). The Oslo, Malmo, and Puerto Rico studies used identical methods for grading the extent of atherosclerotic lesions. These prospective epidemiologic studies with autopsy followup are in general agreement concerning the relationship of serum cholesterol levels and blood pressure to the extent of atherosclerotic lesions in the coronary vasculature. The findings concerning the relationship of cigarette smoking to the extent of coronary atherosclerosis are not uniform. The Honolulu study (56) showed a significant relationship between smoking habits and extent of coronary atherosclerosis. The Oslo study (29) did not show a significant relationship between cigarette smoking and coronary atherosclerosis. The Puerto Rico study (70) also did not show a significant relationship between smoking and the extent of coronary athersclerosis. A somewhat similar study from Japan by Hatano and Matsuzaki (26) indicated a significant relationship between cigarette smoking and coronary artery stenosis. Thus, there is some inconsistency concerning the association between cigarette smoking habits and coronary athero- sclerosis in the prospective epidemiologic studies with autopsy followup. 33 In considering this entire body of evidence, however, the prepon- derance of evidence suggests that cigarette smoking has an effect on the development of atherosclerotic lesions in the coronary artery wall in the U.S. population, and that its effect is not limited to those events immediately surrounding the occlusive episode. Small Arteries in the Myocardium Table 2 reviews those studies that. have examined the relationship between cigarette smoking and lesions of the arterioles within the myocardium. Auerbach et al. (7) found a relationship between smoking habits and thickening of the walls of the arterioles and small arteries of the myocardium. Auerbach et al. (4) also performed a microscopic study of coronary artery lesions in autopsied men in relation to previous smoking histories. In the microscopic portion of this study, fibrous thickening, atheroma, and calcification increased with an increased number of cigarettes smoked per day. Moderate to advanced hyaline thickening of the arterioles in the myocardium was strongly related to smoking. It was found in 98.6 percent of the autopsied subjects with a two pack per day smoking habit and not found in the group of subjects who never smoked regularly. Naeye and Truong (51) reported essentially similar alterations in the intramyocardial arteries, which developed more rapidly in cigarette smokers than in nonsmokers. The Aorta Those studies that provide autopsy and other evidence for the relationship between cigarette smoking and atherosclerosis of the aorta are summarized in Table 3. Wilens and Plair (85) found significantly more severe sclerosis of the aorta in cigarette smokers than in nonsmokers. Sackett and Winkelstein (61) reported that elderly cigarette smokers had signifi- cantly higher rates of aortic calcification, detected on chest X-ray, than did nonsmokers. Sackett et al (601, in an autopsy study, found a significant relationship between the use of cigarettes and the severity of aortic atherosclerosis. An interim report by Strong et al. (75) concluded that atherosclerotic involvement of aortas was greatest in heavy smokers and least in nonsmokers among autopsied men in New Orleans. Most of these studies, reviewed in the 1971 Report of the Surgeon General The Health Consequences of Smoking (801, indicate that differences between heavy cigarette smokers and nonsmokers are particularly great in young individuals, and that heavy smokers have increased surface involvement with fibrous plaques or more advanced atherosclerotic lesions. Since the 1971 review, a study of smoking and atherosclerosis in deceased men in New Orleans has been completed. Several reports 34 TABLE 2.-Autopsy studies of atherosclerosis involving small arteries in the myocardium Study Population Measure of atherosclerosis ReSUlta Auerbach et al (7, 1,164 males Records and Biopsy of Grade of thickness of walls of arterioles' autopsied family myocardium at VA Number of men Percentage of men Grade Grade Grade Grade Grade Grade Age Smoking Total 0 1 2. 3 Total 0 1 2. 3 - (45 None Cigar-pipe ctte3 1-19 Ctte 2&39 ctte 40+ 45-59 None Cigar-pipe ctte l-19 ctte 2cL39 Ctte 40+ 60-69 None Cigar-pipe ctte 1-19 ctte 2&39 ctte 40+ 70+ None Cigar-pipe ctte 1-19 ctte 20-39 ctte 40+ 22 2 4 - 50 1 a5 4 29 - 15 1 13 - 33 - 99 - 50 56 4 35 92 193 67 - 32 2 40 30 - 46 - 9 - 19 1 loo.0 1 3 100.0 31 18 lc0.0 35 46 100.0 10 19 loo.0 12 2 loo.0 8 5 lc0.0 17 16 loo.0 35 64 loo.0 11 39 1Oc.o 36 16 loo.0 22 13 loo.0 44 4.3 100.0 58 135 1WJ.O 21 66 loo.0 18 12 100.0 19 21 loo.0 12 18 1lx.o 12 34 100.0 3 6 loo.0 9.1 66.4 4.5 25.0* 75.0' 2.0 62.0 36.0 4.7 41.2 54.1 - 34.5 65.5 6.7 80.0 13.3 61.5 38.5 - 51.5 48.5 - 35.4 64.6 22.0 78.0 7.1 64.3 26.6 - 629 37.1 47.0 52.2 - 30.1 69.9 - 24.1 75.9 6.3 56.2 37.5 47.5 52.5 - 40.0 60.0 - 26.1 73.9 - 33.3' 66.71 `In the right ventrmdar wall of 1,020 men by age and smoking habits `Percentage8 baeed on less than 10 cases `Ctte indicates cigarettes. TABLE 2.-Continued. Study Population Smoking data BO"TlX Measure of atherosclerosis ResUlts Auerbach et al. (4 1,056 males autopsied at VA Relatives and records Microscopic examination Distribution by percentage of degree of fibrous thickening of myocardial arteries, subepicardial arteries. and hyaline thickening of myocardial arterioles (microscopic myocardial study), by smoking habit standardized by age Current cigarette smokers Demee of findings Never smoked Ex ~1 pack 1-2 packs z+packB Cigar/ cigarette regularly per day per day per day pipe smokers - Myocardial arteries None or minimal slight Moderate Advanced Total S&epicardial arteries None or minimal Slight Moderate Advanced Total 97.3 24.1 2.7 62.2 +16 12.3 - 1.4 100.0 loo.0 74.7 17.5 2.4 1.4 24.9 56.8 35.1 32.7 0.4 19.0 28.8 23.8 - 6.7 33.7 42.1 loo.0 100.0 100.0 100.0 2.9 1.1 22.0 32.0 37.1 29.6 70.6 63.2 39.0 45.0 6.7 4.2 21.0 24.3 0.7 0.6 loo.0 100.0 100.0 1rKl.o 21.5 26.2 64.8 60.5 9.9 11.6 3.8 1.7 loo.0 loo.0 Myocardial arterioles None or minimal Slight Moderate Advanced Total 92.0 2.1 - - - 3.2 8.0 28.7 2.2 1.4 39.6 40.8 - 20.8 9.6 7.9 19.6 19.1 - 40.4 68.2 90.7 40.8 36.9 100.0 100.0 loo.0 loo.0 loo.0 100.0 TABLE 3.-Autopsy studies of atherosclerosis involving the aorta Study Smoking data Measure of Population source atherosclerosis Results Wilens and Plair WI 989 consecutive necropsea at NY VA hospital Patient chart Visual grading Percent of subjects by smoking status and atherosclerosis Severity of Non- Pipe/ sclerosis smoker Heavy Moderate Light cigar Other Number 161 199 288 152 70 119 Percent above average 9.9 25.1 26.4 19.1 10 10.9 Percent average 60.2 61.3 62.5 63.2 60 63.0 Percent below average 29.6 13.6 11.1 17.6 30 26.1 Strong and Richards (74) 1,320 Interview Visual grading Mean percent of intimal surface of abdominal aorta involved with raised lesions autopsies with relatives of males Average number of cigarettes smoked per day aged 25-64 at death Age and race 0 l-24 25+ White males 25-34 35.44 4554 5.%64 Black males 2534 3M4 4&54 55J34 1 7 7 14 33 44 33 52 56 46 63 71 4 7 9 6 20 28 14 37 45 26 51 56 g TABLE $-Continued. Study Smoking data Measure of Population source atherosclerosis Results Sackett and 590 Winkelstein white male (61) admissions to Powell Park Mem- orial In- stitute in 1955 Patient Chest X-ray The relationship between smoking and calcification of the thoracic aorta questionnaire for calcification in thoracic aorta Nonsmokers Smokers Percent with Percent with Probability Age group Number calcification Number calcification value 1 Totals 50-59 61 13 131 11 0.4 192 60-69 90 16 124 26 0.2 214 70 and over 116 37 63 54 0.02 164 Totals 267 25 323 26 - 590 Age-adjusted percent - 22 - 30 - - `Chi-square of independence, twotcded. The relationship between amount smoked and calcification of the thoracic aorta Age group m-59 60-69 70 and over Totals Nonsmokers Light smokers Heavy smokers Percent with Percent with Percent with Number calcification Number calcification Number calcification Totals 61 13 104 9 27 22 192 90 16 107 24 17 35 214 116 37 63 56 5 40 164 267 26 274 29 49 27 590 Age-adjusted percent - 22 - 29 - 32 - TABLE S.-Continued. Study Smoking data Measure of Population Bource atherosclerosis Results Sackett et al. (60) 1,019 Standardized Visual grading Mean ag?+adjusted atherosclerosis ridits versus gr aded use of cigarettes and alcohol consecutive interview with on a numerical autopsies of patient on scale Alcohol Cigarettes white admiwion patienta &/day None 1 :! pack 1'2 pack+ None ,351 ,466 ,498 0.5-1.5 ,424 ,570 .56l3 1.6+ ,426 ,526 ,589 Strong et al. Autopies Interview Visual grading Mean percentage of intimal surface of aorta involved with raised lesions by age, race, and average rate (75) of 741 with relativea and optical of cigarette smoking in the last 10 years of life males 20-64 Bcanning year8 at death Cigarettes pe r day Age and race White males 3-4 4654 55-64 Black males 35-44 45-54 55-64 0 l-24 25+ 16 35 49 29 52 54 48 66 70 3 22 24 12 38 50 21 50 49 $ TABLE 3 -4`ontinued. Study Smoking data Measure of Population source atherosclerosts Results Litsrc (37) 865 autopsies Relatives and records Visual gradmg Prevalence of atherosclerotic lesions in the abdominal aorta in different subgroups (percentage) of males aged 2&79 at death in Yalta Smokrng group Never Lrght Heavy Fatty streak 96.5 92.8 90.7 Fibrous plaque 96.0 96.5 97.5 Complicated lesion 43.0 53.4 60.9 Calcified lesion 25.0 42.3 57.3 Extent of atherosclerotic lesions (percentage of surface) in the abdominal aorta Smoking Fatty group streak Never 7.0 Light 6.1 Heavy 5.8 Fibrous plaque 28.1 31.6 26.5 Complicated lesion 2.0 5.1 4.1 Calcified lesion 1.2 2.2 3.4 TABLE 3.-Continued. Study Smoking data Measure of Population source atherosclerosis Results Rhoads et al. (56-l 124 Japanese American males autop sied as part of the Honolulu heart study Interview with subject Visual by AHA panel method Correlation coefficients among selected autopsy and examination variables' Aorta (N = 124). atherosclerosis grade Age at death Examination variables Height (cm) Relative wt. (%) Cigarettes/day Cholesterol (mg/dl) Triglycerides (mg/dl) Uric acid (mg/dl) Glucose (mg/dl) Hematocrit (%I Vital capacity (liters) Alcohol (pm, Systolic pressure (mm Hg) Diastolic pressure (mm Hgl Mean coronary grade Aorta grade 0.30 3 -0.12 a.10 0.14 0.243 0.14 -0.052 0.15 a.03 X1.23~ -o.08z 0.29 3 0.05 0.503 (96)' I N= number of specimens. sS~gniiicant at 0.05 level a Significant at 0.01 level. `When a correlation coeffXent is based on less than 95 percent of the ~pecmwns available (because of missing data), the number of observations is indicated in parentheses. There were 96 autopsies with both aorta and coronary vesel grades available. 13 wth coronary only. and 28 with aorta only TABLE 3.-Continued. Study Smoking data Measure of Population SO"FX? atherosclerosis ReSUlta Auerbach 1,412 males Family Visual grading Percentage of selected findings by smoking habits and Garfinkel autopsied (5) at VA hos- Percentage of cases' pita1 "Current" cigarette smokers Findings Never smoked 1 pack l-2 pack3 2+ packs Cigar Excigarette regularlv per day per day per day or pipe smoker Thoracic aorta Many or diffuse distribution of plaques Moderate or advanced ulceration Moderate or advanced calcification Thrombus present Abdominal aorta Many or diffuse distribution of plaques Moderate or advanced ulceration Moderate or advanced calcification Thrombus present 16 26 41 37 27 29 4 6 14 12 10 8 56 63 74 74 53 67 4 7 14 11 11 9 28 54 68 79 46 53 7 19 27 27 13 22 63 76 84 88 74 81 7 23 23 31 14 23 lPercentages are adjusted to distribution by age group of all men in study. TABLE 3.-Continued. Study Smoking data Measure of Population source atherosclerosis Results Sternby (71) 60 Interview Visual grading Smoking and atherosclerosis of the aorta autopsies with subject from 703 Raised lesions in the males enrol- Smoking category Number abdominal aorta led in a CHD study Non 3 26 in Malmo. ET. 8 43 Sweden Light 18 53 Heaw 7 83 Smoking and atherosclerosis m peripheral arteries Femoral artery Lower leg artery Smoking Iliac artery Raised Sterosis RalSed Stenosis category N Raised lesions lesions (701 lesions (70) Non 3 17 20 0 2 0 EX 8 18 43 33 18 22 Light 18 29 29 6 3 11 Heavy 17 50 50 35 12 41 g TABLE S.-Continued. Study Population Smoking data Measure of source atherosclerosis Results Tracy et al. Autopsies Interview Visual exam Means of observed minus expected raised-among-lesions GE), fatty streaks among flat surfaces (FaF), (77) of 1.380 with relatives all types of lesions tATL1, and number of cases (N) by age, race, and cause of death according to white and smoking category I, abdominal aorta black males aged 2564 O-E Faf ATL at death Age 0 l-24 25+ 0 1-24 25+ 0 l-24 25+ White basal 2534 3544 45-54 5.5-64 White CHD 25-34 35-44 45-54 55-64 Black basal 2634 3%44 4554 55-64 Black CHD 24-34 35-44 45.54 5564 -3.7 3.9 0.6 25.3 32.1 36.6 26.4 36.6 34.7 -7.3 5.0 12.7 22.8 30.8 35.5 27.9 48.1 64.7 77 6.1 3.6 21.3 28.9 31.4 47.3 57.3 65.8 -0.6 3.0 6.7 33.7 33.1 35.5 56.5 68.6 76.2 X X X X X X X x x -18.7 15.3 6.8 43.2 28.2 39.2 55.3 67.9 68.0 8.0 3.6 1.3 25.7 40.8 33.1 500 81.4 73.4 4.5 5.4 2.2 44.3 37.7 40.1 77.7 82.8 83.7 5.3 -3.5 -3.8 28.6 32.8 36.8 30.7 34.9 38.6 -16.9 -3.1 -3.9 26.5 31.8 33.0 27.8 43.9 45.6 -15.7 -7.3 -5.4 25.0 32.7 37.4 33.8 47.2 60.0 -9.5 a.3 -2.8 29.7 31.6 32.1 43.9 61.6 55.5 X 6.3 X X 39.7 X X 44.6 X X -2.7 9.3 X 28.0 29.9 X 55.1 61.8 X 4.6 4.8 X 34.2 386 X 72.4 73.0 -14.4 -2.8 2.5 41.9 35.8 40.7 62.5 66.2 81.4 ' ATL as % fatty streaks (F) plus raised lesions (RI; FaF=F : (100 - R); O-E in percentage units explained in TABLE 3.-Continued. Study Smoking data Measure of Population 8oUrC.2 athercscleroeie ReSUlts the text. X mdvxtes subgroups having fewer than live members Sorlie et al. ( 70) 139 autopsies of 9.824 Interview Visual with subject evaluation Awxiation of atherosclerosis in aorta with antemortem characteristics. simple correlation coefficients (Puerto Rican heart health program) Puerto Rican males Correlation coefficients aged 35-79 Characteristics measured at exam 1 Total (120) Rural (31) Urban (89) Systolic blood pressure Diastolic blood pressure Serum cholesterol Age, exam 1 Relative weight Physical activity Blood glucose Hematcvxit Education Income Cigarettes smoked Calories (24.hour recall) Starch (24-hour recall) Alcohol (24.hour recall) Total fats (24.hour recall) Triglycerides (fasting) Ventricular rate Vital capacity 0.25 0.27 0.24 0.19 0.29 0.16 0.29 0.38 0.28 0.31 0.39 0.29 4.08 -0.22 4.06 -0.18 -lx21 -0.14 0.14 0.05 0.17 0.23 0.33 0.21 -0.08 a.23 a.03 0.01 -0.01 4.01 032 0.37 0.31 -0.24 -0`5.5 4 12 -0.19 a.45 -0.07 -0.18 4.39 AI 18 -0.19 4.49 a.11 0.11 0.53 0.04 0.07 0.11 0.05 -0.29 -0.28 -0.29 based on the findings in that study, as well as various interpretations of those findings, have been published. Strong and Richards (74) reported the basic findings on the association of cigarette smoking and aortic atherosclerosis in 1,320 autopsied men in New Orleans, 25 to 64 years of age. Aortic lesions were evaluated visually in coded specimens and objectively by analysis of radiographs. Interviewers obtained estimates of cigarette smoking habits of the deceased men from surviving relatives. Data were compared for black men and white men, and also were analyzed in groups according to the presence or absence of diseases thought to be associated with smoking or with coronary heart disease (emphysema, lung cancer, myocardial infarction, hypertension, diabetes mellitus, stroke, etc.). Atherosclerotic involvement of the aorta was greatest in heavy smokers and least in nonsmokers for both races in the total sample, as well as in the basal group (those cases least influenced by the bias of autopsy selection). The lesions were measured not only by visual evaluation, but also by optical electronic scanning of radiographic images of flattened arteries. Atherosclerotic lesions in the abdominal aorta were more extensive in the heavy smokers than in the nonsmokers, and there was an orderly trend of increased lesions with increased smoking. In general, the magnitude of difference in extent of lesions between nonsmokers and heavy smokers was greater in the abdominal aorta than in the coronary arteries. A variety of statistical analyses of smoking measures and atheroscle- rotic lesions was applied to determine the significance of the various differences and trends. All of the analyses confirmed that the differences between the heavy smokers and the nonsmokers in extent of raised atherosclerotic lesions were significant. A one-way multivariate analysis of nine atherosclerotic variables indicated that there were statistically significant differences among the three categories of smokers (heavy, light to moderate, and nonsmokers) for lesions in the abdominal aorta. Following the initial report of Strong and Richards (74), there were three additional publications from this study. Two of these were directed toward interpretation of findings in regard to the effect of cigarette smoking on fatty streaks (the earliest grossly visible lesions of atherosclerosis) and raised atherosclerotic lesions (the more advanced stage of the atherosclerotic process). The other study was directed toward the interrelations of obesity, smoking, and athero- sclerotic lesions in these same cases. The original report by Strong and Richards (74) indicated that raised lesions, the more advanced lesions, were greater in heavy smokers than in nonsmokers. They also reported statistically significant differences for fatty streaks in the abdominal aorta and for fatty streaks in the coronary arteries, with the highest values in the nonsmokers and lowest values in the heavy smokers. The well- 46 recognized problem of evaluating fatty streaks when more advanced lesions of atherosclerosis are present made it difficult to interpret the findings on fatty streaks. Pate1 et al. (54) approached this problem by using a simple two-parameter model of fatty streaks arising from a normal intimal surface at a constant rate and with subsequent conversion to raised lesions at a constant rate. They concluded that in the abdominal aorta, smoking enhances the formation of fatty streaks as well as the subsequent conversions to more advanced lesions, and in the coronary arteries, smoking seems only to enhance the conversion of fatty streaks to fibrous plaques. Tracy et al. (77) evaluated the same data from the New Orleans study on smoking and atherosclerotic lesions. They approached the problem using a different model: N = F -+ R, where N denotes normal intima, F denotes fatty streaks, and R denotes raised lesions. In this model, class A causes are viewed as promoting the process from beginning to end, while class B agents act at the first or the second step, but not at both. Their analysis and interpretation suggest that cigarette smoking has a large class B effect. They concluded that the target tissue of smoking is the fatty streak, and the slowly progressing or regressing fatty streak (formed alike in smokers and nonsmokers) is caused to progress more rapidly or to cease to regress by smoking. Both of these studies, Pate1 et al. (54) and Tracy et al. (73, agree that smoking has a role in the progr&ion of fatty streaks to a more advanced stage of the atherosclerq$c process. Auerbach and Garfinkel in 1980 (5) published findings on smoking habits and atherosclerotic lesions in over 1,400 aortas collected at autopsy from male patients. The extent of atherosclerotic lesions (plaques, ulcerations, and calcification) increased with number of cigarettes smoked, and was also greater in excigarette smokers and pipe smokers than in nonsmokers. The findings were more striking in the abdominal aorta than in the thoracic aorta. Aortic aneurysms were found eight times more frequently among those who smoked one to two packs of cigarettes per day than in nonsmokers. LifSc (37) reported on the relationship of cigarette smoking to aortic lesions based on the Yalta sample from the World Health Organization (WHO) autopsy study of five cities in Europe (87). Information on cigarette smoking was obtained by means of inter- views with the subjects' near relatives. The prevalence and extent of atherosclerotic lesions were evaluated in autopsies of 865 men, aged 20 to 79 years, out of 1,220 deaths occurring in Yalta residents of this age and sex group during the period of study. There were significant positive relationships between smoking and the extent of fibrous plaques, complicated lesions, and calcified lesions in the abdominal aorta. 47 Aortic atherosclerosis has also been evaluated using autopsy followup of prospective epidemiologic studies of cardiovascular disease. Epidemiological studies in Puerto Rico and Honolulu documented selected risk factors, including cigarette smoking habits, during life and had standardized evaluation of atherosclerotic lesions at autopsy (56, 70). Each of these studies reported findings on the relationship of risk factors and aortic atherosclerotic lesions in more than 100 deceased men from large cohorts that had been examined and followed during life. A smaller study from Malmo, Sweden, had some of the same features as these larger studies (71). All of these studies found a significant positive relationship between cigarette smoking and aortic atherosclerosis. The prospective epidemiologic studies with autopsy followup confirmed the relationship between smoking and atherosclerotic aortic lesions found in earlier autopsy studies. The preponderance of evidence suggests that cigarette smoking aggravates or accelerates aortic atherosclerosis, and this effect on atherosclerosis may be more pronounced in the aorta than in the coronary arteries. Cerebral Vasculature The relationship between cigarette smoking and atherosclerosis in the cerebral vasculature has not been extensively evaluated. Two studies that have examined this question are summarized in Table 4. Sternby (71) reported that cigarette smokers had more extensive raised lesions in the basilar artery than had nonsmokers. This study was based on 60 autopsy subjects from 703 men born in 1914 who participated in a study of cardiovascular disease in Malmo, Sweden. Holme et al. (29) reported a positive correlation coefficient between raised lesions in the cerebral vessels and the number of cigarettes smoked; this relationship was not statistically significant, however. The limited amount of information available on the relationship between cigarette smoking and atherosclerosis in the cerebral vasculature does not allow a clear conclusion to be drawn at this time. Pathophysiologic Mechanisms of Tobacco Smoke Studies of Components of Tobacco Smoke The possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking were reviewed in the 1971 Report of the Surgeon General The Health Consequences of Smoking (80). The major components of cigarette smoke considered in that review were nicotine and carbon monoxide. Numerous investigators have studied the effect of nicotine administration, either subcutaneously or intravenously, upon experimentally induced changes in the aorta and coronary arteries of animals. When administered alone, nicotine 48 TABLE 4.-Autopsy studies of atherosclerosis involving cerebral vasulation Study Population Smoking data 8ource Measure of atherosclerosis Result.6 Sternby (711 60 autoplied subjects from 703 male8 in CHD study in Malmo. Sweden Interview with subject Visual inspection Smoking and atherosclerosis m the basilar arteries Smoking category Number Basilar artery raised lesions Non 3 1 EX 8 6 Light 18 3 Heavy 17 7 Holme et al. (29) 129 autopsies out of 16,200 men aged 4049 in Oslo CHD study Interview with subject Visual grading Correlation coefticlent between raised lesions in the cere- bra1 vessels and number of cigarettes smoked per day is 0.090 (not statistically signifxantl. induces certain degenerative or necrotic changes in the arterial wall, but these are characteristically medial changes rather than the intimal changes that characterize atherosclerosis. When nicotine is administered in combination with a high cholesterol diet, it seems to aggravate arterial damage, according to a preponderance of studies. Some studies, however, do not report this synergism between cholesterol feeding and nicotine (16, 84). Schievelbein and associates (66) reported the effect of long-term nicotine exposure on the development of arteriosclerosis in rabbits. They administered nicotine to rabbits not being fed an atherogenic diet. All animals had arteriosclerotic lesions in the aorta and coronary arteries at the end of the experiment, but there was no difference between the control group and the experimental animals administered nicotine. They reviewed the experiments of several authors who studied nicotine and their own animal experiments and concluded that the evidence did not establish a causative role for nicotine in the etiology of arteriosclerosis. A recent report by Liu et al. (38) on experimental arterial lesions in rhesus monkeys with various combinations of dietary hypercho- lesterolemia, hypervitaminosis D(2), and nicotine indicated that the combination of these three factors produced high scores for various measures of arteriosclerotic changes in aorta, coronary, and limb arteries of the monkeys. When the factors were administered singly, however, very little arterial disease was demonstrated over the period of the experiment. The group with all three factors was the only group with significant coronary arteriosclerosis as well as complicated lesions of the arteries of extremities. Dooyse et al. (15) reported the effects of chronic oral consumption of nicotine on the rabbit aortic endothelium. They found that fasting serum levels of glucose, triglyceride, total cholesterol, and LDL cholesterol were elevated in nicotine-treated rabbits as compared with controls. They found no significant differences between the experimental group and the controls for leukocyte, erythrocyte, and platelet counts, or for hematocrit and hemoglobin. Endothelial cells from the aortic arch of the nicotine-treated animals showed exten- sive changes, such as increased cytoplasmic silver deposition, in- creased formation of microvilli, and numerous focal areas of "ruffled" endothelium. The authors concluded that nicotine adminis- tered orally to rabbits has a demonstrable morphologic effect on endothelial cells in the aortic arch. While the evidence for and against a primary role for nicotine in the development or acceleration of atherosclerosis is not conclusive, nicotine is certainly one of the components of tobacco smoke for which there are both some supporting data and a rational conceptu- alization for a role in the pathogenesis of atherosclerotic lesions. There is little doubt that nicotine alone or in combination with other 50 factors, such as hypercholesterolemia or excessive doses of vitamin D, can damage the arterial wall, and arterial injury is widely accepted as one mechanism for predisposing to or accelerating lesions in animal models of atherosclerosis. Carbon monoxide is another major component of cigarette smoke for which there are some data supporting a possible atherogenic role; however, a review of recent literature on the role of carbon monoxide in arterial injury and atherogenesis leads to no consensus. Early studies by Astrup and coworkers (3) on the effect of carbon monoxide in rabbits suggested the theory that carbon monoxide causes endothelial damage, which might promote atherogenesis. Later studies by Astrup's group (2, 32) indicated that the duration of exposure of rabbits to carbon monoxide did not influence the intimal morphology of the coronary arteries or the aorta. They felt that these new data contradicted the theory of carbon-monoxide-mediated endothelial damage as a cause of atherosclerosis. Recent experimental studies have produced a variety of results regarding the effects of carbon monoxide on the development of arterial lesions. Malinow et al. (40) exposed cynomolgus monkeys, fed a standard laboratory diet or a semipurified high cholesterol diet, to carbon monoxide or to room air for 14 months. None of the animals developed a myocardial infarction, and there was no difference in plasma cholesterol levels or in aortic or coronary atherosclerosis attributable to carbon monoxide exposure. Davies et al. (17) studied the effect of intermittent carbon monoxide exposure on experimental atherosclerosis in the rabbit and found there was an increase in coronary artery atherosclerosis in the carbon-monoxide- exposed animals, but they did not find significant differences in the lipid content of the aortas. Armitage et al. (1) studied the effect of carbon monoxide on the development of atherosclerosis in the White Carneau pigeon and found that the severity of coronary atherosclero- sis was significantly greater in birds exposed to carbon monoxide than in nonexposed birds after 52 weeks of exposure, but not after 84 weeks. The severity of atherosclerosis was related to the degree of hypercholesterolemia. They suggested that in the White Carneau pigeon, exposure to carbon monoxide elevates plasma cholesterol levels, and thereby increases the extent of experimentally induced atherosclerotic lesions. They further suggested that compensatory mechanisms may reduce the effect of carbon monoxide exposure on hypercholesterolemia over time. Two reviews in 1979 came to different conclusions concerning the relationship of carbon monoxide and arteriosclerosis. Astrup and Kjeldsen (2) surveyed the cardiovascular effects of exposure of animals to carbon monoxide and concluded that carbon monoxide produces myocardial effects that can lead to decreased myocardial oxygen tension with compensatory increases in coronary blood flow. 51 They stated that their previous findings of arterial intimal changes had not been confirmed. Turner (78) reviewed studies involving carbon monoxide, tobacco smoking, and the pathogenesis of athero- sclerosis, and concluded that carbon monoxide exposure enhances the extent of coronary atherosclerosis in pigeons that have been made hypercholesterolemic by adding dietary cholesterol. Carbon monoxide was without effect on normocholesterolemic birds. They indicated that the level of carbon monoxide exposure, the duration of exposure, and the level of dietary cholesterol are critically interde- pendent factors that can influence the pathogenesis of the disease. Studies by Sarma et al. (62) on the effect of carbon monoxide on lipid metabolism of human coronary arteries provide some support for the idea that carbon monoxide increases endothelial permeabili- ty. They perfused human coronary arteries under sterile conditions in vitro with blood containing high and low concentrations of carbon monoxide. They found no effect of carbon monoxide on lipid synthesis in the arterial wall; however, the arteries that were exposed to carbon monoxide showed a higher uptake of cholesterol from the perfusate as compared with their corresponding controls. Thus, the results of Sarma et al. (62) were in agreement with those of other investigators who have found that carbon monoxide signifi- cantly increases the permeability of endothelial membranes. Schneiderman and Goldstick (67) used a computer simulation of the oxygen transport system of the arterial wall to evaluate the extent of carbon-monoxide-induced hypoxia of the arterial wall under various conditions; the results suggested that the moderate to high carboxyhemoglobin levels found in some smokers may result in a significant reduction in the oxygen tension of the arterial wall. Hugod (31) reported no morphological change in the coronary arteries and aortas of rabbits exposed to low doses of hydrogen cyanide, alone or in combination with 200 ppm carbon monoxide, and nitric oxide for 2 weeks. McMillan (46) reviewed the many substances that may enter the body from tobacco smoke and that have been conjectured as having a role in cardiovascular disease. He concentrated on those substances other than carbon monoxide and nicotine, such as cadmium, zinc, chromium, carbon disulfide, carbon dioxide, tobacco antigens, hydro- gen cyanide, nitric oxide, and polonium-210. He concluded that these substances provide interesting ground for speculation as to their possible role in cardiovascular disease, but that only carbon monox- ide and nicotine offer both data and a rational conceptualization for a role in cardiovascular disease. Studies of Whole Tobacco Smoke McGill (42) reviewed potential mechanisms for the augmentation of atherosclerosis and atherosclerotic disease by cigarette smoking. 52 On the basis of his review of the evidence concerning smoking and serum lipid and lipoprotein concentrations, he suggested that cigarette smoking often causes a slight to moderate elevation of total serum cholesterol concentration, and that smoking may depress HDL concentrations and elevate LDL concentrations. These changes might have the effect of increasing atherosclerosis because increased levels of LDL and decreased levels of HDL have been shown to be related to increased amounts of atherosclerosis as well as to an increased risk of coronary heart disease. Hojnacki et al. (28) studied the effect of acute inhalation of cigarette smoke and consumption of dietary cholesterol on plasma lipoprotein composition in atherosclerosis-susceptible White Car- neau pigeons. They concluded that cigarette smoking can mediate alterations in lipoprotein composition independent of changes in- duced by dietary cholesterol and saturated fat. Sieffert et al. (69) demonstrated endothelial damage and focal platelet aggregation after exposing Sprague-Dawley rats to tobacco smoke for l&minute periods three times a day for 6 and 12 weeks. Scanning electron microscopic examination of perfusion-fixed the racic aortas disclosed elongation of endothelial cells, uplifting of endothelial cells from the basement membrane, areas of endothelial loss, pitting, crater formation, and white blood cell invasion of the underlying intima. They also found platelet aggregation on damaged intima. They did not indicate which one of the constituents of tobacco smoke they suspected as being the cause of these changes. Rogers et al. (58) recently completed an investigation of cigarette smoking, diet-induced hyperlipidemia, and experimental atheroscle- rosis in baboons. The design of the study and interim results are contained in a report by Rogers et al. (57). The baboons in this controlled experiment consumed a diet enriched in cholesterol and saturated fat for 3.3 years and puffed on lighted cigarettes or shams for 2.8 years. The study was designed to determine whether cigarette smoking interacts with diet-induced hyperlipidemia to accelerate the development of atherosclerosis. This hypothesis was based on a report by Keys (35), who found that populations with high total serum cholesterol concentrations and a high incidence of atheroscle- rotic disease have a dose-related relationship between cigarette smoking and the incidence of atherosclerotic disease. However, in populations with low total serum cholesterol levels and a low incidence of atherosclerotic disease, cigarette smoking is not associ- ated with the incidence of atherosclerotic disease. Thus, cigarette smoking might augment atherosclerosis cnly when it interacts with an atherogenic diet. The investigation by Rogers et al. (57, 581, used nonhuman primates-baboons-as experimental animals, and the animals were trained by operant conditiuning techniques to smoke cigarettes in a human-like manner. The diet induced a moderate 53 hypercholesterolemia, which attained a peak of 235 mg/dl 5 months after initiation and declined thereafter to 160 mg/dl at termination. The early report of Rogers et al. (57) disclosed no significant differences in serum lipids or lipoproteins between smokers and shams after 1.6 years of smoking; however, there were some differences that would be expected to accompany the augmentation of atherosclerosis, namely higher LDL/HDL ratios in smokers than in shams. At the completion of the experiment, these trends of differences in lipoprotein concentrations were not present, and the mean serum total cholesterol, serum triglyceride, LDL cholesterol, and HDL cholesterol concentrations of smokers and shams were not significantly different. The LDL/HDL cholesterol ratios of smokers and shams were almost identical. Their observations on LDL/HDL cholesterol ratios in the midcourse of the experiment and again at the end suggested that cigarette smoking either increases the LDL/HDL cholesterol ratio only during hypercholesterolemia or increases the LDL/HDL ratio only in some animals. At autopsy of these baboons, the mean extent of fatty streaks was not significantly different for smokers versus shams in the aorta, femoral, iliac, and innominate arteries. The mean extent of fatty streaks in smokers was significantly greater than in shams for the carotid arteries. The variability in extent of lesions was greater in smokers than in shams, suggesting the possibility that a subset of smokers may have responded positively to smoking by developing increased lesions. This difference in variability of lesions was statistically significant for the thoracic aorta, carotid, and innomi- nate arteries. The authors suggest that the "compensatory" decline in mean serum cholesterol concentration that occurred in the latter part of the experiment could have led to regression of experimental- ly induced lesions. The authors indicate that their results do not support the hypothesis that cigarette smoking, at a level approximately equiva- lent to that of the average human cigarette smoker, augments experimental atherosclerosis in the presence of a moderate level of diet-induced hypercholesterolemia. They did, however, find a signifi- cantly greater extent of fatty streaks in the carotid arteries for the smokers and significantly more variability in the extent of lesions in the smokers. Also, among the small number of animals that died during the course of the experiment, the smoking animals had more extensive involvement with lesions than did the shams. Neverthe- less, there were no dramatic, clear-cut, across-the-board differences between the smoking and nonsmoking animals. The authors con- clude that this experiment cannot be regarded as a conclusive test of the hypothesis that cigarette smoking can augment the formation of fatty streaks associated with dietary-induced hyperlipidemia. 54 McGill's review (42) indicated that smokers have slightly increased erythrocyte counts, hematocrit, and hemoglobin concentrations, but he doubted that the slight changes observed would increase the risk of atherosclerosis. In the experiments with baboons, smokers also had elevated leukocyte counts owing to both increased polymorpho- nuclear leukocytes and increased lymphocytes. These changes might be one manifestation of an altered immune system that might deserve attention as a possible mechanism for accelerating athero- genesis. The smoking baboons had slightly elevated blood glucose levels; it is not known if this change would contribute to atheroscle- rosis. Body weight and blood pressure are slightly lower in smokers than in nonsmokers, and this response to smoking is in the opposite direction with regard to risk of atherosclerotic disease. Smoking and the Hemostatic System McGill indicated that the limited number of recent studies of the effects of smoking on the hemostatic system show little or no effect on clotting action, but marked effects on platelets. Platelet counts are not different in smokers and nonsmokers, but smokers have a decrease in survival time and an increase in platelet turnover (50), increased adhesiveness (49), and increased tendency for aggregation (24,27,36). Ogston et al. (52) found that chronic smoking led to an increased plasma fibrinogen concentration, but acute smoking did not. Janzon and Nilsson (33) found that chronic smoking was associated with increased librinolytic activity of the blood. Davis and Davis (18) studied the effect of cigarette smoking on circulating platelet aggregates as detected by the platelet-aggregate ratio in volunteer subjects. The platelet-aggregate ratios were lower in the smokers, indicating increased circulating platelet aggregates. The authors indicated that the decrease in platelet-aggregate ratio was not mediated through the elevation of plasma nonesterified fatty acid concentration. Fuster et al. (21) found a shortened platelet survival half-life in apparently normal persons who smoked and in persons with a strong family history of coronary disease. Their study suggested a possible relationship among cigarette smoking, strong family history of coronary disease, and platelet activation in the process of coronary atherogenesis in the young adult. Smoking and the Immune System McGill (42) suggested that the leukocytosis observed in smokers may represent in part a manifestation of an immune disorder. Immune complex disease markedly aggravates atherogenesis in rabbits (48) and in baboons (30). Becker and Dubin (10) and Becker et al. (II) have identified a low molecular weight glycoprotein in 55 tobacco smoke that is highly antigenic in man. McGill (42) suggests that differences in sensitivity to antigenic materials could account for the great variation in response to cigarette smoking. He also suggests endothelial injury and increased endothelial permeability as a mechanism for cigarette smoking effects on cardiovascular disease. Becker (9), in summarizing a workshop on immunologic injury and the thrombotic process in atherogenesis, postulated that the capacity of tobacco glycoprotein to activate the intrinsic pathway of coagulation might contribute to the growth of arteriosclerotic plaques and to more lethal complications by initiating thrombus formation. Denburg et al. (19) studied the reactivity of 164 patients with peripheral vascular disease to purified tobacco glycoprotein; they suggested that reactivity to tobacco glycoprotein may he causally related to the development of atherosclerotic vascular disease. Conclusions 1. A preponderance of evidence both from prospective studies with autopsy followup and from autopsy studies with retrospective smoking data indicates that cigarette smoking has a significant positive association with atherosclerosis. This evidence suggests that cigarette smoking has the effect of aggravating and accelerating the development of atherosclerotic lesions in the artery wall and that its effect is not limited to those events related to the occlusive episode. The effects are most striking for aortic atherosclerosis; a significant positive relationship also exists between cigarette smoking and atherosclerotic lesions in the coronary arteries, at least for most high risk populations. Cigarette smoking could also be associated with other factors that precipitate thrombosis, hemorrhage, or vasoconstriction leading to occlusion and &hernia. 2. Some evidence exists that cigarette smoke alters total serum cholesterol concentrations and lipoprotein composition in ways that would be expected to increase the development of athero- sclerosis. Recent studies of the effects of smoking on the hemostatic system indicate effects of smoking on platelet function. 3. 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The Pathogenesis of Atherosclerosis. Baltimore, Williams & Wilkins Company, 1972, 262 pp. (87) WORLD HEALTH ORGANIZATION. Atherosclerosis of the aorta and coronary arteries in five towns. Bulletin of the World Health Organization 53(5/6): 4854X3,1976. 62 SECTION 3. CORONARY HEART DISEASE 63 Introduction Higher rates of disease and earlier mortality in cigarette smokers than in nonsmokers have been documented in a large number of investigations. Of the several disease manifestations that account for the excess disability and death in cigarette smokers, coronary heart disease (CHD) is the leading cause in North America and northern Europe (18, 40,43,45, 67, 94,96, 134, 143, 189,214,224,257). CHD is related to several risk factors, including cigarette smoking. Esti- mates indicate that up to 30 percent of all CHD deaths in the United States are attributable to the cigarette smoking habit (189). Three of the major prospective studies have reported estimates of cigarette-related CHD mortality based on the number of observed versus expected CHD deaths in smokers and nonsmokers. In the ACS 25State study, involving more than 1 million men and women, Garfinkel(73) estimated that of the 12,724 CHD deaths that occurred among all males followed prospectively for 6 years, 5,358 (46 percent) would not have occurred if all male cigarette smokers had the same CHD death rates as did nonsmoking males. Among females, a similar percentage of excess deaths (40 percent) attributed to smoking was noted; however the total number of CHD deaths was not large. Rogot and Murray (224) followed 290,000 U.S. veterans over a period of 16 years. During this time 13,845 CHD deaths were observed among cigarette smokers, whereas only 8,787 were expected. This repre- sents an approximately 40 percent greater observed-toexpected ratio. In the British physicians study, in which 34,000 male British physicians were followed for 22 years, it was reported that cardiovas- cular disease accounted for 52 percent of all excess deaths in smokers, including 31 percent arising from CHD. By contrast, lung cancer was responsible for 19 percent of the cigarette-related excess deaths (232). Whyte (277), using the "attributable fraction" method as advocat- ed by Miettinan (179), reanalyzed data from the Pooling Project study and estimated that 24 percent of first major coronary events were cigarette related and independent of other risk factors. When all three major risk factors were considered together, the proportion of attributable risk increased to 70 percent. Both Lute and Schweitzer (163, 164) and Boden (21) attributed 25 percent of all circulatory diseases to smoking. Both used data derived from estimates provided by the NIH Task Force Report on Preven- tive Medicine (63). These estimates are in close agreement with that published by Richter and Gori (219) that attributed 30 percent of heart disease to smoking; they also estimated that 33 percent of all arteriosclerosis was cigarette related. The latter estimate is identical to those published by the National Cancer Institute and the National Heart, Lung, and Blood Institute in the final report on the program to reduce the risk of disease in smokers (189). 65 In young people-including young women who are otherwise at very low risk for CHD-as many as threequarters of the cases may be attributable to the cigarette smoking habit (244, 257). During the period 1965-1977, there were an estimated 2.8 million premature deaths from heart disease, primarily CHD, in American men and women attributable to the use of tobacco. Furthermore, unless smoking habits of Americans change, over 10 percent of all those now alive may die prematurely of heart disease that will be attributable to the use of tobacco. The number of such deaths may exceed 24 million (189). Annually during recent years, more than one and a quarter million Americans have suffered fatal or nonfatal heart attacks (2, 101, 198). The deaths from CHD have numbered over 500,000 and have exceeded the deaths from any other cause; half or more of these deaths are sudden (139). In addition to these acute manifestations of CHD, more than 5 million Americans are under treatment for chronic manifestations of CHD (2, 198). Millions of others have significant CHD that is undiagnosed. Of those currently undiag- nosed, approximately one-quarter will manifest sudden, unantici- pated death as the first clinical indication of CHD (110, 137, 153). Scientific Investigation of the Relationship Between Coronary Heart Disease and Smoking: Objectives of the Present Review The scientific basis for the judgment that cigarette smoking is a major contributor to CHD in Americans has been presented in the Reports of the Surgeon General beginning in 1971 (264l and emphasized recently in the Reports of 1979 (263) and 1980 (261). A large number of epidemiologic, clinical, and experimental studies using a variety of methods and research designs have accumulated overwhelming evidence of the strong relationship between cigarette smoking and CHD. The possibilities of sample selection bias or confounding of this association by other factors as explanation for this association have been examined exhaustively and do not explain the relationship between cigarette smoking and CHD. In this section, emphasis is placed on critical examination of the relationship between cigarette smoking and CHD incidence and mortality. The independence of cigarette smoking as a predictor of CHD is considered in the context of those other risk factors that also predict the occurrence of CHD. This includes evaluation of the consistency of the relationships between risk factors and subsequent CHD, including those mathematical models for prediction of CHD that have been applied widely among diverse population groups. The examination takes into account sample size, effects of multiple risk factors acting simultaneously, and secular trends in risk factor 66 prevalence. Areas of opportunity for expansion of knowledge are discussed. Mortality studies are summarized with respect to the relationship of smoking and CHD. The large prospective mortality studies provide evidence of the influence of cigarette smoking in large and varied populations, and they provide sufficient numbers of cases for detailed analyses of the influence of smoking intensity and duration, age, sex, race, and smoking cessation on CHD. Coronary Heart Disease Manifestations The major clinical manifestations of CHD are myocardial infarc- tion (MI), which may be fatal or nonfatal; other death from CHD, which may be sudden or not; and angina pectoris, which is the first clinical manifestation in about one-third of new cases (40). In most cases, obstruction to blood flow in the coronary arteries is caused by arteriosclerotic narrowing (34, 39). Some cases are associated with coronary artery spasm with or occasionally without atherosclerotic change in the coronary arteries (39, 87, 174, 202). When there is thrombosis superimposed on the coronary narrowing, myocardial infarction typically results (34). The aggregation of platelets and formation of fibrin thrombi are related tc the acute clinical manifestations of coronary heart disease, and may also play a role in the development of coronary atherosclerosis (187, 230). Several autopsy studies in the United States and elsewhere have shown that atherosclerosis of the coronary arteries is more common in cigarette smokers than in nonsmokers (3, 7, 8, 9, 220, 245, 247). This topic is discussed elsewhere in this Report. Clinical Manifestations and Epidemiologic Criteria for Coronary Heart Disease Events Myocardial Infarction Myocardial infarction (MI) denotes necrosis of a discrete volume of heart muscle resulting from prolonged, severe ischemia following interruption of coronary blood flow. The characteristic symptom is unremitting chest pain that may be associated with sweating, nausea, shortness of breath, dizziness, or loss of consciousness. The role of coronary thrombosis in the evolution of acute myocardial infarction (AMI) has been debated in the past; recently, coronary angiography has been performed in large numbers of patients with AMI. In the majority, coronary thrombosis has been found to be superimposed upon preexisting arteriosclerotic narrowing. In a small proportion of cases, but more commonly in young men and women, MI has been observed in patients with little or no coronary 67 atherosclerosis who have had coronary artery spasm or coronary thrombosis or both (I). Loss of consciousness in acute myocardial infarction is an ominous sign because it often reflects inadequate pumping action of the heart owing either to catastrophically abnormal cardiac rhythm or to severe deterioration of cardiac muscle function. A broad range of cardiac rhythm disturbances may occur, but the most characteristic catastrophic one accompanying myocardial infarction is a chaotic irregularity of muscle fiber contraction (ventricular fibrillation) that results in a cessation of effective pumping by the heart. In such instances, death occurs within several minutes after cessation of blood flow to the brain if the rhythm disturbance is not reversed. In patients who survive long enough to be admitted to the hospital, the diagnosis of AM1 may be made from changes in the electrocardio- gram and increases in serum enzymes (I). In comprehensive clinical epidemiologic studies, the criteria for identifying cases of MI include specific presenting symptoms, electrocardiographic changes, and serum enzyme elevations (40,214). Death from CHD In fatal cases, evidence of CHD may be provided by clinical or autopsy information (40, 214). In the absence of adequate clinical or autopsy evidence, diagnosis of death from CHD is based on documen- tation of a sufficiently short interval from onset of symptoms until death and the absence of another potentially lethal condition (153). Sudden Cardiac Death A large proportion of deaths certified as due to CHD have been sudden, and a significant fraction of these sudden cardiac deaths @CD) have occurred in persons with no prior history of CHD (68, 109, 139, 152, 154, 220). The incidence of SCD increases with age, and it is substantially more frequent in men than in women; in women the incidence of SCD lags behind that of men by 20 years (139). Epidemiologic investigations have shown that the majority of deaths in ambulatory adults that are sudden and unanticipated are associated with severe CHD. In the Baltimore study by Kuller et al. (1531, 71 percent of the deaths (excluding trauma) that occurred within 24 hours of the onset of terminal illness in individuals who had been able to function in the community were from CHD. In those with other causes, more than half were associated with fatty liver. Alcohol consumption appears to have a complex relationship to CHD, and heavy alcohol consumption has been identified as a factor in sudden death in several studies. This relationship has been shown to be independent of the relationship with cigarette smoking (38, 64, 148, 158, 173, 188, 209, 216). Although some difficulty may arise in appropriate designation of unwitnessed deaths, the less frequent and rare conditions are usually differentiated easily from SCD. Criteria for SCD have varied in different studies. Among ambula- tory adults considered to be well who die suddenly, the probability of severe CHD has been shown to be very high both by autopsy data and by clinical data (40, 109, 139, 157, 200, 248). In large population studies, however, information for some cases is often not available to determine the exact interval from onset of symptoms until death; therefore, criteria for sudden death have often included intervals up to 24 hours (153, 156, 200). In a high proportion of such cases, severe CHD has been observed by autopsy examination (10, 12, 50, 68, 109, 153, 160, 200, 208). The physiologic disorders responsible for sudden collapse and cardiac arrest in ambulatory adults have been well documented. In the overwhelming fraction, ventricular fibrillation is the terminal ventricular rhythm disorder; however, profound cardiac bradycardia or cardiac standstill can be the mechanism as well. Ventricular fibrillation may further degenerate into cardiac standstill (33, 47,55, 56, 145, 202). Among patients resuscitated following cardiac arrest, AM1 has been documented during the subsequent hospital course in one-quarter toone-half of the cases; in the others, severe, multivessel coronary atherosclerosis, with or without old MI, has been observed by coronary angiography in three-quarters or more (33, 56,273). Ascertainment of CHD From Death Certificates In large-scale mortality studies the underlying cause of death on death certificates has usually been used to identify the deaths from coronary heart disease. [In recent editions of the International Classification of Diseases, the term ischemic heart disease is preferred over the older term coronary heart disease. Some authors prefer the term arteriosclerotic heart disease. For uniformity, coronary heart disease (CHD) is used throughout this section regardless of the usage in the publications reviewed.] The accuracy of death certificate data has been evaluated through review of avail- able clinical data and retrospective analyses and from available pathological data. Coronary heart disease has been confirmed as probable or likely in the vast majority of cases (183, 184, 236, 284). In a random sample of 1,362 U.S. death certificates in 1960, pertinent clinical and pathological information to determine the cause of death was investigated by Moriyama et al. (182). In the 87 percent of cases for which responses from medical certifiers were obtained, only 7 percent of those certified to be CHD were judged to be incorrect or probably incorrect. The information for diagnosis of CHD was judged to be reasonable or well established in 74 percent and inadequate to determine the cause of death in 19 percent. 69 In recent years, cardiac evaluation has become more prevalent with widespread use of objective diagnostic tests. This should result in even greater accuracy of CHD case ascertainment from death certificates. Angina Pfxtoria Angina pectoris is the first clinical manifestation in about one- third of the new cases of CHD (1331. In the typical form, observed in about 90 percent of clinically diagnosed patients, chest pain or tightness occurs with exertion or excitement and is relieved prompt- ly by rest or nitroglycerin. Such patients usually have fixed obstruction to blood flow due to arteriosclerosis in one or more of the coronary arteries (34, 174,237). Patients with typical angina pectoris are at increased risk for the more serious manifestations of CHD, myocardial infarction, and death from CHD (34, 133, 174, 175, 241). In the atypical form, chest discomfort usually occurs at rest, although it may also occur with exertion, and it is usually relieved by nitroglycerin (87, 174, 175,237,241). This atypical or variant form of angina pectoris has been shown to result from coronary artery spasm that occurs at the site of atherosclerosis in many cases, but in otherwise normal-appearing coronary arteries in others (87, 175, 202). Sudden death is a rather common complication of variant angina (39, 110, 175,202, 241). Conditions other than CHD may cause symptoms that mimic angina pectoris, and definitive diagnosis may require clinical obser- vation over time and the performance of ancillary diagnostic procedures (34, 40). However, in large-scale epidemiologic studies, complete diagnostic evaluation is usually not feasible, and the proportion of cases with underlying severe coronary atherosclerosis has probably varied among the different studies (40, 121, 273). In addition to those in the population who have symptoms of CHD, there are many with significant coronary atherosclerotic obstruction who are undiagnosed. The frequency of clinically silent but physic logically significant coronary artery disease is unknown; it is estimated that in one-quarter of the cases with a new myocardial infarction, the infarction is silent and detected only on followup by electrocardiographic (ECG) examination (I 72). In prospective epidemiologic studies with clinical followup, cases may be classified only by the most severe CHD manifestation, in this order: death from CHD, nonfatal myocardial infarction, and angina pectoris. Thus, the cases classified as angina pectcris are those remaining who have not experienced a more serious CHD event, and as noted above, this diagnosis may lack sensitivity and specificity for coronary atherosclerotic disease. Variation in the strength of association between smoking and angina pectoris may be influenced by these methodological considerations (48,49, 121, 135,229). 70 A number of well-documented, clinical series of patients with angina pectoris and severe CHD confirmed by coronary angiography, surgery, or post-mortem examination have been reported (4, II, 32, 42, 97, 98, 118, 171, 201, 253, 268, 272). These studies provide important information for clinical management and add insights into relationships with risk factors. However, causal inferences must be made with caution when measurements of risk factors have been made after the onset of clinical disease and data from appropriate comparison groups are not available. Epidemic CHD and the Application of Epidemiologic Methodology CHD was thought to be uncommon in the early part of this century when most deaths were caused by infectious disease. Before the mid- century, however, CHD had become the leading cause of death, and year to year increases were large (101, 159). Neither the cause of CHD nor the reasons for the rising epidemic could be explained. Nevertheless, pioneering efforts in cardiovascular epidemiology revealed that certain characteristics were observed more often in CHD cases, and epidemiologic investigations were begun to obtain data with which to make causal inferences (4486, 143). Prospective Cohort Studies: Intensive Population Studies of Risk Factors and CHD In several early investigations, cigarette smoking and several other characteristics were observed to be strongly associated with CHD (60, 136, 276). To clarify the nature of these relationships, defined population samples were examined for personal characteris- tics that could be related to CHD. Intensive observation for subsequent incidence of CHD through reexamination and surveil- lance activities in members of population samples that were free of disease at the baseline examination provided a substantial part of the data from which causal inferences relating to smoking and CHD were made. A number of these are briefly described in the following pages. In each study, smokers were found more likely to develop CHD than nonsmokers. studies in U.S. whites Within the U.S. population, CHD mortality has been highest in white men, and they were investigated most intensively in the early prospective studies. To provide a sufficiently large number of cases for detailed analyses of the relationship of CHD to cigarette smoking and other risk factors, several of the long-term epidemiologic studies agreed to pool their data in the National Cooperative Pooling Project 71 sponsored by the Council on Epidemiology of the American Heart Association and supported by the American Heart Association and the National Heart Institute, now designated the National Heart, Lung, and Blood Institute (168, 214). Five of the studies participating in this effort had used comparable methodology in data collection so that the data from each of these five cohorts could be pooled for analysis. In Table 1, analyses for the pooled data are referred to as "Pool 5." The five cohort studies contributing to the pooled data will be characterized briefly individually, and then analysis of the pooled data will be summarized. Fmmingham Heart Disease Epidemiology Study The Framingham study was initiated by the Public Health Service in 1948. The members of the prospective cohort were 2,282 men and 2,845 women who were aged 29 through 62 and free of CHD at initial examination (40, 86, 133). The cohort was based on a random subsample of the residents of Framingham, Massachusetts; the response rate was 69 percent. The respondents were supplemented by volunteers who had similar characteristics. A standardized cardiovascular examination at entry included information on habits, physical characteristics, and blood chemistries. Reexamination has been carried out biennially for ascertainment of cardiovascular disease and changes in characteristics. Cardiovascular disease case ascertainment has included community and mortality surveillance activities (86, 136). Analyses through 24 years of followup have shown that cigarette smoking is strongly related to MI and death from CHD (40, 133, 135). In Table 1, Framingham data analysis is shown with that of the other cohorts participating in the National Cooperative Pooling Project. The excess risk of MI and death from CHD was found to increase progressively with the number of cigarettes smoked (Table 1). The relationship to angina pectoris has been less clear. In the 12- year and the 24-year followup data analyses, however, male cigarette smokers were observed to experience a higher incidence of angina pectoris than were nonsmokers (40, 135). The effect was stronger at younger ages; after 24 years of followup, the incidence of angina pectoris in those 30 to 39 years old at entry to the study was twice as high in smokers as in nonsmokers (Figure 1). Albany Cardiovascular Health Center Study In 1952 the New York State Health Department established at the Albany Medical College a prospective study of male civil servants working in Albany. Participation was obtained from 87 percent of eligible men aged 40 through 54, of whom 1,823 were free of CHD at initial examination. After 6 years, the incidence of MI and death from CHD was significantly higher in cigarette smokers in compari- 72 TABLE l.-National Cooperative Pooling Project. Analysis of the incidence of CHD by smoking behavior in five participating cohorts individually and in the data pooled for the five cohorts with comparable methodology (Pool 5). Standardized incidence ratio, risk ratios, number of men, person-years of experience, and number of first events smoking behavior Pool 5 Standardized incidence ratio by study group ALB CHGAS CH-WE FRAM TECUM All Nonsmokers Never smoked Past smoker l pack/day 104 120 183 (521 (64 139 106 (151) 108 125 128 119 117 200 190 162 174 151 Risk ratio 21 pack/day Nonamokera 95% confidence interval Low High 2.5 2.7 3.3 2.4 2.2 ( 1 2.1 1.8 2.1 1.6 1.5 ( ) 3.1 4.3 6.2 3.7 3.4 ( 1 Risk ratio >l pack/day Nonsmokers 95% eonfdenoe interval g 3.2 3.7 4.0 2.6 2.6 ( ) 2.6 2.4 2.5 1.2 1.8 ( ) 4.2 6.1 8.4 5.5 4.5 ( ) Number of men at risk G332 1.796 G= 1,926 Person-years of experience 70,970 17,240 11,017 16,072 Number of fti eventa 644 154 123 140 100 100 67 (53) 77 60) (4% (50) 76 (43) 57 (61) 2,162 19,756 1,140 6,885 49 NOTE: ALB: Albany Gardiovaacular Health Center Study CHGAS Chicago Peoples Gas Company Study Cl+WE: Chicq?o Western Ehctric Company Study FRAMz Fnmiiham Heart Dimaw Epidemiology Study TECUM:T ecumaeh Health Study NOTE: ( k haed on fewer than 10 first eventa. SOURCE: Pooling Project Raearch Group (214. son with nonsmokers (48). Subsequent analysis after 10 years of followup confirmed these findings (Table 1). Chicago Peoples Gcs Company Study Beginning in 1958, the Chicago Peoples Gas Company medical department examined 1,264 white men aged 40 to 59 (92 percent of 73 I m Corrected rate a Crude rate Men Smokers 2fi5 I 174 I Nonsmokers 30-39 40-49 50-!j9 30-39 AGE AT ENTRY 151 134 II 40-49 211 150 3. 50-59 FIGURE l.-Twenty-four-year incidence of angina pectoris in men, by cigarette smoking status NOTE: Tbe crude rata have been mrrected to take into account those members of the population who are no longer at risk by reasan of having developed the disorder in question or having been lost to observation by death. SOURCE: Dawber (40). those eligible) who were free of CHD (161, 214). Analysis of the data obtained during an average of 8.8 years of followup revealed a higher incidence of MI and death from CHD in cigarette smokers than in nonsmokers (Table 1). Chicago Western Electric Company Study Beginning in 1957,67 percent of male Western Electric Company, Chicago, employees aged 40 to 55 were examined; 1,98l` were free of CHD (161, 206, 214). After an average followup of 8.3 years, the incidence of MI and death from CHD was higher in cigarette smokers than in nonsmokers (Table 1). Tecumseh Health Study The Tecumseh health study began examination of the entire community of Tecumseh, Michigan, in 1959; participation was obtained from 90 percent (61, 214). Included was a cohort of 1,240 white men aged 40 to 59 who were free of CHD at initial examination. During an average followup of 8.05 years, the incidence of MI and death from CHD was higher in cigarette smokers than in nonsmokers (Table 1). Minnesota Business and Professional Men Study Selected Minnesota business and professional men were first examined in 1948; 284 men aged 40 to 59 years were free of CHD (144, 214). During an average followup of 14.1 years, those who 74 smoked cigarettes experienced a higher incidence of MI and death from CHD than did nonsmokers. Minnesota-Based Railroad Worker Study Among eligible railroad men working in the northwest sector of the United States, 65 percent participated in the Minnesota-based railroad worker study examinations beginning in 1958 (143, 214). Of these men, who were white, aged 40 to 59 years, and free of CHD at first examination, 2,571 were followed for an average of 4.9 years. Those who smoked cigarettes experienced a higher incidence of MI and death from CHD than did nonsmokers. National Coopemtive Pooling Project As indicated above, the data from five of the cohorts participating in the National Cooperative Pooling Project were pooled for those white men who were aged 40 to 59 years, were free of CHD at initial exam, had comparable baseline examinations, and were followed for up to 10 years with comparable case ascertainment (Table 1). The demographic and other characteristics of these cohorts were similar to the characteristics of middle-aged white men in general living in the United States during the same period (190-196). Subjects contributing to the pooled data numbered 8,422; during an average followup of 8.5 years (72,011 person-years), 688 cases of major CHD were observed (214). Major CHD was defined as nonfatal or fatal MI or sudden death from CHD (death in less than 3 hours from the onset of illness). Risk of CHD With Smoking According to the pooled data for men aged 40 to 59, those who smoked a pack or more of cigarettes per day at initial examination experienced a risk for a first major coronary event that was 2.5 times as great as the risk of nonsmokers (Table 1). In these analyses, nonsmokers included those who never smoked, cigar and pipe only smokers, past smokers, and those who smoked less than half a pack per day. Those smoking less than half a pack per day consisted largely of those who smoked occasionally or only two or three cigarettes per day. For each of the five cohorts separately, the relative risks varied from 2.2 to 3.3. The risk was greatest in those with the heaviest smoking habits in all age groups (Table 2), and excess incidence attributable to smoking more than one pack of cigarettes per day tended to increase with increasing age up to age 60; however, with increasing age, relative risk declined. This apparent paradox is due to the rapid rise of CHD incidence with age. The excess incidence in heavy smokers (more than one pack per day) was large and statistically significant for 75 TABLE 2.-National Cooperative Pooling Project. Analysis of the risk of CHD by smoking behavior from the pooled data of the five cohorts* observed with comparable methodology (Pool 5). Average annual risk of first major coronary event, standardized incidence ratio (SIR), risk ratio >l pack per day/nonsmokers, and number of first events, by age group smoking pattern Age @-UP 4cM4 45-49 iti& 5.5-59 60-64 40-64 Average annual risk (per 1,000 man-years) All 3.1 6.4 8.0 22.6 19.9 Nonsmoker (1.5) 3.0 3.6 7.3 15.5 Never smoked (1.9) (0.7) (2.5) 8.7 11.4 Past smoker (0.9) 5.5 4.3 6.1 15.5 l pack/day 4.9 12.2 17.4 22.5 26.8 Riik ratio > pack/day/nonsmokers ( 1 4.1 4.8 3.1 1.7 SIR 100 58 54 63 55 71 104 120 183 3.2' Number of fti events SIR All Never smoked Paat smoker 1 pack/day 34 113 158 194 145 3 2 8 21 21 1 11 10 13 * 18 1 4 6 6 4 2 4 5 26 33 3 7 9 19 15 14 49 64 61 42 10 36 56 48 22 644 55 53 21 60 53 230 172 o See footnote of Table 1 for names of the five study group. ' Approximate 95% confidence interval: 2.642. NOTE: ( ): bad on fewer than 10 first events. SOURCE: Pooling Project Research Group (2I4. each !5-year age group between 45 and 64, and the differences were progressively greater with age up to 60. For those smoking about one pack per day and about one-half pack per day, the excess risks were sizable, but of a lower magnitude. Because of the relatively smaller numbers, the data were not sufficient for evaluation of differences in risks among those who had never smoked, those who had smoked less than one-half pack per day, and former smokers. In the Pooling Project data, the risk for cigar and pipe smokers was not significantly different from either the nonsmoker group or 76 the half-pack per day smokers, but it was significantly lower than that for men who smoked a pack of cigarettes per day (Table 2). However, the position of cigar and pipe smokers on the continuum of risk could not be adequately evaluated from these data because of small numbers. In summary, detailed prospective studies of the incidence of CHD in white males in the U.S. population have demonstrated a clear, strong, dose-related relationship between cigarette smoking and acute myocardial infarction and death from CHD. This cigarette smoking effect was proportionally greater in younger populations, but was present in all age groups examined in these studies. Cigarette smokers in the Framingham study had a high incidence of angina pectoris among the younger age groups, but this relationship was not as strong as the relationship between smoking and myocar- dial infarction. Pipe and cigar smokers had a risk that was not statistically different from the risk of nonsmokers. Ethnic Groups in the United States With Lower Risk of CHD - CHD mortality in blacks is lower than in whites in the United States (75, 76, 197, 225, 236, 259). A case-control study of the incidence of CHD during World War II in young Army men observed a risk ratio of 0.61 in black men relative to white men (120). Reasons for lower rates in black men are not adequately understood, although the smoking habits of blacks have been found to differ from those of whites. Blacks have tended to smoke cigarettes with higher tar and nicotine content, but they have also tended to smoke fewer cigarettes (262). Hypertension is also more prevalent in blacks than in whites (142). On the other hand, plasma lipid levels were reported to be more favorable; high density lipoprotein cholesterol levels (HDLC) were higher and low density lipoprotein cholesterol levels (LDL-C) were lower in black men than in white men aged 20 to 49 (259). HDLC has been negatively associated with CHD, and LDL-C has been positively associated with CHD @Q&4,21 7). The Evans County, Georgia, study was initiated in 1960 to investigate differences in coronary heart disease incidence and risk between blacks and whites for an entire community in a rural, principally agricultural setting (107). All residents of Evans County over age 40 and a 50 percent subsample of those aged 15 to 39 years were eligible; 92 percent of those eligible were examined between 1960 and 1962. Followup examinations from 1967 through 1969 provided a mean followup period of 7 l/4 years. Reexamination for evidence of new CHD was obtained in 91 percent of the 3,102 initially examined members of the population, including 537 black males and 947 white males (83 percent and 93 percent, respectively, of those initially available). In addition, community and mortality 77 surveillance was used to ascertain the incidence cases of fatal and nonfatal CHD. During the 7 l/4 years of followup, 13.6 percent of the black males and 12.7 percent of the white males died. The onset of CHD was observed in 6 surviving and 7 decedent black men and in 40 surviving and 32 decedent white men. The age-adjusted incidence rate for white men was 3.5 times the rate in black men. There were few cases in women, but the incidence rates in black women and in white women appeared to be similar. CHD incidence was higher in smokers than in nonsmokers for the black and the white popula- tions. Beginning in 1965, 9,824 men aged 45 to 64 years who were residents of four rural and three urban areas of Puerto Rico were examined at a clinic in San Juan. The methods used were compara- ble to those used by the Framingham study (85). Of the targeted population samples, over 80 percent attended the medical examina- tion, and over 90 percent of the examined cohort participated in four followup examinations at 2 l/2-year to Syear intervals. The average followup was 8 l/4 years (246). In comparison with men in Framingham, fewer men in Puerto Rico were smokers, and the Puerto Rican smokers consumed fewer cigarettes per day (85). After 2 l/2 years of observation, the incidence of CHD in Puerto Rican men was only half that observed in Framingham, and the difference between smokers and nonsmok- ers was not significant (222). However, after 8 l/4 years of observation and the accumulation of approximately four times as many cases, cigarette smokers had a significantly higher incidence of MI than did nonsmokers; this was true both for those living in the rural areas and for those in the urban areas when considered separately (246'). Japanese Americans have an incidence and mortality from CHD that is intermediate between the very low rates in Japan and the high rates in white Americans (X$222,284). The explanation for this gradient of CHD with migration has been investigated by the Ni- Han-San study centering on a cohort of Japanese Americans living in Hawaii (14, 222). The target cohort of the Honolulu heart study was all noninstitu- tionalized men of Japanese ancestry born between 1900 and 1919 who were living on the Island of Oahu in 1965 (130). Initial examinations were conducted between 1965 and 1968, and participa- tion was obtained from 72 percent of the identified men who were eligible (7,705 men aged 45-69 years and free of CHD). CHD incidence was observed by followup examination (at 2 and 6 years) and by intensive community and mortality surveillance activities. The 2-year incidence of MI and death from CHD was only half of that observed in Framingham men, but was significantly higher in 78 cigarette smokers (85). The relative risk for those smoking 21 or more cigarettes per day was six times higher than for nonsmokers (221). At 6 years of followup, the risk of MI and death from CHD, but not of angina pectoris, was strongly related to cigarette smoking, and the risk increased in proportion to the number of cigarettes smoked per day (130). CHD death rates are lower in Great Britain than in the United States by about one-fourth, and those in Norway are substantially lower than either. In 1962 the National Heart Institute and the National Cancer Institute in the United States, the London School of Hygiene and Tropical Medicine, and the Norwegian Cancer Registry undertook a study to examine differences in death rates among migrant populations to the United States (223). Native-born Ameri- cans were included in the study for comparison. Approximately 32,000 British migrants and 18,000 Norwegian migrants aged 30 to 74, residing in 12 States, were sent questionnaires. For native-born Americans, similar questionnaires were sent to a subsample of 23,CKKl white persons drawn from a 1961 National Health Survey sample covering the same geographic areas. A total of 7,895 CHD deaths occurred (3,193 British, 1,213 Norwegian, and 3,489 native- born deaths). Norwegian migrants exhibited the lowest CHD death rates. British migrants' rates were about equal to those for native- born Americans. The decedent's cigarette smoking status as of October 1962 was requested from the next of kin, Smoking status from October to the end of the study period (1963-1966) was presumed not to be altered. Mortality ratios for CHD were significantly elevated among smokers compared with nonsmokers, particularly at the younger ages. The ratios were 1.9 or greater for both males and females at age 45 to 54 years and decreased somewhat with age. CHD death rates among smokers demonstrated little difference between the three groups, and ratios were greater for female than male smokers in all but two instances. Table 3 provides a summary of these mortality ratios by migrant class, age, and sex. In summary, a number of ethnic groups in the United States have lower rates of CHD, but even in these populations, the risk of MI and CHD death are significantly higher in smokers than in nonsmokers. Studies in Other Countries Cigarette smoking has been found to be related to the incidence of CHD in other countries where long-term followup of large, defined cohorts has been performed. For some cohorts, early data analyses with relatively few cases have not shown significant differences, but later followup analyses with large numbers of cases have usually demonstrated a positive relationship between cigarette smoking and CHD. 79 TABLE 3.4ronary heart disease mortality ratios (smoker versus nonsmoker) of British and Norwegian migrants to the United States and native-born Americans by age, sex, and cigarette smoking stahll3 Aae and mortality ratio (smoker vs. nonsmoker) Group 45-54 55-64 65-74 British migranb Malea 1.9 1.3 1.3 Females 2.9 2.4 1.7 Norwegian migrants Males 2.3 1.5 1.6 Females -1 2.3 2.0 Native-born Americana Males Females NOTE: All nonsmoker ratice are 1.0. `Les.thm 1odeaths. SOURCE Ra@ WZ0. 2.3 2.7 1.4 2.6 2.0 1.3 An international study conducted in seven countries observed large differences in CHD incidence and mortality among 16 cohorts of men aged 40 to 59 at baseline examination in the United States, Europe, and Japan (143). The United States cohort was the railroad men described above in the Pooling Project (214). This cohort experienced a relative risk of CHD with cigarette smoking that was similar to that of other U.S. cohorts of white men (Table 1). The other cohorts of men were residents of Yugoslavia (Dalmatia, Slovenia, Velika Krsna, Zrenjanin, and Belgrade), Japan (Ushibuka and Tanushimaru), Finland (districts in the east and west), Italy (Crevalcore, Montegiorgio, and railroad men in Rome), the Nether- lands (Zutphen), and Greece (Crete and Corfu). In all, 12,763 men were examined, of whom 12,509 were free of evidence of coronary heart disease at baseline examination. During the 10 years of followup, 1,512 deaths occurred from all causes, and 413 were attributed to coronary heart disease. Ten-year CHD death rates were less than 75 per 10,000 for the cohorts living in Crete (Greece) and in Croatia (Yugoslavia) and for the two cohorts in Japan; however, for the cohorts of east and west Finland, the U.S. railroad men, Zutphen (the Netherlands), and Belgrade (Yugoslavia), the CHD death rates were 250 per 10,000 or higher. Although the cohorts participating in the Seven Countries study were not selected as representative of their countries, the CHD death rates of cohorts grouped by country were highly correlated with the CHD death rates for men of the same ages reported in the vital statistics of these countries. Cigarette smoking was strongly related to CHD mortality in those cohorts with both high CHD death rates and relatively large numbers of cases for analysis. For example, among U.S. railroad men, CHD death rates were about three times as high in men who smoked 20 or more cigarettes per day compared with men who had never smoked or men who had stopped smoking. Furthermore, the association between CHD and number of cigarettes smoked daily was stronger in the cohorts with high CHD mortality than in the cohorts with low CHD mortality. Among northern European men as well as United States railroad men, the lo-year age-standardized CHD death rates increased significantly with the level of cigarette smoking, and the risk for northern European men smoking 20 or more cigarettes per day was more than four times greater than for men who had never smoked (Figure 2). For the southern Europeans, however, differences were only twofold and not statistically significant. Age- standardized rates for death from all causes, respiratory tract cancer, and neoplasms were also more closely related to the number of cigarettes `consumed in northern Europe than in southern Europe, and for all deaths the differences were significant in both regions. The lO-year incidence date provide a larger number of cases for analysis, as deaths from CHD represented only about 20 percent of the total CHD incidence in the Japanese and European cohorts. Definite CHD was observed in 351 of the 9,780 men during the followup period. The highest rate (11 percent) was observed in east Finland, and the lowest (0.3 percent) was observed in Crete (Table 4). Rates within countries were similar in general, but in Greece the rates were higher in Corfu than in Crete; in Finland the rate in the eastern district was double that in the western district; in Yugosla- via, the Serbian cohorts in Belgrade and Zrenjanin were similar, but in the farming village of Velika Krsna the rate was only half as high. The Japanese cohorts were small and the incidence too low for evaluation of the influence of smoking. Only 19 men in the two Japanese cohorts were observed to develop definite coronary heart disease during the 10 years of followup. To provide greater stability in analyses, the European cohorts were grouped together by region: the three cohorts in Finland and the Netherlands, the five cohorts in Yugoslavia, and the three Italian cohorts with the two Greek cohorts. The lO-year CHD incidence in Finland and the Netherlands was significantly related to the number of cigarettes currently smoked, and former smokers had a CHD incidence that was twice that of those who had never smoked (Figure 3). In Yugoslavia, the CHD incidence in smokers was nearly twice that of those who had never smoked. Also in Yugosla- via, the CHD incidence was nearly three times higher for those 81 16.2% NEVER STOPPED 10/d 10-19/d N--357 N- 416 N-436 N=712 SMOKING HABIT 5.6% gg > 20/d N=446 CHD DEATHS FIGURE 2.-Age-standardkd N-year death rates from all causes and from coronary heart disease of men in northern Europe (east and west Finland and Zutphen), classified by smoking habit at entry; all thee of cardiovascular disease at entry SOURCE Keys U4.9. smoking 20 or more cigarettes per day at entry compared with those who had never smoked, but no significant differences were observed between former smokers and never smokers (Figure 4). In the Italian and the Greek cohorts, the contrasts were less marked (Figure 5). The incidence of CHD was significantly higher in those northern Europeans and Yugoslavs smoking 10 or more cigarettes per day compared with lighter smokers, never smokers, or ex-smokers. The rates were also higher in the Italian and Greek cohorts, but were not statistically significant. Observation of the Italian cohorts has continued, and 20-year followup data were recently reported (126). With the substantially larger number of cases, a significantly higher incidence of CHD was observed in cigarette smokers than in nonsmokers. The 20-year incidence of CHD increased from 90 per 1,000 in those who had never smoked to 159 per 1,000 in those smoking 10 to 19 cigarettes per day. The incidence in the highest smoking category (20+ cigarettes per day) was slightly lower (140 per 1,000) than the rate in those smoking from 10 to 19 cigarettes per day. A number of prospective studies of CHD have been performed in the United Kingdom. Those with mortality followup-for example, 82 TABLE 4.-Ten-year incidence of coronary heart disease among men free of cardiovascular disease at entry (age-standardized rate per 10,000) Cohort Hard CHD Any CHD N N Rate SE N Rate SE JMmatia 662 13 165 52 40 629 94 Slav&a 880 18 253 60 40 561 88 Tanusbimaru 504 8 148 5-4 20 354 82 East Finland 728 71 1,074 115 201 2,868 166 West Finland 808 45 539 80 129 1,582 129 CEValCOre 956 43 450 67 105 1,080 100 M0hgi0rgi0 708 22 353 69 64 986 111 Zutphen 845 45 513 76 91 1.066 106 Ushibuka 496 11 204 63 23 458 94 ClFk 655 2 26 20 13 210 56 corfu 525 17 337 79 37 688 110 Rome railroad 736 z-5 357 68 57 786 99 Velikn Krsna 487 6 132 52 21 452 94 Zrenjanin 476 12 239 70 37 715 118 TOti . 9,780 351 369.9 ' 19.1 913 943.8 ' 29.6 ' Mean of the cohort rate weighti by the number at rink in each cohort. 8OlJRCE Keyn (143). the British physicians study and the Whitehall study-are reviewed below under the heading Prospective Mortality Studies. Morris and Kagan and associates (185) investigated differences in CHD in drivers and conductors working on London buses. Among other positive associations, those who smoked were found to have a higher 5year incidence of CHD than those who did not smoke. In 1977 Morris, Marr, and Clayton (186) reported followup on workers who were 30 to 67 years of age at examination. The sample was of 337 men living in London and in southeast England who had participated in a `I-day individual dietary survey. By 1976, 45 of these men had developed clinical CHD. Among the CHD cases, cigarette smoking was significantly more frequent than expected, and this was true for each occupational group: bank staff, bus drivers, and bus conductors. Estimated relative risks (compared with nonsmokers) were 3.5 for those smoking 11 to 20 cigarettes and 4.7 for those smoking more than 20 cigarettes (88). The Belfast practitioner's study was initiated in 1964, using experienced, self-selected practitioners to observe the operation of risk factors in middle-aged men who were community residents (88). The sample comprised all men born in the lo-year period 1909-1918 (age 45 to 54 at the beginning of the study) who were registered in six cooperating group practices. Examinations were performed in 69 percent of the designated population sample. Among the 1,202 subjects free of CHD at the initial examination, 104 developed CHD 19.1% 14 6% NEVER STOPPED N 357 N 418 10/d 10-19/d N -- 436 N 712 SMOKING HABIT 9 7% 1 ? 20/d N = 446 OTHER CHD HARD CHD FIGURE 3.-Age-standardized lo-year incidence rate of coronary heart disease of 2,369 men in northern Europe (east and west Finland and Zutphen), classified by smoking habit at entry and then free of cardiovascular disease SOURCE: Keys (14.3). during the &year period of followup. MI occurred in 55 (15 fatal), cardiac ischemia in 5, and angina pectoris in 49. Current tobacco consumption, total years of smoking, and total tobacco consumption were significantly higher in the cases with CHD than in the overall population sample. The Stockholm prospective study examined and followed men and women attending a health survey center in 1961 and 1962 (26). This sample was not a randomly selected population sample of Stockholm, but the incidence of myocardial infarction was similar to that of the Stockholm county population (27). A principal objective was to examine the relationships of fasting plasma triglyceride and choles- terol values to the future development of CHD. In analysis of g-year followup data for 3,168 men, the incidence of MI and death from CHD with all ages combined was about fourfold higher for smokers than for nonsmokers (26). The difference was statistically significant. Risk factors for MI were evaluated in 3,189 men, among whom 130 experienced myocardial infarction during 14 years of followup; cigarette smokers experienced nearly three times the incidence of 84 6.0% r OTHER CHD HARC CHD NEVER N-881 STOPPED 10/d lo-1916 N 367 N=213 N- 771 SMOKING HABIT ,20/d N = 565 FIGURE 4.-Age-standardized lo-year incidence rate of coronary heart disease of 2,797 men in Yugoslavia (Dahnatia, Slavonia, Velika Krsna, Zren@.nin, and Belgrade), classified by smoking habit at entry and then free of cardiovascular disease SOURCE: Keys u4.3. MI experienced by nonsmokers (27). In analysis of risk factors and death during 14.5 years of followup of 3,466 men and 2,738 women, death due to ischemic vascular disease (principally CHD and stroke) was significantly related to smoking in men and in women (22). The Section for Preventive Medicine at the University of Goteborg has observed the relationship of smoking and other risk factors to the incidence and the mortality from CHD in several studies of the Giiteborg population (278). In 1963 a 30 percent sample of men born in 1913 was examined (at age 50) and followed; 88 percent participa- tion was obtained, and 834 were found to be free of CHD. In 1970 a primary prevention trial was begun for examination of 10,000 intervention and 20,000 control subjects 47 to 54 years of age. The 1913 birth cohort experienced a markedly excessive risk of MI with smoking during its first 4 years of observation (275); more than 90 percent of those who had myocardial infarctions were current smokers in comparison with 55 percent of those who did not. Subsequent analyses with Byear followup have confirmed this strong relationship between smoking and CHD; the incidence of fatal 5 1 % 2 4% ~ 6 9% 7 0% 6.9% 1 I OTHER Cl-ID HARD CHD NEVER STOPPED 1 O/d 10-19/d > 20/d N-849 N=521 N=5a2 N-830 N=769 SMOKING HABIT FIGURE 5.-Age-standardized IO-year incidence rate of coronary heart disease of 3,551 men in Italy and Greece (Crew&ore, Montegiorgio, Rome railroad, Crete, and Corfu), classified by smoking habit at entry and then free of cardiovascular disease SOURCE: Keys W~J. and nonfatal MI increased with the quantity of daily tobacco consumption. Pipe and cigar smokers experienced an increased risk similar to cigarette smokers (278). No significant difference was observed for angina pectoris by smoking status. Prospective data obtained in the Norwegian Vegetable Oil workers study beginning in 1965 have been analyzed with respect to risk factors measured at the baseline examination and the incidence of CHD during the following year (199). The defined sample comprised 16,608 men born between 1905 and 1916 who were employed in industries throughout Norway. Randomization to a control group or to a group receiving linolenic acid was performed in 13,000 men 50 to 59 years of age who were well and agreed to participate. Industrial physicians participated in the provision of baseline data and in the ascertainment of cases. Fewer than the expected number of deaths occurred, but the number of deaths from CHD was intermediate between that expected on the basis of the Oslo and the total Norwegian popula- tions. MI was observed in 162 men during the followup; there were no significant differences in CHD incidence attributable to treat- ment with linolenic acid. 86 TABLE 5.-First diagnosed myocardial infarction (probable + possible) in relation to cigarette consumption Rates percentage 5 percent sample Adjusted for age and MetI Infarctions Cigarettes MtWl at diagnmedin Weight/height Elevated sedi- per &Y No. choleateml risk' otx3el-v. yr Unadjusted ratio mentation rate None 228 239.6 5,693 37 l-4 40 244.1 1,094 5-14 162 245.2 3,679 15-24 47 240.7 1,214 f 25+ 9 236.3 191 a 4.19 :~~~~l.% 4.15 :I~;;~..., ;f$l.m Unknown 126 237.0 4.304 42 96 612 241.0 16,175 162 1.00 ' Men with no previous infarction diagnwia SOURCE:Natvigetal.(199). The incidence of MI increased markedly with the level of cigarette smoking; the relative risk of MI for men smoking 25 cigarettes or more per day was over six times that of nonsmokers (Table 5). Smoking was less strongly related to angina pectoris (199). The Oslo study examined and followed 14,000 men aged 40 to 49 who were free of cardiovascular disease and diabetes mellitus at examinations in 1972 and 1973. During 4 2/3 years of followup, searches of discharge records of Oslo hospitals and of death registration by the Oslo health department were used to identify nonfatal and fatal first MIS; sudden deaths without confirmation of MI were excluded (117). The incidence of MI in nonsmokers (never and ex-smokers) was only 40 percent of that in cigarette smokers (117). A ICyear prospective study of men examined in 1964 at age 50 in Glostrup County, Denmark, was reported by Schroll and Hagerup (240). Out of a total population sample of 514 men, 436 were examined; followup for mortality and myocardial infarction was obtained in virtually all patients. This population resided in a middleclass suburb in the western part of Copenhagen and was thought to reflect the change in Danish society from principally agricultural to industrial and to be representative of the total Danish population in 1964. During the l&year followup, 31 men developed first myocardial infarctions, an incidence of 7.1 percent. Fatal MI occurred in 16, and 15 experienced a nonfatal MI. A significantly higher risk of myocardial infarction was observed in those who smoked tobacco at baseline examination. The incidence was as follows: nonsmokers, 6 percent; smokers of 1-14 g per day, 6 percent; smokers of 15-24 g per day, 14 percent; smokers of 25 g or 87 TABLE 6.-Seven-year incidence of fatal and nonfatal first myocardial infarction in 3,772 smokers by category of smoking habit and 440 men who have never smoked Never smokera Cigarette smokera Total > IO/day Cigar smokem T&d > 3/&y Cheroot amokera Total >wday Pipe smokers Total >6ldaY SOURCE: GynteIberg et al. (91). Myocardid infarction per 1,cao men 17 36 43 42 35 48 72 26 34 Relative risk 1.0 2.1 2.5 2.4 2.1 2.8 4.2 1.5 2.0 more per day, 19 percent. Thus, the heavy smokers experienced an incidence of MI that was three times that of nonsmokers. The incidence of fatal and nonfatal first myocardial infarctions in men was observed in 3,772 smokers and 1,440 nonsmokers who had baseline examinations in 1970 and 1971, were aged 40 to 59, and were employed in public and private Copenhagen combanies (91). The initial response rate was 87 percent. Fatal MI was ascertained during 7 years of followup from death certificates; nonfatal MI was ascertained from 5-year followup by questionnaires (79 percent response rate) and from hospital records. Myocardial infarction among t.he nonresponders was included if recorded in the Copenha- gen heart register, which registered all inpatient cases of myocardial infarction in the Copenhagen area. During the followup period, 41 men free of coronary heart disease at baseline examination died from a first myocardial infarction and 129 men had a nonfatal first myocardial infarction. Overall, the relative risk of myocardial infarction was twice as high in smokers as in nonsmokers. The relative risk of fatal and nonfatal first MI in smokers compared with never smokers was as follows: cigarette smokers of more than 10 per day, 2.5; cigar smokers of more than 3 per day, 2.1; cheroot smokers of more than 6 per day, 4.2; and pipe smokers smoking more than six times per day, 2.0 (Table 6). In this study heavy cheroot smokers experienced the highest risk of MI. Finnish men aged 50 to 53 years, insured for 10 or more years with a large Finnish life insurance company, were examined in 1965 and 1966; the examined cohort (1,648 men) consisted of 40 percent of those respondents who had complete data (207). Risk factor data included serum lipids after a 1Zhour overnight fast. A smoker was a person who smoked cigarettes regularly every day; pipe and cigar smokers as well as ex-smokers were excluded from the analysis of smoking effects. With these criteria, 567 men were smokers and 982 were nonsmokers. During 7 years of followup, all deaths were identified, and cause of death was determined from death certificate files. Cardiovascular deaths included those due to coronary heart disease, heart failure, cardiac arrhythmia, cerebrovascular acci- dents, and sudden deaths. Cigarette smoking was associated with increased cardiovascular mortality independently of other risk factors. The North Karelia, Finland, project was started in 1972 to mobilize community intervention for health promotion and disease prevention (235). Substantial risk factor data were obtained from random population samples of two rural counties in eastern Finland. Analysis showed a strong relationship between the major risk factors at the baseline examination (smoking, hypertension, and serum cholesterol) and the subsequent development of CHD. The relation- ship of smoking to the incidence of acute myocardial infarction was independent of the other risk factors (235). Eastern Finland had the highest incidence and mortality from CHD in the world, but the rates have declined substantially coincident with decreasing preva- lence of these risk factors (235). A large defined cohort of men aged 42 to 53 years, born in France and employed in the Paris civil service, was observed for an average of 4 years (range, 2-7 years) following a baseline examination for risk factors in 1965 (218). Those with definite Q waves on initial examination were excluded, leaving 7,453 men at risk. Criteria for CHD were based on those of the Pooling Project and the London Whitehall study (51,218). The overall incidence of CHD was 5.1 per 1,000; MI and CHD deaths accounted for 60 percent of the cases, while 40 percent of the cases were due to angina pectoris. Cigarette consumption, hyperten- sion, hypercholesterolemia, and clinical diabetes mellitus were independently related to the incidence of coronary heart disease. Men in their fifties had a strikingly lower incidence of CHD than men in the United States; this is consistent with French mortality statistics. In univariate analysis, the incidence of CHD was progres- sively higher with increasing number of cigarettes smoked per day among inhalers; noninhalers had an intermediate risk (Figure 6) (218). A defined cohort of 10,232 Israeli civil servants and municipal workers (86 percent of the defined sample) aged 40 years and above were first examined in 1963 and followed for fatal and nonfatal MI 89 w Y w 0 0 g 2 2 22 5 51 -a--- TOBACCO NON - EX- NON- CONSUMPTION SMOKERS SMOKERS INHALERS INHALERS c Tobacco Smokers : 61 8% 16.2 Cigarettes per day NON - NONINHALERS INHALERS SMOKERS ( ' < 10 10-15 215 I c 10 10-19 220 I 1 3.4 1 4.3 1 4.5 1 4.6 1 5.0 1 6.9 1 86 1 21.1 8.0 5.8 11.3 4.3 12.7 197 , 14.0 7.7 5.6 108 4.0 17.3 30.7 and sudden cardiac death (177). Reexaminations were performed in 1965 (97.5 percent reexamination rate) and again in 1968 (98 percent reexamination rate). After 5 years of followup, 9,794 were found to be free of myocardial infarction and there were 427 incidence cases (44 per 1,000). Of these 170 (40 percent) were unrecognized myocardi- al infarctions, half of which had been asymptomatic. The incidence of CHD was significantly related to the daily use of cigarettes, and the relative risk was greater at younger age (81, 176). In multivariate analysis the relationship of smoking to CHD became stronger when other variables were taken into account (81). In summary, there were marked differences in CHD rates for the populations in different countries and different geographic locations. The relationship between cigarette smoking and CHD was more pronounced in those countries with high CHD rates. However, even in those countries with low CHD rates the evidence increasingly suggests a relationship between cigarette smoking and CHD. Cigarette Stoking and Other Risk Factors The strong relationship between cigarette smoking and CHD has been shown to be independent of the other major risk factors in a number of well-designed epidemiologic studies. A number of other factors have also been described as having an influence on CHD risk (119, 124, 133, 159, 214, 251). The magnitude of excess risk observed with these minor risk factors has usually been small in comparison with the excess risk observed with the major risk factors (44 68,143, 214). The independence of the relationship between cigarette smoking and CHD risk has been observed in a straightforward fashion. The excess risk of CHD in smokers compared with nonsmokers exists at both high and low levels of the other risk characteristics associated with CHD. Also, extensive experience has shown that confounding influences can be separated out with multiple logistic analysis (147). Such analyses with adjustment for potentially confounding influ- ences have been made for many characteristics in many of the studies cited in this Report. They include hypertension, elevated serum cholesterol, obesity, family history of CHD, diabetes mellitus, physical inactivity, certain personality characteristics, psychological stress, socioeconomic status, and intake of alcohol and coffee. When the data have been sufficient for adequate analysis, excess risk of CHD has been observed in cigarette smokers independent of the presence (or absence) of other CHD-risk-conferring characteristics. Such observations, made in a very large number of studies, indicate that it is the cigarette smoking habit itself that confers high risk of CHD rather than an associated characteristic (18, 40, 43, 45, 67, 94, 96,143,214,244,257). 91 Behavioral characteristics other than cigarette smoking have been considered important in relation to CHD, but relatively few studies of behavioral characteristics have been conducted in the context of standardized examinations of defined cohorts with consideration of potentially confounding variables. The Western Collaborative Group Study (WCGS) in California met these conditions, and therefore this study will be considered in some detail (24, 66, 71). In the WCGS (229), 3,154 employed men examined in 1960-1961 and found to be free of CHD were characterized for behavioral pattern by a structured interview developed for this purpose and administered by trained interviewers. From tape recordings of interviews, reviewers who had no knowledge of the subjects' history or other characteristics classified the men as Type A personalities according to their manifestation of enhanced aggressiveness, ambi- tiousness, competitive drive, and chronic sense of time urgency. The men were classified as Type B personalities if they manifested less of the Type A characteristics and were more calm and relaxed. The Type A pattern was determined in 1,067 and the Type B pattern in 1,182 of the subjects at risk. Previously recognized risk factors were also measured. Mortality surveillance was obtained, and final followup examinations were performed for this population in 1969. With an average followup of 8.5 years, there were 140 deaths; 31 were attributed to an initial CHD event, 19 to a recurrent CHD event, and 90 to non-CHD causes, including 7 who had developed CHD prior to the onset of the non-CHD terminal illness. CHD incidence was observed in 257 cases. Autopsy examination was performed in 24 of 31 decedent cases; acute coronary thrombosis or acute myocardial infarction was obse~ed in 23, and severe diffuse coronary atherosclerosis was observed in 1 case. CHD death was ascertained in 34 Type A and 16 Type B subjects. The CHD death rate per 1,090 person-years was 2.92 for Type A and 1.32 for Type B subjects. As would be expected from other studies, the CHD incidence cases were older, smoked more cigarettes, were heavier, and had higher systolic and diastolic blood pressures, higher serum cholesterol and triglyceride levels, and higher ratios of beta to alpha lipoproteins. Other positive associations were a history of diabetes mellitus, parental history of CHD, low level of education, and low level of leisure time activity. Occupational physical activity and annual income were not significantly related to CHD incidence. Cigarette smoking was significantly related to the incidence of CHD, and the risk was higher with increasing numbers of cigarettes smoked at the time of the baseline examination; the relative risk with smoking in older men was as great as in the younger men. By personality patterns, those who had been characterized as Type A had an incidence of CHD that was twice as high as the incidence in 92 those who had been characterized as Type B. This difference persisted after adjustment for the other risk factors. In both deciles of age at entry (3M9 and 50-59), the relative risks for current cigarette smokers were higher than for nonsmokers in both Type A and Type B personalities (Table 7) (229). A multiple logistic equation describing the relationships of the conventional risk factors to the incidence of CHD in this study was similar to the Framingham study equation (25). The coefficients for the two studies were not significantly different. Cigarette smoking, serum cholesterol, and systolic blood pressure were independent risk factors and were significantly related to the CHD incidence. The total number of cases and the number by decile of risk were similar, using the equation developed from the WCGS data and the equation from the Framingham study, indicating good relative agreement in risk prediction. In the WCGS analysis, the Type A behavior pattern was found to predict the incidence of CHD independently of the other risk factors. The additional predictive power of the Type A characteristic in the multiple logistic equation was related to some extent to higher levels of the conventional risk factors in Type A individuals. Evidence for the importance of personality characteristics was also observed in the Framingham cohort and in studies by the French- Belgian Collaborative Group (66, 104). In these studies as well, the effect of cigarette smoking on CHD remained independent of personality characteristics. In summary, the evidence from studies with adequate data have clearly demonstrated that cigarette smokers experience higher risk of CHD regardless of their other behavioral characteristics. Interaction of Cigarette Smoking and Other Risk Factors A number of pharmacologically active substances are present in tobacco smoke, and a number of direct physiologic effects have been observed (262) and are reviewed elsewhere in this Report. Recently, evidence has accumulated of an effect of smoking on lipoproteins. Recent population studies have demonstrated an inverse relation- ship between high density lipoprotein cholesterol (HDL-C) and the incidence of CHD (80, 84, 217). Population groups known to be at lower risk for CHD have been observed to have relatively high levels of HDL-C. Thus, HDLC levels have been higher in women in comparison with men, in black men in comparison with white men, and in men in Japan in comparison with men in the United States (5, 106, 146, 260). An adverse influence of cigarette smoking on the levels of HDL-C and other plasma or serum lipoprotein components has been observed in a number of populations. The several classes, or fractions, of these lipid-protein complexes have different functions 93 $ TABLE 7.-Prospective history and findings by behavior pattern Age 39-49 years Age 50-59 years Subjects Subjects Rate of Subjects Subjects Rate of at risk with CHD' CHD = at risk with CHD CHDP Type 5w Type Type Type Type Type Type Type Type Type Type A B A B A B A B A B A B Number of subjects 1,067 1,182 95 50 10.5 5.0 522 383 83 29 18.7 8.9 Parental history of CHD YW 214 197 23 15 12.6 9.0 103 64 20 1 22.8 12.9 No a53 935 72 35 9.9 4.2 419 319 63 22 17.7 8.1 Smoking habits Never smoked 221 315 11 8 5.9 3.0 90 89 10 5 13.1 6.6 Pipe or cigar 191 216 11 6 6.6 3.3 81 78 17 2 24.7 3.0 Former cigarette 110 129 11 5 11.8 4.6 91 41 10 2 12.9 Current cigarette 5.1 545 522 62 31 13.4 7.0 260 175 46 20 20.8 13.4 Current cigarette usage None 522 660 33 19 7.4 3.4 262 208 37 9 16.6 5.1 I-15/day 95 119 3 8 3.7 7.9 65 43 8 1 14.5 2.7 2 16/day 450 403 59 23 15.4 11.4 195 132 33 19 22.9 16.9 Systolic blood pressure, mm Hg 2.36 331 343 38 26 13.5 8.9 196 117 39 11 23.4 11.1 I Coronary heart disease `Average annual rate/l.000 subjects at risk. Difference in rates between type A and type B was tested fur significance by Mantel.Haenszel ye, wth adlustment for factors indicated For each factor, the adjusted asswiatwn between behavior pattern and CHD inadence is aignficant at p < .OOl. SOURCE: Rosenman et al. (2291. in lipid metabolism (41, 78, 213). Most of the cholesterol in the plasma is complexed in the low density lipoprotein cholesterol (LDLC) fraction, which appears to have atherogenic properties, while a lesser proportion of cholesterol is complexed with high density lipoprotein cholesterol (HDL-C), which appears to have antiatherogenic properties (82, 100, 180,230). The HDLC levels in the cigarette smokers in the studies cited above have been found to be significantly lower than in nonsmokers, and in some studies the concentration of HDL-C has been found to correlate inversely with daily cigarette consumption. This relation- ship does not appear to be confounded by other factors. Thus, HDGC is inversely correlated with indices of obesity, such as relative weight, and positively correlated with alcohol intake; adjustment for these characteristics increases the difference in HDLC between cigarette smokers and nonsmokers (79, 99, 105, 212). Additional studies are needed to investigate the complex mechanisms whereby cigarette smoking depresses HDL-C levels and increases the risk for CHD. Blood pressure increases transiently after smoking, mediated by an adrenergic mechanism (37); however, most surveys have demon- strated a small negative association between smoking and blood pressure (263). Recent investigations of this relationship have adjusted for the covariables of weight and alcohol. In an examination of the offspring of Framingham heart study patients and their spouses, multivariate analysis demonstrated a negative correlation between smoking and blood pressure, especially diastolic blood pressure, that was similar to the original Framing- ham cohort (102). A cross-sectional survey of employed men in Australia also demonstrated that, adjusted for weight and alcohol, diastolic blood pressures were slightly lower in smokers (5). In the cohort of the Lipid Research Clinics prevalence study, the small negative correlation between smoking and blood pressure was more apparent for systolic blood pressure (3s). In the cross-sectional and prospective analyses of several study populations in Chicago, how- ever, smoking was associated with higher blood pressure, especially systolic blood pressure (52, 53). Alcohol consumption was not included in these multivariate analyses. If smoking is associated with a slightly lower blood pressure, a rise in blood pressure might be predicted after smoking cessation, especially if smoking cessation is followed by weight gain, but recent studies have not supported this concern. In the Kaiser population, smoking cessation has been associated with only a small weight gain (70). Effects on blood pressure were also small and inconsistent among subgroups. In the Multiple Risk Factor Intervention Trial, smokers who quit lost less weight than those who did not quit (239); controlling for weight, there was no increase in blood pressure with 96 smoking cessation. These studies show that there is little, if any, adverse effect on risk factors following smoking cessation. The benefits of smoking cessation for health in general, and cardiovascu- lar health in particular, far outweigh any objectively observed disadvantageous effect. Although epidemiologic studies do not suggest that smoking causes high blood pressure, concern has been expressed that it may exacerbate the clinical course. Two casecontrol studies in Great Britain (20, 125) and one in New Zealand (57) compared smoking patterns in patients with malignant or accelerated hypertension with those with benign hypertension. In all three, statistically significant associations between smoking and the more severe manifestations of hypertension were demonstrated. A recent clinical study directly observed the blood pressure effects of smoking in mild hypertensives (65). When 16 habitual smokers abstained from cigarettes, their blood pressure was significantly lower than usual. Smoking two cigarettes resulted in a blood pressure increase of 10/8 mm Hg that lasted approximately 15 minutes. Combining coffee drinking with smoking led to an increase in blood pressure to their usual levels that lasted 2 hours. For the most part, recent surveys have supported the traditional finding of a small negative association between smoking and blood pressure. Smoking cessation is not associated with a significant increase in blood pressure, especially if weight gain is avoided. Preliminary studies suggest that smoking increases the likelihood of developing malignant hypertension. Prospective and intervention studies are indicated to further investigate this phenomenon. These findings can be translated into clinical recommendations: (1) nonhypertensive smokers can be assured that smoking cessation will not lead to high blood pressure, especially if weight gain is avoided, and (2) hypertensive smokers should be warned that these two risk factors are synergistic for cardiovascular disease and that the need for risk reduction is increased. Smoking cessation will not complicate the management of high blood pressure, and may reduce hyperten- sive complications. Concomitant monitoring of weight during and after smoking cessation is indicated. Synergistic Effects of Cigarette Smoking When Associated With Other Risk Factors Evidence that the increase in CHD risk associated with smoking may be greater when other risk factors are present than when they are absent has been observed in several investigations. Figure 7 presents the data from the Framingham 12-year followup. The CHD risk increases with increasing levels of blood pressure or serum cholesterol, and at each level of these two risk factors the risk in 97 m Nonsmoker of cigarettes 0 Cigarette smoker 287 1 207 All Frammgham - men 88-120 120-139140-159160-179180-300 96-193 194-220221-249250-534 SYSTOLIC BLOOD PRESSURE SERUM CHOLESTEROL FIGURE `I.-Cigarette smoking at levels of blood pressure and serum cholesterol, X-year incidence NUlE Tbe contribution of cigarette amoking to risk of coronary beart diaeae appears to be independent of other demonstrated rimk factors. At any level of blood pressure or enam cholesterol, cigarette smokers had an excess risk, E-year ineideoce. SOURCE: Knnnel(J3Zl. smokers is greater than the risk in nonsmokers. However, the increment of risk with smoking is not constant, but rather increases with increasing levels of blood pressure or cholesterol. For example, in Figure 7 the increment in risk in smokers with a systolic blood pressure of 80-120 mm Hg is 32 (49 minus 17), while the increment for smokers with a systolic blood pressure of 140-159 is 101 (150 minus 49). These data suggest that cigarette smoking interacts with the other two major risk factors to produce a combined risk that is greater than the sum of the risks that would have been produced by the same risk factors acting separately. Pooling Project data are also consistent with a synergistic effect of cigarette smoking with hypertension and hypercholesterolemia (Figure 8) (19). Evidence of synergism has been found in other studies as well. In the Ni-Hon-San study, the effect of cigarette smoking on CHD incidence in the presence of high serum cholesterol appeared to be more than additive in Japanese Americans living in Hawaii. The same effect was not observed in Japanese men living in Japan, who in general had substantially lower serum cholesterol levels (221). Evidence of synergism was observed in the Stockholm prospective study and the Goteborg studies (Figure 91(27,278). The synergistic interaction between the major risk factors may also explain the observation that the actual incidence of CHD in 98 170 160 150 140 130 z 120 ; 110 a F 100 P 90 2 80 70 60 50 40 30 i 23 54 54 I - 1 None SM only c or H SMBC C&H of 3 only Sh!?. H (no SM) 103 - 92 RISK FACTOR STATUS AT ENTRY' - FIGURE 8.-Major risk factor combinations, N-year incidence of first major coronary events, men age 30-59 at entry, Pooling project ' Definitiona of the three major risk factors and their symbols: hypercholestemlemia (0. 2 250 mg/dh; elevated blood pressure (H). diastolic pressure 290 mm H&C; cigarette smoking (SW, any current use of cigar&tea at entry NOTE: All rates were age adjusted by lo-year age groups to the U.S. white male population, 1980. SOURCE: The Pooling F'mject Reseereh Gmup (214). populations with low levels of serum cholesterol is substantially lower than the incidence predicted by the multiple logistic equations derived from the Framingham population (85, 91, 124, 143, 146). If the synergistic interaction is present at low levels of the major risk factors to the same degree as at high levels of risk factors, then the impact of cigarette smoking on blood pressure in a low cholesterol population would he expected to be smaller than that measured in high cholesterol populations such as in the United States and Western Europe. The multiple logistic equations do not separate out effects that are due to synergistic interactions, and they distribute the synergistic effects to the separate risk factors as though there were no interaction among the risk factors in producing CHD. These equations treat the risk factors as though the effects of the risk 99 FIGURE 9.-Risk factors for disease according to population studies NOTE P = probability of nonfatal and fatal myocardial mfarction for a Sayearsld man during 13 years' followup. 85.5 men bon in 1913 SOURCE: Wdhelmsen (278) factors were additive. This limitation of the multiple logistic equation technique leads to an overprediction of the number of CHD cases to be expected in a population on the basis of smoking habits when that population has very low levels of another major risk factor such as serum cholesterol levels. Therefore, the very low levels of CHD observed in cigarette smokers from populations with very low serum cholesterol levels may reflect the synergistic nature of the interaction among the major risk factors rather than the absence of a CHD risk associated with cigarette smoking in those populations. The possibility also exists that the cigarette smokers in some of these populations have not been smoking for a sufficient duration or with a sufficient intensity to manifest an effect on coronary artery disease. Analytical and methodological refinements appear to be needed for better understanding of the biological significance of synergism (147). Nevertheless, the evidence is clear that cigarette smoking greatly increases the risk of CHD in individuals already at increased risk because of other risk factors. 100 Risk of CHD in Women Young and middle-aged women experience only one-fifth the incidence and mortality from CHD of men (16, 40, 94, 102, 139, 244, 255, 283). These rates are steeply age dependent, and rates in young and middle-aged women lag behind those in men by about 10 years. Reasons for the sex-dependent. differences are incompletely under- stood, but this protective influence of female sex is partly due to differences in cigarette smoking and other behavioral variables (6, 58, 103,127, 128, 150, 151, 166, 170,203,204,210,227,234,243,244, 255, 267, 270, 280). During the 1950s and 196Os, when the previously reported large- scale investigations of smoking and CHD were conducted, relatively few women smoked, and on the average, those who did began at an older age,.smoked fewer cigarettes, and inhaled less than men (261). During the past two decades, women have begun to smoke cigarettes at younger ages, and their cigarette smoking habits have become more like those of men (261). Observations by a number of investigators have shown that the incidence of CHD in recent years in women who smoke cigarettes is far greater than the very low rates that are observed in women who do not smoke, and the incidence of CHD in women who smoke heavily may be similar to the incidence in men. To observe the effect of cigarette smoking in women more specifically, studies have been performed to take account of poten- tially confounding influences on the occurrence of CHD. Slone et al. (244) in Boston observed cases and matched controls from a large number of U.S. hospitals between July 1976 and December 1977. During this l&month period, 55 cases of nonfatal MI were identified in women under age 50 who had not used oral contraceptives within the month prior to admission and who had not been under treatment for heart disease or related disorders. The estimated relative risk for smokers compared with nonsmokers was 6.8 (p 65 1.00 1.5 1.3 None-alight Moderate-deep ACS Male 4534 25-.%&e 55-64 65-74 n-84 Female 4.544 5544 65-74 75.84 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 2.67 3.17 1.83 2.01 1.31 1.63 1.29 1.20 1.82 2.15 1.61 1.89 1.30 1.78 1.13 -2 L Number of deaths too small for statistical reliability. `Number of deaths tax small to compute. presented in Tables 10, 11, and 1`2. Table 13 provides data from two studies that examined the risk of coronary heart disease mortality by length of time smoked. In general, they show that the more total years of smoking exposure the greater the overall risk of CHD mortality. In the study of Canadian veterans, a progressive dose-response relationship was observed with number of cigarettes smoked per day. The CHD mortality ratio increased from 1.55 in those smoking 1 to 9 cigarettes per day to 1.78 among those who reported smoking 20 or more cigarettes per day. A similar relationship was found in the American Cancer. Society 9-State study, where the excess CHD mortality rate varied from 29 percent in smokers of 1 to 9 cigarettes per day to 140 percent in smokers of 41 cigarettes or more per day. In the American Cancer Society 25-State study, the number of CHD deaths was large enough to conduct a detailed examination of the relationship between the dose of cigarette smoke exposure and the subsequent coronary heart disease mortality. The mortality ratios for males in the group 45 to 54 years of age increased from 2.35 in those who smoked 1 to 9 cigarettes per day to 3.35 in those who smoked 40 or more cigarettes per day. In the next oldest age group, those 55 to 64 years of age, the mortality ratio increased from 1.54 in those who smoked 1 to 9 cigarettes per day to 2.13 in those who smoked 40 or more cigarettes per day (Table 14). The mortality ratio also increased with depth of inhalation. In the 45- to 54-year-old 116 TABLE il.-Coronary heart disease mortality ratios by age began to smoke, prospective studies Study Age Nonsmoker ratio Smoker Mortality ratio by age of initiation us. veterans 5 14 1519 W24 2% 55-64 1.00 1.96 1.64 1.65 1.56 65-74 1.00 2.03 1.66 1.54 1.55 ACS 2.5State <14 15-24 2% Males 45-54 1.00 3.47 3.11 2.37 55-64 1.00 2.08 1.99 1.70 6&74 1.00 1.54 1.62 1.17 FemallX3 45-54 1.00 -' 2.03 2.00 55-64 1.00 - 1.64 1.74 65-74 1.00 - - 1.36 Males 1.00 3.65 1.90 1.67 Swedish 516 17-16 219 M&9 1.00 . Females 1.00 ' Number of deaths tao small to calculate ratio. 1.90 1.70 1.70 2.00 1.10 1.30 age group, the mortality ratio increased from 2.67 in those who inhaled not at all or only very slightly to 3.17 in those who inhaled moderately or deeply (Table 10). There was also a consistent dose- response relationship when the age at which the individual started smoking was considered. The younger the age at which regular smoking began, the greater the mortality ratio. In the 45-54 age group the mortality ratio increased from 2.37 in those who began smoking at age 25 or older to 3.47 in those who began smoking prior to age 15 (Table 11). For women, the excess mortality in the American Cancer Society 25State study generally paralleled the dose-response relationship observed in men, but the CHD deaths were too few for evaluation of the risk related to the age at which smoking was begun. A similar relationship was demonstrated in the study of California men in various occupations. The mortality ratio increased from 1.39 for those men who smoked half a pack per day to 1.74 for those who had smoked 1 l/2 packs or more per day. Mortality ratios increased with the duration of smoking from 1.05 in those who had smoked from 1 to 9 years to 1.77 in those who had smoked 20 years or more. The study of British physicians also examined the question of a dose-response relationship. They found a steady increase in CHD mortality with increasing number of cigarettes smoked per day. The death rate from ischemic heart disease increased from 501 per 100,000 in those who smoked 1 to 14 cigarettes per day to 677 per 117 TABLE 12.-Coronary heart disease mortality ratios by amount smoked, prospective studies Study M&S Females cigs/bY Ratio cigs/bY Ratio U.S. veterans Nonsmoker 1.00 l-9 1.24 l&20 1.56 2139 1.76 40+ 1.94 ACS 9-State JapeSe Nonsmoker 1.00 l-9 1.29 lo-20 1.89 21-40 2.15 41+ 2.41 Nonsmoker 1.00 1-14 1.59 15-24 1.79 25-49 2.11 50+ 2.82 (For female data, see Table 9) ACS 25State Nonsmoker 1-19 20+ 1.00 1.90 2.55 (For female data, see Tables 9 and 14) Canadian veterans Nonsmoker 1.00 l-9 1.55 10-20 1.58 21+ 1.78 British physicians Swedish California mupationa Sti physicians Nonsmoker 1.00 Nonsmoker 1.00 1-14 1.47 1-14 0.96 15-24 1.58 1624 f 2.20 25+ 1.92 25+ 2.12 Nonsmoker 1.00 Nonsmoker 1.00 1-7 1.50 l-7 1.20 8-15 1.70 l&15 1.60 16+ 2.20 16+ 3.00 Nonsmoker 1.00 about 112 pk 1.39 about 1 pk 1.67 about 1 l/2 pk 1.74 Nonsmoker 1.00 l-10 1.33 l&19 1.42 29-34 1.77 350rmOlV 2.18 100,000 in those who smoked 25 or more cigarettes per day. Depth of inhalation was analyzed after adjusting for age and amount smoked. Those responding that they did inhale experienced a 57 percent higher mortality rate than those responding that they did not inhale. A dose-response relationship was also reported in the U.S. veterans study, the study of mortality in northeast England, the 118 TABLE 13.-Coronary heart disease mortality ratios by number of years having smoked, prospective studies Study Number of years having smoked Nonsmoker < 5 5-9 lo-14 15-19 2&29 3cM9 240 Canadian veterans 1.00 1.4 1.7 1.5 1.7 1.6 1.5 1.6 l-9 lo-19 20+ California occupations 1.00 1.05 1.13 1.77 TABLE 14.-Coronary heart disease mortality ratios, males and females, by age and amount smoked, ACS %-State study Number oi 4.544 55-64 65-74 75-64 cigarettes/day M F M F M F M F Nonsmoker 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 l-9 2.36 9.94 1.54 1.26 1.26 1.10 1.17 -' E-19 3.09 2.00 1.92 1.64 1.61 1.42 1.39 - 2%39 3.11 2.67 2.04 2.01 1.56 1.65 1.11 - 40+ 3.35 - 2.13 - - - - - ' Number of deaths too small to wmpute. Swedish probability sample study, the Stockholm prospective study, and the study of 29 health districts in Japan. Mortality from CHD in the Whitehall study was higher in inhalers than in noninhalers, but the relative risk was reduced after adjusting for cigarette consump tion and tar yield. Among inhalers, the risk increased with the amount smoked; this trend was less evident in those not inhaling. Thus, in those studies that have had an adequate number of deaths to examine the question of a dose-response relationship between cigarette smoking and death from coronary heart disease, a clear dose-response relationship has been demonstrated for the number of cigarettes smoked per day, depth of inhalation, age at initiation of the smoking habit, and total duration of the smoking habit. The risk of coronary disease mortality is lower with fewer cigarettes smoked per day, but the evidence presented in the prospective mortality studies does not suggest a threshold for this effect. There is no evidence to suggest that any level of cigarette smoking is safe with regard to coronary heart disease risk. 119 Low Tar and Nicotine Cigarettes There has been a major change in the tar and nicotine yield of the cigarettes being smoked by the U.S. population over the last 30 years. The impact of this decline in tar and nicotine yield on the risk of developing coronary heart disease in individuals smoking lower yield cigarettes has been examined in detail in the 1981 Report of the Surgeon General The Health Consequences of Smoking: The Chang- ing Cigarette (262). There are essentially no epidemiological data on the risk of very low yield cigarettes (those below 5 mg of tar). The American Cancer Society 25-State study did, however, address the relative risk of those who smoked cigarettes with varying yields of tar (95). Groups were matched for age, race, number of cigarettes smoked per day, age at which smoking began, place of residence, occupational exposures, education, and history of lung cancer or heart disease. CHD mortality was calculated for two 6-year periods (196CL1966 and 1966-1972) for those smoking low, medium, or high tar and nicotine cigarettes. The men and women (both in early and late periods) who smoked cigarettes with high tar and nicotine yield experienced higher CHD death rates than those who smoked low tar and nicotine cigarettes (Table 15). Additional analyses were per- formed after further matching of the groups with respect to history of stroke; diabetes mellitus; hypertension; usual amount of exercise; obesity; consumption of aspirin, tea, coffee, and alcohol; and occupa- tion. Although this procedure resulted in fewer matched subjects, the results were comparable to the analyses above; CHD mortality in the low tar and nicotine cigarette smokers was 86 percent of that of the high tar and nicotine cigarette smokers. However, this slight reduction in CHD mortality associated with smoking low tar and nicotine cigarettes disappeared if an increase in the number of cigarettes smoked per day occurred. Those smokers of low tar and nicotine cigarettes who smoke between 20 and 30 cigarettes per day experienced a 10 percent higher coronary heart disease mortality than did smokers of 1 to 19 high tar and nicotine cigarettes. In addition, a comparison of matched subjects who never smoked regularly with those who smoked low tar and nicotine cigarettes revealed that the low tar and nicotine cigarette smokers experienced a 66 percent higher coronary heart disease mortality rate. Data from the Framingham study on the incidence of coronary heart disease (30) have not shown a lower CHD risk among filter smokers compared with nonfilter smokers. Data from the Whitehall study have been published that examine tar yield by number of cigarettes smoked per day in inhalers and noninhalers for CHD mortality. This is presented in Table 16. While no clear pattern is evident for noninhalers, among inhalers there was a tendency for the highest CHD rates to be seen in those smoking cigarettes with the highest tar yield (108). In a recent study 120 TABLE 15.-Adjusted number of coronary heart disease deaths and mortality ratios during each of two periods of time, by sex and by tar and nicotine content of cigarettes usually smoked sex Period ' High tar Medium tar Low tar and nicotine and nicotine end nicotine Male Female Female Total Male Male Female Female Total . Adjusted number of CHD deaths 696.5 632.5 645.6 336.0 345.6 274.2 318.7 277.5 257.4 265.6 228.0 215.5 1.616.8 1,#3.3 1.392.7 Mortality ratios 1.00 0.91 0.93 1.00 1.03 0.82 1.00 0.87 0.81 1.00 0.86 0.81 1.00 0.92 0.86 `Period 1: 1960-1966; Period 2: 1966-1972 SOURCE: Hammond et al. wh TABLE le.-Ten-year coronary heart disease mortality per hundred (and number of deaths) standardized for age and employment grade, according to cigarette consumption and tar yield, Whitehall study Inhalers Noninhalers l-S/day 1@19/day > m/day I-9/day 1&19/day > 2O/day ~ ___ ___ ___ ___ ~ Tar (m&i@ Rate No. Rate No. Rate No. Rate No. Rate No. Rate No. 18-23 2.68 (14) 5.63 (71) 6.60 (101) 3.94 (14) 4.91 (17) 6.05 (20) 24-32 3.81 (7) 6.57 00) 6.23 (36) 1.78 (3) 9.03 (10) 4.27 (6) 2% 7.42 CD) 6.47 (37) 7.84 (10) 5.06 (4) 4.75 (4) 0.00 (0) Total 4.29 (44) 5.98 (138) 6.56 (147) 3.46 (21) 5.73 (31) 5.16 (26) NOTE: Rate for lifelong nonsmokers of cigarettes = 2.75 (70). SOURCE: Higgenbottam et al. (108. (240), tar and nicotine content of the cigarettes was documented; those men who smoked low yield cigarettes did not have a lower risk for myocardial infarction than those smoking higher yield cigarettes. The relative risk of developing coronary heart disease in persons smoking low yield cigarettes and persons smoking high yield cigarettes is further confounded by the possibility that those who 121 TABLE 17.-Coronary heart disease mortality ratios for male cigarette, pipe, cigar, and mixed pipe and/or cigar smokers, prospective studies Study Nonsmoker U.S. veterans' 1.00 Mortality ratios Cigarette pipe aw Mixed pips and/ smoker smoker smoker or cigar smoker 1.58 1.02 1.12 ACS 9-Stat.e 1.00 1.70 - 1.28 Swedish 1.00 1.70 1.40 ACS 25State' 1.00 1.90-2.55 1.08 British physicians 1.00 ' Smoker group are "pure" smokers only. ' Age 5664 only. 1.62 1.03 smoke low yield cigarettes may smoke greater numbers of cigarettes per day or may alter the manner in which they smoke those cigarettes to increase the yield from the cigarette. The available data are conflicting concerning a possible reduction in risk of CHD for those smoking the lower yield cigarettes; further evidence is needed before this question can be definitively answered. Pipe and Cigar Smoking A number of studies have addressed the question of.the relative risk for CHD from smoking pipes and cigars compared with cigarettes. Those prospective mortality studies containing data that address this question are presented in Table 17. In general, the risk for coronary heart disease mortality of smoking pipes and cigars is substantially lower than the risk of smoking cigarettes. This is generally felt to be due to the tendency of pipe and cigar smokers not to inhale smoke into the lung. If this is the mechanism of this lower risk, then the tendency of those who switch from cigarettes to pipes and cigars to continue to inhale the smoke may minimize or eliminate the reduction in risk for coronary heart disease that might be expected after switching to pipes and cigars from cigarettes. Cessation Whether the excess coronary heart disease mortality that occurs with cigarette smoking decreases over time following cessation of cigarette smoking is a question of great importance for those individuals who are currently smoking cigarettes. Data from the prospective mortality studies that have examined this question are presented in Table 18. 122 TABLE 18.-Cessation of smoking and coronary heart disease mortality ratios, prospective studies Study Continuing smoker Eksmoker U.S. veterana Swedish males females ACS 25&&e Canadian veterans British physicians males Japanese males in 29 health dietricte 1.58 1.16 1.70 1.50 1.30 1.50 l-19' 20+ 1-19 2O+ 1.87 2.06 1.26 1.62 1.60 1.46 1.62 1.29 1.71 1.34 TABLE 19.-&essation of smoking and CHD mortality ratios, by length of time off cigarettes and number of cigarettes smoked daily, ACS 2!5- State study, 6year followup Years stopped smoking Amount smoked per day l-19 20+ None, current smoker 1.87 2.06 Le3sthan1 2.00 2.13 1-4 1.43 2.00 5-9 1.44 1.45 10 or more 0.99 1.35 All ex-emokers 1.26 1.62 In the American Cancer Society 25-Stat.e study, the mortality ratios in former smokers compared with continuing smokers were progressively lower with increasing intervals of smoking cessation. For those who had smoked less than 20 cigarettes per day, the CHD mortality after 10 years of cessation was comparable with that of those who had never smoked regularly. However, for those who had smoked 20 or more cigarettes per day, the CHD mortality rate remained 35 percent higher even after 10 years (Table 19). The British study of physicians also conducted a detailed analysis of the effects of cessation. The relative risk for males 30 to 54 years of age was 1.9 for those who had discontinued smoking for less than 5 years, but it was 1.3 for those who had discontinued smoking for 5 or more years. Those who discontinued smoking for 15 years or more had a relative risk that remained slightly above 1. Those aged 30 to 123 TABLE 20.PHD mortality ratios by length of time off cigarettes Study Mortality ratios "ke Nonsmoker Yeare off cigarettes comments <5 5-9 l&14 5+ British 3s54 1.00 1.9 1.3 1.4 1.3 phyaiciam 5544 1.00 1.9 1.4 1.7 1.3 e@yr foump) 85+ 1.00 1.0 1.3 1.2 1.1 lO Swedish m&n 1.00 1.50 1.00 (l@yr followup) Japanese males in29health dietrict3 (1Csj-r folbJwup) 1.00 1.00 54 25 1.15 0.90 2.10 1.82 Smokers who consumed <2oo,ooo cigaretteal lifetime Smokers who consumed >2wloo cigarew/ lifetime 64 had a relative risk of 1.3 after 15 years, while those 65 and over had a relative risk of 1.1 (Table 20). The Swedish national probability sample study examined former smokers who had stopped in the 10 years prior to 1963. A relative risk of 1.6 existed for those who had smoked 20 years or more prior to quitting, but the relative risk was 0.9 for those who had-smoked less than 20 years before quitting. Those at younger ages had greater residual relative risks than those in the older age groups. Among those who had stopped smoking 10 or more years prior to the beginning of the study, no significant excess risk of coronary disease was observed. The results in women were consistent with those in men, but the cases were too few for detailed analysis (Table 20). In the Japanese study of 26 health districts, former smokers exhibited relative risks that were related inversely to the time since smoking cessation; the residual risk was directly proportional to the number of cigarettes smoked prior to quitting. Data from the X-year followup of U.S. veterans provides informa- tion on CHD mortality for ex-smokers by the number of cigarettes smoked per day (Table 21). Those ex-smokers with the lowest smoking exposure levels as measured by the number of cigarettes consumed per day had the lowest CHD mortality ratios. When all ex- smokers were analyzed by the length of time since cessation (Figure 13), ex-smokers who had been abstinent for 20 or more years had a CHD mortality ratio virtually identical to lifelong nonsmokers (1.00 versus 1.05). Friedman et al. (69) found that the benefits of quitting 124 TABLE 21.~ssation of smoking and CHD mortality ratios of current smokers versus ex-smokers, by number of cigarettes smoked daily, U.S. veterans study, M-year followup No. cig/daily Current smoker Ex-smoker Nonsmoker 1.00 1.00 l-9 1.24 1.02 lo-20 1.56 1.14 2139 1.76 1.31 40+ 1.94 1.30 AU smokers 1.66 1.16 SOURCE: Begot and Murray (224). A 8 C D E FIGURE lb-Coronary heart disease mortality rates by number of years stopped smoking, U.S. veterans study, N-year followup NOTE: A = Btopped b than 5 years: B = stopped 5-9 years; C = stopped 10-14 years; D = tipped 15-19 years; E = stopped 20 or more years. SOURCE: Begot and Murray GW. smoking could not be explained by differences in other risk factor levels between continuing smokers and quitters. Thus, cessation of cigarette smoking resulted in a reduction in the risk of CHD in each of the mortality studies that have examined the question. There appears to be some residual excess CHD risk in those ex-smokers who smoked heavily for extended periods of time prior to 1% quitting, and the magnitude of this residual risk is proportional to the total lifetime exposure to cigarette smoke. Populations With Low Rates of Smoking Mortality has been studied in several population groups that have abstained from cigarette smoking for religious reasons. These include Seventh Day Adventists in California, Mormons living in Utah, members of the Reorganized Church of Jesus Christ of the Latter Day Saints living in Missouri, and Old Order Amish living in Indiana, Ohio, and Pennsylvania. Seventh Day Adventists in California prohibit the use of tobacco and alcohol and advocate a well-balanced diet that includes a relatively large grain and fruit content. As reported by Wynder and Lemon (285), the Seventh Day Adventists have experienced excep- tionally low coronary heart disease as well as low cancer mortality. Cardiovascular mortality from 1969 to 1971 in Mormons and non- Mormons living in Utah was studied by Lyon et al. (165). Utah has the lowest per capita consumption of cigarettes and alcohol of the 50 States, and this is attributable to the Mormon Church's position against the use of tobacco and alcohol. Below the age of 65, both Mormons and non-Mormons in Utah had significantly lower core nary heart disease mortality than the average for U.S. whites, but above the age of 65 only Mormons had significantly lower rates. Mormon men and women in comparison with non-Mormon men and women living in Utah experienced 25 percent and 29 percent fewer deaths, respectively, from coronary heart disease. The rates were lower in Mormons than in non-Mormons at all ages. Below the age of 65, Mormon men and women experienced CHD mortality rates only 66 percent and 51 percent, respectively, of the rates for coronary heart disease that were experienced by U.S. whites. The mortality of Missouri residents who were members of the Reorganized Church of Jesus Christ of Latter Day Saints (RLDS) was compared with the mortality of other white Missouri residents and of Utah residents for the period 1971-1978 (167). The RLDS advocates abstinence from the use of tobacco, alcohol, and hot drinks. A well- balanced diet is recommended, with ample whole grains, fruits, and vegetables but with moderate intake of meat. The total mortality rate for Missouri RLDS residents was 22.6 percent lower than that of other Missouri white residents and 14.4 percent lower than that of Utah residents. CHD mortality was 17.4 percent lower than CHD mortality for other Missouri whites. The CHD mortality of RLDS members appears to be intermediate between that of Mormons living in Utah and that of U.S. whites. Mortality among Old Order Amish living in Ohio (1960-1975), Indiana (1967-1972), and Pennsylvania (1970-1975) was reported by 126 Hamman et al. (92). This unique population group is rooted in a rural lifestyle reminiscent of 19th century America. Their diet has been incompletely characterized, but probably is relatively high in fats and carbohydrates. Tobacco use has been widespread among men, but principally limited to pipe and cigar smoking and tobacco chewing. Alcohol intake is thought to be limited to consumption at home, and excessive intake is uncommon. Mortality of the Amish was compared with mortality of the non-Amish residents in the study counties. The non-Amish residents included an unknown proportion of those who were former members of the Amish faith and members of other conservative religious groups who shared components of the Amish lifestyle. Amish men, but not women, 40 to 69 years of age had significantly lower total mortality (61 percent and 98 percent, respectively) and cardiovascular mortality (65 percent and 89 percent) than did the non-Amish residents living in the same counties. Lower cardiovascular disease mortality for the Amish men was highly significant in all three States. Conclusions 1. Cigarette smoking is a major cause of coronary heart disease in the United States for both men and women. Because of the number of persons in the population who smoke and the increased risk that cigarette smoking represents, it should be considered the most important of the known modifiable risk factors for CHD. 2. Overall, cigarette smokers experience a 70 percent greater CHD death rate than do nonsmokers. Heavy smokers, those who consume two or more packs per day, have CHD death rates between two and three times greater than nonsmokers. 3. The risk of developing CHD increases with increasing exposure to cigarette smoke, as measured by the number of cigarettes smoked daily, the total number of years one has smoked, and the degree of inhalation, and with an early age of initiation. 4. Cigarette smokers have a twofold greater incidence of CHD than do nonsmokers, and heavy smokers have an almost fourfold greater incidence. 5. Cigarette smoking is a major independent risk factor for CHD, and it acts synergistically with other risk factors (most notably, elevated serum cholesterol and hypertension) to greatly in- crease the risk of CHD. 6. Women have lower rates for CHD than do men. In particular, CHD rates for women are lower prior to the menopause. A part of this difference is due to the lower prevalence of smoking in women, and for those women who do smoke, to the tendency to smoke fewer cigarettes per day and to inhale less deeply. 127 Among those women who have smoking patterns comparable to male smoking patterns, the increments in CHD death rates are similar for the two sexes. 7. Women who use oral contraceptives and who smoke increase their risk of a myocardial infarction by an approximately tenfold factor, compared with women who neither use oral contraceptives nor smoke. 8. Cigarette smoking has been found to significantly elevate the risk of sudden death. Overall, smokers experience a two to four times greater risk of sudden death than nonsmokers. The risk appears to increase with increasing dosage as measured by the number of cigarettes smoked per day and diminishes with cessation of smoking. 9. The CHD mortality ratio for smokers compared with nonsmok- ers is greater for the younger age groups than for the older age groups. Although the smoker-to-nonsmoker mortality ratio narrows with increasing age, smokers continue to experience greater CHD death rates at all ages. 10. Cigarette smoking has been estimated to be responsible for up to 30 percent of all CHD deaths in the United States each year. During the period 1965 to 1930 there were over 3 million premature deaths from heart disease among Americans attrib uted to cigarette smoking. Unless smoking habits of the American population change, perhaps 10 percent of all persons now alive may die prematurely of heart disease attributable to their smoking behavior. The total number of such premature deaths may exceed 24 million. 11. Cessation of smoking results in a substantial reduction in CHD death rates compared with those of persons who continue to smoke. Mortality from CHD declines rapidly after cessation. Approximately 10 years following cessation the CHD death rate for those ex-smokers who consumed less than a pack of cigarettes daily is virtually identical to that of lifelong non- smokers. For ex-smokers who had smoked more than one pack per day, the residual risk of CHD mortality is proportional to the total lifetime exposure to cigarette smoke. 12. Epidemiologic evidence concerning reduced tar and nicotine or filter cigarettes and their effect on CHD rates is conflicting. No scientific evidence is available concerning the impact on CHD death rates of cigarettes with very low levels of tar and nicotine. 13. Smokers who have used only pipes or cigars do not appear to experience substantially greater CHD risks than nonsmokers. 128 Appendix: Prediction of CHD The probability of developing CHD may be accurately predicted within populations that are stratified by risk scores based on daily use of cigarettes and the levels of the other major risk factors. This may be accomplished efficiently using the multiple logistic equation, which provides for simultaneous consideration of multiple risk factors (40, 80, 84, 85, 88, 91, 126, 130, 133, 135, 137, 139, 143, 159, 168, 214, 221, 246). Furthermore, the reproducibility of the relation- ship between risk factors and the subsequent development of CHD may be tested among different population samples. As demonstrated in the investigations cited above, the risk of CHD in white populations in the United States and northern Europe has been shown to be predictable based on a knowledge of cigarette smoking, blood pressure, and serum cholesterol. In other population groups with lower incidences of CHD, relative risk has been predicted well, although the magnitude of risk has been overestimated. Such predictability confirms the importance of the major risk factors to the development of CHD. Pooling Project The relationships among a number of characteristics measured at baseline examinations and the subsequent development of CHD was studied intensively in the Pooling Project, in which the experience of five major prospective studies of defined cohorts were compared and combined. From these analyses it was concluded that the levels of the three major risk factors-cigarette smoking, blood pressure (systolic or diastolic blood pressure), and serum cholesterol-ac- counted for most of the risk predicted by the variables considered; the other variables were relative weight and ECG abnormalities. Furthermore, the relationships of the risk factors to CHD were similar among the cohorts considered. Ranking of Risk On the basis of the observed relationships among the levels of the major risk factors and the subsequent incidence of CHD in the pooled data, the men in each of the cohorts could be ranked by order of expected risk. With the men thus ranked in quintiles of estimated risk from low to high, the incidence of CHD was found to be nine times higher for the men in the uppermost quintile than for the men in the lowermost quintile. Genemlizability To test the generalizability of the relationship between these risk factors and the subsequent incidence of CHD (in other words, the prediction of future CHD events from given individual characteris- 129 tics), the multiple logistic equation describing the relationship of risk factors to subsequent events in the combined data from the cohorts contributing to the pooled data were applied to other cohorts. In the cohort of U.S. railroad men, there was good correspondence between the number of first major coronary events predicted and the numbers observed by quintile of risk; 45 percent of CHD events were observed in the highest quintile and 74 percent were observed in the upper two quint&s. The total number of estimated cases was 133 as compared with 112 actually observed in the cohort of U.S. railroad men (`Table 22). Comparability of Framingham Study Results With the Results in the Other cohorts The mathematical relationships between the risk factors and the subsequent incidence of CHD for the Framingham study men were near the averages observed for the other four cohorts in the Pooling Project (Tables 23 and 24). The Framingham study results have been compared with the results of other cohort studies in the United States and elsewhere (25, 77, 85, 182); therefore, it is of interest to consider in some detail the closeness of agreement between the prediction of CHD by Framingham data and by the other cohort data in the Pooling Project. In univariate analyses for each study by CHD event and risk factor, it was found that the Framingham coefficients were not significantly different from those of the other cohorts, except for a higher coefficient for serum cholesterol in the Tecumseh cohort and a higher coefficient for cigarette smoking in the Chicago Gas Company cohort (Table 23). The Framingham coefficient for smoking was slightly lower than the average for the other cohorts. Risk Indices for Individual Use Multivariate risk-scoring indices for estimating the risk of CHD based on daily use of cigarettes and the levels of other characteristics have been developed for prediction of the risk of CHD in individuals. These include RISKO, developed by the Michigan Heart Association, the Framingham Risk Index, based on the Framingham study experience, and the Self-Scoring Risk Test, based on the experience of the Chicago Western Electric Company cohort (54,138,178). The discriminative power of RISK0 and the Framingham Risk Index to identify individuals who would develop CHD was evaluated in the experience of Los Angeles County safety personnel (256). Personnel who were free of symptoms (4,066 individuals) were examined and followed in the 1971 to 1979 time frame with a less than 3 percent loss to followup (256). Subsequent to initial examina- tion, 71 developed CHD, these symptomatic cases were characterized by a higher proportion of cigarette smokers (60 percent compared with 37 percent), higher systolic blood pressures, higher serum 130 TABLE 22.-Prediction of lo-year risk of a first event for men of two studies (Minnesota business and professional men and Minnesota-based railroad workers) from parameters of the multivariant logistic analysis for Pool 6, age 40-59 at entry Quintilea of expected or predicted risk Pool 5 Minnesota business and professional men Minnesota-based railroad workers (6,875 men) G!SO men) , (2,422 men) Predicted, Predicted, mrrected for corrected for duration of duration of Expected OtWlWd Predicted followup ' ObSWWd Predicted followup' OlXWWd I ::I N V All V/I V-I Percentage of event.9 in V Percentage of events in VI + v 41.3' 30.0' 29 21.1 1.0 18.4 2.0 37.6 3 53.6 16.9 34.8 6.3 17.0 8 16.5 101.1 71.2 51.8 73.5 106 71 51.6 77.1 2.2 1.6 27.9 39.6 3.3 4.5 57.0 80.9 4 7 125.0 71.4 30.6 44.2 91.3 63.2 21.7 15.0 31.0 44.7 15 5 31.0 12.4 145.5 106.8 164 119.3 3.1 55.3 6.3 113.0 6 107.1 64.7 133.7 31.7 65.5 33 68.2 264.0 192.0 251 182.5 5.5 97.4 11.2 199.1 12 214.3 115.2 237.0 56.4 116.1 50 102.9 623.1 90.6 621 90.3 13.4 47.7 27.4 97.5 32 114.3 271.5 112.1 133.0 54.9 112 46.2 6.4 8.7 5.3 5.3 4.0 6.8 6.8 6.3 222.7 162.0 222 161.4 4.5 79.0 9.2 161.5 9 160.7 98.3 202.2 48.1 99.1 42 36.4 42.4 40.4 40.8 40.8 37.5 42.2 42.4 44.6 65.7 66.8 64.0 64.0 56.3 66.3 66.3 74.1 `Mean durstion of followup for Pool 5 men wae sirably leee then for Minnesota bueineee end pmfasional men. Since the relationship between ege end incidence of major coronary events is curvilineer (exponential). not linear. a correction factor wee derived from the 1970 U.S. life table for white men startmg et ege-predicted numbers of even@ rates were multiplied by this correction factor-2.044--to obtain the numbera of events and rata for different duration of followup. `Mean duration of followup for Pool 5 men wee sizably greeter then for Minnmota-based railroad workers. A correction factor-O. i WI--wan derived by the method deecribed in the footnote above. `Number of events. `Rate per Loco. SOURCE: Pooling Project Reaeerch Gmup W4. TABLE 23.-Standardized univariate logistic coefficients for deaths from myocardial infarction, CHD, and all causes, by study and risk factor Flnminghem Aumny Chicago Gee Chicago W.E. Tecunueh Myccardial infarction or CHD death SBP 0.3373 0.2695 0.3123 0.2511 0.5633 DBP 0.3126 0.2645 0.3169 0.2797 0.5059 chol~ml 0.3433 0.3614 0.2665 0.3271 0.7KIl' Relative weight 0.2775 0.2365 0.1496 0.0703 40136 Smoking 0.3115 0.1450 0.6964' 0.3049 0.5133 Death all cauwa SBP 0.4671 0.4671 DBP 0.3664 0.4006 ChOleetelUl 0.1155 0.1321 Relative weight 0.0540 -0.1452 Smoking 0.3676 0.3745 0.4102 0.2426 0.1615 -0.0921 0.5606 CHD death SBP 0.4860 0.3103 0.3663 DBP 0.4136 0.3394 0.2816 Cholesteml 0.2872 0.2550 0.2474 Belative weight 0.3223 0.0490 0.1967 SmOlKing 0.3327 0.4612 0.6060 0.4166 0.3362 0.0796 0.1645 0.3226 0.3212 0.4056 0.2344 0.0765 0.2311 0.2926 0.4906 0.4533 ' Am214 0.5546 0.5331 0.5518 0.6566' 0.0453 0.4623 ' Differs signifiaratly from Framingham (p< .cw. `DiEfee eigdicmtly from Fmmi&am (p < .01X NOTE: The coeff~cienta here are given in leas precision for eae ofcomparim~. For each oxfikient in the atudien other than Fmmingham. a teat statistic was calculated ta teat whether it differed significantly from the compmable mefftient for Fnunii. Thaw that did were appropriately marked. The test etatidic in the differma between the coeficients divided by the atanderd error of the differenm. The standard error of tbe difference in calcul&ed by taking the quare root of the sum of the variance of the meffkienta. Under appropriate nolwllity aLlmmption0, tlh statietic in B standard normel deviat.e. SXJRCE: Mccee end Gordon w93. cholesterol, slightly greater prevalence of excess body fat, and less frequent regular exercise. The risk scores of cases in comparison with noncases were significantly higher with RISK0 and with the Framingham Risk Index. In stepwise discriminant analysis, the Framingham Risk Index and RISKO, separately and in combination, identified the group with elevated levels of risk factors that experienced a higher incidence of CHD than the group with low levels of the risk factors. Blacks and Whites in Evans County, Georgia In looking for an explanation of the large difference in CHD incidence rates between black and white men in the Evans County study (see above), the incidence at different levels of risk factors was evaluated (28, 107, 258). Although cigarette smoking and other risk factors were strongly related to the incidence, differences in baseline characteristics did not appear to explain the higher rates of CHD in white men. However, white and black sharecroppers and farm 132 TABLE 24.-Standardized multivariate logistic coefficients for deaths from myocardial infarction, CHD, and all causes, by study and specified set of risk factors Mb MbY Chicago Gas Chicago W.E. Tecumaeh Myoaudkl infarction or CHD death SBP 0.3432 0.2426 0.3376 0.2342 0.5524 Cholenteml 0.2905 0.3534 0.2187 0.3056 0.7989' smo!&lg 0.3374 0.4227 0.7010 ' 0.2820 0.5509 DBP 0.3022 0.2725 0.3694 0.2680 0.5222 Choleateml 0.2893 0.3462 0.2176 0.2979 0.7705 ' Smoking 0.3352 0.4359 0.7240 ' 0.2934 0.5647 Death all caueea SBP Choleeteml Smoking DBP Choleateml Smoking CHD death SBP ChOk.BtMO\ Smok@ DBP Cholesteml Smoking 0.5483 0.4254 0.4495 0.275 ' 0.4742 0.0209 0.0992 0.1307 0.0260 0.4617 ' 0.4845 0.3453 0.6033 0.3206 0.5614 0.4306 0.3983 0.2855 0.3382 0.4971 0.0279 0.0937 0.1339 0.0145 0.4391' 0.4855 0.3638 0.6012 0.3372 0.5880 0.5292 0.2897 0.3936 0.2981 0.5720 0.2033 0.2406 0.1661 0.2025 0.9164' 0.4027 0.4107 0.8076 0.2092 0.4989 0.4200 0.3126 0.3309 0.3799 9.5752 0.2038 0.2324 ox@3 0.1995 0.8918' 0.3806 0.4273 0.8200 0.2273 0.5140 ' Differs signiicantly from Framingham (p < .06). `Differs migniticantly from Framingham (p< .Ol). NOTE The coefficients here are given in less precision for ease of comparison. For each coeffkient in the studies other than Framingham, a test statistic wan calculated ta teat whether it differed significantly from the comparable coefkient for Framingham. Thana that did were appropriately marked. The test statistic in the differma, between the coeffacienta divided by the ntandanl error of the difference. The standard error of the difference ia calculated by taking the equare root of the sum of the variance of the coeffkients. Under appropriate aormatity assumptions, this stabtic is a standard Norma deviate. SOURCE: Mccse and Gordon wm laborers had similarly low incidences, but the numbers of cases were too few for more definitive analysis of the influence of occupation (29). At all levels of the major risk factors, the incidence of CHD was higher in white than in black men, but some differences were smaller in the higher ranges of the risk factors. The absolute rates for white men were higher than for black men whether they were smokers (including ex-smokers) or nonsmokers, but the relative risk for white male smokers compared with nonsmokers was 2, whereas the relative risk in black male smokers compared with nonsmokers was 3 (107). Multivariate analyses were performed to evaluate differential risk between the black and the white men in Evans County (146). A multiple logistic model for the white men was developed using as 133 explanatory variables smoking, diastolic blood pressure multiplied by age, abnormal electrocardiogram, and cholesterol multiplied by age. This predicted the total incidence and the cases by decile of risk quite well among the white men. When this model was applied to the risk factor levels of the black men ranked by decile of relative risk, four times as many cases were predicted as had been observed (54 predicted, but only 13 actually observed). However, when the multiple logistic model was constrained by an appropriate constant, the number of cases fit the black data satisfactorily. This is consistent with the view that cigarette smoking and the other risk factors are as important in the blacks as in the whites, but that the blacks were protected by some factor that was not accounted for in the analysis (146). The Seven Countries Study In the Seven Countries study, the risk of CHD in U.S. railroad men resident in the northwest sector of the United States was compared with the risk of CHD in men living in contrasting environments in Europe and Japan. In the Pooling Project, the U.S. railroad men were found to have levels of risk factors comparable to the other principal cohorts, but the total number of cases was 16 percent lower than the number predicted by average parameters of the Pooling Project data. `I'he relationships of risk factors measured at entry to the subsequent incidence of CHD were less uniform in those cohorts of the Seven Countries study with a low incidence of CHD events, and the absolute incidence at specified levels of the risk. factors was significantly different. With parameters developed from the data of the U.S. railroad cohort and using the risk factors cigarette smoking, systolic blood pressure, serum cholesterol, body mass index, pulse rate, and age, 226 CHD deaths were predicted for the northern European cohorts, whereas 272 CHD deaths were actually observed. Although the predicted number of cases based on the experience of U.S. railroad men underestimated the number observed in the northern European cohorts by 20 percent, there was excellent correlation between predicted and observed cases by decile of risk. Furthermore, the absolute rate in the northern European cohorts was close to that predicted by average U.S. experience as observed in the Pooling Project. In contrast to the northern European cohorts, the southern European cohorts had substantially fewer CHD deaths than were predicted by the multiple logistic equation based on the experience of the U.S. railroad cohort. As shown in Figure 14, 66 percent more cases were predicted than observed; however, rank order by decile of risk correlated closely (r = 0.92). Consistent with these differences, 134 E z 25 2 20 8 g 15, Total number of cases of myocardlal ~niarct~on or coronary death Predlcled = 69 2 Observed = 151 0 5 10 15 20 25 30 35 X= "HARD" CASES PREDICTED IN DECILE FIGURE 14.-Ten-year incidence of coronary death or myocardial infarction (hard CHD) in northern Europe, in the deciles of probability estimated from the logistic coefficients from the data on the men in southern Europe and the number of such incidence cases actually observed in those deciles SOURCE: Keys (14.3. Predicted = 35.9 Observed = 91 0 2 4 6 8 10 12 14 16 16 20 x=CHD DEATHS PREDICTED IN DECILE FIGURE 15.-Ten-year deaths from coronary heart disease in northern Europe, predicted in the deciles of probability estimated from the logistic coefficients from the data on the men in southern Europe and the number of coronary deaths actually found in those deciles 8om Keya w3l. 135 multivariate equations for CHD incidence and for CHD deaths based on southern European experience underpredicted CHD incidence and death rates for the cohorts in northern Europe by a factor of 2.5 (Figures 14 and 15). Nevertheless, by rank order of risk, correlation between predicted and observed events was excellent (r = 0.98). 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Additional major reductions in disability and death from stroke can come largely from preventive measures, not from further innovations in treatment of the completed catastrophe. Formulation of a preventive program is greatly aided by an understanding of the epidemiology of cerebrovascular disease, including the chain of circumstances leading to its occurrence, the identity of vulnerable subgroups of the population, the existence of modifiable predisposing factors, and the natural history of the disease. Magnitude of the Problem Cerebrovascular diseases, both ischemic and hemorrhagic, are a public health problem of major proportions. They constitute the third leading cause of death, after coronary heart disease and cancer, and are responsible for 9 percent of all deaths in the United States (33). There are about 1.8 million stroke victims in the United States, and about a half-million new events occur each year; there are approximately 200,000 deaths annually in the United States from strokes. In the Framingham study it was estimated that the chances of suffering a stroke before age 70 are 1 in 20. The incidence was found to double in each successive decade after age 45. Although stroke incidence becomes substantial only after age 65,20 percent of strokes occur before that age. In men, the average annual incidence of atherothrombotic brain infarction is only one-third that of myocardial infarction, with stroke incidence lagging behind myocar- dial infarction by more than 10 years. In women, on the other hand, brain infarction incidence and myocardial infarction incidence are virtually identical (56). The reasons that brain infarction is manifest- ed later in life than CHD in men and exhibits little male predomi- nance are unclear. In the United States, stroke mortality is higher among blacks than among whites, and the difference decreases with age. The Stroke Entity There are three major specific forms of cerebrovascular diseases: (1) cerebral insufficiency associated with transient blood flow deficiencies; (2) cerebral infarction caused either by the blocking of a vessel by an embolism or by thrombosis; and (3) cerebral hemor- rhage, including parenchymal and subarachnoid. The terms "stroke" TABLE l.-Percentage of change in mortality rates of causes of death in persons aged 35 to 74, by sex and color, United States, 1966-1976 Percentage of change Cause of death white men white Nonwhite women men NOklWhit.+ women All Coronary heart disease -21.0 -26.5 -30.7 -39.1 -24.3 Cerebrovascular diseases -30.6 -30.4 -43.7 -47.1 -32.7 Major cardiovascular diseasea -20.9 -26.1 -33.2 -40.7 -24.6 All causes -15.3 -16.4 -24.0 -32.7 -17.3 SOURCE: Stamler Go). and "cerebral vascular accident" are nonspecific; they refer to a variety of clinical entities and are usually used in reference to syndromes accompanying ischemic or hemorrhagic lesions. The underlying process of a stroke may be an atheroma (i.e., fatty deposit in the inner lining of an artery wall), thrombosis, embolism, a bleeding disorder, a developmental anomaly, an aneurysm, inflam- mation, failure of flow, or increased blood viscosity. The chief causes of cerebral ischemia are atherothrombosis and embolism. Intracrani- al hemorrhage is generally due to hypertensive intracerebral hemorrhage, rupture of a saccular aneurysm, or bleeding from an arteriovenous malformation. A cerebral embolism usually originates in the heart, particularly when atria1 fibrillation, rheumatic valvu- lar deformity, myocardial infarction with a mural thrombus, or a valve prosthesis is present; it may also arise from ulcerated atheroma in the carotid, vertebrobasilar, or middle cerebral arteries. The main trunk of the middle cerebral artery and its branches are the most common sites for the formation of intracranial thrombosis. The reliability of stroke diagnoses and case ascertainment in diverse populations has presented problems for epidemiological and clinical research. With the fairly recent development of new technology such as computer-assisted tomography, however, the accuracy and the quality of differential diagnosis as to type of stroke are improving. It is unlikely that any single etiology or set of risk factors applies equally to all types of stroke. Atherothrombotic brain infarction is the most common variety of stroke, accounting for about 59 percent of the total number of strokes in the Framingham population (56). Cardiovascular Risk Factors Since the underlying pathologic features of atherosclerosis in the cerebral, cardiac, and peripheral circulation are virtually identical, 160 it is not unexpected to find that they share a number of precursors. Although some significant differences in their impact exist, there are a number of modifiable risk factors common to brain and myocardial infarction (22). In fact, when five major cardiovascular risk factors (systolic blood pressure, serum cholesterol, glucose intolerance, cigarette smoking, and electrocardiogram-left ventricular hypertro phy (ECG-LVH)) are considered jointly as a cardiovascular risk profile, they are actually more highly predictive of brain infarction than of coronary heart disease (24). The top decile of multivariate risk using this profde identifies half the strokes evolving in the Framingham population, compared with only 25 percent of the coronary events (22). However, for cerebrovascular @isease, systolic blood pressure and ECG-LVH were the chief determinants of this multivariate predictive capacity. In addition to these risk predictors, various cardiac impairments such as coronary heart disease, cardiac failure, and atria1 fibrillation are major predisposing factors (55). Cigarette smoking, which is a major predictor for coronary heart disease, has been less consistently predictive for cerebrovascular disease; but nevertheless appears to play a significant role among men at younger ages. Hypertension A consistent finding in epidemiologic studies is that elevated blood pressure is the most important risk factor for stroke. This seems to apply for virtually all varieties of stroke (56). It is the key risk factor for intracerebral hemorrhage, occlusive cerebral vascular disease, and perhaps subarachnoid hemorrhage (28). About 50 to 60 percent of strokes occur in the 20 percent of the population with definite hypertension. Hypertension predisposes powerfully to stroke at all ages and in both sexes, and even mild elevations in blood pressure double the risk. The stroke risk for isolated systolic hypertension is substantial, and the exclusive use of diastolic pressure to judge the risk in the elderly with systolic hypertension can be misleading. No component of blood pressure, including the pulse pressure, mean arterial pressure, or diastolic pressure, is more closely related to stroke incidence than systolic pressure (25). Also, lability of the pressure has not been shown to reduce the risk, and it is not safe to use the lowest pressure recorded to determine whether treatment is indicated. Blood Lipids Lipids and their lipoprotein vehicles, closely linked to coronary disease incidence, are of uncertain importance for stroke. Neither cholesterol nor triglyceride levels have any predictive value beyond age 55, when strokes are common, and partition of the serum total cholesterol into its atherogenic low density lipoprotein (LDL) and 161 protective high density lipoprotein (HDL) components does not clarify the role of cholesterol in stroke as it does for coronary heart disease in advanced age (II). In women there is actually a paradoxi- cal, strong negative association of brain infarction incidence with LDL cholesterol. This inverse relationship to atherogenic cholesterol has also been noted in Japanese men and for intracerebral hemor- rhage (19). Hence, further clarification is needed. Glucose Atherothrombotic brain infarction incidence is increased threefold in diabetics. In contrast to coronary heart disease, the impact of impaired glucose tolerance does not diminish with advancing age and is not greater for women than for men. The effect of diabetes mellitus is independent of other risk factors, but is greatly influ- enced by coexistent hypertension or cardiac disease (23). Cardiac Disease Even if asymptomatic, cardiac changes such as EC!G-LVH, cardiac enlargement on X-ray, atrial fibrillation, coronary disease, cardiac failure, or rheumatic heart disease powerfully predispose to the occurrence of strokes. ECG-LVH is the most powerful EZG predictor. Atrial fibrillation, chronic as well as intermittent, increases stroke risk sixfold, and when accompanied by rheumatic heart disease, seventeenfold (55). Although each contributes independently to risk, coexistent hypertension further augments the risk associated with any cardiac impairment. Environmental Factors Few modifiable environmental contributors to stroke incidence have been convincingly demonstrated. The demonstrated association of obesity with stroke incidence appears to derive mainly from the higher blood pressure and glucose intolerance that it promotes. Physical activity is weakly and inconsistently related to stroke incidence (55). The apparent influence of coffee intake disappears on adjustment for coexistent alcohol and cigarette use. Alcohol seems to be associated with an increased risk of stroke in some studies, possibly because of higher blood pressure in alcohol users. Cigarette Smoking The contribution of cigarette smoking to the incidence of stroke may vary depending on the type of stroke or clinical manifestation of cerebrovascular disease. The evidence for such a relationship suggests that smoking is more strongly associated with premature (i.e., before age 55) and nonfatal strokes than with fatal strokes (22). 162 With 16 years of followup data on 293,000 insured U.S. veterans, Rogot and Murray (43) reported that 653 excess stroke deaths were associated with cigarette smoking, producing a mortality ratio of 1.47. Earlier, with 8.5 years of followup, Kahn (21) had found stroke mortality to be 1.4 times higher in smokers and rates to increase with amount smoked. In the more recent study, a slight dose- response relationship was found for both current and ex-smokers, with mortality ratios lower among former smokers than among current smokers. Mortality ratios for stroke were near unity for smokers of only cigars or pipes-l.07 and 0.99, respectively (43). A study of 54,460 men employed in British industries revealed no relationship between the cigarette habit and stroke mortality over 3 years, but demonstrated a threefold excess coronary mortality (3). Kuller (28), in a review of the epidemiology of stroke, concluded that there was no consistent evidence of a relationship of cigarette smoking to stroke in several population and casecontrol studies. Data after 24 years of followup in the Framingham study showed no overall statistically significant relationship between the incidence of atherothrombotic brain infarction (ABI) and cigarette smoking among males. The stroke incidence was lower in nonsmoking males only between the ages of 45 and 54, and no clear dose-response was evident (56'). In a comparison of stroke prevalencenot specified as to type-among Japanese in Japan, Hawaii, and California, prelimi- nary analyses revealed positive correlations between stroke and increased blood pressure, ECG-LVH, and cigarette smoking for all ages (20). Paffenbarger et al. (37) found no relationship between cigarette smoking and stroke in a 22-year followup of 3,666 long- shoremen. In an earlier study of chronic diseases among male former students at Harvard, Paffenbarger and Wing (38) noted a slight excess of nonfatal stroke among those who had smoked during college. They also found that hypertension, overweight, and short stature were predisposing characteristics for stroke in later life. The data must be interpreted with some caution, however, because they were abstracted from existing school records and the smoking information was not collected in a standardized manner. In a Canadian retrospective study (I), a relative risk of 2.4 (p < 0.001) was found for stroke and smoking, but these results are also subject to potential bias in the recording of the smoking history. Hammond and Horn (15) studied the relationship between smok- ing and disease among 187,783 white men, 50 to 69 years old, followed from May 1952 through October 1955. Of the 11,870 deaths during this period, 1,050 were from cerebral vascular lesions. A statistically significant mortality ratio of 1.30 was found for smokers and a dose-response relationship was apparent. TABLE 2.-Mortality ratioa for cerebrovascuhr disease related to smoking, United &a* 19691 Mortality ratioa (iV=4,099), by age M/daY 40-49 50-a 60-69 70-79 Never emoked 1-9 lo-19 20-30 >a Never emoked 1.00 l-9 1.60 lo-19 2.60 m-30 2.90 >m 5.70' 1.00 2.79 1.14 2.21 1.94 Males 1.00 1.96 1.48 2.03 2.40 Femalea 1.00 1.26 2.70 2.37 3.62' 1.00 1.00 1.90 0.95 1.44' 0.92. 1.62 1.22 1.72 0.63' 1.00 126 2.16 1.83 1.00 0.83 0.67 a 1.29 - In a large-scale prospective study of male British physicians, Doll and Hill (8) found that the results differed somewhat between the 10th and 20th year of followup. A stroke mortality ratio of 1.2 was found for smokers at the lO-year followup, with no dose-response relationship evident. After 20 years of followup, a relative risk for cerebral thrombosis of 1.52 was found for heavy smokers and a strong dose-response relationship was apparent (9). In an analysis of the 1,094 deaths that occurred among female British physicians who had been followed for 22 years, Doll et al. (7) found no effect of smoking on mortality from cerebral thrombosis; however, there were only 66 such deaths. The American Cancer Society studied prospectively more than a million men and women enrolled in 1959, following them for 13 years. With 6 years of followup, mortality ratios for cerebral vascular disease were found to be increased among male and female smokers compared with nonsmokers, with the highest ratios evident among the 40- to 49-year-olds (Table 2). The excess risk was not present in either sex past age 70. There was no significant dose- response relationship (13, 14). A study of the differences in mortality ratios by the type of cigarette smoked (29) and a later analysis of data from the American Cancer Society study indicated lower mortality ratios from stroke among males who smoked low tar and nicotine or filtered cigarettes than among smokers of higher tar and nicotine cigarettes or of "plain" cigarettes (6). No such differences were found among 164 females. A study conducted by the Tobacco Research Council in England showed mortality ratios that were lower, but not signifi- cantly so, among smokers of lower tar and nicotine cigarettes (s). In 1965, Ostfeld began a prospective study among random samples of the elderly in Cook County, Illinois, to determine variables associated with stroke. They found that stroke-prone persons can be identified even among the elderly. Stroke risk was higher among the blacks and among persons with preexisting cardiovascular disease, transient ischemic attacks (TIAs), diabetes mellitus, or hypertensive cardiovascular disease. Cigarette smoking was, however, unrelated to any class of stroke in the elderly, with or without preexisting cardiovascular precursors (36). Kimura (26) reviewed the results of six prospective studies of cardiovascular disease in Japan and found a correlation of cigarette smoking with myocardial infarction when accompanied by abnor- malities in serum cholesterol and blood pressure; no relationship of cigarette smoking to stroke was noted. Okada et al. (34) studied stroke prospectively in Japanese men 40 years old or older residing in two rural communities and found relative risks of intracerebral hemorrhage and brain infarction among nonsmokers that were not statistically significantly lower than those in smokers. In an &year prospective study of a random sample of 35- to 59- year-olds in two counties in eastern Finland, age, blood pressure, diabetes mellitus, and previous stroke were found to be predictive of stroke incidence in both men and women. Cigarette smoking and serum triglyceride levels were found to be positively associated with stroke among men, but not among the women (47). In an effort to predict coronary heart disease and other mortality rates, Menotti et al. (32) analyzed 14 CHD risk factors using a multiple logistic function model. The study included 1,524 men between 40 and 59 from two rural areas in Italy who were measured for all 14 risk factors upon entry. After 15 years, 37 men had had a stroke. Of the 14 risk factors considered, age and blood pressure were the only factors found to be significantly associated with stroke risk, ranking 1 and 2, respectively. Smoking ranked third for predicting stroke, but was not statistically significant. In a retrospective study (16') of 126 stroke patients and 212 matched controls in Tilburg, Holland, a significantly increased risk of stroke associated with cigarette smoking was not found. Hyperten- sion was found to be related to stroke, and the risk was age dependent, being strongest among the younger patients. An investigation in Finland (10) of 128 men and 85 women under 50 years of age with ischemic stroke revealed 1.5 times as many cigarette-smoking men and three times as many cigarette-smoking women in the stroke group as in the Finnish population of the same age. Hypertension, abnormal electrocardiographic findings, and oral 165 contraceptive use in women were also shown to increase risk. In a large prospective study (40) of women under 55 years of age in California who were followed for 6.5 years, cigarette smoking increased the risk of subarachnoid hemorrhage 5.7 times and use of oral contraceptives increased it 6.5 times. The relative risk was 21.9 among women who both smoked and used the pill compared with nonsmoking nonusers. In a case-control study (4) involving 12 university hospitals, 598 nonpregnant women with strokes between age 15 and 44 were identified. Compared with controls, current use of oral contraceptives was considerably higher in women with thrombotic strokes (ninefold) and somewhat higher in women with hemorrhagic strokes. It was also found that 74 percent were current or past smokers. In an investigation of 75 hemiplegics aged 18 to 50 years, Steinmann (51) found that cardiac disease and hypertension were the predominant risk factors. In men, but not in women, heavy smoking was a risk factor. Further confirming the general impression that cigarette smoking is a stroke risk factor in young men are the results of three cas+ control studies. Among 100 male stroke patients, aged 40 to 69, Koch et al. (27) found a relative risk of 11.2 for smokers of more than 20 cigarettes a day. In a study (30) of 56 male and 34 female patients under 66 years of age with cerebral hemorrhage or infarction, significantly more stroke patients than their matched controls were found to be smokers, and more smoked at least a pack of cigarettes a day. Other factors predisposing to stroke in this study population were high blood pressure, oral contraceptive use, and a family history of stroke, plus cerebral neoplasm and thrombocytopenia. In another study (521, among 39 male and 28 female ischemic stroke patients, cigarette smoking was found significantly more frequently among male cases than among matched controls. In the young females, use of oral contraceptives was the predominant risk factor. Haberman et al. (12) summarized mortality and incidence studies dealing with smoking and stroke (Tables 3 and 4). They pointed out that the relationship between smoking and cerebrovascular disease is not a uniform finding of the epidemiologic studies of this disease process. The authors cautioned that the studies are not strictly comparable because of variations in methodologies, but they suggest- ed that an association between smoking and stroke may exist but be age dependent. An age dependency is suggested by the Framingham and Paffenbarger studies. Transient Ischemic Attacks Some evidence connects cigarette smoking with transient ischemic attacks (TIA). In a 6year followup for TIA of 7,895 men aged 45 to 68 years in the Honolulu heart study (411, prior cigarette smoking was 166 TABLE 3.-Results of stroke incidence studies Study Type' Date Relationship between stroke and smoking' Approximate relative risk HiX&ii WaShiIlgtOll Framingham Manitoba Rural Japan Harvard Walnut Creek Bu- sg- P P 195a64 1961-71 194%73 197c-71 1964-70 1916-66 196%76 1965-78 CI Stroke CI ABI CI Stmke Nonfatal CI SAH None None None Yes. Not Sip Yea. Sig? Yea. Not sig Yes. SLg Yes. sii Yes. Sig? 0.9 0.8-1.1 1.1-2.7 (males) 2.4 1.9-2.7 1.6 5.7 3.8 ' P denoted prospective; R denotes retmspxtive. `CL oerebml infarction; AEU: atbemthrombotic brain infarction; SAH: subarachnoid hemorrhage `? denotes doubt about the 8tudy de&x SOURCE: Haberman et al. uzl. TABLE 4.-Results of stroke mortality studies NaUh? Type' Date Relationship between stroke and smoking Approximate mortality ratio LQ*0Mll&?Il WaShillgtOll Harvard rkml British doctora (10 year) British docton, (20 year) American Cancer Swiety P 196149 None 1.1 P, R 1962-71 None 0.9 P 1916-66 YeS 2.1 P 1964-62 Yea 1.3-1.9 P 1961-61 None 1.2 P' 1961-71 Yes 1.1-1.5 P 1959-65 Yes 1.3-2.8 ' P denota pmnpective; R denotea retrcapective `Baaed on cerebral thmmlmia ody. SOURCEz Ii&m- et d. (Ia). associated with TIA, even in multivariate analysis taking other risks into account. However, Ostfeld et al. (3s) found conflicting results. Subarachnoid Hemorrhage A retrospective study (2) of patients with subarachnoid hemor- rhage demonstrated an association with cigarette smoking. In this study, smoking was estimated to increase the risk of a subarachnoid hemorrhage almost fourfold in both sexes. In the Walnut Creek contraceptive study this was confirmed, with a 5.7-fold increased risk compared with nonsmokers (39). Also, in a 6.5year followup of this cohort of 16,759 white middle-class women aged 18 to 54, cigarette smoking was associated with a fivefold to sevenfold relative risk of subarachnoid hemorrhage and also with a 4.8fold risk for other strokes (40). 167 Smoking Cessation Controlled clinical trial data measuring the effect of smoking cessation on cerebrovascular disease are not available; observational studies have been published. In the 16year followup of 293,000 insured veterans (43), specific causes of death were studied in relation to smoking status. Mortality ratios for ex-smokers were found to be much lower than for current smokers. For stroke, the mortality risk for the ex-smoker rapidly returned to the nonsmoker rate after the cessation of smoking. Koch et al. (27) found an increased risk of stroke in young patients that was not detectable in ex-smokers after 1 year. Oral Contraceptives Oral contraceptives (OCs) have been widely used for more than 20 years, and many reports suggest that women who use them are at increased risk of stroke (4, 5, 18, 44, 53, 54). Firm, undistorted prospective data on the risk of cigarette smoking in women taking OC!s are sparse, owing to the generally low incidence of stroke in women of childbearing age. Reliance is placed chiefly on retrospec- tive data subject to unavoidable selective bias or on multicenter prospective data based on small numbers of events. Such data as exist strongly suggest a synergistic effect of smoking and oral contraceptives that may be related to "hemorrhagic stroke" (42, 46). In 1969, the Walnut Creek Contraceptive Drug Study began a long- term study of the effects of OC use on the health of women aged 18 to 54 at study initiation. After 6.5 years of followup, Petitti and Wingerd (39) analyzed the data from 15,260 women. The authors found relative risks associated with OC use of 6.5 and 7.6 for subarachnoid hemorrhage and thromboembolism, respectively. The risk of subarachnoid hemorrhage for smokers was 5.7 times that for nonsmokers; the relative risk of subarachnoid hemorrhage for women who smoked and used oral contraceptives was 21.9. Among the small number of ex-users, past use significantly increased the risk of subarachnoid hemorrhage, but not of other vascular diseases (39). In another study, cigarette smoking in itself was evidently not a demonstrable risk factor for stroke among women, even at an early age (42). In a two-part review article, Stadel(48, 49) indicates that CC use multiplies, rather than adds to, the risk of age and other factors in the development of myocardial infarction (MI) and stroke. On the basis of a total of only 31 cases reported in two studies and 134 reported in a third, Stadel (49) further indicates that current and past use of OCs appears to increase the risk of subarachnoid hemorrhage in women near age 35 or older (17). Stadel suggests that the risk of cardiovascular disease among current users of oral 168 TABLE B.-Annual death rate for oral contraceptive users related to age, duration of use, and smoking habits User characteristic Annual death rate AgegrouP 1634 years MY- 4549 year8 Duration of use 5years Smoking habit Nonsmoker Smoker SOURCE: McQusen (31); Royal college ofoemml Ractitionen (II). 1 per 20,GOo 1 per 3,ooo 1 per 700 1 per S,ooo 1 per 2,ooo 1 per 10,ooo 1 per 3,ooo contraceptives is related to the estrogen and progestogen content of the pill. A large prospective study in England (46,000 British women) found that both the incidence and the mortality rates of a variety of diseases, including cerebrovascular disease, were increased among users of oral contraceptives versus nonusers (4s). The number of stroke deaths in the Royal College of General Practitioners (RCGP) study was small; thus, risk estimates were subject to error. Women over 35 and women who smoked and took oral contraceptives were found to be at substantially higher risk than were nonsmokers and nonusers of GCs. Additional analysis of the RCGP study including followup through 1976 showed that current or previous users of oral contraceptives had a standardized mortality rate for cerebrovascular disease 4.7 times that of controls. Increases in total death rates were found among older women, women who had used the pill for 5 or more years, and women who smoked cigarettes (44) (Table 5). Results from a c ase-control study conducted by the Collaborative Group for the Study of Stroke in Young Women (5) showed that cigarette smoking and the use of oral contraceptives were indepen- dent risk factors for subarachnoid hemorrhage; the relative risk was 2.6 for smokers and 4.1 for users of GCs. When a heavy smoker also took oral contraceptives, the risk increased to 6.1 or 7.6, depending upon the control group used for comparison. In an earlier report, the same group (4 reported that risk of cerebral ischemia or thrombosis was approximately nine times greater among women using oral contraceptives than among nonusing controls. They also reported 169 lower incidence rates among black women than among white women and that more of the cases than of the controls were or had been regular smokers. The data suggest that cigarette smokers who use oral contracep tion are at significantly increased risk of stroke and that this risk may result from a synergistic interaction between cigarette smoking and the use of oral contraceptives. Preventive Implications Declining trends in stroke mortality and the marked geographic variation suggest that cerebrovascular disease may not be an inevitable consequence of aging or of genetic makeup. High risk candidates can be identified using a general cardiovascular risk profile. There is as yet no conclusive evidence that intervening to lower lipids, reduce overweight, provide exercise, treat diabetes mellitus, or stop cigarette smoking will in fact reduce stroke risk. However, former cigarette smokers appear to have a lower risk of stroke than do continuing smokers. The key to stroke prevention is early, vigorous, sustained control of hypertension and the cardiac impairments that escalate the risk. Cigarette smoking cessation may also play a role, particularly in young male stroke candidates or in women using oral contraceptives. Summary A preventive approach to stroke is imperative because central nervous system damage often leads to an irreversible functional deficit. Less than a third of stroke victims have symptoms warning of the impending stroke. The similarity of factors predisposing to stroke and those increasing susceptibility to coronary heart disease and congestive heart failure indicates that vascular disease of the brain is part of a larger problem of cardiovascular disease. The measures indicated for prevention of stroke include those recom- mended for prevention of coronary heart disease, occlusive peripher- al arterial disease, and congestive heart failure. Hypertension is clearly the major contributor to stroke incidence. Cigarette smoking also contributes, especially in younger populations, and may be important because of its demonstrated relationship to coronary heart disease and congestive heart failure, which powerfully contrib- ute to stroke risk. Cigarette smoking cessation is indicated as part of a comprehensive program of risk factor modification to avoid atherosclerotic cardiovascular disease, including stroke. Women cigarette smokers experience an increased risk for sub- arachnoid hemorrhage; the use of both cigarettes and oral contracep- tives appears to synergistically increase this risk. 170 Conclusions 1. Data from numerous prospective mortality studies have shown an association between cigarette smoking and cerebrovascular disease. This risk is most evident in the younger age groups, and the effect diminishes with increasing age, with little or no effect noted after age 65. No consistent dose-response effect has been demonstrated. 2. Women cigarette smokers experience an increased risk for subarachnoid hemorrhage. However, the use of both cigarettes and oral contraceptives greatly increases the risk for subarach- noid hemorrhage among women. 171 References (1) ABU-ZEID, H.A.H., CHOI, N.W., MAINI, K.K., HSU, P.-H., NELSON, N.A. Relative role of factors associated with cerebral infarction and cerebral hemorrhage. Stroke 8(l): 166-112, January-February 1977. (2) BELL, B.A., SYMON, L. 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Proceedings of the VIII World Congress of Cardiology, Tokyo, September 17- 23,1978. (51) STEINMANN, B. Zur Pathogenese der Apoplexie im Alter unter 50 Jahren. [On the pathogeneeis of apoplexy in pereons below 50 years of age.] Schweiterische Medizinieche Wochemchrift 99(31): 109%1196,1969. (52) TURNHEIM, M., HAVELEC, L., HEISS, W.-D., SUMMER, K. Eigenarten iachaemischer insulte bei jungen Emachsensen. [Characteristic features of ischemic strokes in young adults]. Weiner Klinische Wochenechrifl 89(4): 106110,1977. (53) VESSEY, M.P., DOLL, R. Investigation of relation between use of oral contraceptives and thromboembolic disease. British Medico1 Journal 2(6599): 199-295, April 27,1966. (54) VESSEY, M.P., DOLL, R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. British Medico1 Joumol2@658): 651657, June 14,1969. (55) WOLF, P.A., DAWBER, T.R.. KANNEL, W.B. Heart disease as a precursor of stroke. In: Schoenberg, D.S. (Editor). Neurological Epidemiologv Principles and Clinical Applications. Advances in Neumloe. Volume 19, New York, Raven Press, 1978, pp. 667677. (56) WOLF, P.A., DAWBER, T.R., THOMAS, H.E., Jr., KANNEL, W.B. Epidemic logic assessment of chronic atrial fibrillation and risk of stroke: The Framingham study. NeuruZogy 28(10): 973-977. October 1978. 175 SECTION 5. ATHEROSCLEROTIC PERIPHERAL VASCULAR DISEASE AND AORTIC ANEURYSM 177 Atherosclerotic Peripheral Vascular Disease Introduction The peripheral arteries include those branches of the aorta supplying the upper and lower extremities and the abdominal viscera. Most peripheral arterial occlusive disease is due to athero- sclerosis, although other conditions such as fibromuscular dysplasia, muscular entrapment, cystic adventitial degeneration, and arteritis may cause obstruction of the peripheral arteries. Symptomatic atherosclerotic peripheral vascular disease (ASPVD) occurs most often in the vessels of the lower extremities. The anatomic location of such disease is usually classified according to the major arterial segments involved, including aortoiliac, femoro-popliteal, and tibio- peroneal artery occlusive disease. Occlusive lesions of the origins of visceral arteries commonly involve the renal arteries and the mesenteric arteries, including the celiac and superior and inferior mesenteric arteries. With many asymptomatic patients, peripheral arterial occlusive disease can be detected on physical examination. Symptomatic patients are usually classified according to the severity of presenting complaints; for example, patients may be classified as suffering intermittent claudication (leg pain brought on by exercise and relieved by rest), ischemic rest pain, or, the most severe complaint, tissue necrosis, including gangrene or ischemic ulceration. Patients with renal artery occlusive disease may present with severe and uncontrollable hypertension, although such patients may respond to medical treatment for hypertension. Patients with arterial occlusive disease of the mesenteric arteries may present with acute ischemia of the intestine, due to thrombosis or embolization, or with more chronic symptoms of pain aggravated by eating and weight loss. The diagnosis of peripheral arterial occlusive disease can usually be made from the history and physical examination, including the evaluation of peripheral arterial pulsations and detection of arterial bruits. However, more accurate and objective diagnosis of peripheral arterial occlusive disease is possible with noninvasive diagnostic techniques, particularly Doppler ultrasound or plethysmography. Arteriography is reserved for patients with symptoms sufficient to make them candidates for surgery, and is not usually required for the diagnosis of peripheral arterial occlusive disease. The majority of patients with peripheral arterial disease may be candidates for medical therapy such as exercise regimens and reduction of known risk factors through cessation of smoking, control of diabetes mellitus, dietary measures to control hyperlipide mia and obesity, and medical management of hypertension. Inten- sive foot hygiene and avoidance of trauma are additional important medical measures for patients with lower extremity ASPVD. The 179 newly developed treatment of balloon dilatation (percutaneous transluminal angioplasty) may be used to restore pulsatile flow for severely symptomatic patients. Surgical therapy is required in only about 10 percent of the patients with advanced arterial occlusive disease. One surgical approach is arterial reconstruction, usually involving endarterectomy or bypass with vein or prosthetic grafts of diseased segments. Sympathectomy is infrequently used, but it may be helpful in patients with cutaneous ischemia, for whom restoration of pulsatile flow is not possible. Amputation of limbs with advanced arterial occlusive disease that cannot be remedied by surgical reconstruction remains in use, but it is required by only about 5 percent of all patients presenting with peripheral arterial occlusive disease. Risk Factors for Peripheral Arterial Occlusive Disease The most powerful risk factor predisposing to atherosclerotic peripheral arterial occlusive disease is cigarette smoking (47); in fact, the rarity of peripheral arterial occlusive disease in patients who have never smoked was noted by Eastcott as early as 1962 (23). The epidemiologic evidence linking cigarette smoking to atherosclerotic peripheral arterial occlusive disease is discussed in detail below. Several studies have suggested hyperlipoproteinemia as a risk factor contributing to atherosclerotic peripheral arterial occlusive disease. The type of hyperlipoproteinemia and the degree of associa- tion with peripheral vascular disease appear to be different, how- ever, from the hyperlipoproteinemia associated with coronary artery disease. Zelis et al. (92) reported that patients with Type III hyperlipoproteinemia are particularly susceptible to the develop ment of peripheral vascular disease, and they noted objective improvement in the peripheral circulation with medical treatment of this disorder. Greenhalgh et al. (30) reported that fasting serum lipid concentrations were abnormally high in 44 percent of a consecutive series of 116 patients with proven peripheral vascular disease. In 39 percent of the patients the serum triglyceride level was raised, and in 15 percent the serum cholesterol level was increased. Ballantyne and Laurie (5) evaluated 353 consecutive patients with peripheral vascular disease and showed a predominance of Type IV hyperlipoproteinemia in males, but a predominance of Type IIa hyperlipoproteinemia in females. Patients with peripheral vascular disease and Type IIa or Type Ilb hyperlipoproteinemia were more likely to have associated coronary artery disease. Eighty-four percent of the patients were cigarette smokers, with the majority smoking more than 10 cigarettes daily. There was no relationship between cigarette consumption and the occurrence of hyperlipopro teinemia. However, Farid et al. (25) found that in 122 patients with angiographically proved peripheral arterial occlusive disease, heavy smoking seemed to be associated with an unexpectedly high propor- tion of an abnormal lipid pattern: 43 percent of the males exhibited Type IV hyperlipoproteinemia. Lawrie et al. (51) surveyed 4,477 healthy males and females in the west of Scotland and found a high prevalence of hyperlipoproteinemia of Type II and Type IV. Hyperli- poproteinemia occurred more frequently in survivors of myocardial infarction, but also occurred, though to a lesser extent, in patients with peripheral vascular disease. Olsson and Eklund (57) evaluated 160 men and 123 women with digit plethysmoraphy and found that most atherogenic lipoprotein abnormalities associated with disease of the lower extremities involved the relatively triglyceride-rich part of the low density lipoprotein (LDL) fraction and the relatively cholesterol-rich part of the very low density lipoprotein (VLDL) fraction. These authors found a deleterious influence of smoking even in the preclinical stage of peripheral vascular disease. Davignon et al. (18) evaluated 114 French Canadian patients with angiographically proved periph- eral vascular disease. The severity of atherosclerosis correlated positively with plasma triglyceride concentration, but cigarette smoking was the risk factor most frequently found in patients with peripheral vascular disease. In contrast, Erikson et al. (24) did not find a positive correlation between arteriographic changes in 30 patients with intermittent claudication and serum concentrations of lipids and lipoproteins. Trayner et al. (80) compared 32 patients with peripheral vascular disease to control subjects. The vascular disease study group had a significantly higher incidence of hypertriglycerid- emia, more marked for the males, and had lower levels of high density lipoproteins (HDL) than did the control subjects. The study group also had a twofold higher prevalence of cigarette smoking than control subjects. Control patients who smoked also had lower levels of HDL than those who did not smoke. Phillips et al. (61) also established a relationship between an increase of VLDL triglyceride and cigarette smoking, while HDL cholesterol decreased with cigarette smoking. Hypertension is associated not only with coronary and cerebrovas- cular disease, but also with peripheral arterial occlusive disease (46). Larson et al. (50) established an interaction of hypertension and hypercholesterolemia in an experimental study of mongrel dogs, suggesting that the combination of these two risk factors produces alterations in lipid composition in the canine aorta that appears to be geometric rather than arithmetic in nature. However, Stehbens (74) claimed that epidemiologic studies are less conclusive than experimental studies in establishing the relationship of risk factors in atherosclerosis. He postulated that local hemodynamics associated with hemodynamic stress, rather than the level cf lipid intake, is the principal factor governing the accumulation of lipid in the vessel wall. It is clear that multiple risk factors have been associated with atherosclerosis not only in the coronary and cerebrovascular arterial beds but also in the peripheral circulation. Ftosen et al. (6.5) evaluated the association of risk factors in 109 patients with peripheral arterial occlusive disease. The arterial disease was established by clinical and arteriographic examination and classified into three anatomic groups-aortoiliac, combined aortoiliac and femoropopliteal, and femoropopliteal disease. Type IV hyperlipoproteinemia and glucose intolerance were significantly more common in patients with isolated femoropopliteal disease. Cigarette smoking was the most prominent risk factor in all groups, occurring in 90 percent of patients with aortoiliac or combined disease and in 75 percent of patients with femoropopliteal artery disease. The onset of clinical symptoms occurred at an average of 8 to 10 years earlier in smokers than in nonsmokers. Heyden et al. (35) established that smoking and coffee drinking interact in affecting LDL and total cholesterol, but coffee drinking alone did not appear to affect blood lipids. Criqui et al. (16') reviewed the relationship between cigarette smoking and HDL cholesterol in 2,663 men and 2,553 women aged 20 to 69 years in 10 North American populations of the Lipid Research Clinics Program Prevalence Study. Cigarette smoking was associated with substantially lower levels of HDL cholesterol; this association was dose related. Hulley et al. (37) found the same association in a longitudinal study of 301 high-risk males 35 to 57 years of age. After 1 year's intervention on diet, hypertension treatment, and smoking counseling, both smoking frequency and serum thiocyanate were significantly and independently associated with the changing plasma HDL-cholesterol concentration. A relationship linking cigarette smoking and abnormal lipoprotein metabolism comes from the report of Topping et al. (78), which found that patients with both Type III hyperlipoproteinemia and cigarette smoking suffer abnor- malities of liver metabolism of cholesterol-rich "remnants." Such impaired hepatic metabolism may result in hyperlipoproteinemia and subsequent peripheral vascular disease. Sllmmary of Epidemiologic Studies Because peripheral arterial occlusive disease does not pose as severe a mortality threat as coronary artery disease does, there have been fewer major epidemiologic studies of peripheral vascular disease. However, the underlying pathologic lesion, atherosclerosis, remains the same in the two conditions, and there is increasing evidence of an association between peripheral vascular disease and similar lesions in the coronary or cerebrovascular beds. Both clinical and angiographic correlates of peripheral arterial disease with concomitant coronary artery disease were suggested by the reports of Friedman et al. (281, Kuebler et al. (49), Silvestre et al. (72), and Hertzer et al. (34). These reports not only suggest a clinical relationship between peripheral and coronary artery occlusive disease, but also indicate that the perioperative and long-term risks of treatment for peripheral vascular disease are strongly influenced by the presence of concomitant coronary artery disease. Several publications have extensively reviewed the evidence associating cigarette smoking with peripheral arterial occlusive disease (81, 82, 83). Early studies by Juergens et al. (44), Begg (7), Schwartz et al. (71), and Widmer et al. (87) documented a much higher prevalence of cigarette smoking (usually exceeding 90 per- cent) in patients with peripheral arterial occlusive disease, when compared with control patients without vascular disease. Data from the Framingham study (4s) suggest that cigarette smoking is one of the major risk factors in the development of intermittent claudica- tion (Table 1). Over a X-year period of followup, a higher total incidence and a higher annual incidence of intermittent claudication were noted in smokers as compared with nonsmokers. This differ- ence was statistically significant for all age groups of both sexes. Using multivariate analysis to control for other risk factors, this relationship of smoking to intermittent claudication became stron- ger. Many other investigators have noted a high prevalence of ciga- rette smoking in patients with peripheral arterial occlusive disease. Tomatis et al. (77) found that 98 percent of patients with aortoiliac disease and 91 percent of patients with femoropopliteal disease were cigarette smokers. Astrup et al. (3) found a significant correlation between the frequency of severe intermittent claudication and the consumption of more than 15 cigarettes a day in nondiabetic patients with peripheral vascular disease. A significant difference between heavy smokers and other smokers was not found, however, for the development of gangrene. Further, the development of claudication did not vary with the number of years of smoking or the total number of cigarettes consumed in a lifetime. Weinroth and Herz- stein (84) noted a 50 percent greater incidence of peripheral arterial occlusive disease in diabetics who smoked than in those who did not, Juergens et al. (44) followed 520 patients with nondiabetic peripheral arterial occlusive disease, approximately 50 percent of whom contin- ued to smoke despite medical advice to quit. Of those who continued to smoke, approximately 10 percent eventually required amputation, but no amputations were necessary in patients who successfully stopped smoking. Horowitz et al. (36) reported that age was a significant factor in the prevalence of arterial disease, with nearly half of the cases occurring in patients over the age of 70. A higher percentage of patients with lQ!! TABLE L-Average annual incidence (over 16 years) of intermittent claudication according to cigarette habit at examination Age at examination and cigarettes smoked per day Subjects at risk' Men Rate per 10,coO Actual Smoothed Subjects at risk' Women Rate per 10,OQO Actual Smoothed * MY- 6290 16 15.9 7933 4 3.8 None 2342 6 9.8 4514 3 2.4 Under 20 903 17 13.4 1876 0 4.0 20 1466 30 16.3 1090 9 6.5 over 20 1523 16 24.9 422 12 10.6 55-64 years 4484 51 51.3 5959 19 19.3 None 2170 28 27.6 4276 19 17.5 Under 20 743 61 43.6 1030 19 21.6 20 a79 40 66.7 434 0 26.7 Over 20 670 in 107.9 197 76 33.1 65-74 years 1326 57 56.6 1924 31 31.2 None 190 44 55.2 1541 19 23.6 Under 20 254 98 51.3 266 94 45.3 20 167 90 59.5 I9 0 66.5 over20 111 0 61.7 29 172 164.2 ' Numhen of subjecta at rislr according to cigar&em smoked do not add to tot& shown because same subjecta a?eintheunkn~category. `The "amwthed" rates an based on the mean of the individual probabilities of development of intermittent ckudication in ti 2 yeam following examioa tion. where individual probability h calculated awarding to cigar&e we at examination using the values of the parameten atiited in Wing the logistic function to the oavmnee of intermittent claudication in the sex-age group. NOTE: The trend is aigniticantly Merent from zao at the 0.05 level for women 65 to 74 yearn of age and at the 0.01 level for men 65 to 64. SOURCE lbumel and Shurtleff (481. arterial disease smoked than did patients without arterial disease. A higher percentage of males than of females had peripheral arterial occlusive disease. De Backer et al. (21) likewise noted an increase in intermittent claudication with increasing age, but also found a significant correlation of serum cholesterol, systolic blood pressure, blood glucose, and cigarette smoking in patients with intermittent claudication. Future epidemiologic studies of peripheral vascular disease must take into account the merits and limitations of the clinical diagnosis of peripheral arterial occlusive disease. Horowitz et al. (36) suggest that the judgment of trained paramedical personnel compares favorably with that of physicians in screening large numbers of patients for peripheral vascular disease. De Backer et al. (21) emphasized the importance of using ankle systolic blood pressure measurement with Doppler ultrasound to 184 objectively screen patients for peripheral arterial occlusive disease. Such useful techniques have been emphasized by Marinelli et al. (54) in a large epidemiologic study of vascular disease in patients with diabetes mellitus. In addition to clinical studies, several autopsy surveys have reported an association between smoking and peripheral atheroscle- rosis (59, 60, 66, 67, 75, 89). Such studies have supported a direct association between smoking and the formation of abdominal aortic fatty streaks, as well as their subsequent conversion to raised lesions. Most reports of peripheral vascular disease emphasize the predom- inant occurrence of this disorder in males (88). However, diabetes mellitus may predispose females to peripheral arterial occlusive disease in a frequency similar to that of males. Broome et al. (12) reported on 15 women with aortoiliac occlusive disease, all of whom were cigarette smokers (mean, 20 cigarettes a day), and none of whom had diabetes mellitus. The temporal trend toward increased smoking by women may significantly increase their risk of peripher- al arterial occlusive disease. The Framingham heart study (47) found that the incidence of peripheral vascular disease was increased among smokers and that cigarette smoking was as strong an independent risk factor in women as in men. Heavy smokers had a threefold increase in the incidence of peripheral arterial occlusive disease. Weiss (86) evaluated 245 women with peripheral arterial occlusive disease. The risk in ex-smokers who had not smoked for 5 years or more was nearly normal, with a risk ratio of 1.06. Patients who had not smoked for 1 to 5 years had a risk ratio of 1.70. Patients who continued to smoke, but smoked less than one pack a day, had a risk ratio of 11.53, and those who smoked more than a pack a day had a risk ratio of 15.56. The risk for arterial occlusive disease was particularly associated with the proximal aortoiliac segment and was less associated with distal or femoral-popliteal artery disease. This study described both a dose-response effect and a benefit following cessation of smoking. There have been few studies of the association of visceral arterial occlusive disease and cigarette smoking. Mackay et al. (53) reported on the correlation of smoking and renal artery stenosis. They found that smoking was nearly twice as common in patients with nonma- lignant hypertension associated with renal artery stenosis as in those patients with hypertension of comparable severity without renal artery disease. Previous studies documented that a higher proportion of smokers was noted in patients with malignant hypertension (IO, 39). Cigarette smoking was present in 20 of 22 patients with malignant hypertension and associated renal artery stenosis (53). Cigarette smoking appears to be the only form of tobacco consumption associated with an increased risk of developing periph- era1 arterial occlusive disease. Smith (73) reported that no cases of intermittent claudication were found in patients who used only smokeless tobacco (snuff, chewing tobacco), provided that patients with a history of diabetes mellitus, heavy ethanol intake, or dietary problems were excluded. Frishman (29) reviewed the effects of involuntary smoking on the cardiovascular system. Although levels of carbon monoxide common- ly found in cigarette-smoke-filled environments have been demon- strated to decrease exercise tolerance in patients with existing angina pectoris and intermittent claudication, studies are not available to document the role that passive smoking might play in the etiology of atherosclerotic cardiovascular disease (69). Clinical Investigations in Humans In several studies, the effect of cigarette smoking or the constitu- ents of cigarette smoke on the human peripheral vascular system has been investigated. Cryer et al. (17) studied the effects of cigarette smoking, sham smoking, and smoking with adrenergic blockade in 10 subjects. There was a significant increase in the mean plasma norepinephrine and epinephrine levels associated with smoking. The smoking-related increase in pulse rate, blood pressure, blood glycer- ol, and blood lactate-pyruvate ratio was prevented by adrenergic blockade. These findings were attributed to local norepinephrine release from adrenergic axon terminals within tissues rather than to increments in circulating catecholamines. In experiments comparing cigarettes of varying nicotine content, the subjective recognition of different cigarette brands may influence the results of clinical experiments. Ossip et al. (58) have suggested that nicotine extraction filters be used to minimize the within-subject differences due to the recognition of cigarette brand. The influence of the type of beta blocker used in therapy of patients who are cigarette smokers was investigated by Trap-Jensen et al. (79). These authors found that the use of a nonselective beta blocker, propranolol, during smoking caused a marked rise in diastolic and mean blood pressure and forearm vascular resistance, due to the blockade of adrenaline- induced vasodilatation, which is mediated by beta-2 receptors in the resistance vessels. Selective beta-l blockade with atenolol attenuated the systolic blood pressure and the tachycardiac responses induced by cigarette smoking. Several studies have suggested an association between cigarette smoking and the level of circulating hemoglobin. Castleden et al. (14) evaluated 61 male nondiabetic smokers with peripheral artery disease and compared them with age-matched nondiabetic male smokers and nonsmokers admitted for routine inquinal herniorrha- phy. They found a significant association between smoking and hemoglobin levels and a highly significant correlation between smoking and peripheral vascular disease. In addition, the carboxy- hemoglobin generated by smoking was associated with increased platelet adhesiveness, decreased fibrinolytic activity, and increased plasma fibrinogen. Yamori et al. (91) suggested that the hematocrit was increased in proportion to the number of cigarettes smoked and that this may be a mechanism for increased mortality rate from cardiovascular diseases in smokers. Other hematologic effects of cigarette smoke have been observed in blood platelets and with fibrinolysis. Davis and Davis (19) studied 18 volunteers to assess the effect of cigarette smoking on platelet aggregation. The smoking of two unfiltered tobacco cigarettes during a 2Cminut.e period resulted in a significant increase in the platelet aggregate ratio. During this time, the mean plasma nonesterified fatty acid concentration remained unchanged. These same authors (20) subsequently reported that the increase in the platelet aggregate ratio resulting from smoking two unfiltered cigarettes could be prevented with pretreatment with one aspirin tablet. Janxon and Nilsson (43) evaluated the fibrinolytic activity in vein walls among 71 randomly selected heavy smokers and 41 nonsmokers from a population of men born in 1914 residing in Malmo, Sweden. After 12 hours' abstention from tobacco, the smokers were found to have the same fibrinolytic activity as nonsmokers. Smoking six cigarettes during 3 hours increased the fibrinolytic activity in the blood, presumably hecause of the combined effects of nicotine and carbon monoxide. Several studies of the effects of smoking on the peripheral circulation have involved noninvasive measurement of limb blood flow using plethysmographic techniques. Janzon (40) used a water- filled plethysmograph to study 71 randomly selected heavy smokers and 41 nonsmokers from the study group of men born in 1914 and residing in MalmS, Sweden. The smokers were found to have lower systolic and diastolic arm blood pressure and lower systolic blood pressure in the big toe with greater pressure gradients from the arm to the big toe compared with nonsmokers. During reactive hyper- emia, smokers had decreased blood flow and increased peripheral vascular resistance. This same author (42) studied the acute effect of smoking on heart rate, blood pressure, and calf blood flow in 20 randomly selected 59-year-old male heavy smokers (more than 15 g of tobacco per day). After smoking two cigarettes, there was a significant increase in blood pressure and heart rate. Blood flow and resistance to blood flow in the calf did not change at rest, but during reactive hyperemia, the resistance to blood flow decreased and calf blood flow increased, an effect attributable to the peripheral vascular effects of nicotine. Janzon (41) evaluated 51 randomly selected 59-year-old heavy smokers for changes in peripheral vascu- lar function after smoking cessation of 8 to 9 weeks. He noted an 187 increase in blood flow during reactive hyperemia in patients who stopped smoking and a decrease in blood flow in patients who continued to smoke. Isacsson (38) performed venous occlusion plethysmography on the calf of 809 randomly selected 55-year-old men residing in Malmij, Sweden. Sixty-two percent of the total population examined were cigarette smokers. A history of intermit- tent claudication was present in 20 subjects, but arterial insufficien- cy could be clinically demonstrated in only 6 of the 20. Ilio-femoral occlusive disease was found in another eight patients. These patients had a higher prevalence of systolic hypertension, hypercholesterol- emia, hypertriglyceridemia, and lipoprotein abnormalities. The amount of smoking was inversely related to the magnitude of the arterial flow capacity in the legs and directly related to the presence of occlusive arterial disease. More ex-smokers had high blood flow capacity than had a low flow capacity. The arterial flow capacity in the legs was reduced in direct proportion to the tobacco consumption per day. Coffman (15) used plethysmographic and isotope methods to document cutaneous vasoconstriction, increased skeletal muscle blood flow, and decreased venous distensibility in human subjects after tobacco smoking or nicotine injection. Recent studies have employed Doppler ultrasound to document changes in blood velocity and transit time following cigarette smoking. Sarin et al. (68) noted a reduction in mean digital artery blood flow velocity of 42 plus or minus 6 percent following the smoking of a single cigarette in 10 male volunteers. Lusby et al. (52) evaluated the effects of cigarette smoking on hemodynamics in the large and small vessels of patients with peripheral arterial occlusive disease. Using Doppler probes, large vessel response to smoking was evaluated by measurement of pulse transit time delay. Patients with occlusive arterial disease had significant shortening in transit time delay, suggesting a stiffening in the main vessels in response to smoking. Such changes were not seen in control patients without peripheral arterial occlusive disease. A digit pulse volume recorder was used to measure the amplitude of digit pulsation, a measure of small vessel hemodynamics. The digit pulse amplitudes decreased significantly in response to both low and high nicotine cigarettes, and patients tended to self-titrate their nicotine intake. Due to this maintenance of nicotine level, the study failed to demonstrate a benefit on small vessel hemodynamics accompanying a switch from high to low nicotine cigarettes. Recent studies suggest that tobacco allergy may play a role in the development of the cardiovascular effects of cigarette smoking. Becker and Dubin (6) reported that approximately one-third of healthy smoking and nonsmoking volunteers exhibited immediate cutaneous hypersensitivity to a glycoprotein antigen purified from cured tobacco leaves and found in cigarette smoke. Denburg et al. 188 (22) skin-tested 164 peripheral vascular disease patients with puri- fied tobacco glycoprotein. The authors also performed basophil degranulation tests to assess in vitro reactivity to tobacco glycopro- tein. Immediate skin-test hypersensitivity to tobacco glycoprotein was found in 11 percent of patients with angiographically demon- strable peripheral vascular disease; a control group of normal patients was not skin tested. The basophil degranulation test was positive in 60 percent of smokers compared with 24 percent of nonsmokers (p < 0.01). Forty-three percent of skin-test-negative and 91 percent of skin-test-positive patients with peripheral vascular disease had a positive basophil degranulation test. Only 3 percent of patients with negative basophil degranulation tests had a positive skin test. The percent of patients with positive skin tests increased in proportion to the severity of angiographic peripheral vascular disease. What role tobacco hypersensitivity may play in the develop ment of peripheral atherosclerosis remains to be elucidated. A final area of clinical epidemiologic study is the relationship of maternal smoking to the fetal cardiovascular system. Asmussen (2) studied the umbilical artery, umbilical vein, and vessels of the placental villi of newborn children in relation to the maternal smoking history. His studies documented that severe damage to vessel walls is associated with maternal tobacco smoking during pregnancy. These fetal vascular changes may lead to vascular lesions later in life. Experimental Studies in Animals In several experimental animal studies, the relationship between cigarette smoking and atherosclerotic peripheral vascular disease has been investigated. Birnstingl et al. (9) evaluated the effect of short-term exposure to carbon monoxide on platelet adhesion in rabbits. In rabbits exposed on several occasions to an atmosphere containing 400 parts per million carbon monoxide for 6 to 14 hours, there was a highly significant increase in platelet stickiness immedi- ately after exposure to carbon monoxide, followed the next day by a significant fall to levels below the preexposure value. Richardson (62) evaluated the effects of nicotine and tobacco smoke on capillary blood flow in the rat. Red blood cell velocity in single capillaries within the mesenteric tissue of anesthetized rats was evaluated immediately before and after either intravenous injection of nicotine or inhalation of tobacco smoke. Blood velocity changes associated with tobacco exposure were considered to be passive consequences of changes in systemic arterial blood pressure. This study did not evaluate differential effects on various vascular beds of cigarette smoke or nicotine. Fisher et al. (27) evaluated the effect of exposure of cholesterol-fed rabbits to the smoke of one cigarette daily over an ll- to 19month 189 period. The study failed to demonstrate quantitative or qualitative differences in atherosclerosis in the aorta or coronary or visceral arteries or significant changes in serum lipids. Rooyse et al. (II) administered nicotine in the drinking water of New Zealand white rabbits during a 25-week period. Fasting serum levels of glucose, triglyceride, total cholesterol, and LDL cholesterol were elevated in the nicotine-treated rabbits compared with the controls. However, there was no significant difference between nicotine-treated and control animals in leukocyte, erythrocyte, and platelet counts or in hematocrit or hemoglobin. Endothelial cells from the aortic arch of nicotine-treated animals showed extensive changes, including in- creased cytoplasmic silver deposition, increased formation of micro- villi, and numerous focal areas of "ruffled" endothelium (projections from the cell surfaces). Marshall et al. (55) evaluated the effects in minipigs of exposure to cigarette smoke or varying concentrations of carbon monoxide for l- to X-hour periods. Cigarette smoke and short carbon monoxide exposure resulted in adherence of platelets to the endothelium. After longer exposures, microscopic thrombi were found in the vessel walls. Underlying degeneration in the endothelial cells developed upon exposure to carbon monoxide. Recent investigations have involved the training of subhuman primates to smoke cigarettes in order to assess the effect on the peripheral circulation and hematologic factors. Schwartz et al. (70) have summarized data on experiments in baboons taught to smoke cigarettes. Rogers et al. (63) reported on 36 young adult male baboons who were fed an atherogenic diet. Twenty-eight baboons were randomly assigned to smoke 43 cigarettes daily, and 18 baboons were taught to puff air under equivalent experimental conditions. The cigarette-smoking baboons demonstrated significantly higher carbon monoxide and thiocyanate concentrations in blood and cotinine concentrations in the urine than did the nonsmoking baboons. There were no significant differences found in serum total cholesterol, VLDL, and LDL cholesterol or triglyceride concentra- tions in the smokers compared with the controls. Smoking baboons had significantly higher fasting glucose concentrations and lympho- cyte counts. Platelet counts, platelet aggregation, food and water intake, and body weight were not significantly different in the two groups. Such experimental models may provide a valuable method to assess the long-term effects of smoking on the peripheral vascular system of primates. Intervention Studies There is considerable indirect evidence that cessation of smoking may significantly influence the effect of medical or surgical therapy on peripheral arterial occlusive disease. Unfortunately, the tendency 190 of some patients with peripheral arteral occlusive disease to con- tinue smoking often defeats the purpose of medical intervention. Thiruvengadam et al. (76) evaluated the effect of diseases at different organ sites upon the smoking habit of chronic smokers. A significant reduction or cessation of smoking was observed in subjects with cardiovascular, pulmonary, neoplastic, or gastointestinal disease, diabetes mellitus, or cirrhosis of the liver. Medical advice played a role in the reduction for only 19 percent of the subjects. Other reasons for reduction or cessation of smoking were socioeconomic factors, aggravation of disease, or belief in a possible relationship between smoking and the disease. Only subjects with psychiatric illnesses and peripheral vascular diseases showed no significant reduction in the smoking habit in comparison with the controls. Of 89 subjects with peripheral vascular disease, 12 increased their smoking with the advent of disease. Feinleib and Williams (26) emphasized that peripheral vascular disease risk is elevated only in cigarette smokers and not in cigar or pipe smokers. Smokers who quit gradually approach the lower risk of nonsmokers. Birkenstock et al. (8) reported on the role of cessation of smoking on the medical therapy of 390 patients with peripheral vascular disease who were either ineligible or unfit to undergo operative treatment. Conserva- tive management included foot hygiene, walking exercise, cessation of smoking, a low cholesterol diet, and vitamin E therapy. Of 277 patients who smoked, 164 were able to stop smoking. Eighty-five percent of patients who stopped smoking showed improvement in symptoms of peripheral vascular disease on the medical regimen, in comparison with only 20 percent who improved among those who continued to smoke. The degree of improvement was greater in ex- smokers than in nonsmokers. No patient with diabetes mellitus who continued to smoke improved under medical management. Cessation of smoking appears to play an important role in the long-term success of reconstructive arterial surgery. Wray et al. (901 recorded a significantly higher rate of late arterial occlusion in patients who had undergone aortofemoral bypass and who persisted in smoking when compared with patients who stopped smoking postoperatively. In 30 patients who continued to smoke, 9 late occlusions occurred, but no occlusions developed in 16 patients who ceased smoking postoperatively. Myers et al. (5s) reported a retro- spective study of 217 patients undergoing aortofemoral (135) or femoropopliteal (107) vascular reconstruction. Patients who stopped smoking or smoked no more than five cigarettes daily after their operation had late patency rates of approximately 90 percent for aortofemoral reconstruction and 80 percent for femoropopliteal vein grafts. Patients who continued to smoke more than five cigarettes daily had a late complication rate approximately three times greater after aortofemoral reconstruction and four times greater after femoropopliteal vein grafting, compared with examokers. The late patency rate was approximately inversely proportional to the number of cigarettes smoked per day after the operation. The incidence of late complications was not correlated with the number of cigarettes smoked prior to operation. Burgess et al. (13) noted that among patients whose below-knee amputation failed to heal, six of seven (85 percent) were cigarette smokers, whereas among those whose distal amputations healed, only half were smokers. Aortic Aneurysm Nature of Abdominal Aortic Aneurysm Abdominal aortic aneurysm refers to the dilatation or expansion of the aortic wall due to degenerative or inflammatory destruction of the components of the wall. The vast majority of abdominal aortic aneurysms are due to atherosclerosis, although other conditions, including infection, trauma, dissection, or inherited metabolic dis- ease (Ehlers-Danlos syndrome) may be causes. The dilatation may involve only a portion of the arterial wall (saccular aneurysm), but most often involves generalized fusiform enlargement of the artery. Most abdominal aortic aneurysms are located distal to the renal arteries and proximal to the aortic bifurcation. Abdominal aortic aneurysms may coexist with aneurysmal changes in the iliac, femoral, or popliteal arteries. Less commonly, an aneurysm may involve the entire aorta, including the suprarenal and descending thoracic aorta (thoracoabdominal aneurysm). Most abdominal aortic aneurysms are asymptomatic and are discovered incidentally during a physical examination or on X-ray examination of the spine or abdominal organs. Symptoms, such as back pain or shock, are usually associated with the complication of rupture and constitute the main threat of abdominal aneurysm. Less commonly, distal embolization may lead to acute or chronic periph- eral arterial occlusive disease. Although palpation of aortic enlarge- ment is the best clinical indicator of abdominal aneurysm, abdomi- nal B-mode ultrasonography is the most accurate noninvasive method to estimate the exact size of the aneurysm. Arteriography is seldom used before an operation unless there is associated occlusive peripheral vascular disease or a suspicion of renovascular hyperten- sion; this is because the arteriogram may often not depict the true size of the aneurysm owing to the mural thrombus contained within the aneurysm. Surgical repair with a prosthetic graft is recommend- ed for all abdominal aortic aneurysms more than 5 cm in diameter unless associated diseases make the operative risk greater than that of the prognosis of the aneurysm. The risk of rupture increases exponentially with the diameter of the aneurysm. 192 TABLE S.-Mortality ratios and deaths (n in parentheses)' from nonsyphilitic aortic aneurysm related to smoking, prospective studies, United States Author and year Number and type of population Data Followup Number collection years of deaths Cigarettes per day pipes Cigars Comments Hammond and Horn 1958 (32, 33) Kahn 1966 (45) 187,783 white Questionnaire males in 9 and followup states, !50-69 of death years of age certiticate U.S. male Questionnaire veterans, and followup 2,265,674 of death person-years certificate 1.5 8.5 68 491 NS' 1.00 (25) (expected) SM' 2.72 (66) (p39 . . . . . 7.26 (17) NS ._................ 1.00 (58) Current cigarettes 5.24 (234) l-9 cigarettes/day. 2.12 (13) 10-20 . . . . . 5.53 (124) 2139 ..t.. 5.95 (76) NS-1.00 (58) NS-1.00 (56) SM-1.13 (8) SM-2.06 (24) Hammond & 358,534 males, Questionnaire 6 337 NS .................. 1.00 Data apply Garfinkel 445,875 females, and followup I-9.. ................ 2.62 only to males, 1969 40-79 years of of death lo-19 ............... 3.85 M-69 years (31) age at entry certificate 20-39 ............... 4.54 of age >40.. ............... 8.00 Weir and 68,153 Questionnaire 5-8 51 NS .................. 1.00 SM includes Dunn California and followup All .................. 2.64 ex+mokers; 1970 male workers, of death f10.. ............... 2.44 NS includes (85) 35-64 years of certificate 220 ................ 2.88 pipe and age at entry 230.. ............... 2.54 cigar smokers ' Unless otherwise specified, disparities between the total number of deal he and the individual categories are due to the exclusion of occasional, miscellaneous, or former smokenr. `NS = nonsmokers; SM = smokers. Summary of Epidemiologic Data Several large epidemiologic studies have suggested an elevated incidence of death from ruptured abdominal aneurysm in smokers compared with nonsmokers (31,32,33,45,85) (Table 2). Anderson et al. (I) analyzed 344 autopsies for causes of death and relationship to smoking history. The male to female ratio was 1.9:l.Q with a smoking incidence of more than double that of the general popula- tion. The overall longevity of men was less than that of women. There was an inverse relationship between smoking and longevity. Five diseases that accounted for 39 percent of the deaths of smokers were bronchogenic carcinoma, peptic ulcer, aortic aneurysm, acute myocardial infarction, and centrilobular emphysema. The 15 rup tured abdominal aortic aneurysms were in 13 male and 2 female smoking patients. Auerbach and Garfinkel (4) evaluated atherosclerosis and aneu- rysm of the aorta relative to smoking habits and age. In 1,412 aortas collected at autopsy from 1965 to 1970 from male patients, there was a direct relationship between the extent of atherosclerotic lesions and both smoking habit and age. The aortic lesions were graded for formation of plaques, ulceration, and calcification. The complexity of the plaques increased with the number of cigarettes smoked and was greater in ex-cigarette smokers and pipe or cigar smokers than in nonsmokers. More extensive alterations were found in the abdomi- nal aorta than in the thoracic aorta. Aneurysms were found eight times more frequently among those smoking one to two packs of cigarettes per day than among nonsmokers. Black subjects showed about one-half the number of aneurysms and fewer extensive atherosclerotic lesions than did white subjects. At ages over 65 years, abdominal aortic aneurysms were found in 11 percent of all men and in 16 percent of the heavy smokers. Rogot and Murray (f%) evaluated the smoking relationship to causes of death among U.S. veterans. Over a X-year period, there was a significant reduction in mortality rate with the number of years of smoking cessation. Aortic aneurysm, along with bronchitis and emphysema and lung cancer, were among the diseases in which substantial excess risk remained even after 20 years' cessation of cigarette smoking. Conclusions 1. Cigarette smoking is the most powerful risk factor predisposing to atherosclerotic peripheral arterial disease. 2. Smoking cessation plays an important role in the medical and surgical management of atherosclerotic peripheral vascular disease. 194 3. Death from rupture of an atherosclerotic abdominal aneurysm is more common in cigarette smokers than in nonsmokers. 195 References (I) ANDERSON, A.E., Jr., FORAKER, A.G. Smoking, mortality, and sex in a community hospital necropsy population. Southern Medical Joumal74(9): 1097-1100, September 1981. (2) ASMUSSEN, I. 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PHARMACOLOGICAL AND TOXICOLOGICAL IMPLICATIONS OF SMOKE CONSTITUENTS ON CARDIOVASCULAR DISEASE 203 Introduction Cardiovascular diseases are the leading causes of death in most of the technologically advanced countries of the Western Hemisphere, accounting for approximately half of all deaths annually in the United States (see Appendix A). The most common among these diseases are atherosclerosis and coronary heart disease; their ischemic complications result in increased morbidity and mortality. Coronary heart disease is the leading cause of death in the United States, accounting for two-thirds of all cardiovascular deaths (9s). It is generally acknowledged that coronary heart disease is a multifactorial process; that is, a variety of factors are involved in the development and clinical manifestations of this disease. Therefore, it is not a simple task to determine the etiology and time course of atherogenic development. In addition, the study of atherosclerosis is singularly difficult because no model in the experimental animal exactly replicates the human disease in physiological, morphological, and clinical detail. Investigations in human subjects are further limited by the inability to diagnose the disease in preischemic phases (44). Most studies of the pathology of cardiovascular diseases (CVD) have been based on autopsies by coroners or on hospital populations in which only a limited fraction of decedents have been examined. Individuals may show considerable variance in the degree of atherosclerosis identified at autopsy, limiting the value of retrospec- tive analysis (137). In 1971, the U.S. Government established the Task Force on Arteriosclerosis to assess research needs and to make recommenda- tions on priorities for future program plans in this area. Most of the recommendations of this task force have been implemented during the past decade, and important advances have been made in basic and clinical research (96'). Most important, major epidemiological associations of cardiovascular disease risk not only have been established, but also have been supported by examinations of the arterial wall itself, enabling an increased understanding of the basic mechanisms of disease processes. Research in cell and molecular biology has provided new informa- tion about the interaction of blood-borne components, such as cholesterol, with the arterial wall. Basic research regarding this risk will help to increase our understanding of the effects of other circulating components, such as inhaled cigarette smoke constitu- ents, and will elucidate the susceptibility of arterial cells to these effects. The most firmly established modifiable risk factors for atheroscle- rotic CVD are hypercholesterolemia, hypertension, and cigarette smoking. In addition to these, diabetes mellitus, lack of exercise, obesity, and type A behavior have all been suggested as contributors to the multifactorial process known as atherogenesis (82). The assessment of any risk factor, such as cigarette smoking, must be made within the constellation of other risks, i.e., susceptibility to disease that is predicted by multifactorial analysis (53, 82). In the case of cigarette smoking, we are faced with an extremely difficult effort in determining direct cause and effect phenomena that are attributable to single factors. Over 4,000 different com- pounds have been identified in tobacco smoke (45), and the determi- nation of the direct or indirect actions of each upon the arterial wall seems an impossible task. We will attempt, however, to examine the major components believed to be associated with increased risk for CVD and to remember the multiple risk factors that might be associated with the development of cardiovascular dysfunctions in cigarette smokers. The variety of possible pharmacological and toxicological implica- tions of smoke and its constituents-and the absence of firm proof