A Reference Edition Selected Chapters From 1971 Through 1975 Reports With Cumulative Index For All Reports 19641975 U.S. Department of Health, Education, and Welfare Public Health Service cmltar for Dii Control Athnta, Gewpia 30333 THE HEALTH CONSEQUENCES OF SMOKING A Reference Edition Selected Chapters From 1971 Through 1975 Reports With Cumulative Index For All Reports 1964-1975 U.S. Department of Health, Education, and Welfare Public Health Service Center far Diia50 Controi Atlanta, Georgia 30333 1976 HEW Publication Nd. (CDC) 78-8357 October 1977 Honorable Thomas P. O'Nelll Speaker of the House of Representatives Kashfngton, D.C. 20515 Dear ?fr. Speaker: As required by Section 8(a) of the Public Health Cigarette Smokfng Act of 1969 (Public Law 91-222). enclosed is the 1976 Report to Congress on the Health Consequences of Smoking. This year's report includes the "Bibliography on Smoking and Health - 1975," the official abstract bulletin of the National Clearinghouse for Smoking and Health. Bureau of Health Education. Center for Disease Control. Public Health Service. It presents the scientific information published since last year's report to Congress. Also part of this year's report is 'The Health Consequences of Smoking. a Reference Edition." a compilation of selected chapters from previous reports to Congress. This reference edition was prepared to emphasize the fact that the major health risks from smoking are know" and that recent scientific information refines the understanding of these relatlonshlps. Without doubt. cigarette smoking is a cause of cardiovascular disease. various types of cancer, and respira- tory disease. Its toll lo illness and premature death 1s needless and preventable. Because of ny strong commitment in reducing the morbidity and mortality which result from smoking. the Department 1s conducting a major review of its prograrrm 1" this field in order to introduce administrative and legislative proposals to combat this problem. Sincerely. Joseph A. Cslifano. Jr. Eoclosure PREFACE ?e health consequences of cigarette smoking are well established. ad have bee; clearly understood for several years. The causal re- k ionships between cigarette smoking and an excess risk of devel- Fing cardiovascular disease, respiratory tract cancers, and chronic 1 structive lung disease, as well as the risk to the fetus, are well cumented and accepted by the scientific and health communities. r the past several years, new additions to the literature have bstantiated i' these risks and further explained the mechanisms which smoking produces disease, disability, and death; however, search has identified no new major health risks. Therefore, it ems appropriate at this time to prepare a reference document viewing the full range of health hazards due to smoking. is reference report consists of selected chapters from previous ports to the U.S. Congress which present summations of the i own health hazards from smoking. Because the 1971 report was review of all information on smoking and health at that time, chapters were included from reports prior to that time. This `ference, coupled from the annual Bibliography on Smoking and le E alth, represents a complete description of major smoking and alth information. e scientific evidence is clear and unavoidable, and the important k now is to convert this knowledge into programs for reducing d eliminating the preventable death and disability related to the oking habit. Theodore Cooper, M.D. Assistant Secretary for Health TABLE OF CONTENTS Page PREFACE ~.._...___.___._..__________..._.......... ... 111 TABLEOFCONTENTS . . . __. . _. _ _ _. _ _. . . . . . . . . . . _. . . . . v PREVIOUS PUBLIC HEALTH SERVICE REPORTS ON SMOKING AND HEALTH _ _ . _ _ _ _ _ . . . _ . . . . . . . . . . . . . . . vii ACKNOWLEDGEMENTS . . . . _ _ . _ . _ . . . . . _ . . . _ _ _ _ _ . . . . . . . . ix CHAPTER 1 CHAPTER 2 CHAPIER 3 CHAPTER 4 CHAPTER 5 CHAPTER 6 CHAPTER 7 CHAPTER 8 CHAPTER 9 Overview (197.5 Report) _ . . . . . _ . . . . _ . _ _ . . _ . _ . . . 1 Cardiovascular Disease _ . . _ . . . . _ . . . . _ _ _ . . _ _ _ _ . . . 9 Part 1 (1971 Report, Chapter 2) _ _ . . . . . . _ . . . _ . _ . _ . 11 Part 2 (1975 Report, Chapter 1) . . _ . . . . . . . . . _ . . . . _ 131 Chronic Obstructive Bronchopulmonary Disease (1971 Report, Chapter 3) . . . . . . . _ . . . _ _ . . _ . . . . . . 161 Cancer (1971 Report, Chapter 4) . . . . _ _ _ . . . . . . . . . _ 257 Pregnancy (1973 Report, Chapter 4) . . . . . _ . _ . . . _ . . _ 411 Peptic Ulcer Disease (1973 Report, Chapter 5) . . . . . _ _ _ . 465 Involuntary Smoking (1975 Report, Chapter 4) . . . . . . . . 479 Allergy (1972 Report, Chapter 7) . _ . _ _ . . . . . . _ . . . . . 509 Tobacco Amblyopia (197 1 Report, Chapter 7) . . . . . . . 527 CI-IAPIER 10 Pipes and Cigars (1973 Report, Chapter 6) _ . . . . . . . . _ _ 535 CHAPTER 11 Exercise Performance (1973 Report, Chapter 7) . . . _ . _ . _ 607 CHAPTER 12 Harmful Constituents of Cigarette Smoke (1972 Report, Chapter 9) . _ . . . . . _ . _ . _ _ . . _ . . _ _ _ . 621 INDEX This Report . . . _ . . _ _ . . . . _ _ _ . . . _ . . . . _ . . _ _ . . . _ 635 CUMULATIVE INDEX (1964 - 1975) _ . . . . . . _ _ . _ . . . . . . . _ . . . . . 000 Previous Public Health Service Reports on Smoking and Health Reviews of the scentitic evidence linking smoking to health effects began in 1964 with Smoking and Health, Report of the Advisory Committee to the Surgeon General of the Public Health Service or as subsequently referred to "the Surgeon General's Report." After this report, Public Law 89-92 was passed requiring supplemental reports to Congress on this subject. In compliance, three reports were submitted: 1. The Health Consequences of Smoking, A Public Health Service 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. In April 1970, Public Law 91-222 amended the previous law and called for an updated report on the health effects of smoking no later than January 1, 197 1, with annual reports thereafter. The Health Consequences of Smoking, A Report of the Surgeon General: 1971, a comprehensive review of all the scientific literature available to the National Clearinghouse for Smoking and Health and with emphasis on the most recent additions to the literature was that updated report. Since then, the following annual reports on the health consequences of smoking have been submitted: 1. The Health Consequences of Smoking, A Report of the Surgeon General, 1972. 2. The Health Consequences of Smoking, 1973. 3. The Health Consequences of Smoking, 1974. 4. The Health Consequences of Smoking, 1975. Each report since the original "Surgeon General's Report" has reviewed the scientific literature relevant to the association between smoking and Vii cardiovascular diseases, non-neoplastic bronchopulmonary diseases. and cancer. Smoking as related to the following diseases and condiiions has been reviewed periodically in the reports: Pregnancy(1967.1969, 1971,1972,1973) Peptic Ulcer Disease (1967,197 1,1972,1973) Public Exposure to Air Pollution from Tobacco Smoke (1972,197s) Noncancerous Oral Disease (1969) Tobacco Amblyopia (197 1) Allergy (1972) Harmful Constituents of Cigarette Smoke (1972) Exercise Performance (1973) Pipe and Cigar Smoking (1973) Overview: The Health Consequences of Smoking (1975) . . . vlu ACKNOWLEDGMENTS Preparation of this reference edition, The Health Consequences of Smoking, was the responsibility of the National Clearinghouse for Smoking and Health; Charles A. Althafer, Acting Director; David M. Burns, Medical Staff Director; Priscilla B. Holman, Technical Editor; Donald R. Shopland, Technical In- formation Officer. Individual chapters comprisin, 0 this reference volume are from reports which were prepared under the direction of Daniel Horn, Ph.D., Director of the Clearinghouse,-currently on assignment to the World Health Organization. The following persons served as medical staff directors or consultants for the preparation of the reports whose chapters are included in this reference edi- tion: Elvin E. Adams, M.D.; Daniel P. Asnes, M.D.: David M. Burns, M.D.; David G. Cook, M.D.; John H. Holbrook, M.D.; Paul Schneiderman, M.D.; and H. Stephen Williams, M.D. The following persons provided assistance and advice for the preparation of reports whose chapters are included in this reference edition. Reviewers' AncJerson,`William H., M.D. - Chief, Pulmonary Disease Section, University of Louisville, School of Medicine, Louisville. KY. Anthonisen, Nicholas, I?., M.D., Ph.D. - Director, Respiratory Division for the Health Sciences Center, Winnipeg General Hospital, Winnipeg, Canada. Auerbach, Oscar, M.D. - Senior Medical Investigator, Veterans Hospital, East Orange, NJ. Ayres, Stephen M., M.D. - Professor and Chairman, Department of Internal Medicine, St. Louis University Medical School, St. Louis, MO. Baker, Carl, M.D. - Director, Program Policy Staff, Health Resources Ad- ministration, U.S. Department of Health, Education, and Welfare, Wash- ington, D.C. tBellet, Samuel, M.D. - Director, Division of Cardiology, Philadelphia -_ General Hospital, Philadelphia, PA. Bing, Richard .I, M.D. - Visiting Assoctie in Biomedical Engineering, California Institute of Technology, Pasadena, CA. Bock, Fred G., Ph.D. - Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, NY. Boren, Hollis, M.D. - Professor of Medicine, University of South Florida Medical Center, Tampa, FL. Boutwell, Roswell K., M.D. - Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI. Brass, Irwin, M.D. - Director of Biostatistics, Roswell Park Memorial Institute, Buffalo, NY. `Current addresses. `Deceased. ix Cooper, Theodore, M.D. - Assistant Secretary for Health, U.S. Department of Health, Education and Welfare, Washington, DC. Cornfield, Jerome - Research Professor of Biostatisticr, University of Pittsburgh Graduate School of Public Health, Biostatistics Project, Bethesda. MD. Earl, Christopher J., M.D. - National Hospital, London, England. Epstein, Frederick H., M.D. - University of Zurich, Zurich, Switzerland. Falk, Hans L., Ph.D. -`Associate Director for Program, National institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Farr, Richard, M.D. - Director, Department of Medicine, Section of Allergy and Clinical Immunology, National Jewish Hospital and Research Center, Denver, CO. Ferris, Benjamin G., Jr., M.D. - Professor, Department of Physiology, Harvard School of Public Health, Boston, MA. Finklea, John F., M.D. - Director, National Institute for Occupational Safety and Health, Center for Disease Control, Public Health Service, U.S. Department of Health, Education and Welfare, Rockville, MD. Fitzpatrick, Mark J., M.D., M.P.H. - Fairhaven Medical Associates, Inc., Fairhaven. MA. Frazier, Todd M. - Assistant Director. Harvard Center for Community Health and Medical Care. Harvard School of Public Health, Boston, MA. Freston, James, M.D. - Associate Professor of Medicine; Chairman, Divisions of Gastr.oenterology and Clinical Pharmacology, University of Utah Medical School. Salt Lake City, UT. Goldsmith, John R., M.D. - Medical Epidemiologist, Epidemiological Studies Laboratory, California State Department of Health, Berkeley, CA. Gori, Gio B., Ph.D. - Deputy Director, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD. Hanna, Michael G., Jr., Ph.D. - Director of Basic Research, Frederick Cancer Research Center, Frederick, MD. Harkavy, Joseph, M.D. - Clinical Professor of Medicine(Emeritus1, the Mount Sinai Medical School of the University of New York, New York, NY. Harke, H. -P., Ph.D. - Forschunginstitut der Cigarettenindustrie, e.V., Hamburg, Germany. Higgins, fan T. T.. M.D., F.R.C.P. - Professor, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Ml. Hoffmann, Dietrich, Ph.D. - Member, and Chief, Division of Environmental Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, NY. Israel, Robert A. - Acting Deputy Director, National Center for Health Statistics, Public Health Service. U.S. Department of Health, Education, and Welfare. Rockville, MD. `Current addresses. `Deceased. X Jennings, Michael, M.D. - Epidemic Intelligence Service, Center for Disease Control located at Ohio Department of Health, Columbus. OH. Keller, Andrew Z., D.M.D., M.P.H. - Chief, Research in Geographic Epidemiology. Medical Research Service. Veterans Administration Central Office, Washington, DC. Kirsner, Joseph, M.D. - Professor of Medicine, University of Chicago School of Medicine, Chicago, IL. Knox. David L., M.D. - Associate Professor, The Wilmer Opthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore. MD. - Kolbye, Albert C., Jr., M.D., J.D. - Director, Office of Sciences, Bureau of Foods, Food and Drug Administration, U.S. Department of Health, Education and Welfare, Washington, DC. Kotin, Paul, M.D. - Senior Vice President of Health, Safety, and Environ- ment Division, Johns-Manville Company, Denver, CO. Krumholz, Richard A.. M.D. - Medical Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering, OH. Lenfant, Claude, J. M., M.D., - Director, Division of Lung Diseases, National Heart and Lung Institute, National Institutes of Health, Bethesda, MD. Liebow, Averill A., M.D. - Professor and Chairman, Department of Pathology, University of California at San Diego, LaJolla, CA. Lilienfeld, Abraham, M.D. - University Distinguished Service Professor of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD. Lowell, Francis C., M.D. - Chief, Allergy Unit, Massachusetts General Hospital, Boston, MA. MacMahon, Brian, M.D. - Professor, Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA. McLean, Ross, M.D. - Professor of Medicine and Chief of Pulmonary Services, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC. McMillan, Gardner C., M.D. - Assistant Director for the Etiology of Arteriosclerosis and Hypertension, National Heart and Lung Institute, National Institutes of Health, Bethesda, MD. -_ - _ Manning, Kathleen M., R.N. - Department of Staff Development, Boston City Hospital, Boston, MA. Meyer, Mary 8.. Mrs. - Assistant Professor of Epidemiology, The Johns Hopkins University, Baltimore, MD. Mitchell, Roger S., M.D. - Chief of Staff, Veterans Administration Hospital. Denver, CO. Murphy, Edmond A., M.D. - Professor of Medicine and Biostatistics. The Johns Hopkins University, Baltimore, MD. Nettesheim, Paul, M.D. - Group Leader, Respiratory Cnrcinogenesis Group. Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN. ' C~mnc addresses. `Deceased. xi Newill, Vaun A., M.D. - Executive Office of the President, Office of Science and Technology, Washington, DC. Paffenbarger, Ralph S., Jr., M.D. - Epidemiologist, California State Depart- ment of Health, Berkeley, CA. Parker, Charles W.. M.D. - Professor of internal Medicine, Division of Immunology. Washington University Medical School, St. Louis, MO. Peters, John M., M.D. - Associate Professor of Occupational Medicine, Harvard University School of Public Health, Boston, MA. Peterson, William F., M.D. - Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, Washington, DC. Petty, Thomas L., M.D. - Professor of Medicine; Head, Director of Pulmonary Medicine, University of Colorado Medical Center, Denver, CO. Rall, David P., M.D. - Director, National institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Rauscher, Frank J., M.D. - Director, National Cancer Program, National Cancer Institute, National Institutes of Health, Bethesda. MD. Reinke, William A., Ph.D. - Professor, Department of International Health, The Johns Hopkins University, 8altimore. MD. Renzetti, Attilio D. Jr., M.D. - Professor of Medicine, and Head, Pulmonary Disease Division, The University of Utah Medical Center, Salt Lake City, UT. Ringler, Robert L., Ph.D. - Deputy Director. National Heart and Lung Institute, National institutes of Health. Bethesda, MD. Robins, Morton, M.D. Health Consultant, Westat, Inc., Rockville, MD. Saffiotti, Umberto. M.D. - Associate Director, Carcinogenesis Program. Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD. Schuman, Leonard M., M.D. - Professor and Head, Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, MN. Shimkin, Michael B., M.D. - Professor of Community Medicine and Oncology, School of Medicine, University of California at San Diego, LaJolla, CA. Stamler, Jeremiah, M.D. - Professor and Chairman, Community Health and Preventive Medicine and Dingman Professor of Cardiology, Northwestern University Medical School, Chicago, IL. Underwood, Paul B., Jr., M.D. - Professor, Department of Obstetrics and Gynecology, and Director of Gynecologic.Oncology, University of South Carolina Medical School. Charleston, SC. Van Duuren, Benjamin L., M.D. - Professor of Environmental Medicine, institute of Environmental Medicine, New York University Medical Center, New York, NY. Victor, Maurice, M.D. - Professor, Department Head, Neurology, Case Western Reserve, Cleveland, OH. Wynder, Ernest L., M.D. - President and Medical Director. American Health Foundation, New York, NY. xii The following staff persons at the National Clearinghouse for Smoking and Health or at the Center for Disease Control contributed to the preparation of one or more reports whose chapters are included in this report: Richard H. Arnacher, Elaine Bratic, Marjorie L. Brighman, Kathryn Carlysle. Emil Corwin, Winthrop N. Davey. M.D., Lillian Davis. Mary E. Dement. Julia M. Puller, Sandy Harris, Annabel W. Hecht, Gertrude Herrin. Priscilla B. Holman, Robert S. Hutchins, Theresa Klotz, Jennie M. Jennings. Nancy S. Johnston, Sanda Lager, Seth N. Leibler, Ed. D., Rosalie Levine. Mary Mitchell, Dan Nemzer, Mildred Ritchie. James A. Robertson. Donald R. Shopland, Kathleen H. Smith, Elsie Van Valkenburg, and Richard W. White. . . . Xl11 Chapter 1 Oveniew - The Health Consequences of Smoking Source: 1975 Report, Overwew - The Health Consequences of Smoktng. pages 1 8. 1 OVERVIEW - HEALTH CONSEQUENCES OF SMOKING The statement, "Warning: 77re Surgeon General Has Determined That Cigarette Smoking Is Dangerous to Your Health," has been required by law on cigarette packaging since 1970 as a part of the Public Health Cigarette Smoking Act of 1969. This Act was a response by the U.S. Congress to the scientific information on the health consequences of cigarette smoking summarized in reports then avaiIabIe (the Surgeon General's Report of 1964 and the subsequent 1967, 1968, and 1969 PHS Health Consequences of Smoking). This Act was passed because a series of important questions concerning cigarette smoking and health had been answered. The following discussion summarizes the basic questions, the methodology used to determine the answers, and the answers themselves. The initial question to be answered concerning the health consequences of smoking was "`Are there any harmflt/heaIth effects of smoking cigarettes?" The answer to this question was provided in two ways. First, it was demonstrated that some diseases occurred more frequently in smokers than in nonsmokers. Second, a causal relationship was established between smoking and these diseases. Concern about the possible health effects of smoking started when scientists began looking for an explanation to account for the rapidly increasing death rate from lung cancer. The early retrospec- tive studies showed a link between lung cancer and smoking. The first prospective studies, however, found that only oneeighth_of.the excess overall mortality found among smokers could be accounted for by lung cancer; the rest was 1argeIy due to coronary heart disease, chronic respiratory disease, and other forms of cancer. They also found that the effect on overall mortality was largely confined to cigarette smokers rather than the users of other forms of tobacco. However, demonstrating an association by statistical probability is not enough to establish the causal nature of a relationship. Deterpining that the association between smoking and excess death rates is cause and effect was a judgment made after a number of criteria had been met, no one of which by itself is sufficient to make this judgment. These criteria as listed in the Surge0;: General's 3 Advisory Committee Report (1964) were the consistency, strength, specificity, temporal relationship, and coherence of the association. In addition, con.vincing theories about the mechanisms whereby smoking contributes lo the various diseases responsible for the excess mortality among cigarette smokers were developed from the evidence on the biochemical, cytologic, pathologic, and pathophysiologic effects of cigarette smoking, thereby providing the necessary support for the decision that the relationship was causal. The most important specific health consequence of cigarette smoking in terms of the number of people affected is the development of premature coronary heart disease (CHD). Boih prospective and retrospective studies clearly established that cigarette smokers have a greater risk of death due to CHD and have a higher prevalence of CHD than nonsmokers. Long-term followup of healthy populations has confirmed that a cigarette smoker is more likely to have a myocardial infarction and to die from CHD than a nonsmoker. Cigarette smoking has been shown to be one of the major independent CHD risk factors and to act in combination with other major alterable CHD risk factors (high blood pressure and elevated serum cholesterol). Autopsy studies have shown that persons who smoked cigarettes have more severe coronary athero- sclerosis than persons who did not smoke. Physiologic studies and animal experiments have indicated several mechanisms whereby these effects can take place. A second major health consequence of smoking is the develop- ment of cancer in smokers. Cigarette smoking was firmly established as the major risk factor in lung cancer. The risk of developing lung cancer was found to be 10 times greater for cigarette smokers than for nonsmokers. The risk of developing lung cancer increases with the number of cigarettes smoked per day and is greater in cigarette smokers who report inhaling, who started smoking at an early age, or who have smoked for a greater number of years. Smokers of filter cigarettes have been shown to have a lower risk of developing lung cancer than smokers of nonfiiter cigarettes, but the risk remains well above that for nonsmokers. The risk of developing cancer of the larynx, pharynx, oral cavity, esophagus, pancreas, and urinary bladder.was also found to be significantly higher in cigarette smokers than in nonsmokers. Pipe and cigar smokers were found to have elevated risks for the development of cancer of the oral cavity, pharynx, larynx, and esophagus when compared to nonsmokers. Fewer pipe and cigar smokers than cigarette smokers report that they inhale. As a result lungs of pipe and cigar smokers receive much less 4 exposure to smoke than the lungs of cigarette smokers. This is probably the primary reason for the lower incidence of cancer of the lung for pipe and cigar smokers compared to cigarette smokers. Women have had far lower rates of lung cancer than men. This has been attributed to the fact that fewer women than men smoke and the fact that women smokers generally select filter and low tar and nicotine cigarettes. However, the percentage of women smokers in the United States has increased steadily in the last 30 years, and since 1955 the death rates from lung cancer in women have increased proportionately more rapidly than the rates for men, reflecting this increased proportion of women smokers. The tar from cigarette smoke has been found to induce malignant changes in the skin and respiratory tract of experimental animals, and a number of specific chemical compounds contained in cigarette smoke were established as potent carcinogens or cocarcino- gens. Malignant changes including carcinoma in situ were found in the larynx and in the sputum exfoliative cytology. of experimental animals exposed to cigarette smoke. Nonmalignant respiratory disease is a third area of smoking- induced morbidity and mortality. Cigarette smokers have been shown to have more frequent minor respiratory infections, miss more days from work due to respiratory illness, and report symptoms of cough and sputum production more frequently than nonsmokers. Retrospective and prospective studies with long-term followup have found that cigarette smoking is the primary factor in the develop- ment of chronic bronchitis and emphysema in the United States. Cigarette smokers have also been found to be more likely to have abnormalities of pulmonary function and have higher death rates from respiratory diseases than nonsmokers. Data from autopsy studies have shown that cigarette smokers were more likely to have the macroscopic changes of emphysema, and that these changes are closely related to the number of cigarettes smoked per day. MUCOUS cell hyperplasia has been found more often in cigarette smokers. Cigarette smoke aIso inhibits the ciliary motion responsible for cleansing the respiratory tract. An additional area of health concern has been the effect of cigarette smoking during pregnancy. Mothers who smoke cigarettes during the last two trimesters of their pregnancy have been found to have babies with a lower average birth weight than nonsmoking mothers In addition cigarette smoking mothers had a higher risk of having a stillborn child, and their infants had higher late fetal and 5 neonatal death rates. There are some data to show that these risks due to cigarette smoking are even greater in women who have a high risk pregnancy for other reasons. These effects may occur because carbon monoxide passes freely across the placenta and is readily bound by fetal hemoglobin, thereby decreasing the oxygen carrying capacity of fetal blood. Having established that cigarette smoking is a significant causal factor in a number of serious disease processes, two additional questions became important. They are "Can the health consequences to the individual be averted by stopping smoking or by changing the cigarette. " and "What are the overall public health consequences of cessation and of the changes made in cigarettes?" The first question is the simpler of the two to answer. In the individual, cessation of cigarette smoking results in a rapid decline of the carbon monoxide level in the blood over the frrst 12 hours. Symptoms of cough, sputum production, and shortness of breath usually improve over the next few weeks. A woman who stops smoking by the fourth month of her pregnancy has no increased risk of stillbirth or perinatal death in her infant related to smoking. The deterioration in pulmonary function tests that occurs in some smokers becomes less rapid than that of continuing smokers. The death rates from ischemic heart disease, chronic bronchitis, and emphysema also become less than those of the continuing smoker. The risk of developing cancer of the lung, larynx, and oral cavity declines relative to the continuing smoker in the first few years after cessation and IO to 15 years after stopping smoking approximates that of nonsmokers. A smoker who switches to filter cigarettes and has smoked them for IO years or longer has a lower risk of developing lung cancer than a smoker who continues to smoke nonfilter cigarettes. The risk to a filter cigarette smoker, however, still remains well above that of a nonsmoker. The public health benefits of cessation are more difficult to determine than the effects of cessation on the individual. Just as cause-specific death rates have reflected the effect of cigarette smoking on certain diseases, they should also reflect any substantial benefits to be gained by cessation or reduction in cigarette smoking. Several factors combined to produce a reduction in per capita dosage of tobacco exposure in the United States for the years 1966-1970. First, per capita consumption of cigarettes declined from 4,287 cigarettes per person in 1966 to 3,985 in 1970. Second, during this period there was a slow but significant decrease in the average tar and nicotine content of cigarettes as well as a decrease in the amount of 6 tobacco contained in the average cigarette. The decline in per cnplfa consumption during those years occurred in the face of a substantial , increase in the proportion of young women becoming smokers as cornpared to women of previous generations and SO reflected t predominantly a decrease in cigarette consumption by men. Since 1970, although the per capita consumption of cigarettes has increased. the average levels of tar and nicotine have continued to decline, making it more difficult to predict what has happened to per capita dosage. Examination of cause-specific death rates for the period of this declining per capita consumption reveals that there was a downturn in the male death rate from ischemic heart disease beginning in 1966 which reversed the upward trend that had occurred over the previous two decades. This decline in the death rate from ischemic heart disease has not occurred in women. The male death rate from chronic bronchitis has also been declining since 1967, and the male death rate for emphysema has declined since 1968 when it was first recorded as a separate category. Female death rates for these two diseases have not shown these trends. Despite the impressive coincidences of the decline in death rates among males occurring at the same time that there was a decline in per capita cigarette consumption, it is impossible to be certain of the exact cause of the decline in the death rates. These diseases are influenced by a variety of factors in addition to cigarette smoking such as blood pressure and air pollution. Some of these factors have also been subject to major control efforts which may have contributed to the decline in the death rates. In addition, there have been therapeutic advances in the treatment of these problems which may also have helped lower the death rates. A decline in male death rates from lung cancer should also follow the decline in per capita consumption. This rate would not be influenced as much by changes in other etiologic factors or changes in therapy because cigarette smoking causes from 85 to 90 percent of all lung cancer and there have been no major improvments in survival due to changes in therapy. With lung cancer, however, two additional considerations must be kept in mind. A decline in death rates from lung cancer would be expected to lag several years behind a decline in per capita consumption. In addition, the decline in consumption and switch to low tar and nicotine cigarettes occurred 7 predominantly in the younger age groups where death rates from Lung cancer are low. For these reasons, it is necessary to look at lung cancer death rates by age group rather than total lung cancer death rates. The lung cancer rates by age groups for 1971 suggest a decline in the lung cancer rates for the younger males (under 4S), but the confidence limits on these trends at present remain wide enough that it is impossible to say whether this is a real decline or merely a leveling off. The national health statistics broken down by 5-year age groups are currently available only through 1971. The data by age group from a few more years will be necessary to determine whether the changes in smoking behavior which have taken place have reversed the trend of the preceding 4.0 years of continually increasing lung cancer rates in men. In 1971, the last year for which detailed mortality statistics are available, the accumulated exposure to cigarettes reached its peak among men born between 19 I5 and 1919, a group then in their early 50's. Cumulative exposure has continued to decline with each successive S-year birth cohort born since then. The trends of the last few years offer some hope that the peak of the "lung cancer epidemic," as some have termed this phenomenon, may have been reached with this group and that future years will show a slow but consistent decline. 8 Chapter 2 cardidar~s Pan I - 1971 Rspori, Chapter 2, 15 - 174. paQa Pan I1 - 1975 Remrt, Chapter 1. 9 - 38. paws Chapter 2 Cardiovascular Diseases Part I Contents Introduction Paga Smoking and Obesity . _ . : i - . . . . . . . . _`. . . . . . ii-; `. `. : :!; 39 Smoking and Electrocardiographic Abnormalities. I.--I; 43 Smoking and Heart Rate . : .`;-:t.`: ;:i;..' i, .;- .I ..,> _, .`_*.*._`. . . . . 43 The Effect of Cessation of Cigarette Smoking on Coronary i Heart Disease.. . .";. ; ::; ::`;f: _ 1';. e5'.:1'l . , . .". `: i 1` ; 5' . . :' . . . ,-.y'T. 43 The Constitutiona] Hypothesis ;: .;~J:-~-~,~: ;:!;:Y,< ,`t.: ;:,I )y.F.> 44 Autopsy Studies Relating Smoking, ~Atheros~lerosis, and ~' "- ti Sudden CHDDeath . . . . .`;:..`; .!..`~...`.~.~.;:`....~~`~.I':i'~'):: 48 Experimenta Studies Concerning `the `Relationship of ' Coronary Heart Disease and Smoking . . `. .: : : : : . ; : . `. .`." `.' 52 Cardiovascular Effects of Cigarette Smoke and Nicotine . * - , _ , -`.":" ." I `;I,' a;;:, . . .._.............._........ 52 Coronary Blood Flow _ . . . . _ . `. .I,o.y'L'; P .:t &j.`;;:!:`! *1! !&j `<>*<..a.irTJr; ;`- . . . . . . . . . . . ..-....... ) :54 Cardiovascular Effects of Carbon Monoxide . ;i .`i; I. 5 ::f. 1 .`i'.55 Effects of Smoking on the Formation of Atherosclerotic _,`. Lesions -- .-..- I-, II-- . .I `i . . . . . . . . . . . .._. . . ...`::. . . . . . ..-.. .:;r'.. . The Effect of Smoking on Serum Lipid Levels . . J:~!:~ ;; ?:s- 59 .f 61 The Effect of Smoking on Thrombosis . i; ;:;J.:. :Y,:.,`~~~~l~`~~~ 62 Other Areas of Investigation - _L. ._ . , : ., . . ., . . . . ., . . - - .-. :. 2 - , . . . , -* , ?Z I. . Iit. i . . . . . . ,:;-, '..,,' *- . :; 62 Nonsyphilitic Aortic Aneurysm . . y.;. . `. . . .:. ;`I-. . .,;r:t:!.r.~r.- .' 63 Peripheral Arteriosclerosis . ;`.`. .: ; . .-::`;:!u. ;. ;. . . .: ::1?-:3!;.$68 -`.,:r--`:;i~ ,`) -, .,? := i ,*,-' ,r` `. Experimental Evidence.`:".~~.;.",~,~!,I^;.!;.-f!~,.: ~~~;, ,:,r-: I- .69 Thromboan.itis ObIiteran;Y :`~:x-~iif*:i?~~. f;:F:nfi- ./-:s;f :+.3 `,;Q-j . . . . . . . . . ..`................ Summary and Conclusions . . . . . . -. .- `eiIj,ure -, `!::,y-;.p::2, . . . ...* :..- . . . . . s..: . . . . -. _ _...,, W..`.`. I-.--. 13 -Coronary Heart Disease . . . . _ . _ . _ . _ . . Coronary Heart Disease . . . . _ . _ . _ . _ . . Pap Pap ..-..-....a.. ..-..-....a.. 70 70 Cerebrovascular Disease . . . . _ . . _ . _ . . . . Cerebrovascular Disease . . . . _ . . _ . _ . . . . . . . ..-...... . . . ..-...... Nonsyphilitic Aortic Aneurysm . _ . . . . . . Nonsyphilitic Aortic Aneurysm . _ . . . . . . 71 71 . . . . . . ..---. . . . . . . ..---. Peripheral Vascular Disease _ . _ . . . ; -. . . Peripheral Vascular Disease _ . _ . . . ; -. . . 71 71 . . . . . ..-.... . . . . . ..-.... 71 71 References.. _ _ . : :... . . . _ ; :;.;+;ii;;T F References.. _ _ . : :... . . . _ ; :;.;+;ii;;~ F .' .' `,............~`.""" `,............~`.""" 71 71 ,.. ,.. FIGURES FIGURES `11 National Cooperative Pooling Project, Inter-Society Com- 3 ~ssion for Heart Disease Resources, :;. `!,: .+ ..; I, ,,., i c r . . .2-i.-. ,"`+."...j_.~ 1g p Risk of coronary heart diseas;?"(l2 years) according to .-- ..&; . . cigarette smoking habit and-presence of "p&&&ing j';. factors" .(men 30-59 at entry). Framingham Heart $!. cl -\- `Study. .`:`---.`:.`:`.`::"-"`:`::.-"` " a.. . . . . :. :. . . . . . . . -s- : I . - .;,;.-.;-;,' ratio: "i'ca 17-51 2. 3. Estimated coronary heart disease'death year follow-up, and frequencies of paired combinations of six high-risk characteristics in college, for all ages at death _ . . . .I ", `_ . . . . . . . . . . . . . . . . . . . . . . . ;..ii- ,-..... . . 21 4. Relationship between smoking status and serum choles- terol level at initial examination, and incidence of chn- ical coronary heart disease in men originally age 40-59 free of definite CHD. Peoples Gas Light and Coke Company Study, 1958-1962.. . . . -1.. . . . . . . . . .,. :. . . . . . ~. -39 6. Average annual incidence of first myocardial infarction among men in relation to overall physical activity, class, and smoking habits ,,(age-adjusted rates per 1,000) . . . . ..'.~.........; . . . . . . . . . . . . ..1..~.....-.'40 . :.: 1i- 1 _,a , . . ::._a , _ .;. _-<. .; :...I _, :-. aLIST OF kABiESs' -, . . ; . J. ~..~~j'~'.-~~~;jsij~ -: , : . (A indicates tables located in Appendix at end of Chatte;? ::, ji;L2,. .._ .._ . . . L . . . . ._. ,. I 1. Sudden death and acute mortality with first major.-: coronary episodes . 1 . ; :`; . ! :.I:. .e.:. :. ; ;r:`.`.-. . . r-y:: 19 2. Coronary heart disease mortality ratios related to smoking-prospective studies. _ -mci-J; ;IJedz:i.>< ..`;`.`.=~:rc-, ,.22 3. Sudden death from coronary heart disease related to :`. - ' smoking _ ..; -. ;r - - .-; . . . . :< ;`.-; . -`. ..-i;! _ ;`: /. `$i*;;. .`.:r!-!f; 26 4. Coronary heart disease morbidity as .-related .to .<%TL?-~ smoking. _ .; :. . . . .:. . . . . . .;. . . . . . . . -; 1 :.;-:-:,:.- ;,;~&;_?~~ 5. Coronary heart disease morbidity as related to smO~~,R~~.~ &d ing-angina pectoris-prospective studies Y.`: i -.-. .rX2 33 A 6. Coronary heart disease- morbidity and modid+- r retrospective studies `. . .-. . . . .`. . .' .`.- ; y'. ;-. ::w, ~.>,:Ai.:-,.L:~t8g . . . . . : . . - A 7. Differences in serum lipids between smokers and non- r"c!l'%. smokers. .1---- --. . . . . . . . . . . . . *.......-...... . :. . . -.94 EI ~_ - -- 14 usr 0~ TABLES (CONT.) [A indicates tables located in Appendix at end of CII~~~~, ^ Page A 8. Blood pressure differences between smokers and non- i smokers . . . .-;.: 7:. m-i,;`.-,r- :- .I.. -:..;; . . . . :.:.-.r`.-.::~):.`,, 99' 9. Death rates from coronary heart disease, by systolic - +J k -L - blood pressure: ILWU mortality study, 1951-1961 38 10. Death rates from coronary heart disease, by diastolic : !:J::' -, % ..L blood pressure : ILWU mortality study, 1951-1961 38 .-II. Death rates from coronary heart disease, among hy- ..?- ;;bl: pertensives and nonhypertensives : ILWU mortality ' 1 t-j ; study, 1951-1961_. ;:..:F:': ;`I. ;;;~;;.f~.i ;+ j: F?;< :i.yi-i.>{rg ,38 ,12. Death rates from coronary heart disease among men. ,a; without abnormabties related to cardiopulmonary `diseases by weight classification in 1951: ILWU morfa1if.y study, 1951-1961. : ;":`;`!?":?~~`:?;!:?;~-I:;`-.::`;:! 41 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 incidenceof 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 -- -- 101 category and behavior type for men 60-59 years of age . . . . . _ . . .`. . _ . .3 . . _`. . . .: .-T. .`1 .: . . . ..-. _ . . 302 19. Autopsy studies of atherosclerosis _ . . _ . . . . . . . . . . . . 49 A 20. Experiments concerning the effects of smoking and nicotine on animal cardiovascular function . . . . ; . 103 A 21. Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans. . 109 A22. Experiments concerning the effect of nicotine or smoking on catecholamine levels - 115 e.......,....... A 23. Experiments concerning the atherogenic effect of nicotine administration - .- 116 . . . ..-.................. 41 41 42 42 LIST OF TABLES (CONT.) (A indicates tales located in Appendix at end of Chapter) Page 24. Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia _ 60 425. Experiments concerning the effect of smoking and nicotine upon blood lipids (Human Studies) *' rx.-.--rclf- .----s 119 C125a.Experiments concerning the effect of smoking and.lmPKG./DAY `1,' . 1 ' `.' 196' .s , . ,: .z..A:,, ___; 37 - 12 x7 - NONE ANY ONE . 7'. P PREDISPOSING FACTORS (CHOLESTEROL > 250. HYPERTENSION. DIABETES) *SIGNIFICANTLY DIFFERENf FROM "NONSMOKER" P<.D5 ,. .$. ._ = <. , 7 ,: :; : _ + 3 _- . . .= `.- E~CURE Z-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. (9.4). _ $-, f `.: ; .I< 1.. -- _- :,;: _, :. ;. ,_* :: : : _ < . . ;;.. 1, .F : -`. I * ,`< : : ;' r.. -- ., _ : ; 1 s-j ^I __ .;,` -i I . _- I +. .Y 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 Health Insurance Plan of Neti 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 etidence has been published concerning the relationship of ciga- rette smoking and the incidence of angina pectoris. While some 20 CI**nttn --I 3 SF. BP 130+ --B 2.4 . 131 2 140 1.4 1.4 LO 238 201 1 324 442 373 clI!Il 644 O- I CI~."ttsl `-A 3 H,ilhl <69 -B 2.0 2 ---.. 1.5 96 I.3 124 1.0 Z?? 1 Lllllh 199 346 468 394 875 0 no rpxt-A SP. BP no+ -6 . _- :`:. I O- i C' ! . k. .1. 2 1.1 1.9 ). 7b 1.3 124 102 1.0 1.1 - 149 1 232 4`2 ,- sp. BP 130+ _A hnnl dud --II : . . ; 2.5 3 2 ' 1 10 3 .._ 2 I -0 3 _ 2 I -0 3 2 1 -0 3 /- A+ A- A+ TABIF. 2.-Cormry heart disease mortality (Ati number of dathm [SM = SmoLcn AMhOG .* __. ,a=, amnh. Nmbcr,d .~. --. `: ; pOD&tiOn " Data rcfermm cdkctIon Hunmoad 187.7BS QucaLIm- ;"I a% 6.297 NS . . . . . ..!!l.OO (709) md rhItcmrkm nab.? md __-.___ -.----.-Msmokcn .1.70 (assl) - Horn. fne.t.ba - 1968. ' c&-69 ,e*n V.SA oflpr - mate. -\ (,,, ,I). _, _. , : : t `. `(v26 . . . . . . ..*.43 (50). : : ,, ,- I .- ,, . . ,(;:, 7 stmbel a.743 male Question- e 162 NS . . . . . . ..LOO md Gc.eU eSti phy- enrim and :.. i _ -;:,..>-.c -2 1966 skiam. fOUOW-Up I.__ _, l-20 . . . . ...1.48 swit.mr- of death hnd . -7 ' ">20 ________ 1.76 (`c: 1, crrti6ute. (150). .-- i ~~ Bat. Appmri- Quatioa- 6 mat.& `. , naircmd L :-7 j _ 2.000 NS . . . . .._. 1.00 1966 Allsmoker, .I.60 (1380) Ctnadn 78,cmo fOlhLWD c- ; ,tt,;j .-is ;, `Z I;,.. ;:_- 20 ..:..::1.78 (277) --,: returns. `- r. a: ; _L;;,~ -2 ,I ,kF ., lrdm 1966 U.S.A. . (88). us. In& Qoestion- 8% 10,890 NS ________ 1.00 (2997) vctcrula nrire and Allsmokcrs .1.74 (4160) : 2.266.674 fouoov-up :, -.. :" 1-3 ..-.__-. 1.39 (43SP ; :`..`. Del-m ~I. of dalb _ry t :- ..`I IO-20 _.._. .1.78 (2102) 1' : : i Jan. I ' ecrticlute. ' PI-39 . I ; I ___.._ 1.84 (1292) ; . . 1 fl .,y.-, : ; : : 7-q ;-`,l,. c 2 . . --?>39...... . .-.f.OO (266) i. Hhw. 266,118 Rmincd in- * 1 91 NS ____ ____ 1.00 fl7) . nmks LIcdiulu- l2 62 NS ..__ .-..l.OO (27)) ratios related to smoking-prospective studies dlcmn b parentheses)' NS = Nonamokenl - _.- . . .~ __-_ Cigars I. ,... NS..l.OO .- `- : NS ..`. so-Sb 6649 6-I 6548 . . . . . 1.00 190) 1.00 (142) 1.00 (204) 1.00 (273) . rI.C : b,.?zmG SM..1.28 (420) ..AUsmokcrs .193 (765) 1.85 (962) 1.66 (921) 1.41 (718) .<., .,,,:,!;,.; Pipu . . . . . . ..I.38 (36) 1.98 (60, 1.17 (49) 127 (68) NS..l.W - -""l20 . . . . i::.Z.Kl (203) 2.47 (199) 1.92 (129) 1.66 (78) .t z -s:. :;.$> ). ,, ' Data WDIJ : . . 7. . . . : : ~. ._ or& to maks . . 4red40-49 -. md irea CucED~t entw.NS Include Dive, .___ ~. ~----. ._.-._. --- __. _.._ -..- _. -. --._-. . ~~~___~ _ -- .- ..--- eksrmd : .-I : I a:;-. I, . ..-f.. er-amoken. Sd-bb bsmb 85-64 : . NS . . . . . . . ..l.OO 1.00 1.00 :t.: . I-14 . . . . . .x73 : 1.40 1.71 ! ? _ : lb24 . _. . .4.46 1.79 1.27 . . : i.%. >26 . . . . . ...1.36 1.92 1.68 --. -..-.- _ _. _ _ _. .~ _ .- _- - _- - - NS. .I.@, sy..1.46 .I : - ;.:-.. ._, : : Tllsu 2.-Coronaty heart disease mwtdity ratios (A&ml number of dacha (SM = Smokrn 5mond :c4*!`1L- :, C..,`.". ti-.:t !N-z _' ., ;-:-- -._ : . . . . `2 t:.!iJ` . : : . . I; ,.. :.., :. c i:..Z!.- :. . . . ._ :: Paffcnbu- 60.000 m& BUClIlIIT 17-61 1.146 NS . . . . . . . . 1.00 zcr md ._ former intervIew -..--r-mddxd 24 . . . . . ...1.60 (886) (D20 . . ..z.os 1970. men 8664 screeninp U.8& Jean of and follow- (zra). m. 09 of dcnth CcrtIflc~Cs. Tad.x _,K71 m.l* lntcrvlew. 6 ,_ 46 NS . . . . . .._ 1.00 (4) ,* ., o ? ?o?? railroad md rmulqr . <20 . . . . . . . .I.97 (20) I < i. 1970.. -Db?m foollaw-up - USA 4&69 ye=n ULPL- -.: :c, (-:, ;I! >2@ . . . . . . . .S.60 (22) c: (18s). of aamat Ln.t,on. ! : `.Z. :, 1 !I,i;; <.`.I . `:-, < , .:`. Pooh T.427 white XedIcrI a- 10 239 NS ._._ me m&s . . . . .I.00 (27) unIaatlm Amdan :.,_ `. :- 20 . . . . `. . . . S.00 (68) -:,,L. ___ .- _ .--w------y--_ .: -, <-; tJ=b -_. :. _ `) - ,,.. :-., I/ 1970. ., ... * ,,, US& :.. (Jr). - : _.! , _`., + I .). `- .; ,. _.' - r. , ,:I-; ,._ .. _-. ., _, 24 related to smoking-prospective ntudies (cont.) .hom in 9.~theses)I .,s'? ' NS = Nona.a~cn] ^ A'..- --.+-.. --. .- : T, `. : - I r - - ---~ --- -,o-" as--51 ,s-4* , .`-.. ----- - ------ - .. NS . ..`...... 1.90 1.00 1.00 ,:i, `I',3 ' .;.; (DA.: :. .>t,. - __. __ ._. . .:vl_.,: "I _ 7:..:..-?,1 ,r; -:; ;ic :I -,;.'z ,l?:.z:. : .' L-c,:-..- .?I- I(: ..`i -5 . ,,' ~. . . . _~ ~. ~. -. _ SC-II b6-6b 65-d& .86-m . ..NSincluda __ `. `5 .: us _ ,....... 1.00 1.00 1.00 .`: 1.00 -, i; ?: DfDa mad : I-.. 2 &IO . . . . . ...4.22 2.06 1.41 1.17 .I>l!~.`dpsm. `: ,I .- i- l. -, r: `.(T ___ 520 . . . . . ...6.14 a.17 1.64 .i 1.26 '!I!&:&. ml inchlda ^ ,.. 7.' -_-. *Jo . . . . . . ..I357 ldl 1.66 .,r 1.86 ..rrf?,eramoktn.- ' e.2 .ro . . . . . . ..i.sa a.16 1.42 :-I 1.42 <>,I! .- . :- 7 . r-' AU . . . . . . ...6.24 2.96 l-66 i 1.24 ..' _ TMLE 3.Pudden death from coronary Project. Amcriua aart hwciation. 1970. U.SA. (88). TABLE 4.-Coro7uzry heart disease (Risk rstlos-actus1 number of CHD [S?d = Smokers NS = Nonsmokcn Dorh 2.282 nula Dctdkd 10 24a mro- NS . . . . . . . . . . . . 1.00 (62) cc al.. F~minghlm. mcdkd CSKdM AU smokers . _. .2.36(191) 1964. 3W2 yean usminn- infrrc- <20 . . . . . . . . . .I.98 (44) . USA. of Lge. tian snd tions and 20 . . . . . . ..__.._ 2.06 (64) (84). 1,913 m&s folka-up. CHD >20 . . . . . .._.. 3.04 (83) An=w. dathx. X9-66 ran of sgc. 8Lunlcr 1.329 CHD- Int.e?vicv 4 46 CHD NS . . . . . . . . . . . . 1.00 (2) ct& free mrk mnd uamio- 1666. anDlo7rn of stion 4th =`; ;ig;;t.ty: 2.92 (6) 4 USA. PcoulQ Gas clinic < 6 vbca..... (177) _ COUlD=V folbr-up. l&19 cigarette.3.67 (8) 40-59 ,an of *se. > 6 PIPCS..... 4 96 mak. Male* 92 femak 40-58 CED in- NS . . . . . . . . . . ..l.OO (1) duding EX . . . . . -. . . ...6.63 (10) deaths, Clg.rrttea . . . . .6.20 (36) msirm. and Femakm ,nyocudIII NS . . . _. . . . . . . . 1.0 (21) idsrctlon.. EX . . . . . . . ._ . . , 0.80 (1) Cfp.RtrcS . . ...1.02 (X0 26 heart disease related to smoking of death shorn fn Darentbesca) Ci~rcttesldru Clean, Dive Comment Never smoke3 ........... 1.00 (16) 1.00 (16) See t&k 1 for der.crlDthn of 210 ............... z.. .. .t.90 (23) 1.86 (13) Pooling Project. 20 . .:.: ...... . ....... .x.90 (60) z-20 .................... 5.36 (40 morbidity US related to smoking msoifstrtions shown in psrcothesea)' EX = Exxsmokcnl PROSPECTIVE STUDIES-Continued Pipes, clears Age variation cornmenb Dats include CHD deaths. only on m&s 4049 remn of we md f rrr of CHD on entry. NS includa, PIPeE. c&w% and cx-smoken. NS include cr-smokera. Includn all CHD. Mole&ntinued M.Zk. Recxrmination 80 and WdT N-59 Of pdenb 1.00 (7) SM . . ..l.SO(Z) WOJ spread l.z?(ll) 60 and over cwer 1y,.a-yar 1.96(23) SY . ...0.86(6) Femah-contlnued period. but dsta are re- 1.00(47) DOdZd in 1.11 (6) tcrma of 0.42 (2) 4-year in& dence r.tes. Actual number of CHD inci- dents derived from dsta on incidmce and tot4 In smok- ha CLsl. 27 TABLE 4.-Coronary heart disease (Rhk rrtIm--sctrul number of CHD (SM = Smokcn NS = Nonamatcm PROSPECTIVE STUDIES eAUthOr. *-. Number knd Lkt, Polkm- Number ot camtrr. t7De Of eolkctlcm UP incidenti Clgl3rtttM/&T rdcrarcc pOpllhti0n la- Jenkins. 3,lfJZ mda Initid 4% 104 m,o- NS __ . . . . ..- . ..I.00 (21) et 8L. 19-69 ,cIn m&cl1 UldLl EX ._.___ . . . . . . 1.47 (16) 1968. of sge at usmin8- hhrrtbnm. Cumnt _ ., ._. .2.78 (68) U.S.A. mtl7. uon rnd o-lS/daT ._-._. t1.as (46) (901. fol!er-up >I6 _ -.*-.. . . . . . WI6 (69) br -t aunlnr- uon8- Kmoel. 6.127 mslea Y&d l2 226 myc- kr,c,a rnforc:ifm et al.. and females crur.fnstbn UIdW M&8 1968. to-59 yt*ra end follow- Snflrc- NS . . .,* . . . . . . . 1.00 (21) U.S.A. of *pz. UP- tiorl~. AU slid . . . . . . . . 1.61(16a) (94). a80 CHD. aesvy SM . . ..I.86 (69) Ri.k of CHD (owrdI) Mdu NS .._____ _ . .._ 1.00 (61) l-10 . . . . . . . . . . . I.24 (25) II-20 . . . . . . ..__ 1.80 (90) >20 . . . . .._..._ 2.41 (76) Shapiro 110.000 male Bwelioc mcd- a Tot&l Mok. et IL. sod femak kd ioter- un*pecl- NS . . . _. . . . __ .I.OO 1969. cnr0lk3 ricr md tied. At1 cul~cnt . . . .2.14 U.S.A. of Ecmhh rxamin*ticm cigsrettea (p20 . . , . . . . . . .2.33 Greater I >40 . . . . . . . . . ..B.JC New York (HIP) a-4 le.= of .gc. K,. 9,186 m&s Iotervie~ 5 65 dcatha. NS. EX 1970 In 6 coun- and r-- 80 nwocIIr- Ytlp+ (SM <20) I. .1.00(306) tria lo-59 Isr foibw- dial in- AU current ah& Icall of np examins- f.rction% PinLnd (>20) . . . . . ..1.31(103) .*e at entrY. lion br 128 8ngir-m ItAb Lxrl NdhU- DCCti?iU. Dhysici*nr 156 other lands - C- (III). t428 totaL 28 mwbidity as related to smoking (cont.) mmnifahtioos show in p~renthmcs)' EX = Ex-emokersl PROSPECTIVE STUDIES--Continued (~o.ol) fD20 . . . . . . . . . . . 1.17 (13) myocardial infarctions. DtUIZl 13,145 male Dsta only up to 14 Total un- et rl., p*tienb in on *cur ape&&d. 1970 periodic health incidents U.S.A. examination extracted (55). clinics. from clinic recorda. POOtiIlp 7.427 while Medical 10 638 Prujtct. mrla 30-59 examination Includea Never Fmokcd .l.OO (63) American ,can of xnd follow- fatal and 20 . . . . . . . . . ..3.28(164) 1970. infarction USA. nnd audden car). death. Pmxl CL IL. 1.939 Wntcrn Screening lP63, Ekctric co. crsmination COTOMW TJmsa rmk workera and CaBCS 167) (li.4). prticipatinp history. NS .__ .__.... . 23 In. prmpcc- l- 7 _ . . . . . . . 2 tire atw3Y 8-12 . . . . . . . . _ 9 for 4% ,C.rn. la-17 . . . . . . . . - 6 18-22 .----- 41 .._..... - 23-27 , . . . . . . . a >28 ___ . . . . . . . 9 30 ,/. ,,... y. -I .`J. ~- ,J ., -1 . . , : . . . ,, , ,, -.. :' ,. . ._ .:,, .-; _ , :s. ! ,`.' .' ; 1. i, :i:;.-, . . :* ;-,2 . I,,.i: , ,.Z' `: ,_ ,>' f `., ; -' ' .; .,. , : ,I ..- ` tios JO-19 .( ; bo-bf 60-59 t Includea ; SM 1.00(26) 1.00(126) 1.00(167, NS. EX. and ." _._ I,. tHlgb <20 cigarettes/ . --: . , day. .I SM 2.17(10) 0.90 (31) 1.41 (63) :>ZOei`~a- . . . .`.d ..I )*,-J.. .iz- ._, ; , r&es/dry. ,' I :.:.* ;`.. ,_I.' -: ,`., : Include. all ' . CHD blrt __ I .._. . . .,_. _.. :.I :: :,:-* I ;-car. ,., -; `.. : - . . r `- .' czcludr. ._. 1.26(60 ' = . i . . -.. 1. . . -* . . . ..1..--- :. . .-, `. 1; ,.,., -; , =...; ,. I : ,,, +i : 1;. -*. __ .:. studies have shown an increased risk of this manifestation among smokers, others have not (see table 5). From these longitudinal studies, it has become increasingly clear that cigarette smoking is one of several risk factors for CHD and that it exerts both an independent effect and an effect in conjunc- tion with the other risk factors. The basic concept may be ex- pressed as follows: The more risk factors a given individual has, the greater the chance of his developing CHD. The importance of the constellation of coronary risk factors which include cigarette smoking, high blood pressure, and high serum cholesterol in pre- dicting the risk for CHD is illustrated in figures 1 through 3. Other risk factors are included in certain of these figures and are dis- cussed below. Knowledge of the effects of cigarette smoke on the cardiovascu- lar system has developed concurrently with the knowledge derived from the epidemiological studies. Nicotine, as well as cigarette smoke, has been shown to increase heart rate, stroke volume, and blood pressure, all most probably secondary to the promotion of catecholamine reIease from the adrenal gland and other chromaffin tissue. This release of cateeholamines is also considered to be the cause of the rise in serum free fatty acids observed upon the in- halation of cigarette smoke. Studies concerning the effect of nico- tine on cardiac rhythm have also suggested that smoking might contribute to sudden death from ventricular fibrillation. In addition, research efforts have also been directed toward the effects of smoking on blood clotting and thrombosis; since many _ cases of sudden death and myocardial infarction are associated with thrombosis in a diseased coronary artery branch. Cigarette smoking may be associated with increased plateIet aggregation in Vitro and thus might play a role in the development of such throm- bi or platelet plugs in viva. , Other mechanisms have been investigated. Because cigarette smoking has been shown in some studies to be related to the prev- alence of angina pectoris as well as to the incidence of myocardial infarction, it has been suggested that smoking enhances the de- velopment of atherosclerotic lesions. Autopsy and experimental studies have shown that cigarette smoking plays a role in athero- genesis. The administration of nicotine has been observed to in- crease the severity of cholesterol-induced atherosclerotic lesions in exper+nental animals. Attention is presently being given to carbon monoxide, which is present in cigarette smoke in such concentra- tions as to cause carboxyhemoglobin concentrations in the blood of smokers as high as 10 percent. Based on research in animals, it is reasonable to conclude that the atherosclerotic process may be enhanced, in part, by the relative arterial hypoxemia in cigarette 32 ;f .' ,;p, - -. $,,:" : 1(' -: : TABLE S.-Coronary heart disease morbidity aa related to smoking -angina pectoris+woapective atudiee .+, . (Rl#k +.l~-utu~l number of CHD mrnlfntatlon# shown In parenthesn)~ `,,. ;, ,;, -. ! [SY = Smokera NS z Nonsmokers] Cll?#M -. Clmrcttedday wd DiDC. :.-, : .I `., : AgevarIatIon ,. `t `.I " Commcntr ?`. . . NS Include ez- Malu Fmalsc M&b Male* t (PCO.01) >4o ..*,..a . . . . . . . - 4.12 - ' Unb c4h-d~ ~e~ltlcd. dlwultla between the total number of ,A , -ntf-Ulom *ad the bum OK the lndlrldurl wnoklns caegx,ries .re due to the acluslon of citbw aculonal, mLcelLne0ur. mlred. or ex-rmokrtn. 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. EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, bath 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 deveIoping 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 enrolIed in the Health Insurance Plan (HIP) of New York City showed a significantly increased 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 MORBLLIITY 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. (541, Keys, et al. (III), and Taylor, et al. (185) 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 perday increases. Similarly, the HIP data of Shapiro, et al. (17.2) sha$ 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 &year CHD incidence in males age 40 to 59 from seven countries. As summarized in table 4, cigarette smoking &as 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 sjmifi- e-ant for the 13 other population samples which varied in size from 505 m 962 individuals, from the five other countries. (Smoking was not considered in the two Japanese populations.) men more cases . . 35 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 bv mvo- cardial infarction. RETROSPECTIVE STUDIES Table A6 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 facto&-are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as we11 as asympto- matic hyperglycemia), electrocardiographi~~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 36 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 deveIoping 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 Ievels 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- &,ed that smokers show increased serum IeveIs 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 tidings diflicult 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 `&eases the risk of CHD in each of the cholesterol groups. Smoking and Hypwtemion 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 A 8). 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 amok- 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, ham been shown to elevate CHD mortality independently botb'of its effect on blood pressure and of the effect of hypertension on CL-ID. Smoking and Phyticul inactivity The recent study by Shapiro, et al. (172) of more fhan 110,00fr TABLE Q.-Dsath rate6 from coronas hem9 dineuse, b sy&& b&d $wuMc: 4664 . . . . . . . . . . . . . . . . `.:. - lO Never cig.rruc./day smoked r~~ulrb _ ._ . . .1.00l1.841) l.OO(1.841) Yale da. only CUlTCUt clemrettc amaken . _. . _ ._ l.DO(1.063) 2.66 (2.822 ) stoD,Xd 20 . . . . . . . . . ..-....... 1.08 (70) 1.06 (80) AU cx-dnardte smokers . -1.16 (263) 1.28 (6641 N Total &finite myacardial infarction ever smoked .._...._._... _ . . . . . . .._...... . . . . . . ..I.00 Current cigarcite smokers ......................... 1.87 StDPM S6 Yeara ................................. .0.78 AR CHD &aLhs Never smoked . . . ._. . . . . . . .1.00(27) >`j4 wck/dsy _ _.._.___. ._ .1.66(34) 1 wck/dq . . . _ . . . .._. . ..1.70(.66) >1 Drck/dry . . . . . . . . . .._.. 3.00(68) Exsmokcrx . . _ . . . . . . . . . . . . 0.80(19) Pirmf major CormION event 1.00 (63) See table 4 1.66 (72) for description 2.08(205) of Pmlinp 3.28 (154) PrOiKt. 1.25 (61) TAEKE 16.-Annual probability of death front coronary heart da%ease, in current and discontinued enwkers, by age, maximum amount smoked, and age started Bmoking .-e-v._ _ ..___. 0 601 - 601 - lo-20 198 608 811 661 7.149 S60 766 612 698 &`I(' -.__ . . . . . . .._ 0 1.016 - 1.016 - lo-20 1.601 1.169 1.478 1.21t 21-M l.710 l.ur 1.ma 1.0911 * For - group 66-74, ~r.,b.blUUa for dkeantlnrrsd -ken o R for 10 Or mOrr - d dh-- adinn.~cc dacc d.t. for the 64 ,err dk.zantLntunu craw .R not riven. Sxmcx: thmtldd, J, Yft&c~I. 8. (44). Bud cm da@ derived Irma IhIm. 1. A. (#I). 42 Smoking and Electrocardiographic Abnormalltzes 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 13, from the prospective study by Borhani, et al. (279, reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smokzng and Heart Rate Recent analysis by Berkson, et al. (25) 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 the 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; 43 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-16 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 36 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 (1771, increased blood pressure (27)) elevated resting heart rate (251, physical in- activity (172), obesity (27), and electrocardiographic abnormali- ties (27) have been controlled, cigarette smokers still show higher rates of CHD than nonsmokers. It haa been suggested by some (39, f7U) that the relationship between cigarette smoking and CHD has a constitutional basis. That is peopIe 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 epidemic logic data bear on this hypotheeis. 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 44 Type A behavior pattern of Rosenmann, et al. (159) which is characterized by competitiveness, excessive drive, and an enhanced sense of time urgency. The prospective study organized by the western Collaborative Group indicates that individuals who ex- hibit this type of personality are more likely to have or develop CHD than those without it (Type B), whether or not they smoke. When the incidence rates of CHD are analyzed with respect to smoking and personality types (tables A 17, A 18)) it is noted that in both Type A and Type B individuals the incidence of CUD is greater among cigarette smokers than among nonsmokers. This research indicates that both personality type, as measured in these studies, and cigarette smoking contribute independently as risk factors to the development of CHD. To what extent such behavior patterns are determined constitutionally or represent acquired characteristics is still open to question. The other type of research designed to study the genetic hypoth- esis has made use of data from registries of twins. Cederlof, et al. (37, 38, 39, 40) have utilized the Twin Registries of Sweden and the Veterans Follow-Up Agency of the U.S. National Academy of Sciences-National Research Council to investigate the relative contributions of heredity and smoking to cardiovascular and bron- chopulmonary symptom prevalence. Data obtained by mailed ques- tionnaires were analyzed for the following characteristics: zy- gosity of the same-sex twin pair, urban-rural residence differences, smoking concordance, and history of various symptoms. Compari- sons were made between smoking discordant monozygotic (iden- tical) pairs and smoking discordant dizygotic (fraternal) pairs, and between unmatched twin pairs and matched twin pairs. Smok- ing discordance has been defined somewhat differently in various reports but, in general, describes twin pairs in which the smoking habits differ between the two members of the same twin pai: Analyzing the data obtained from 9,319 Swedish twin pairs (`72.3 percent of the possible respondents), Cederlof, et al. (39) found that respiratory symptoms were more common among smok- era in both the unmatched and matched smoking discordant twin pair groups. The authors analyzed the data in two distinct man- ners. Group A analysis, which did not control for genetic factors ntihzed two groups; the first composed of all the firstborn, and the second of those listed second on the birth certificates. Group B analysis utilized MZ and DZ t&n pairs which were discordant for smoking, thereby controlling genetic factors. "Angina pedoris," a8 defined by a certain pattern of responses to the questionnaire, was found to be more prevalent among smokers in Group A, but this difference was not present when the data from Group B were an- alyzed. Males in the first group exhibited a "hypermorbidityratio" 45 of 1.6, whiIe 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. ~8s analyzed. Analysis of the smoking-discordant matched twin pairs (Group B) revealed no association between smoking and cardiovascular symp- tams among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors concIuded that this Iack 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 utiliyed the U.S. Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris Mween 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 (188) has questioned the value of a mailed questionnaire to diagnose heart disease. The questionnaire as originalIy con- structed was used and validated by interview technique alone (157, 158). Cederlof, et al. (40) 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 46 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 cIinicaIIy affected, and of the 136 reporting as negative, three had symptoms of angina pectoris. Other major difificulties 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 etioIogy 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- tically stable base for deriving any conclusions at the present time. huge, 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- Went in those cotwins with a higher consumption of tobacco than h 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 PothO~Ogica~ data relating smoking and CJID, 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 ihe cardiovascular system been shown to be a "clear" and eon- gist& one (170). His views are contrary to those of most re- achers in this fieid. mhough the data from the twin studies are inconclusive with regard to a role for genetic factors in heart disease, it w&Id be surprising if genetic factors did not play such a role. It is open to 47 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 ci&rette smoking habits and the cardiovascular pathology of th,ose.individuaIs 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 X89 individuals who died suddenly and unexpectedly, apparently from the first acute clinical episodes of CHD. The authors nofed 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 survlvmg 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 autipsy 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 amoking 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. (IZ), Avtan- dilov, 8 al. (IS), Sackett, et al. (165), and Strong, et al. (~82) round that aortic and coronary atherosclerosis were more common and more severe among smokers than amongnonsmokers. Auerbach, et al. (12) .Gted 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 diab&; 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 40 TAEILE lO~Autopet( studiea o/ athsroaclaroaia (Flguta la pwmthnn an number of Indivldualc In that amoklnc ertrn0r7)~ [SM = anoken NS = nonmokcrs] AdhOt, 7*rr, Aubpr7 D&tA COUl-li~. DODUktlOC, collcctlon Comment4 odjwkd rrrulk) No othcro- NkTO6b Slight NS .;.., ,.,. 6.6 (69) --.`-. 67.8 Cumnt elgarctte <20 *.,.*1 l.6(139) 30.9 20-39 .,.,0.8(299l lg.7 >49 ,,.`.;.0.6(144) 18.1 the percentage of men with .?I o dv*need deorn of M0hub. Advonccd coronary d,herolckm~k 21.8 16.8 wu hlpbcr .mong elsn- - rette rmokcn thnn among nonrmokem and that the 873 29.2 ' pcrecntagc hcreued 42.1 87.4 with amount of elgrretts 96.4 46.9 I 8moklng. This relation- lblp DM'dlted CvCIl nhm cad" were mhtehed for age and UUI~ of death. TABIX 19.-Autopsy studies oj athumsch'osia (cm:.) (?`I- In DuSrrthC.4. w number of IndlrlduLL in that fimOkiU ukmr7)' [9X = mmken NB = noo~mekenl Ln Anthor, 0 Y-t AntaDtoprl Dab OoOMtn, DODUbtk"3 ' wnudm Ckamtta DCr dw conctuliona cornlnmta rdmu Avtandlh, 219 mab and Nat BDrChdd, fh,SDWdW #(I# of maan a,~ of athbtcrobrutb b&BU The rutbar eoncluda that Cawa of dath 9l-&mro- 1966, 141 f*mmb but there rarer in inn47 mat of covmary a.rkriar. the wont ehanga rm Acrotle, lOZ-wcldrntA, Flunrlr ~~~D~l~. 180 9X uid Rlpht COTOMY ortsru h/1 mrona.ry orby found In the left and 202varloru dlrcua. (Ia). 220 NS. srd Nf mf NS rlsklt ??????? o ?????? tT-tent for +~.lltuncr a049 ,*.tla.s(ao, Lscaz) ma 2.2 nlth h mvcra changer of hlffcrenca klwcen 40-49 . , tzs.ecao 11.6(27) tu.a 4.4 hi clreu.m.8a artery means II llgnldunt so-t.9 ..tae.a(so, 14.8(89) t27.9 9.9 &rid wti. at P26 clmrettes/day . . ..17(10) 14117) 29(12) 16(111 .-. `~IGJW dm-wlre ~~eclAed, dlsparitlcs bctwen the total number of ln- 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, VieI, et al. (200) 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, 19.2, 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, myocardia1 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 experimenti. In humans, Irving and Yamamota (89) and Von Ahn (202) duplicated the 52 effects of cigarette smoking by the administration of nicotine intra- VenOUSlY. Similar results in animals were noted by Kien and Sherrod (112). The mechanism by which cigarette smoke and hence nicotine in- duces these changes has been of interest to numerous investigators. Nicotine has long been known as a stimulator of both sympathetic and parasympathetic ganglia. Research has centered, therefore, on the function of catecholamines, mainly epinephrine and norepi- nephrine, as mediators, of these responses. Using isolated rabbit atria1 myocardium, Bum and Rand (55) noted that the prior ad- ministration of reserpine to the perfusate blocked the increased rate and amplitude of contraction seen following the administra- tion of nicotine. West, et al. (208) showed that the in vivo cardiac stimulating effect of nicotine was blocked by tetraethylammonium chloride. Leaders and Long (125). Romero and Talesnik (156), and, more recently, Ross and Blesa (160) have all demonstrated this blockade in animals using agents such as pentolinium, hexa- methonium, guanethidine, and reserpine. More direct evidence of the catecholamine-releasing effect of nicotine has been found by Watts (203) and Westfall, et al. (209, 210, 221) (table A22). Among animal subjects, nicotine adminis- tration and the inhalation of the smoke of standard cigarettes caused significant increases in peripheral arterial epinephrine lev- els, while cornsi!k cigarette smoke inhalation evoked no such change. In humans, cigarette smoking was found to be associated with a significant increase in urinary epinephrine excretion. The source of these nicotine-released catecholamines, particu- larly those which mediate the immediate and local cardiac re- sponses to intracoronary injections of nicotine, is felt to be the myocardial chromaffin tissue (35, 160). The more widespread effects are most probably mediated by hormones released from the adrenal gland. According to recent research of Saphir and Rapaport, catechol- amine release may not be the sole mediator of these responses (166). These investigators reported that intra-arterial injections of nicotine into the mesenteric circulation of cats were followed within 1 to 2 seconds by enhanced myocardial performance, in- creased left ventricular systolic pressure, and increased systemic resistance. Sectioning of the mesenteric afferent nerves led to a diminished response. The authors concluded that the cardiovascu- lar response to nicotine may also be neurogenic in nature. Nadeau and James (14.2) injected `nicotine directly into the sinus node artery of dogs and noted an initial bradycardia, due probably to direct vagal stimulation, followed by tachycardia, due probably tb catecholamine release. 53 That the presence of nicotine may predispose the myocardium, particularly a hypoxic or previously damaged myocardium, to ar- rhythmia formation is suggested by the research of Balazs, et al. (161, Bellet, et al. (21), and Greenspan, et al. (74). Balazs pro- duced myocardial lesions in dogs either by pretreatment with iso- proterenol or ligation of the anterior descending coronary artery; It was found that while normal animals did not develop arrhy- thmias upon challenge with small doses of intravenous nicotine, the animals with damaged myocardiums responded with increased arrhythmia formation shortly after their spontaneous arrhythmias bad ceased. More recently, Bellet, et al. (20) studied the effect of cigarette smoke inhalation on the ventricular fibrillation threshold in anesthetized dogs. They observed a statistically significant de- crease in the threshold following smoke inhalation. Greenspan, et al. (74), using isolated dog right ventricular myocardium, ob- served that nicotine perfusion increased the automaticity of the Purkinje fibers system and decreased the conduction velocity. The authors consider that these two nicotine-induced effects probabIy predispose the myocardium to the initiation of arrhythmias. CORONARY Bmn FLOW Studies in animals and humans (tables A20, A21) have noted alterations in coronary blood flow (CBF) following the inhalation of cigarette smoke or the administration of nicotine. Generally, exposure of the normal subject to these agents results in an in- crease in flow. Kien and Sherrod (112), Leb, et al. (126), Ross and Bless (160), Travel], et al. (189), and West et al. (208)) working with normal animaIs, and Bargeron, et al. (179, working with normal humans, have demonstrated this response. As with the other cardiac responses to the administration of nicotine, it has been found that the augmentation in CBF is most probably due to the release of catecholamines. Using instantaneous coronary arte- rial flow measurement in dogs, Ross and Blesa (160) were able to reproduce the effects of intracoronary nicotine with the adminis- tration of epinephrine and were able to bIock the response to nico- tine by pretreatment with pentobnium. The direct action of catecholamines on the coronary arteries may not, however, be solely responsible for the increase in CRF seen with cigarette smoking and intravenous nicotine administra- tion. It appears that the catecholamine-induced increase in myo- cardial work and therefore in myocardial oxygen requirement is a prerequisite for the increase in CBF. Kien and Sherrod (112), using tracbeostomized dogs, found that without blood pressure and cardiac output changes CRF did not increase following either the inhalation of cigarette smoke or the administration of nicotine 54 intravenously, although CBF did increase folIowing such changes. Recent work by Leb, et al. (126) has utilized Rb8' as a radioactive marker in order to distinguish capillary flow from overall totai CBF. The authors consider that this capillary flow represents that portion of CBF which is effectively involved in nutrient and oxygen exchange. The researchers observed that the increase in effective coronary flow was almost proportional to the nicotine- induced increase in myocardial oxygen consumption. However, the increase in total coronary flow which may be due to increased myocardial shunting was far in excess. Thus, the increased work evoked by the effect of nicotine on the myocardium may induce local hormonal release in the myocardium and coronary vessels leading to coronary vasodilatation and increased CBF. This homeostatic response to increased work appears to be fully effective only in the subjects with normal coronary arteries. Bellet, et al. (22), working with normal dogs and dogs that had under- gone either coronary artery ligation or artificially-induced coro- nary artery narrowing, noted that the increase in CBF following the intravenous administration of nicotine was significantly less among the animals with coronary insufficiency. Work with humans discussed above has revealed a similar increase in CBF with smok- ing in normaIs. Regan, et al. (1.54) studied seven men with EKG- proven myocardial infarction and observed that cigarette smoke evoked slight increases in myocardial oxygen consumption in only three patients and caused no overall rise in CBF. A number of other investigators have noted that patients with overt CHD do not respond to the stimulus of cigarette smoke as readily as do normals (67,149,164). Thus, patients with compromised coronary circulation may not be capable of increasing their coronary flow in the face of the in- creased demands of a myocardium stimulated by nicotine or ciga- r&e smoke. In the normal state, the heart responds to increased oxygen demands by increasing coronary flow because even at rest oxygen extraction is almost at a maximal level. Any further in- crease in extraction may produce coronary sinus p0, values incom- Nible with proper tissue oxygenation. CARDIOVASCULAB EPFECTS OF CARBON MONOXIDE Carbon monoxide (CO) is a colorless and odorless gas, low levels of which have significant effects on human and animal physi- ok%?y which are just now beginning to be understood. According to WCjynder and Hoffmann (21.5). it is present in cigarette smoke in concentrations of approximately 2.9 to 5.1 percent. The concen- tration of CO in smoke is subject to many factors, among them 55 the type of tobacco and the porosity of cigarette paper. The con- centration of CO in smoke has been found to increase significantly toward the last puffs of the cigarette. According to Chevalier, et al. (41). a concentration of approxi- r&&ely 4 percent CO in cigarette smoke will produce alveolar levels elf around 0.04 percent which, equilibrated with hemoglobin, result in carboxyhemogIobin (COHb) concentrations of from 3 to 10 per- Cent. A number of investigators have compared COHb levels in smokers and nonsmokers. Goldsmith and Landaw (73) reported the analysis of expired air samples obtained from 3,311 longshore- men. Using a regression analysis, they calculated the concentra- tion of COHb and found that nonsmokers showed levels of 1.2 per- cent while those smoking over 2 packs per day had IeveIs of 6.8 percent and that smokers of lesser amounts had intermediate Ievels. Occupational exposure accounted for the mean nonsmokers' level being over 1.0 percent, an uriusual finding in comparison with other studies. Kjeldsen (113) interviewed and obtained blood samples from 934 CHD-free smokers and nonsmokers. The mean COHb level for 196 nonsmokers was 0.4 percent while all inhaiing emokers had a mean level of 7.3 percent. All 416 cigarette smokers, regardless of inhalation or amount smoked, showed a mean level of 4.0 percent. Carbon monoxide has many varied and significant effects on human physiology. An overall review of these effects may be found in a discussion by Lilienthal (127) or more recently in an exten- aive review by the United States Public Health Service National Air Pollution Control Administration (ISA). Apart from its effects Oti respiratory and circulatory function, CO has been found to affect certain central nervous system functions adversely. These effecta are probably due to interference by CO with the proper oxygenation and oxidative metabolism of the tissue in question. CO interferes with oxygen transport in a variety of ways. First, the affinity of hemoglobin for CO is approximately 200 times lz'reater than its afiinity for oxygen, and thus CO can easily dis- PlsCe oxygen from hemoglobin. Second, CO shifts the oxyhemo- globin dissociation curve. By increasing the avidity with which oxygen ia bound by hemoglobin, CO interferes with 0, release at the tissue level. This is of greatest importance at the tissue level where the oxygen content of the capillary blood has been reduced b Proximately 40 percent saturation: Here the shift can sub- tintially dec&e the oxygen tension supplying the tissues. Third, and of more recent note, is the possible interference by 0 with the homeostatic mechanism by which 2, 3-diphosphogly- -rate (2, 3-DPG) controls the affinity of hemoglobin for oxygen. BUM and Jandl (54) have recently reviewed the various experi- 36 merits concerning this glycolytic intermediate. The question of whether the low levels of CO present in the blood of smokers can affect this homeostasis is presently under investigation (29, l&?), and firm conclusions cannot be drawn at this time. Apart from its effect on hemoglobin affinity, CO appears to induce arterial hypoxemia, and this may act as an additional cause of tissue hypoxia. Ayres, et al.