Th e Health Consequences of Smoking A Report of the Surgeon General: 1971 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service For sale by the Superintendent of Documents, U.S. Government Printing OI%x Washington, D.C. 2040'2 - Price $1.75 This report is a comprehensive review of more than 20 years of research into the problem of smoking and health. This re- search has been carried on under the sponsorship of many groups in this country and abroad, including governments, universities, private research institutions, voluntary health agencies, and the tobacco industry. Seven years ago, an advisory committee to the Surgeon General concluded that cigarette smoking is a serious hazard to health and is related to illness and death from lung cancer, chronic broncho- pulmonary disease, cardiovascular disease and other diseases. In the intervening years, a great deal of new research has been com- pleted. This has resulted in a growing understanding of the bio- mechanisms whereby cigarette smoking adversely affects the hu- `man organism and contributes to the development of serious illness. It is encouraging that cigarette consumption in this country is declining. If this decline can be maintained, it will result in better health for our population and in fewer deaths among those of our @tizens who are in their most productive years of life. JESSE L. STEINFELD, M.D., Surgeon General. Acknowledgments The National Clearinghouse for Smoking and Health, Daniel Horn, Ph.D., Director, was responsible for the preparation of this report. Daniel P. Asnes, M.D., was consulting editor. Staff direc- tor for the report was David G. Cook, M.D. The professional staff has had the assistance and advice of a number of experts in the scientific and technical fields, both in and outside of the government. Their contributions are gratefully acknowledged. Special thanks are due the following: ANDERSON, WILLIAM H., M.D.-Chief, Pulmonary Disease Section, University of Louisville School of Medicine, Louisville, Ky. AKTHONISEN, NICHOLAS, R., M.D.-Ph. D.--Associate Professor, Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada. AUERBXH, OSCAR, M.D.-Senior Medical Investigator, VA Hospital, East Orange, N.J. AYRES, STEPHEN M., M.D.-Director, Saint Vincent's Hospital and Medical Center of New York, Cardiopulmonary Laboratory, New York, N.Y. BAKER, CARL, M.l).-Director, National Cancer Institute, National Institutes of Health, Bethesda, Md. BELLET, SAMUEL, M.D.-Director, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa. BI~`G, RICHARD J., M.D.-Professor, of Medicine, California Institute of Tech- nology, Pasadena, Calif. BOCK, FRED G., Ph. D.-Ijirector, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, N.Y. BOREN, HOLLIS, M.D.-Professor of Medicine, Marquette School of Medicine, Wood VA Hospital, Milwaukee, Wis. BOUTWELL, ROSWELL Ii., M.D.-Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wis. COOPER, THEODORE, MD-1 iirector, National Heart Institute, National In- stitutes of Health, Bethesda, Md. CORNFIELD, JEROME-Research Professor of Biostatistics, University of Pitts- burgh Graduate School of Public Health, Riostatistics Project, Bethesda, Md. EARL, CHRISTOPHER J., M.L).-National Hospital, London, England. EPSTEIX, FREDERICK H., M.D-Professor of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich. FALK, HANS L., Ph. I).--.Associate Ijirector for Laboratory Research, National Institute of Environmental Health Sciences, Research Triangle Park, N. C. FERRIS, BENJAMIN G., JR.. M.I).-Professor, Department of Physiology, Har- vard School of Public Health, Boston, Mass. FITZPATRICK, MARK J., M.D., M.P.H.-Obstetrician, Perinatal Biology and In- fant Mortality, National Institute of Child Health and Human Development, National Institute of Child Health and Human Development, National In- stitutes of Health, Bethesda, Md. FRAZIER, TODD M.-Assistant Director, Harvard Center for Community Health and Medical Care, Harvard &ho01 of Public Health, Boston, Mass. GOLDSMITH, JOHN R., M.D.-Head, Environmental Epidemiology Unit, Cali- fornia State Department of Public Health, Berkeley, Calif. HANNA, MICHAEL G., JR., Ph. D.-Biology Division, Oak Ridge National Lab- oratory, Oak Ridge, Tenn. HIGGINS, IAN T. T., M.D., M.R.C.P.-Professor, Department of Epidemiology, University of Michigan Schclol of Public Health, Ann Arbor, Mich. HOFFMANN, DIETRICH, Ph. D.-Division of Environmental Toxicology, Ameri- can Health Foundation, New York, N.Y. ISRAEL, ROBERT A.-Director, Division of Vital Statistics, National Center for Health Statistics, U.S.P.H.S., U.S. Department. of Health, Education and Welfare, Rockville, Md. KELLER, ANDREW Z., D.M.D., M.P.H.-Chief, Research in Geographic Epide- miology, Veterans Administration Central Office, Washington, D.C. KIRSNER, JOSEPH, M.D.-Professor of Medicine, University of Chicago School of Medicine, Chicago, Ill. KNOX, DAVID L., M.D.-Associate Professor, The Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, Md. KOLBYE, ALBERT C., JR., M.D., J.D.-Deputy Director, Bureau of Foods, Food and Drug Administration, U.S. Department of Health, Education and Wel- fare, Washington D.C. KOTIN, PAUL, M.D.-Director, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. KRUMHOLZ, RICHARD A., M.D.--Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering, Ohio. LIEBOW, AVERILL A., M.D.-Professor and Chairman, Department of Path- ology, University of California at San Diego, La Jolla, Calif. LILIENFELD, ABRAHAM, M.D.--Professor and Chairman, Department of Chronic Diseases, Johns Hopkins School of Hygiene and Public Health, Baltimore, Md. MACMAHON, BRIAN, M.D.-Professor of Epidemiology, Harvard University School of Public Health, Boston, Mass. MCLEAN, Ross, M.D.-Medical Consultant, Regional Medical Program of Texas, Austin, Tex. MCMILLAN, GARDNER C., M.I).--Chief, Arteriosclerotic Disease Branch, Na- tional Heart and Lung Institute, National Institutes of Health, Bethesda, Md. MITCHELL, ROGER S., M.I).-Director, University of Colorado Medical Center, Webb-Waring Institute for Medical Research, Denver, Colo. MURPHY, EDMOND A., M.D., SC. D.-Associate Professor of Medicine and Bio- statistics, The Johns Hopkins Hospital, Baltimore, Md. PAFFENBARGER, RALPH S., JR., M.D.-Chief, Bureau of Adult Health and Chronic Diseases, California State Department of Public Health, Berkeley, Calif. PETERS, JOHN M., M.D.-Associate Professor of Occupational Medicine, Har- vard University School of Public Health, Boston, Mass . PETERSON, WILLIAM F., M.D.--Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, Washington, D.C. PETTY, THOMAS L., M.D-Associate Professor of Medicine, University of Colorado Medical Center, Denver, Colo. vi SAFFIOTTI, UMBERTO, M.D.--Associate Scientific Director for Carcinogenesis Etiology, National Cancer Institute, National Institutes of Health, Beth- esda, Md. SCHUMAN, LEONARD M., M.D.-Professor and Head, Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, Minn. SHIIMKIK, MICHAEL B., M.D.-Coordinator, Regional Medical Program, Uni- versity of California at San Diego, La Jolla, Calif. STAMLER, JEREMIAH, M.D.-Executive Director, Chicago Board of Health, Health Research Foundation, Chicago, 111. UNDERWOOD, PAUL B., JR., M.D.--Associate Professor, Department of Ob- stetrics and Gynecology, University of South Carolina Medical School, Charleston, S.C. VAN DUUREN, BENJAMIN L., M.D.-Professor of Environmental Medicine, In- stitute of Environmental Medicine, New York University Medical Center, New York, N.Y. VICTOR, MAURICE, M.D.-Professor of Neurology, Department of Neurology, Case Western Reserve, Cleveland, Ohio. WYNDER, ERNEST L., M.D-President and Medical Director, American Health Foundation, New York, N.Y. The following professional staff of the National Clearinghouse for Smoking and Health contributed to the preparation of this re- port: John H. Holbrook, M.D., Richard W. White, Robert S. Hutch- ings, Elaine Bratic, Annabel W. Hecht, Richard H. Amacher, Donald R. Shopland and Jennie M. Jennings. Special thanks are due Nancy S. Johnston, Kathryn Carlysle, Mary E. Dement, and Mildred H. Ritchie. vii Contents Page PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... 111 ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Chapter 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Chapter 2. Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . 15 Chapter 3. Chronic Obstructive Bronchopulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Chapter 4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Chapter 5. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Chapter 6. Peptic Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Chapter 7. Tobacco Amblyopia . . . . . . . . . . . . . . . . . . . . . . . 431 CHAPTER 1 General Considerations, Preparation of the Present Document, and Summary of the Report GENERAL CONSIDERATIONS The first major development in the modern history of the effects of smoking on health occurred in 1950 with the publication of four retrospective studies on smoking habits among lung cancer pa- tients and among controls (1, 4, 6, 7). At that time, the question was, "Are smokers more likely to get lung cancer than nonsmok- ers?" Although some epidemiologists were satisfied that the an- swer was in the affirmative, others turned for confirmation to prospective studies in which the smoking habits of large popula- tions were recorded and the populations followed to identify sub- sequent mortality. The first report of Hammond and Horn in 1954 (Z), showed significantly elevated overall death rates for smokers as compared to nonsmokers. This elevation in death rates, almost entirely confined to those who smoked cigarettes, together with the evidence for a gradient according to the amount smoked, changed the question from one concerning only lung cancer to one concern- ing overall death rates and from one concerning smoking to one primarily concerned with cigarette smoking. In effect, the question became, "Do cigarette smokers have higher overall death rates than nonsmokers and smokers of pipes and cigars?" With the publication of the later reports of the major prospec- tive studies in the late 1950's and early 1960's, it became clear that cigarette smokers had higher overall death rates than nonsmokers, as well as higher death rates from a number of individual causes of death. The question then became, "Why?" When the Advisory Committee on Smoking and Health to the Surgeon General was established in 1962, it undertook the evalua- tion of the scientific evidence up to that time. The conclusion of the Committee in its 1964 Report was that: "Cigarette smoking is a health hazard of sufficient importance in the United States to war- rant appropriate remedial action." Not only did the Committee conclude that the evidence clearly showed that male cigarette smokers do in fact have higher death rates than nonsmokers but that the convergence of epidemiological, experimental, and path- ological evidence also clearly indicated a cause-and-effect relation- ship for several of the implicated diseases, particularly cancer of the lung and chronic bronchitis. In several other important dis- eases, the evidence on biomechanisms to explain epidemiological 3 associations was felt to be inadequate at that time to draw firm conclusions about a cause-and-effect relationship. Three and one-half years later, when The Health Consequences of Smoking: A Public Health Service Review, 1967 was published, the conclusions of the 1964 review were taken as a starting point, and the nature of the task of interpreting the scientific evidence was restated as follows : 1. How much mortality and excess disability are associated with smoking? 2. How much of this early mortality and excess disability would not have occurred if people had not taken up cigarette smoking? 3. How much of this early mortality and excess disability could be averted by the cessation or-reduction of cigarette smoking? 4. What are the biomechanisms whereby these effects take place and what are the critical factors in these mechanisms? That and subsequent reviews in 1968 and 1969 have provided some answers to these questions, particularly in summarizing the evidence for various theories as to how cigarette smoking affects the human organism to produce elevated disease and death rates. At least five different processes have been suggested whereby cigarette smokers experience higher mortality or morbidity rates than do nonsmokers. 1. Cigarette smoking initiates a disease process by producing progressive irreversible damage. In this case, the total effect would be approximately proportional to the total accumulated dosage experienced over the years. Cessation of smoking leaves impaired function which does not improve appreciably but does not continue to deteriorate from continued exposure to cigarette smoke. How- ever, such function may deteriorate through aging or through exposure to other harmful agents. It appears that such a relation- ship probably exists for chronic obstructive lung disease and pos- sibly for the development of atherosclerotic heart disease. 2. Cigarette smoking initiates a disease process with continual repair and recovery until some critical point is reached at which the process is no longer reversible. The total effect would therefore be affected to some extent by accumulated exposure but would be affected also by the level of contemporary smoking. Cessation of smoking would result in a rapid reduction of risk provided the critical level initiating an irreversible process has not been reached. The evidence supports this kind of mechanism accounting both for the high dose-response relationship in lung cancer and for the reduction in risk from lung cancer among ex-smokers. 3. Cigarette smoking promotes a disease process either by providing positive support to the development of a pathological condition or by interfering with and diminishing the normal capa- 4 bility of the organism to cope with and defend against a disease process. This may take place by promoting the development of a subclinical disease to a clinically recognizable one, by promoting a mild disease state t.o a more severe form, or by increasing fatality rates of severe disease states. This type of mechanism could ac- count for modestly increased mortality rates for a number of se- vere diseases for which there is no evidence that cigarette smoking itself has a role in initiating the disease. Some of the excess mor- tality from infectious respiratory disease and from coronary heart disease might take place through this kind of mechanism. 4. Cigarette smoking produces a set of temporary conditions which increase the probability that a critical event will occur with attendant disability and possibly fatal consequences. For example, there is evidence to support the theory that each cigarette can pro- duce a set of conditions which increase the probability of myocar- dial damage through increased demand for oxygen at a time when the suppy is diminished. Presumably, once the supply/demand im- balance is alleviated, the probability of myocardial damage would revert to its normal level. Cessation of smoking should have an almost immediate effect of reducing the risk sharply for morbidity or mortality produced through this mechanism. 5. Cigarette smoking may be artificially related to excess dis- ability or death by way of a close association with some other con- dition or exposure which is found at a high level in smokers, but not in nonsmokers, and is itself responsible for the disease. The one cause of death for which cigarette smokers have elevated death rates that is generally interpreted in this way is cirrhosis of the liver. Since most heavy consumers of alcoholic beverages are smok- ers, and since alcohol consumption is an important part of the process that produces cirrhosis of the liver, the high rate of cirrho- sis among cigarette smokers is discounted as resulting from this kind of artificial relationship. Some authors have proposed that there may be genetic factors that link smoking and certain diseases in this fashion. Obviously, the cessation of smoking would have no effect on morbidity or mortality from diseases which are artificially related to smoking. These different ways in which cigarette smoking can be related to elevated morbidity and mortality rates are important considera- tions in attempting to estimate the potential public health benefits of giving up smoking, For some types of relationship, there would be no benefits ; for some, rather small benefits ; for some, substan- tial benefits, taking place over a long period of time; and for others, substantial benefits taking place rather rapidly. During the past few years, a sharp reduction has taken place in the cigarette smoking habits of the U.S. population. The Na- 5 tional Center for Health Statistics has recently published a com- parison of smoking habits in the US. in 1955 and 1966 based on two large scale household surveys (5). These showed a drop in cigarette consumption in men under 55 years of age but no appre- ciable change among those 55 or over. Among women, every age group showed an increase in the eleven year period. A recent sur- vey conducted for the National Clearinghouse for Smoking and Health, based on a much smaller sample (approximately 5,000 interviews), was conducted in the Spring of 1970 (3) (table 1). Even with the smaller number of cases, it is clear that a much larger drop took place in the four years from 1966 to 1970 than in the eleven years from 1955 to 1966. The drop extended to the age group 55-64 among men, again with no appreciable drop among men over age 65. For the first time, the increase in smok- ing among women leveled off, or even dropped slightly among women under 55. The increase among women over 55 was of a lesser magnitude than previously observed. TABLE I.-Percentage of Current Smokers of Cigarettes (regu- larly or occasionally) by sex and age. U.S. Surveys: 1955 and 1966 (CPS-Current Population Surveys) and 1970 (NCSH- Survey conducted for National Clearinghouse for Smoking & Health) .I Male Female CPS CPS NCSH CPS CPS NCSH ALW 1955 1966 1'970 1956 1966 1910 18-24 --__------ 53.0 48.3 247.0 33.3 34.7 231.1 25-34 ---------- 63.6 58.9 46.8 39.2 43.2 40.3 35-44 _---_-__-- 62.1 57.0 48.6 35.4 41.1 39.0 45-54 _-_-___--- 58.0 53.1 43.1 25.7 37.3 36.0 55-64 --~_---~-~ 45.8 46.2 37.4 13.4 23.0 24.3 65+ ----__-_-- 25.8 24.6 23.7 4.7 8.1 11.8 11955 survey based on approximately 46,000 persons; 1966 survey based on approximately 35,000 persons; 1970 survey based on approximately 5,000 persons. 2 Estimated. With the massive changes in smoking behavior which have taken place among adults in the past few years, largely as an expression of the desire to protect health, changes should be ex- pected in mortality rates among those groups which have experi- enced the greatest reduction both in accumulated dosage and in concurrent dosage. An analysis of U.S. mortality rates for 1970 and the years to follow will provide a very valuable addition to the knowledge concerning the effects of smoking on death rates. PREPARATION OF THE PRESENT DOCUMENT Following the publication of Smoking and Health-Report of the Advisory Committee to the Surgeon General-in 1964, the fol- 6 lowing documents were published as reviews of the medical litera- ture concerning the health consequences of smoking, as called for by Public Law 89-92 : 1. The Health Consequences of Smoking, A Public Health Serv- ice Review: 1967. 2. The Health Consequences of Smoking, 1968 Supplement to the 1967 PHS Review. 3. The Health Consequences of Smoking, 1969 Supplement to the 1967 PHS Review. These documents reviewed the medical literature which had been published since the original Surgeon General's Report. This format of publishing a supplement to a supplement has become unwieldy, particularly in the light of the lack of availability of the previous reviews to the general public. Therefore, when Public Law 91-222 was signed into law on April 1, 1970 calling for an eighteen month interval between the last report and the new re- port, the decision was made to review the entire field with em- phasis on the most recent additions to the literature. The National Clearinghouse for Smoking and Health has the responsibility for continuous monitoring and compilation of the medical literature on the health consequences of smoking. This is accomplished through several mechanisms : 1. A scientific review corporation is on contract to extract arti- cles on smoking and health from the medical and scientific litera- ture of the world. This organization provides a semi-weekly acces- sions list with abstracts and copies of the various articles. Trans- lations are called for as needed. Articles of pertinence are identi- fied by a series of code words and phrases. 2. The National Library of Medicine, through the Medlars sys- tem, sends the National Clearinghouse for Smoking and Health a monthly listing of articles in the smoking and health area. These are reviewed, and pertinent articles are ordered. 3. Staff members keep up with the current contents of medical and scientific literature and identify articles of pertinence. Initial drafts of the present review were prepared by Clearing- house staff and consultants who reviewed the previous reports and identified those articles which have been important in the develop- ment of knowledge in this field. These were abstracted and placed into tabular form, and a draft text of the report was prepared. The first drafts of the individual chapters were sent to experts for review, criticism, and comment with respect to the articles re- viewed, those articles not included, and conclusions. The drafts were then revised on the basis of these comments and rewritten until they met with general approval of the reviewers. The final 7 drafts were reviewed as a whole by the Director of the National Clearinghouse for Smoking and Health, the Director of the Na- tional Cancer Institute, the Director of the National Heart and Lung Institute, the Director of the National Institute of Environ- mental Health Sciences, and by six additional experts both within and outside of the Public Health Service. SUMMARY OF THE REPORT CARDIOVASCULAR DISEASES Comnary Heart Disease 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease, including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smoking of pipes and cigars is appreciably less than that incurred by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physical inactivity) show that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coronary arteries. 5. The cessation of smoking is associated with the decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms : a. Cigarette smoking, by contributing to the release of catecho- lamines, causes increased myocardial wall tension, contraction velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient increase in cor- onary blood flow and oxygenation. c. Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the availability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. Summary Statement of Recent Additions to Knowledge Relating Smoking and Coronary Heart Disease.-A number of epidemi- ologic studies have provided additional evidence concerning ciga- rette smoking as a significant risk factor in the development of CHD. Experimental studies on animals have suggested that ciga- rette smoking, particularly the absorbed nicotine and carbon mon- oxide, contributes to the development of atherosclerosis. Cerebrovascular Disease 1. Data from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cere- brovascular disease. 2. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conclusions concerning pathogenesis. However, some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. Nonsyphilitic Aortic Aneurys,m Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. Peripheral Vascular Disease 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. Cigarette smoking has been observed to alter peripheral blood flow and peripheral vascular resistance. CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE 1. Cigarette smoking is the most important cause of chronic obstructive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- 9 duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma, although it may increase the frequency and severity of asthmatic attacks in patients already suffering from this disease. 3. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers, while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. How- ever, exposure to excessive atmospheric pollution or dusty occu- pational materials and cigarette smoking may act jointly to pro- duce greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. Pathological studies have shown that cigarette smokers who die of diseases other than COPD have histologic changes charac- teristic of COPD in the bronchial tree and pulmonary parenchyma more frequently than do nonsmokers. 9. Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than among nonsmokers. 10. Cigarette smokers appear to develop postoperative pul- monary complications more frequently than nonsmokers. Sunzmal'y Statement of Recent Additions of Knowledge Relat- kg to Chronic Obstructive n,,onchopul??zonar!! Disease.-Studies have demonstrated that cigarette smokers show increased symp- toms and pulmonary dysfunction as well as mortality from COPD when compared to nonsmokers. Investigations of alpha,-antitryp- sin deficiency in relationship to pulmonary emphysema have sug- 10 gested that cigarette smoking may act jointly with hereditary fac- tors in the pathogenesis of pulmonary emphysema. A pathological study on animals has shown that long-term inhalation of cigarette smoke produces lesions characteristic of pulmonary emphysema. Lung Cancer. CANCER 1. Epidemiological evidence derived from a number of prospec- tive and retrospective studies, coupled with experimental and pathological evidence, confirms the conclusion that cigarette smok- ing is the main cause of lung cancer in men. These studies reveal that the risk of developing lung cancer increases with the number of cigarettes smoked per day, the duration of smoking, and earlier initiation, and diminishes with cessation of smoking. 2. Cigarette smoking is a cause of lung cancer in women but accounts for a smaller proportion of the cases than in men. The mortality rates for women who smoke, although significantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least partially attributable to differences in exposures : the use of fewer cigarettes per day, the use of filtered and low "tar" cigarettes, and lower levels of inhala- tion. Nevertheless, even when women are compared with men who apparently have similar levels of exposure to cigarette smoke, the mortality ratios appear to be lower in women. 3. The risk of developing lung cancer among pipe and/or cigar smokers is higher than for nonsmokers but significantly lower than for cigarette smokers. 4. The risk of developing lung cancer appears to be higher among smokers who smoke high "tar" cigarettes, or smoke in such a manner as to produce higher levels of "tar" in the inhaled smoke. 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing smokers. ,There is evidence to support the view that cessation of smoking by large numbers of cigarette smokers would be followed by lower lung cancer death rates. 6. Increased death rates from lung cancer have been observed among urban populations when compared with populations from rural environments. The evidence concerning the role of air pollu- tion in the etiology of lung cancer is presently inconclusive. Fac- tors such as occupational and smoking habit differences may also contribute to the urban-rural difference observed. Detailed epi- demiologic surveys have shown that the urban factor exerts a small influence compared to the overriding effect of cigarette smok- ing in the development of lung cancer. 11 `7. Certain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer. Cigarette smoking interacts with these exposures in the pathogenesis of lung cancer so as to produce very much higher lung cancer death rates in those cigarette smokers who are also exposed to such substances. 8. Experimental studies on animals utilizing skin painting, tracheal instillation or implantation, and inhalation of cigarette smoke or its component compounds, have confirmed the presence of complete carcinogens as well as tumor initiators and promoters in tobacco smoke. Lung cancer has been found in dogs exposed to the inhalation of cigarette smoke over a period of more than 2 years. Cancer of the Laqmx 1. Epidemiological, experimental, and pathological studies support the conclusion that cigarette smoking is a significant fac- tor in the causation of cancer of the larynx. The risk of develop- ing laryngeal cancer among cigarette smokers as well as pipe and/ or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. Oral Cancer 1. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. 2. Experimental studies suggest that tobacco extracts and to- bacco smoke contain initiators and promoters of cancerous changes in the oral cavity. Cancer- of the Esophagus 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esoph- agus. The risk of developing esophageal cancer among pipe and/ or cigar smokers is greater than for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association between esophageal cancer and alcohol consumption and that alco- hol consumption may interact with cigarette smoking. This com- 12 bination of exposures is associated with especially high rates of cancer of the esophagus. Cancer of the Urinary Bladd,er and. Kidney 1. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacco usage and cancer of the kidney is less clear-cut. 2. Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the metabolism of tryp- tophan and may in this way contribute thereby to the development of urinary tract cancer. Cancer of the Pancreas Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. The significance of the relationship is not clear at this time. Summary Statement of Recent Additions of Knowledge Relating Smoking and Cancer.-Epidemiological studies have confirmed that cigarette smokers incur an increased risk of dying from lung can- cer and that those smokers who switched to filter cigarettes incur a lesser risk. Pathological studies have shown that cancer of the lung and cancer of the larynx have been found in animals exposed to the long-term inhalation of cigarette smoke. SMOKING AND PREGNANCY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birthweight and an increased incidence of prematurity, defined by weight alone. There is strong evidence to support the view that smoking mothers have a significantly greater number of unsuccessful pregnancies due to stillbirth and neonatal death as compared to nonsmoking mothers. There is insufficient evidence to support a comparable statement for abortions. The recently published Second Report of the 1958 British Perinatal Mortality Survey, a carefully designed and controlled prospective study involving large numbers of Patients, adds further support to the conclusions. PEPTICULCER Cigarette smoking males have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effectiveness of standard Peptic ulcer treatment and to slow the rate of ulcer healing. 13 TOBACCO AMBLYOPIA Tobacco amblyopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mecha- nisms, particularly in handling the cyanide component of tobacco smoke. INTRODUCTION REFERENCES (I ) DOLL, R., HILL, A. B., Smoking and carcinoma of the lung. Preliminary report. British Medical Journal 2: `739-748, September 23, 1950. (2) HAMMOND, E. C., HORN, D. The relationship between human smoking habits and death rates. Journal of the American Medical Association 155: 1316-1328, August 7, 1954. (3) HORN, D. Address given at National Conference on Smoking and Health, San Diego, Calif., September 9-11, 1970. 13 pp. (4) LEVIN, M. L., GOLDSTEIN, H., GERHARDT, P. R. Cancer and tobacco smok- ing. A preliminary report. Journal of the American Medical Asso- ciation 143(4) : 336-338, May 27, 1950. (5) NATIONAL CENTER FOR HEALTH STATISTICS. Changes in cigarette smoking habits between 1955 and 1966. U.S. Department of Health, Education, and Welfare, April 1970. 33 pp. (6) SCHREK, R., BAKER, L. A., BALLARD, G. P., DOLGOFF, S. Tobacco smoking as an etiologic factor in disease. I. Cancer. Cancer Research 10: 49-58, 1950. (7) WYNDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. A study of six hundred and eighty four proved cases. Journal of the American Medical Association 143(4) : 329-336, May 27, 1950. 14 CHAPTER 2 Cardiovascular Diseases Page 21 38 38 39 40 Introduction ........................................ Epidemiological Studies. .............................. Coronary Heart Disease Mortality ................. Coronary Heart Disease Morbidity ................. Retrospective Studies. ............................ The Interaction of Cigarette Smoking and Other CHD Risk Factors .................................. Smoking and Serum Lipids ................... Smoking and Hypertension. ................... Smoking and Physical Inactivity ............... Smoking and Obesity ......................... Smoking and Electrocardiographic Abnormalities. Smoking and Heart Rate ..................... The Effect of Cessation of Cigarette Smoking on Coronary Heart Disease ..................................... The Constitutional Hypothesis ........................ Autopsy Studies Relating Smoking, Atherosclerosis, and SuddenCHDDeath ................................ Experimental Studies Concerning the Relationship of Coronary Heart Disease and Smoking ................ Cardiovascular Effects of Cigarette Smoke and Nicotine.. .................................... Coronary Blood Flow ............................ Cardiovascular Effects of Carbon Monoxide ......... Effects of Smoking on the Formation of Atherosclerotic Lesions ....................................... The Effect of Smoking on Serum Lipid Levels ........ The Effect of Smoking on Thrombosis .............. Other Areas of Investigation. ..................... Cerebrovascular Disease ............................. Nonsyphilitic Aortic Aneurysm ........................ Peripheral Arteriosclerosis ........................... Experimental Evidence. .......................... Thromboangiitis Obliterans ........................... Summary and Conclusions ............................ 40 41 41 41 43 47 47 47 48 52 56 56 58 59 63 65 66 66 66 67 72 73 73 74 17 Coronary Heart Disease .......................... Cerebrovascular Disease .......................... Nonsyphilitic Aortic Aneurysm .................... Peripheral Vascular Disease ...................... References .......................................... FIGURES 1. National Cooperative Pooling Project, Inter-Society Com- mission for Heart Disease Resources . . . . . . . . . . . . . . . 2. Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of "predisposing factors" (men 30-59 at entry). Framingham Heart Study.......................................... 3. Estimated coronary heart disease death ratios in a 17-51 year follow-up, and frequencies of paired combinations of six high-risk characteristics in college, for all ages at death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Relationship between smoking status and serum choles- terol level at initial examination, and incidence of clin- ical coronary heart disease in men originally age 40-59 free of definite CHD. Peoples Gas Light and Coke Company Study,1958-1962....................... 5. Average annual incidence of first myocardial infarction among men in relation to overall physical activity, class, and smoking habits (age-adjusted rates per 1,000) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . LIST OF TABLES (A indicates tables located in Appendix at end of Chapter) 1. Sudden death and acute mortality with first major coronary episodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Coronary heart disease mortality ratios related to smoking-prospective studies . . . . . . , . . . . . . . . . . . 3. Sudden death from coronary heart disease related to smoking..................................... 4. Coronary heart disease morbidity as related to smoking..................................... 5. Coronary heart disease morbidity as related to smok- ing-angina pectoris-prospective studies . . . . . . . A 6. Coronary heart disease morbidity and mortality- retrospective studies . . . . . . . . . . . . . . . . . . . . . . . . A 7. Differences in serum lipids between smokers and non- smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 74 75 75 75 75 23 24 25 43 44 23 26 30 32 37 93 98 18 LIST OF TABLES (CONT.) (A indicates tables located in Appendix at end of Chapter) A 8. Blood pressure differences between smokers and non- smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Death rates from coronary heart disease, by systolic blood pressure: ILWU mortality study, 1951-1961 10. Death rates from coronary heart disease, by diastolic blood pressure: ILWU mortality study, 1951-1961 11. Death rates from coronary heart disease, among hy- pertensives and nonhypertensives : ILWU mortality study, 1951-1961............................. 12. Death rates from coronary heart disease among men without abnormalities related to cardiopulmonary diseases by weight classification in 1951: ILWU mortality study, 1951-1961 . . . . . . . . . . . . . . . . . . 13. Death rates from coronary heart disease, by electro- cardiographic findings in 1951: ILWU mortality study, 1951-1961............................. 14. 1958 status with respect to heart rate, blood pressure, cigarette smoking, and ten-year mortality rates, by cause (1,329 men originally age 40-59 and free of definite coronary heart disease) Peoples Gas Com- pany Study,1958-1968....................... 15. The effect of the cessation of cigarette smoking on the incidence of CHD . . . . . . . . . . . . . . . . _........... 16. Annual probability of death from coronary heart dis- ease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking A 17. Incidence of new coronary heart disease by smoking category and behavior type for men 39-49 years of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A 18. Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19. Autopsy studies of atherosclerosis . . . . . . . . . . . . . . . . A 20. Experiments concerning the effects of smoking and nicotine on animal cardiovascular function . . . . . . A 21. Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans. . -422. Experiments concerning the effect of nicotine or smoking on catecholamine levels . . . . . . . . . . . . . . . x 23. Experiments concerning the atherogenic effect of nicotine administration, . . . . . . . . . . . . . . . . . . . . . Page 103 42 42 42 45 45 45 46 46 105 106 53 107 113 119 120 19 LIST OF TABLES (CONT.) (A indicates tales located in Appendix at end of Chapter) 24. Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia . . . . . . . . . A 25. Experiments concerning the effect of smoking and nicotine upon blood lipids (Human Studies) . . . . . . A 25a. Experiments concerning the effect of smoking and nicotine upon blood lipids (Animal Studies) . . . . . . A 26. Experiments concerning the effect of carbon mon- oxide exposure upon blood lipids . . . . . . _ . . . . . . . . A 27. Smoking and thrombosis . . . . . . . . . . . . . . . . . . . . . . . . 28. Deaths from cerebrovascular disease related to smoking..................................... 29. Deaths from nonsyphilitic aortic aneurysm related to smoking-prospective studies . . . . . . . . . . . . . . . . . . A 30. Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system . . . . Page 64 123 127 129 130 68 71 133 20 INTRODUCTION Coronary Heart Disease (CHD) cuts short the lives of many men in the Western World in their prime productive years. More Americans die from heart disease than from any other disease. In 196'7, in this country, a total of 345,154 men and 227,999 women were classified as dying of arteriosclerotic heart disease (ASHD) (196)) a category which consists largely of what is commonly called CHD. During the years from 1950 to 1967, the age-adjusted death rate from ASHD increased 15.1 percent (196, 197). Besides the many deaths attributed to CHD, much morbidity results from this disease. The National Health Examination Sur- vey of 1960-1962 estimated that 3.1 million American adults, ages 18 to 79, had definite CHD and 2.4 million had suspect CHD, togethes representing about 5 percent of the population. It was further estimated that of Americans under age 65, almost 1.8 mil- lion had definite CHD and 1.6 million had suspect CHD (195). `There are several manifestations of CHD, all related in part to the basic process of severe atherosclerosis, a disease of arteries in which fatty materials (lipids) accumulate in the form of plaques in the walls of medium and large arteries. This process, as it occurs in the coronary arteries, leads to stiffening of the wall and narrow- ing of the lumen which, when severe, result in a diminution in the blood supply to the cardiac muscle. Angina pectoris, a major mani- festation of CHD, results from diminution in blood supply relative to the needs of the myocardium. If the blood supply to a portion of the myocardium is completely obstructed, due for example to the formation of a thrombus at the site of atherosclerotic narrowing, necrosis or death of a portion of heart muscle may occur. This occurrence is known as a myocardial infarction. In many cases, a disturbance of cardiac rhythm occurs at the time of thrombosis, and the patient may die immediately. It is estimated that approxi- mately 25 percent of patients suffering coronary artery occlusion die within the first three hours following the occlusion (table 1) (88). Not infrequently, sudden death occurs in patients with severe coronary atherosclerosis but without a demonstrable arterial occlu- sion. In these cases, it is thought that the meager blood flow to a Portion of the myocardium becomes so diminished with respect to cardiac needs as to lead to a fatal arrhythmia, as well as to, per- haps, a myocardial infarction. 21 CIGARIEITE SMOKING(S) AT ENTRY-WITH CONTROL OF SERUM CHOLESTEROL (C) AND DIASTOLIC BLOOD PRESSURE (W-AND TEN YEAR INCIDENCE AND MORTALITY RATES. 7,594 WHITE MALES AGE 30-59 AT ENTRY, POOLING PROJECT RATE PER 1.000 150- FIRST MAJOR CORONARY EVENT RATE PER 1,000 150- ALL CHD DEATHS 82 loo- 92 loo- 7 I ,,_(_ 1 ju 50- 45 50- W-I ). .i' (, 20 '*a,,' (_ '.1. /" o- RISK NONE S C OR H S+C OR FACTORS OF 3 ONLY ONLY SSH NUMBER 28 97 74 167 OF EVENTS C+H C+H NONE S +s OF 3 ONLY 31 82 17 50 384 595 1,249 2,018 1,302 1,794 384 595 NUMBER 1,249 2,018 1,302 1.794 OF MEN National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for first major coronary event (incling nonfatal MI. fatal MI. and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. Al! rates age.adjusted b white male population 1960. Graphs present rates for noncigarette VS. cigarette smokers at entry wdh srmultaneous control o { IO-year age groups to the U.S. blood pressure and serum cho- lesterol level. For this latter analysis, the following cutting points were used: (a) Cigarette smoking S -any use at entry (b) Serum cholesterol C - 250 mg./dl. (c) Diastolic blood pressure H - 90 mm. Hg. SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). C OR H S+C C+H C+H ONLY OR S-j-H +s 41 90 12 42 FIGURE l-National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for first major coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960. Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum cholesterol level. For this latter analysis, the following cutting points were used: (a) Cigarette smoking-S-any use at entry (b) Serum cholesterol-C-2250 mg./dl. (c) Diastolic blood pressure-H-290 mm. Hg. SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). TABLE l.-Szcldden death and acute mortality with first major coronary episodes Author. year. Number and country, type of reference population Data collection Event Number of events Proportion per 1,000 events (as calculated on the basis of age- adjusted rates) Comment Pooling Project. American Heart Association, 1970. U.S.A. (88). 7,594 males Medical exam- All first major coronary males 30-59 ination and episodes, nonfatal and fatal. 501 l,ooo.o yem-s of age follow-up. Sudden death (death at entry. within 3 hours of onset Ten-year of acute illness). 123 245.5 experience. All acute deaths with first episodes. 166 329.3 Data from the Pooling Project, Council on Epidemiology. American Heart Association. a national cooperative project for pooling data from the Albany civil servant. Chicago Peoples Gas Co., Chicago Western Electric Co., Framingham Community, Los Angela civil servant, Minneapolis-St. Paul business men, and other prospective epidemiologic studies of adult cardiovascular disease in the United States. SOURCE: Inter-Society Commission for Heart Disease Resources (88). Representative references include: (54. 9L, 14.9. 177) and others listed as 6a-6k in Inter-Society Commission for Heart Disease Resources report. ,- I - I CIGARETTE SMOKING: 0 NONE >l PKG./DAY 196' 123 NONE ANY ONE 12 9.7 PREDISPOSING FACTORS (CHOLESTEROL 3250, HYPERTENSION, DIABETES) `SIGNIFICANTLY DIFFERENT FROM "NONSMOKER" P<.O5 FIGURE 2-Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of "predisposing factors" (men 30-59 at entry). Framingham Heart Study. SOURCE: Kannel, W. B., et al. (94). Numerous epidemiological studies have indicated that cigarette smokers have increased mortality ratios for CHD ; that is, cigarette smokers show significantly increased death rates compared with nonsmokers (table 2). The risk incurred by cigarette smoking in- creases with increasing dosage and, as measured by mortality ratios, is more marked for men in the younger age groups, under age 60, although the absolute increment in death rates experienced by smokers over that of nonsmokers continues to increase with increasing age. Table 2 lists the mortality ratios found in the major studies. Certain of these studies, including those at Framingham, Massachusetts, the He&h Insurance Plan of New York City (HIP), and at Tecumseh, Michigan, have analyzed morbidity as well as mortality from CHD and have indicated that the risk of developing fatal and nonfatal CHD is greater among cigarette smokers than among nonsmokers (tables 3 and 4). Conflicting evidence has been published concerning the relationship of ciga- rette smoking and the incidence of angina pectoris. While some 24 I I ) I , I 0 2 1 0 Cl#lrcttcr -A No SC-M -6 1.0 1.2 354 1.0 5Zk mL 66 31 483 175 85 1112 Clsarttbr -A M./JK<12.9 -6 20 15 96 1.3 122 10 279 fld 153 391 469 289 978 Cigarettes -A $3. BP 130+ -B Cigarettes -A Height <66 -B 1.5 2.4 i5i 140 2.0 9s 124 Cigarettes -A Parent dead -9 1.6 No sport -A Ht., %40 .2.41 (118) Follow- Number (Yeuaprs, of deaths Cigarettes/day Doyle 2,282 males. Detailed 10 93 NS .l.OO (20) et al., FLW"- medical All smoken .2.40 (73) 1964. ingham. examina- <20 . . .2.00 (17) U.S.A. 30-62 years tio" and 20 .1.70 (20) (54). of age. follow-up. 8 >20 .3.50 (36) 1,913 males. Albany, 39-55 years of age. Doll and Approxi- Question- 10 1.376 NS _. .l.OO Hill. "lately "sire and All smokers .1.35 1964, 41.000 follow-up 1-14 .1.29 Great male British of death 15-24 ,127 Britain physicians. certificate. >25 .1.43 (50). Strobe1 3,749 male Question- s 162 NS . . .l.OO and Gsell Swiss phy- naire and 1965 sicians. follow-UP l-20 .1.48 Switzer- of death >20 . .1.16 land certificate. (180). Best, Approxi- Question- 6 2.000 NS _. .l.OO 1966 mately naire and All smokers .1.60 (1380) Canada 78.000 follow-up - 20 .1.78 (277) veterans. Kahn 1966 U.S.A. (98). U.S. male veterans 2,265,674 person y-2al.S. Hirayama. 265,118 1967. Japanese Japan adults over (84). age 40. Question- naire and follow-up of death certificate. - Trained in- terviewers and follow- up of death certificate. s/r, 10,890 NS .l.OO (2997) Allsmokers .1.74 (4150) l-9 1.39 (439) 10-20 .I.78 (2102) 21-39 . 1.84 (1292) >39 2.00 (266) 1 91 NS .l.OO (17) l-24 __ ., .1.13 (69) >25 .l.OO (5) Kannel 5,127 males Medical ex- 12 52 NS _. .l.OO (27) et al.. and females amination SM>20 ,220 125) 3 (P20 . ..2.51 (203) 2.47 (199) 1.92 (129) 1.56 (73) Data apply only to males aged 40-4s and free of CHD at entry. NS include pipe. cigar and ex-smokers. 35-44 45-64 65-84 NS .l.OO 1.00 1.00 1-14 .3.73 1.40 1.71 16-24 .4.45 1.73 1.27 225 .1.36 1.92 1.68 NS. .l.OO SM. .1.45 Cigars 30-49 50-69 70 and over NS. .I.OO NS .l.OO 1.00 1.00 SM. .0.98 (16) 20 ,. _. __ .1.85 (65) 1.76 (184) 1.73 (28) SM. .0.96 (95) cigar.4 NS. .l.oo 34. .1.04 (628) Pipes NS. .l.oo SM. .1.08 (386) Prefimin- arY report. ' "P" values specified only for those provided by authors. 27 TABLE 2.-Coronary heart disease mortality ratios (Actual number of deaths [SM = Smokers Author, Year. Number and country, b-P.2 of reference population Follow- Number Data of Cigarettes/day collection (Y%) deaths Hammond 358,534 and male!3 Gartinkel, 445,875 1969, females U.S.A. age 40-7s (76). at entry. Question- naire and follow-up of death certificate. - 6 14.819 Make Females NS .l.OO 1.00 1-9 .1.27 0.84 lo-19 .1.60 1.22 20-30 .1.73 1.52 >40 .1.77 0.61 Paffenbar- 50,000 male Baseline 17-51 1,146 NS . . . . .l.OO ger and former interview matched 3M .1.50 (385) (p20 .2.08 (154) (p20 .3.60 (22) U.S.A. 40-59 years exam- (183). of age at ination. entry. Weir and 68,153 Csli- Question- 5-8 1,718 NS .l.OO Dunn. fornia male mire and All smokers .1.60 1970, workers follow-up 210 .1.39 U.S.A. 35-64 years of death 520 1.67 (205). of age at certificate, >30 ,, .I.74 entry. Pooling 7,427 white Medical ex- 10 239 NS .l.OO (27) Project, nK+les amination 20 ._.. .3.00 (68) Associa- entry. GO". 1970, U.S.A. (88). 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional. miscellaneous, mixed. or a-smokers. 28 wleted to snloliing-l)rospective stztdies (cont.) shown in parentheses) ' NS = Nonsmokers] Cigars, pipes Age variation Comments 41/-&Y NS .1.00 1-u .l.fiO IO-19 ,. .2.69 ?ll-30 3.76 >40 5.51 NS 1.00 l-9 .1.31 10-19 .2.08 20-30 .3.62 >40 .t3.31 Ml&d 51,-59 60-CY 1.00 1.00 1.59 1.48 2.13 1.X2 2.40 1.91 2.79 1.79 FtVTll7lCS 1.00 1.00 1.15 1.04 2.37 1.79 2.68 2.08 3.73 t2.02 70-79 1.00 1.14 1.41 1.49 1.47 tBased on 5-S deaths. 1.00 0.76 0.9R 1.27 JO-44 45-5: 55-69 NS .l.OO 1.00 1.00 (P40 ....... .7.93 All ........ .6.24 45-54 55-64 65-69 1.00 1.00 1.00 2.05 1.41 1.17 3.17 1.64 1.26 3.33 1.66 1.36 3.15 1.42 1.42 2.95 1.56 1.24 NS includes pipes and cigars. SM includes ex-smokem 1.00 (27) 1.20 (24) 29 TABLE 3.-Sztdden death frow coronary (Mortality ratios--actual number Author year, country, reference Numbw and type of population Data Follow-up collection years - Number of deaths Pooling Project, American Heart Association, 1970. U.S.A. (b-8). 7,427 white males 30-5s years of age at entry. Medical examination and follow-up. 10 145 TABLE 4.-Coronary heart disease (Risk ratios--actual number of CHD [SM = Smokers NS = Nonsmokers PRCISPECTIVE STUDIES Author, Year. Number and Data Follow- Number of country. type of collection UP incidents reference population years Cigarettes/day Detailed 10 243muo- NS .l.OO (52) medical examina- tion and follow-u*. cardial All smokers ._ .2.36(191) infarc- <20 _. _. .1.98 (44) tions and 20 . . . . . . . . . . ...2.05 (64) CHD >20 3.04 (83) deaths. Doyle 2.282 males et al., Framingham, 1964, 3C-62years U.S.A. of age. (5.4). 1,913 males Albany, 39-55years of sge. stam1er 1,329 CHD- et al., free male 1966, employees of U.S.A. Peoples Gas (177). CompanY 4b-59 years of age. Epstein, 6,565 male 1967, and female U.S.A. residents (61). of Tecumseh. Mich. Interview 4 46 CHD NS ._ ._ .l.oo (27 and exarnin- ation with 20 cigarettes. 3,83 (2S) > 5 cigars. ._ I > 5 pipes..... - Initial medical examinit- tion and repeat follow-up examinlr- tions. 4 96 male. M&8 92 fern& 40-59 CHD in- NS .__... . ..l.OO (1) &ding EX ._. ._..... 6.53 (10) deaths, Cigarettes .5.!20 (36) angina, and Females myocardial NS _. .l.OO (21) infarctions. EX .0.89 (3) Cigarettes .1.02 (14) `Unless otherwise specified. disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous. mixed, or ex-smokers. 30 /,! r11.f rlisease related to smoking ,,f deaths shown in parentheses) Cigarettes/day Cigars, pipes Comment St.v.cr smoked ........... 1.00 (15) 1.00 (15) See table 1 for description of 10 .................. .1.90 (23) 1.36 (13) Pooling Project. 20 ................... .1.90 (50) >2" ................ ..3.3 6 (44) ,uorbidity as related to smoking manifestations shown in parentheses) 1 EX = Exsmokersl PROSPECTIVE STUDIES-Continued Pipes, cigars Age variation CO"l"X"ts Data include CHD deaths, only on males 40-49 years of age and free of CHD on entry. NS includes pipes, cigars. and ex-smokers. NS includes a-smokers. Includez all CHD. Males-Continued 60 and over 1.00 (7) SM 1.27(11) 1.96 (23) SM FCmales-Continued 1.00(47) 1.31 (5) 0.42 (2) M&8 40-59 .1.80(Z) 60 and Gwer . ...0.86(6) Reexamination of patients was spread over l$$-byear period, but data are re- ported in terms of 4-year inci- dence rates. Actual number of CHD inei- dents derived from data on incidence and total in smok- ing class. 31 TABLE 4.-Coronary heart disease (Risk ratios--actual number of CHD [SM I Smokers NS = Nonsmokers PROljPECTIVE STUDIES Author, year. country, Number and type of reference population Jenkins, 3,182 males et al., 39-59 years 1968, of age at U.S.A. entry. (90). Data collectioll Initial medical examina.. tion and follow-up by repeat examina- tions. Follow- UP Years 4:; Number of incidents Cigarettes/day 104 myo- NS . . . . . . . . . . ..I.00 (21) eardial EX ........... .2.47 (15) infarctions. Current ...... .2.78 (68) O-15:day ..... .t1.39 (45) >I6 .......... ..3.0 6 (59) K@.ollel, 5,127 males et al., and females 1968. 30-59 YQB1`S U.S.A. of age. (9.5). Medical 12 examina,.ion and follow- UP. Shapiro 110,000 male Baseline med- 3 et al., and female ical inter- 1969. eor0llee5 view and U.S.A. of Health examination (172). Insurance and regular Plan of follow-up. Greater New York (HIP) 35-64 y-ears of age. 228 myo- Myocardial Infarction cardial M&8 infarc- NS ._ .l.OO (21) tions. All SM 1.51(153) 380CHD. Heavy SM .I.85 (59) Risk of CHD (mwrall) M&8 NS ._ .l.OO (61) l-10 .1.34 (25) 11-20 .1.80 (90) >20 .2.41 (76) - Total Moles unspeci- NS .l.OO fied. All current .2.14 cigarettes ( p20 . . . . . . . . ...2.33/ >40 . . . . ...6.36 Keys 1970 Yugo- slavia Finland Italy Nether- lands GrWCe (Ill). 9,186 males Interviewr. 5 65 deaths. NS, EX in 5 coun- and rcgu- 80 lnYocar- (SM <20) .1.00(305) tries 40-59 lar follow- dial in- All current gears of up examina- farctions. 020) .1.31(103) age at entry. tion by 128 angina local pectoris. physicians. 155 other t428 total. `Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed. or es-smokers. 32 morbidity as related to smoking (cont.) manifestations shown in parentheses)' EX = Ex-smokersl PROSPECTIVE STUDIES-Continued Pipes, cigars Age variation Comments ~PO.Ol) (P20 . . . . . . . . ...1.17 (13) U.S.A. controls in s examina- myoeardial (4% 49). clinical trial of tions. infarctions. a diet high in unsatu- rated fat. DU"" 13,148 male Data only up to 14 Total un- et al.. patients in on new specified. 1970 periodic health incidents U.S.A. examination extracted (55). clinics. from clinic records. Pooling 7.427 white Medical 10 538 Project, males 30-59 examinai ion Includes Never smoked .l.OO (53) American years of and follow- fatal and 20 ,328 (154) 1910. infarction U.S.A. and sudden (88). death. Paul et al.. 1,989 western Screening 1963. Electric Co. exami"a:ion COTOWQ/ U.S.A. male workers and cases (87) (148). participating history. NS 23 in a prospec- l-7 2 tive study 8-12 9 for 455 years. 13-17 6 18-22 41 23-27 3 >28 9 `Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individtial smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 34 morbidity as ,related to smoking (cont.) manifestations shown in parentheses)! EX = Ex-smokersl PROSPECTIVE STUDIES-Continued Pipes, cigars Age variation Comments All CHD including EKG diagnoses. No data on NSasa separate group. 30-39 40-49 50-59 t Includes tLow NS, EX, and SM 1.00(25) 1.00(125) 1.00(157) <20 cigarettes/ %High day. SM 2.17(10) 0.90 (31) 1.41 (53) $>2OCiga- rettes/day. Includes all CHD but ezcludes death. No data avail- able comparing smokers and nonsmokers. 1.00(53) 1.25(64) GmmmaTy controls (1,786) 33 7 11 12 30 2 6 (P20 . . .1.15(18) smokers. Albany. 39-55 years of age, Jenkins 3,182 males Initial medical 4% 29 NS ..l.OO (9) NS include et al., wed 39-69 examination All current former pipe 1968, at entru. and follow- cigarettes . ..1.44(16) and ciaal U.S.A. up by repeat >16 ,. ,, ._ ..1.63(14) smokers. (90). examina- tion. KanlWl 5,127 males Medical 12 107 et al.. and females examination NS U.S.A. years of age and follow- Heavy SM. .ZO (94). 30-59 "P. cigarette3 . . NS Cigarette SM M&8 1.00 (16) .2.04(17) FWLflkl .1.00(68) .0.65(16) Shapiro 110.000 male Baseline 3 Total Males Females M&8 M&8 t CP40 . . . . . . ..4.85$ 1.20 >40 ., .10.15 2.m 6.15 follow-up. FlWUdC8 NS .l.OO 1.00 1.00 Current cigarettes .1.56 1.67 0.97 <40 .1,67 1.63 1.04 ": >40 - 4.12 - t Unless otherwise specified, disparities between the total number of to the exclusion of either occasional, miscellaneous. mixed, or ex-smokers. manifestations and the sum of the individual smoking categories are due smokers caused by the increased carboxyhemoglobin level. With respect to the acute event of myocardial infarction, atten- tion has been focused on the role of nicotine. Nicotine stimulates the myocardium, increasing its oxygen demand. Other experiments have demonstrated that in the face of diminished coronary flow (due to partial occlusion from severe atherosclerosis in man or to partial mechanical obstruction in the animal), nicotine does not lead to an increase in coronary blood flow as seen in the normal individual. These effects exaggerate the oxygen deficit when the supply of oxygen has already been decreased by the presence of carboxyhemoglobin. Thus, a marked imbalance between oxygen demand (which has been increased) and oxygen supply (which has been decreased) is created by the inhalation of CO and nico- tine. This imbalance may contribute to acute coronary insufficiency and myocardial infarction. EPIDEMIO.LOGICAL STUDIES Numerous epidemiological studies, both retrospective. and pros- pective, have been carried out in various countries in order to iden- tify the risk factors associated with the development of coronary heart disease (CHD) . Many of these studies have included smok- ing as one of the variables investigated. Tables 2 to 4 present the major findings. CORONARY HEART DISEASE MORTALITY Table 2 lists the various prospective studies concerning the rela- tion of CHD mortality and smoking. These studies demonstrate the dose-related effect of cigarette smoking on the risk of developing CHD. For example, the Dorn Study of U.S. Veterans as reported by Kahn (93) reveals progressively increasing mortality ratios, from 1.39 for those smoking 1 to 9 cigarettes per day to 2.00 for those smoking more than 39 cigarettes per day, Although the data are not detailed in the accompanying tables, several of these stud- ies have also shown that increased rates of CHD mortality are associated with increased cigarette dosage, as measured by the degree of inhalation and the age at which smoking began. Although not as striking, the data for females reveal the same trends. In most studies, the smokers' increased risk of dying from CHD appears to be limited mainly' to those who smoke cigarettes. Some studies that have investigated other forms of smoking have shown much smaller increases in risk for pipe and cigar smokers when compared to nonsmokers. However, the recent study by Shapiro, et al. (172) of a large population enrolled in the Health Insurance Plan (HIP) of New York City showed a significantly increased 38 risk for the development of myocardial infarction and rapidly fatal myocardial infarction for a group consisting of both pipe and cigar smokers. Table 3 details the findings of the American Heart Association Pooling Project on sudden death. The Pooling Project, a national cooperative project of the AHA Council on Epidemiology, is de- scribed in table 1 (88). Cigarette smokers in the 30 to 59 year age group incurred a risk of sudden death from CHD substantially greater than that of nonsmokers. Pipe and cigar smokers were observed to show a risk slightly greater than that of nonsmokers (table 3). The relative risk of CHD mortality is greatest among cigarette smokers (as well as among those with other risk factors) in the younger age groups and decreases among the elderly. In table 2, Hammond and Horn found that for those smoking more than one pack per day, the risk is 2.51 in the 50 to 54 year age group and 1.56 in the 65 to 69 year age group. Although the relative risk for CHD among smokers decreases in the older age groups, the actual number of excess deaths among smokers continues to climb since the differences in death rates between smokers and nonsmok- ers continue to rise. CORONARY HEART DISEASE MORBIDITY Tables 4 and 5 list the prospective studies carried on in a num- ber of countries to identify the risk of CHD morbidity incurred by smoking. Here, CHD morbidity includes myocardial infarction as well as angina pectoris. Certain studies, notably those of Doyle, et al. (54)) Keys, et al. (111) , and Taylor, et al. (183) include a number of CHD deaths in their data that could not be separated out using the information provided in their respective reports. As noted in the discussion on CHD mortality, the CHD risk ratio increases significantly as the number of cigarettes smoked per day increases. Similarly, the HIP data of Shapiro, et al. (I?`?) show that the elevated morbidity ratios declined with increasing age as has been shown for mortality ratios. A recent monograph edited by Keys (111) dealt with the 5-year CHD incidence in males age 40 to 59 from seven countries. As summarized in table 4, cigarette smoking was found to be associ- ated with an increased incidence of CHD in the U.S. railroad worker population, 2,571 individuals (183). None of the differences in ratio between smokers and nonsmokers was statistically signifi- cant for the 13 other population samples which varied in size from 505 to 982 individuals, from the five other countries. (Smoking was not considered in the two Japanese populations.) When more cases 39 become available to provide greater statistical stability to the rates, this. intercultural comparison should prove illuminating. The results of those studies which have separated out angina pectoris as a manifestation of CHD are presented in table 5. Doyle, et al. (54) found no relationship between this manifestation of CHD and cigarette smoking. Both Jenkins, et al. (90) and Kannel, et al. (94) observed increased risk ratios among male cigarette smokers although these differences were not statistically signifi- cant. More recently, Shapiro, et al. (172) found a significantly increased risk for angina among their male cigarette smokers as well as increasing risk ratios with increasing dosage among both males and females, particularly in the younger age groups. A variety of hypothetical explanations have been advanced to account for this seeming contradiction. Among these are the relatively small number of cases, the difficulties associated with the definitive diagnosis of the syndrome, and differences in the methods of clas- sifying those cases of angina pectoris which are followed by myo- cardial infarction. RETROSPECTIVE STUDIES Table A 6 presents data from the various retrospective studies of CHD prevalence. Most of these are case-control studies and show an increased percentage of smokers among those with clinical CHD when compared with a selected control population, usually without apparent CHD. Two of these studies include data on mortality. THE INTERACTION OF CIGARETTE SMOKING AND OTHER CHD RISK FACTORS The preceding section has reviewed the epidemiologic evidence which supports the judgment that cigarette smoking is a signifi- cant risk factor in the development of CHD. Many of the studies discussed above have identified a number of biochemical, physio- logical, and environmental factors, other than cigarette smoking, which also increase the risk of developing CHD. These risk factors include elevated serum lipids (particularly serum cholesterol) and hypertension, which, with cigarette smoking, are considered to be of greatest importance. Other factors are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as well as asympto- matic hyperglycemia), electrocardiographic abnormalities, and a positive family history of premature CHD (88). A number of these studies have also found that these factors, when present in the same individual, exert a combined effect on the risk of developing CHD. Figures 1 through 3 depict this inter- action of risk factors. As may be noted in Figures 1 and 2, the 40 additional factor of smoking greatly increases the risk of develop- ing CHD among those people already at high risk because of other factors. Furthermore, these studies have shown that the effect of smok- ing on the risk of developing CHD is statistically independent of the other risk factors. That is, when the effect of the other factors is statistically controlled, smoking continues to exert a significant effect on increasing the risk of developing and dying from CHD. Smoking and. Serum Lipids The interaction of smoking and serum lipid levels in the develop- ment of CHD should be considered in the light of information con- cerning the relationship of smoking to serum lipid levels. Table A7 presents studies which deal with the association between smoking and lipids, notably cholesterol, triglycerides, and lipoproteins (con- cerned with lipid transport). While some of the studies have indi- cated that smokers show increased serum levels of these lipid con- stituents, others have not. The populations investigated and the methods of the various studies show significant variation. This lack of comparability makes interpretation of the findings difficult. It is clear, however, that in the presence of high serum choles- terol, cigarette smoking increases the risk of CHD. Figure 4 de- picts the data from the Chicago Peoples Gas, Light and Coke Com- pany study which show that smoking greatly increases the risk of CHD in each of the cholesterol groups. Smoking and Hypertension Some epidemiological studies have indicated that smokers tend to have lower mean systolic and/or diastolic blood pressures than nonsmokers, while other studies have not found this to be the case (table A8). Reid, et al. (155)) in a study of 1,300 British and American postal workers, found that the blood pressure difference between the smoking and nonsmoking groups was eliminated after controlling for body weight. Tables 9 through 11, derived from the study by Borhani, et al. (27)) demonstrate the following associations : That for both smok- ers and nonsmokers, the risk of dying from CHD increases with increasing diastolic or systolic pressure, and that the risk of mor- tality from CHD is higher among smokers than among nonsmokers in each blood pressure group. Cigarette smoking, therefore, has been shown to elevate CHD mortality independently both of its effect on blood pressure and of the effect of hypertension on CHD. Smoking and Physical Inactivity The recent study by Shapiro, et al. (272) of more than 110,000 41 TABLE 9.-Death rates from coronary heart disease, by systolic blood pressure: ILWU mortality study 1951-61 (Coronary heart disease rts classified under IX Code 420) Smokers Nonsmokers Systolic blood Person-years Death Person-years Death Age group pleSSure in 1961 of observation rate' of observation rate' 45-54 (130 1,877 27 2.413 8 139-149 2,066 34 2,912 l? 150-169 740 95 1,177 26 >170 369 109 672 45 55-64 . . <130 1,067 84 1.560 26 13&-149 1,380 94 2,401 525 150-169 647 93 1,558 46 >170 524 210 1,117 126 1 Rate per 10,000 person-years of observation. 2 plOO lOO 1,527 26 1,700 6 2,115 47 2,947 17 961 52 1,507 33 448 89 1.020 20 1.059 104 1.447 221 1,521 59 2,704 15 669 194 1,521 346 369 163 954 147 1 Rate per 10,000 person-years of observation. 2 p20 cigarettes/day NWer and Garfinkel, 1969. U.S.A. (76). smoked regularly . . ,_ .1.00(1,841) current cigarette smokers 1.90(1,063) stopped 20 1. .1.08 (70) AI1 ex-cigarette smokers .1.16 (263) l.OO(1.841) Male data only 2.55 (2.822) 1.61 (62) 1.51 (154) 1.16 (135) 1.25 (133) 1.06 (80) 1.28 (564) Shapiro et al.. 1969. U.S.A. (17s). Pooling Project, American Heart Association 1970. U.S.A. (88). Total definite myocardial infarction Never smoked .................................... .l.OO Current cigarette smokers ........................ .1.87 Stopped 25 years ................................. .0.76 AU CHD deaths Never smoked ., .1.00(2'7) >`h pack/day .1.65(34) 1 pack/day ._ ,... _. .1.70(86) >l pack/day .3.00(68) Ex-smokers .0.80(19) First major coronary event 1.00 (53) See table 4 1.65 (72) for description 2.08(205) of Pooling 3.28(X4) Project. 1.25 (51) TABLE 16.-Annual probability of death from coronary heart disease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking Age started smoking 15-W 20-24 Maximum daiLv number of &a- r&es smoked Current smokers Discontinued Discontinued for five or Current for five or more years smokers more years (Probability X10 s, 56-64 . . ,_. . . 0 601 501 - lo-20 798 568 811 551 21-39 969 766 872 698 65-74 1 . . 0 1.015 1.015 lc-20 1;501 1,169 11478 1,213 21-39 1,710 1,334 1,573 1,098 1 For age group 65-14. probabilities for discontinued smokers are for 10 or more years of dis- continuance since data for the 5-9 year discontinuance group we not given. SOURCE: Cornfield. J., Mitchell. S. (4.5). Based on data derived from Kahn, H. A. (93). 46 Smoking and Electrocardiographic Abnormalities Electrocardiographic (ECG) abnormalities such as T-wave and ST-segment changes as well as a number of arrhythmias are use- ful indicators of CHD and may, therefore, be predictive of the development of clinically overt CHD manifestations. The results summarized in table IS, from the prospective study by Borhani, et al. (27), reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smoking and Heart Rate Recent analysis by Berkson, et al. (23) of the data derived from the Chicago Peoples Gas, Light and Coke Company study of middle-aged men revealed that resting heart rates of 80 or greater were associated with an increase in the risk of death from CHD. These authors found that this association was independent of the other major coronary risk factors. Table 14 presents i`ne interaction between smoking, blood pres- sure, and elevated heart rate in increasing the risk of CHD mor- tality. This study shows that cigarette smoking increases CHD risk in the presence of elevated heart rate as well as in its absence. THE EFFECT OF CESSATION OF CIGARETTE SMOKING ON CORONARY HEART DISEASE A number of epidemiological studies have been concerned with the CHD incidence and mortality among ex-cigarette smokers as Compared with current smokers (51, 76, 88, 90, 93, 172). These studies are listed in table 15. Table 16 presents the data derived by Cornfield and Mitchell (45) from the Dorn Study of U.S. Veterans (93). Ex-cigarette smokers show a reduced risk of both myocardial infarction and death from CHD relative to that of continuing ciga- rette smokers. The Pooling Project (88) and the Western Collab- orative Study Group (192) which adjusted for the other risk fac- tors of elevated serum cholesterol and blood pressure observed this relationship. Hammond and Garfinkel (76) noted that cessation of smoking is accompanied by a relative decrease in risk of death from CHD within 1 year after stopping. This decreased risk of CHD among ex-smokers further strength- ens the relationship between smoking and CHD. It must be noted, however, that the group of ex-smokers is composed of individuals who have stopped smoking for a variety of reasons. Those who stop because of ,ill health and the presence of symptoms are gen- erally at high risk and can bias the group results in one direction; 47 those healthy persons who stop as part of a general concern about their health and may adopt a number of self-protective health prac- tices are generally at low risk and can bias the group results in the other direction. Therefore, ex-smokers as a group are not fully representative of the entire population of smokers and may have limited value in predicting what would happen if large numbers of cigarette smokers stopped smoking purely for self-protection. Cer- tain incidence studies, such as the Pooling Project (88)) were initi- ated with only clinically healthy individuals. The data from such studies, as well as those from the British physicians study, contain ex-smoker data less influenced by these biases. Fletcher and Horn (63) have recently presented data derived from the British physicians study of Doll and Hill. Over the past lo-15 years, cigarette smoking rates among British physicians have declined significantly in comparison with those of the general British population. The information presented by these authors concerning all cardiovascular diseases showed that for individuals between the ages of 35 and 64, the age-adjusted death rate for CHD declined by 6 percent among physicians and rose by 10 percent among the male population of England and Wales during the period from 1953-57 to 1961-65. THE CONSTITUTIONAL HYPOTHESIS The effect of smoking on the incidence of CHD has been found to be independent of the influence of the other CHD risk factors. When such risk factors as high serum cholesterol (177)) increased blood pressure (27)) elevated resting heart rate (23)) physical in- activity (2 72), obesity (27)) and electrocardiographic abnormali- ties (27) have been controlled, cigarette smokers still show higher rates of CHD than nonsmokers. It has been suggested by some (39, 170) that the relationship between cigarette smoking and CHD has a constitutional basis. That is people with certain constitutional make-ups are more likely to develop CHD, and the same people are more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and CHD is thus largely fortuitous and that the significant relationships are between the genetic make-up of the individual and CHD and between the genetic make-up of the indi- vidual and his becoming a cigarette smoker. Two sets of epidemio- logic data bear on this hypothesis. It has been maintained that people with a certain temperament are more likely to smoke and also more likely to develop CHD. These characteristics have been demonstrated for those with the 48 of 1.6, while those in the second group were found to have one of approximately 1.1. The authors concluded that this difference be- tween the two groups provides better support for the importance of constitutional factors as against the importance of cigarette smoking in the development of angina pectoris. A similar study was done using the responses of 4,379 U.S. Vet- eran twin pairs (approximately 60 percent of estimated available total) who completed the mailed questionnaires (38). Cederlof, et al. found a significantly increased prevalence of chest pain and "angina pectoris" among smokers when Group A was analyzed. Analysis of the smoking-discordant matched twin pairs (Group B) revealed no association between smoking and cardiovascular symp- toms among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors concluded that this lack of association among the monozygotes and its presence among the dizygotes and unmatched pairs strengthens the case for a constitu. tional hypothesis. A major problem in ,these studies is the small number of cases available and, therefore, the statistical instability of the results, In the Swedish study, among the 274 monozygotes, only 19 smokers and 16 nonsmokers were classified as having angina pectoris while among the 733 dizygotes, 25 smokers and 25 nonsmokers were so classified. In neither group was the difference between the prev- alence ratios found in the Group A analysis and that in the Group B analysis of statistical significance. Analysis of the data on women shows a similar lack of significance. Similar criticisms may be made of the study which utilized the U.S. Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris between the low-cigarette-exposure and high-cigarette-exposure dizygotic groups was not present among the monozygotes. The authors ques- tioned whether the excess morbidity associated with cigarette smoking found in the dizygotic group was causal as it was not pos- sible to reproduce the association when studying monozygotic smoking-discordant twin pairs. As noted above, the numbers in this study are also small so that the differences in rates do not approach statistical significance. Tibblin (288) has questioned the value of a mailed questionnaire to diagnose heart disease. The questionnaire as originally con- structed was used and validated by interview technique alone (157, 158). Cederlof, et al. (~$0) conducted a study to determine the validity of this questionnaire as a mailed instrument by personally interviewing and examining 170 of the twin pairs who had replied. Of the eight males who were diagnosed as having "angina pectoris" by the questionnaire. four were found to be free of symptoms on 50 clinical examination, while among 204 responding negatively, two were found to have angina by clinical criteria. None of the 11 women who were diagnosed as positive by questionnaire was found to be clinically affected, and of the 136 reporting as negative, three had symptoms of angina pectoris. Other major difficulties associated with these studies include the problems of using prevalence data in the investigation of a disease (CHD) from which a significant number of those affected die shortly after the onset of symptoms, the inclusion of ex-smokers in the smoking population, and the low numbers of heavy cigarette smokers in the Swedish population. In general, the problems of using twin registries to study the etiology of cardiovascular disease with mortality and morbidity ratios in the neighborhood of 2 to 1 are much more difficult than in studying the etiology of bronchopulmonary disease in which the relationships are of the order of magnitude of 4 to 1. More recently, Friberg, et al. (69) reported on mortality data from the Swedish Twin Registry. The authors suggested that part of the increased mortality observed among smokers when com- pared with nonsmokers was not due to smoking per se but to fac- tors associated with smoking. The very small numbers of total deaths presently available (47 deaths among 706 dizygotic pairs and 13 deaths among 246 monozygotic pairs) do not provide a sta- tistically stable base for deriving any conclusions at the present time. Hauge, et al. (81) have recently reported on the influence of smoking on the morbidity and mortality observed in the Danish Twin Register. Among 762 monozygotic and same-sexed dizygotic twin pairs, angina pectoris was found to be significantly more fre- quent in those cotwins with a higher consumption of tobacco than in those with a lower or no consumption. A similar tendency was observed for myocardial infarctions but was not of statistical significance. Seltzer, who has been a proponent of the constitutional hypothe- sis, in a recent review of some of the experimental, clinical, and pathological data relating smoking and CHD, concluded that the evidence from these areas has not "reasonably substantiated" the "hypothesis" of the acute effect of cigarette smoking on the coro- nary circulation, nor has the chronic effect of cigarette smoking on the cardiovascular system been shown to be a "clear" and con- sistent one (170). His views are contrary to those of most re- searchers in this field, Although the data from the twin studies are inconclusive with regard to a role for genetic factors in heart disease, it would be surprising if genetic factors did not play such a role. It is open to 51 question whether findings from twin studies can be used to distin- guish between the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exogenous influence such as cigarette smoking and the hypothesis that genetic factors "cause" both heart disease and smoking. AUTOPSY STUDIES RELATING SMOKING, ATHEROSCLEROSIS, AND SUDDEN CHD DEATH A number of researchers have investigated the cigarette smoking habits and the cardiovascular pathology of those individuals dying suddenly from CHD and of large populations of individuals with and without histories of overt CHD. Spain and Bradess (175) recently analyzed the smoking habits of 189 individuals who died suddenly and unexpectedly, apparently from the first acute clinical episodes of CHD. The authors noted a close correlation of a history of cigarette smoking with this type of sudden death and also with shorter survival times following the acute episode. This association was strongest in those persons under 50 years of age. The authors also observed that those surviving very short pe- riods of time showed a notable lack of intracoronary artery throm- bi at autopsy and that the frequency of thrombi present increased with increasing survival time. They suggested that thrombi found at autopsy may be the result rather than the cause of certain instances of myocardial infarction, particularly of lesions showing subendocardial necrosis. This finding is of significance in the study of the effect of smoking on myocardial metabolism and oxygen supply and demand rather than on thrombus or platelet plug formation. While the autopsy study of Spain and Bradess (175) concerned sudden death among smokers, other autopsy studies from various countries have been directed towards the relationship of cigarette smoking to the presence of atherosclerotic disease in the aorta and coronary arteries. These are concerned with the long-term effects which smoking has on the cardiovascular system and are sum- marized in table 19. The studies of Auerbach, et al. (12)) Avtan- dilov, et al. (13)) Sackett, et al. (165)) and Strong; et al. (182) found that aortic and coronary atherosclerosis were more common and more severe among smokers than among nonsmokers. Auerbach, et al. (12) noted that this relationship persisted when the cases were matched for both age and cause of death or when the follow- ing cases were excluded; men with a history of diabetes; men who had died of any type of heart disease; and men whose hearts weighed 400 grams or more. Sackett, et al. (165) found that the 52 (Figures in parentheses are number ut individuals in that smoking category)' [SM = smokers NS = nonsmokers] Author. Year. countru, reference Autopsy population Data collection Cigarettes per dny Conclusions Comments Wilens 989 consecutive Routine clinical Severity of am-tic sclerosis The authors conclude that Smoking data unavailable and Plair, male autopsies records of Above average Average Below average in 60 percent of cases. the for 120 cases. 1962, at New York previous and NS . . . 9.9(161) 60.2 29.8 degree of sclerosis at Each aorta specimen given U.S.A. City VA present <20 . 19.1(162) 63.2 17.8 autopsy was e"mme"- an "atherosclerotic age" (214). hospitals. admissions. 20-30 .,,,..... 26.4(288) 62.5 11.1 surate with age of patient. by comparison with a >30 .t25.1(199) 61.3 t13.6 regardless of smoking standard. If "athero- habits. In the remaining sclerotic age" was found 40 percent there is evi- to be 10 years more than dence that cigarette real age. the aorta was smoking may be ass"- said to show above- ciated with an above- average sclerosis. average degree of aortic tp40 . . . . ..0.6(144) 18.1 36.4 45.9 smoking. This relation- have overt CHD ship persisted even at death. when cases were matched for age and cause of death. 1 unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the cn w exclusion of either occasional. miscellaneous, mixed, or ex-smokers. TABLE 19.-Autopsy studies of atherosclerosis (cont.) (figures in parentheses are number of individuals in that smoking category)' [SM = smokers NS = nonsmokers] !E Author, year, Autopsy Data cou"trY. population collection Cigarettes per day Conclusions CO"l"l.3h reference Avtandilov. 269 male and Not specified, Comparative size of mean area of alhe+osclerotic ~&WUI The author concludes that Causes of death 96-athero- 1966, 141 female hut there were: in inner coat of eosmkwu a+teriea. the worst changes were sclerotic, lO%accidental. RUSB~IS autopsies. 130 SM and Right ~o?`onaw artery Left cosona~~ artery found in the left and POP-various diseases. (16). 220 NS. SM NS SM NS right coronary arteries tT-test for sjgnificance 30-3s Q5.5(30) 1.3(32) t6.3 2.2 with less severe changes of difference between 40-4s t23.6 (34) 11.6(27) t1e.e 4.4 in circumflex artery means is significant 60-59 ..t36.3(39) 14.8(39) 127.9 9.9 and aorta. at P25 cigarettes/day .12 (9) 31(14) 26(25) 39(20) The authors conclude that: This report concerns o"Iy "Atherosclerotic in- ages 26-64. volvement of aorta and No data on statistical coronary arteries is significance provided. greatest in heavy smokers and least in nonsmokers." NS . Negro 4(14) 3 (3) 16(11) 17(14) l-24 cigarettes/day 3(39) ll(31) 14(30) 28(22) >25 cigarettes/day .17(10) 14(17) 29(12) 16(11) `Unless Otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional. miscellaneous, mixed, or a-smokers. severity of aortic atherosclerosis, as measured both by intensity and duration, increased with increasing use of cigarettes and that this dose-relationship persisted when the patients were matched for the consumption of alcohol. On the other hand, Viel, et al. (ZOO) concluded from their study of accidental deaths in Chile that "no relationship between atherosclerotic lesions and the use of tobacco was discernible." Examination of the data (provided in graph form only) indicates that heavy smokers showed consistently higher percentages of diseased areas than nonsmokers, but appar- ently these differences were not statistically significant when sub- jected to an analysis of variance. Thus, in addition to the acute effects which smoking exerts on cardiovascular physiology, cigarette smoking is associated with a significant increase in atherosclerosis. EXPERIMENTAL STUDIES CONCERNING THE RELATIONSHIP OF CORONARY HEART DISEASE AND SMOKING Several areas of interest in cardiovascular pathophysiology have been investigated in the search for the mechanisms by which ciga- rette smoking contributes to cardiovascular disease, particularly coronary artery disease. Previous Public Health Service Reviews (191, 192, 193, 198) have described in detail and commented on the results of experiments by many teams of researchers. Central to the discussion which follows is a concept of cardiac physiology which provides a framework for analysis and under- standing of the varied research. That concept concerns the dynamic balance between myocardial oxygen need and supply. CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE The inhalation of tobacco smoke or the parenteral administra- tion of nicotine has been found by many researchers to be asso- ciated with a number of specific acute cardiovascular responses. These responses have been observed in human as well as animal subjects, including increased heart rate, blood pressure, cardiac output, stroke volume, velocity of contraction, myocardial contrac- tile force, myocardial oxygen consumption, arrhythmia formation, and electrocardiographic or ballistocardiographic changes (tables A20 to A22). The effect of these responses on coronary blood flow will be discussed in a following section. That the acute effects observed following the inhalation of ciga- rette smoke are due primarily to the nicotine present in the smoke may be seen in the results of a number of experiments. In humans, I